Due to the continuing high suicide rates among young men, there is a need to understand help-seeking behaviour and engagement with tailored suicide prevention interventions. The aim of this study was to compare help-seeking among younger and older men who attended a therapeutic centre for men in a suicidal crisis. In this case series study, data were collected from 546 men who were referred into a community-based therapeutic service in North West England. Of the 546 men, 337 (52%) received therapy; 161 (48%) were aged between 18 and 30 years (mean age 24 years, SD=3.4). Analyses included baseline differences, symptom trajectories for the CORE-34 Clinical Outcome Measure (CORE-OM) and engagement with the therapy. For the CORE-OM there was a clinically significant reduction in mean scores between assessment and discharge (p<0.001) for both younger and older men. At initial assessment, younger men were less affected by entrapment (46% v 62%; p=.02), defeat (33% v 52%; p=.01), not engaging in new goals (38% v 47%; p=.02), and positive attitudes towards suicide (14% v 18%; p=.001) than older men. At discharge assessment, older men were significantly more likely to have an absence of positive future thinking (15% v 8%; p=0.03), have less social support (45% v 33%; p=.02) and feelings of entrapment (17% v 14%; p=.02) than younger men. Future research needs to assess the long-term effects of help-seeking using a brief psychological intervention for young men in order to understand whether the effects of the therapy are sustainable over a period of time following discharge from the service.

Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). CAFs exhibit a pro-tumor effect in vitro and have been implicated in tumor cell proliferation, metastasis, and treatment resistance. Our objective is to analyze the geospatial distribution of CAFs with proliferating and apoptotic tumor cells in the ccRCC tumor microenvironment and determine associations with survival and systemic treatment. Pre-treatment primary tumor samples were collected from 96 patients with metastatic ccRCC. Three adjacent slices were obtained from 2 tumor-core regions of interest (ROI) per patient, and immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, and caspase-3 to detect CAFs, proliferating cells, and apoptotic cells, respectively. H-scores and cellular density were generated for each marker. ROIs were aligned, and spatial point-patterns were generated, which were then used to perform spatial analyses using a normalized Ripley's K function at a radius of 25μm (nK(25)). The survival analyses used an optimal cut-point method, maximizing the log-rank statistic, to stratify the IHC-derived metrics into high and low groups, and multivariable Cox regression analyses were performed accounting for age and International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall survival (OS) from the date of diagnosis, OS from the date of immunotherapy initiation (OS-IT), and OS from the date of targeted therapy initiation (OS-TT). Therapy resistance was defined as progression-free survival (PFS) <6 months, and therapy response was defined as PFS >9 months. CAFs exhibited higher cellular clustering with Ki-67+ cells than with caspase-3+ cells (nK(25): Ki-67 1.19; caspase-3 1.05; P = .04). The median nearest neighbor (NN) distance from CAFs to Ki-67+ cells was shorter compared to caspase-3+ cells (15 μm vs 37μm, respectively; P < .001). Multivariable Cox regression analyses demonstrated that both high Ki-67+ density and H-score were associated with worse OS, OS-IT, and OS-TT. Regarding CAFs, only a high H-score was associated with worse OS, OS-IT, and OS-TT. For caspase-3+, high H-score and density were associated with worse OS and OS-TT. Patients whose tumors were resistant to targeted therapy (TT) had higher Ki-67 density and H-scores than those who had TT response. Overall, this ex vivo geospatial analysis of CAF distribution suggests that close proximity clustering of tumor cells and CAFs potentiates tumor cell proliferation, resulting in worse OS and resistance to TT in metastatic ccRCC.

Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) family that identify pathogen-associated molecular patterns derived from microbes and activate immune cell response. Following TLRs ligation, different adaptor and transcription molecules such as myeloid differentiation primary response gene 88 (MyD88) and nuclear factor kappa B (NF-kB) are recruited that initiate inflammatory signaling pathways. The human Toll-like receptor 10 (hTLR10) is a novel member of the PRRs family with a regulatory function of immune responses because of unique cytoplasmic domains which lead to induction of both inflammatory and anti-inflammatory properties. Recent studies have reported the association of TLR10 polymorphisms with many inflammatory diseases and human cancer. Engagement of TLR10 on the surface of the epithelium and macrophages leads to the production of proinflammatory cytokines and chemokines, while other studies have proven an anti-inflammatory role of TLR10. Accordingly, TLR10 suppresses proinflammatory cytokine production via negative regulation of MyD88 and the Akt (protein kinase B) and MAPK (mitogen-activated protein kinase) signaling pathways. This review aimed to provide answers for these conflicting findings (Inflammatory and anti-inflammatory properties of TLR10) to further identify distinct biological functions of TLR10.

SARS-CoV-2 infection produces a response of the innate immune system causing oxidative stress and a strong inflammatory reaction termed ‘cytokine storm’ that is one of the leading causes of death. Paraoxonase-1 (PON1) protects against oxidative stress by hydrolyzing lipoperoxides. Alterations in PON1 activity have been associated with pro-inflammatory mediators such as the chemokine (C-C motif) ligand 2 (CCL2) and the glycoprotein galectin-3. We aimed to investigate the alterations in the circulating levels of PON1, CCL2 and galectin-3 in 126 patients with COVID-19 and their interactions with clinical variables and analytical parameters. A machine learning approach was used to identify predictive markers of the disease. For comparisons, we recruited 45 COVID-19 negative patients and 50 healthy individuals. Our approach identified a synergy between oxidative stress, inflammation and fibrogenesis in positive patients that is not observed in negative patients. PON1 activity was the parameter with the greatest power to discriminate between patients who were either positive or negative for COVID-19, while their levels of CCL2 and galectin-3 were similar. We suggest that the measurement of serum PON1 activity may be a useful marker for the diagnosis of COVID-19.

Objective: The objective of the present study was to evaluate the activities of daily living using the Barthel Index, before and after the infection by SARS-COV-2 and to see if the results vary according to sex. Methods: The activities of daily living of 68 cohabiting geriatric patients, 34 men and 34 women, in 2 nursing homes were measured before and after SARS-COV-2 infection using the Barthel index. Results: The Covid 19 infection affects the performance of daily life activities in institutionalized elderly in nursing homes, and it does so especially the older the subject, regardless of sex. Conclusions: The Covid 19 pandemic, in addition to having claimed some victims, especially in the elderly population, has reduced the ability of these people to carry out their activities of daily life, considerably worsening their quality of life despite have been able to overcome the disease.

The aim of this systematic review and meta-analysis is to evaluate the prevalence of depression, anxiety, insomnia, stress, PTSD, and distress in Chinese healthcare workers (HCWs) and the changes in prevalence before and after the peak incidence of COVID-19 in China. 20 cross-sectional studies assessing the aforementioned psychological outcomes were included. Eligible studies were searched from the following databases: PubMed, Scopus, and Web of Science. Comparative analysis based on the time period of the included studies was conducted to assess changes in prevalence before and after peak incidence. Additionally, subgroup analyses based on study quality, province, survey tools, gender and healthcare profession, frontline or non-frontline working status, and severity of psychological outcomes were conducted to evaluate the prevalence of outcomes across various study methods, geographic regions, and professions. The findings of this study suggest that the overall prevalence of depression, anxiety, insomnia, stress, PTSD, and distress before peak incidence were 36.2%, 34.2%, 22.4%, 31.3%, 9.8%, and 56.7% as opposed to 31.8%, 24.1%, 34.4%, 59.0%, 20.9%, and 40.7% after the peak. The higher prevalence of depression, anxiety, and distress prior to the peak incidence of COVID-19 in China and of insomnia, stress, and PTSD thereafter serve as evidence that the mental health decline of HCWs is dynamic and should be addressed with adaptive approaches that provide tailored treatments.

Adequate serum vitamin D and iron levels are thought to positively influence physical training adaptations and mood. The purpose of this prospective, observational, study was to investigate relationships between serum 25-OH vitamin D and serum ferritin levels with body composition and athlete burnout symptoms. Seventy-three collegiate athletes (49 female) from 7 indoor and outdoor sports were tested pre-season and post-season for: nutrient biomarkers (serum 25-OH vitamin D and serum ferritin) via venipuncture; body composition (total lean mass, bone mineral densi-ty/BMD, and % body fat) via dual energy x-ray absorptiometry (DXA) scans; and athlete burnout symptoms (post-season) via the athlete burnout questionnaire (ABQ). When male and female co-horts were combined, significant relationships were noted between pre-season serum 25-OH vit-amin D versus the change (∆: post-season minus pre-season) in both BMD (r=-0.34;p=0.0003) and % body fat (r=-0.28;p=0.015). Serum ferritin ∆ was significantly associated with lean mass ∆ (r=-0.34;p=0.003). For burnout symptoms, serum 25-OH vitamin D ∆ significantly explained 20.6% of the variance for devaluation of sport in the male cohort only. Across time, serum 25-OH vitamin D levels increased while serum ferritin levels decreased, non-significantly, in both males and fe-males. Relationships between nutrient biomarkers and body composition were opposite of physio-logical expectations.

Dupilumab is used to treat atopic dermatitis patients who have proven to be refractory to previous treatments. The aim of this study was to assess evolution and patient reported outcome measures in adult patients with moderate-to-severe atopic dermatitis treated with Dupilumab in routine clinical practice. The outcomes were evaluated and registered at baseline and weeks-16, 40 and 52. The variables evaluated were: diseases severity, pruritus, stressful life events, difficulty to sleep, anxiety and depression, quality of life, satisfaction, adherence to the treatment, efficacy and safety. Eleven patients were recruited between Nov 14th 2017 and Jan 16th 2018. Demographic variables: 90% Caucasian, 82% women. Clinical variables: Mean duration of AD =17.7 (±12.8), 91% had severe disease severity. At baseline, SCORAD mean score = 61.7 (±15.5); itch was reported by 100% of patients; itch Visual Analogue Scale mean range of 8 (6-10); HADS mean total score =13.9 (±5.5); DLQI mean score =13.3 (±8.3): EQ-5D-3L mean range = 57 (30-99). At week-52 there is a significant reduction of SCORAD scores, HADS total score and improved quality of life. ¡This study confirms that Dupilumab, used for 52-weeks under routine clinical practice, maintains the improved atopic dermatitis signs and symptoms obtained at week-16, with a good safety profile.

Introduction: Over decades, much have been said and done regarding under-five mortality in Ethiopia. The country has been following the lead of sustainable development goals and UNICEF with its transformation plan targets. However, unless the efforts supported by status assessing studies, it might be difficult for the country to progress. Thus, the current study was directed to identify the prevalence and associated factors of under-five mortality in 2019. Methods: According to the study criteria, we extract and cleaned data in STATA v. 15.0. The data then weighted as per the sampling weight, primary sampling unit, and strata before analyzing in STATA 15.0. Data management consisted of descriptive (mean, standard deviation, and proportion or percent) and association statistics. We deliberated binary logistic regression for this analysis and we checked each variable at 0.25 p-values to include in the model. The final p-value to declare association was p <0.05 and AOR with 95% CI was also applied to describe the results. The data source was the Ethiopian Mini Demographic Health Survey (EMDHS) 2019. EMDHS collected the data from 8,885 in a face-to-face manner with a 99% response rate. Results: From 5,527 numbers of weighted women with under-five analysed in this study, the proportion of under-five mortality was 277.23(5.02%). Factors like 2nd birth order 0.52(0.35, 0.79), 3rd-4th 0.49(0.28, 0.84), 1-2 ANC visits 0.24(0.12, 0.49, ANC visit three’ 0.14(0.07, 0.28), ANC visit four and above 0.22(0.14, 0.36), in marriage mother 0.43(0.19, 0.96), ‘1-2 under-five children 0.02(0.011, 0.03), and greater than three under-five children 0.007(0.0007, 0.004) were all negatively associated with under-five mortality rate. Conclusion: To obtain the exalted outcome out of this study, the government might need to increase antenatal care, women education, institutional delivery, and the modern contraceptive methods use through enhanced community mobilization, health education using community health workers, increasing access to essential cares of mothers and children, and the policy commitment for the issues related to family size, birth order, and birth interval.

In this ‘New Normal' post-COVID-19 modern world, people's health is becoming increasingly important to track. An advanced technology that uses sensory instruments to track and record critical parameters and communicates with others is the need of the time. It's difficult to keep track of all of the medical parameters and post-operative data of people with non-communicable diseases like diabetes and heart disease on a continuous basis. The system discussed here to be designed for patients who are confined to their homes, particularly when going out and being exposed to the outer world is prohibited. This paper proposed a groundbreaking health management system based on the Internet of Things (IoT) for accessing patient medical parameters in both local and remote areas. When a person's wellbeing becomes urgent, this initiative seeks to send an emergency alert to family members or loved ones. A cloud server records data from the patient's temperature sensor and pulse sensor; the data is analyzed using support vector machine algorithms to identify irregular conditions, and an emergency message is sent to the rest of the family via a mobile application, as well as a warning message to the nearest hospital.

Inflammation associated endothelial dysfunction represents a pivotal contributor to atherosclerosis. Increasingly evidence has demonstrated that interleukin 1 receptor (IL1-R) / toll-like receptor (TLR) signaling participated in the development of atherosclerosis. Previous studies indicated the therapeutic potential of anti-inflammatory therapy in anti-atherosclerosis. The present study examined the effect of IL-1R-associated kinase 1 and 4 inhibitors (IRAK1/4i) in regulating endothelial dysfunction. IRAK1/4i showed little endothelial toxicity at concentrations from 1 to 10 μM. Inhibition of IRAK1/4 alleviated endothelial activation induced by LPS in vitro evidenced by attenuated monocyte adhesion to the endothelium. Mechanistically, blockade of IRAK1/4 ameliorated the transcriptional activity of NF-κB. Taken together, our findings demonstrated that dual inhibition of IRAK1 and IRAK4 attenuates endothelial dysfunction, suggesting pharmaceutical inhibition of IRAK1/4 might be a potential strategy to combat endothelial dysfunction and atherosclerosis.

Seasonal influenza is a common cause of hospital admission, especially in older people and those with comorbidities. The objective of this study was to determine influenza vaccine effectiveness (VE) in preventing intensive care admissions and shortening the length of stay (LOS) in hospitalized laboratory-confirmed influenza cases (HLCI) in Catalonia (Spain).A retrospective cohort study was carried out during the 2017-2018 season in HLCI aged ≥ 18 years from 14 public hospitals. Differences in means and proportions were assessed using a t-test or a chi-square test as necessary and the differences were quantified using standardized effect measures; Cohen’s d for quantitative and Cohen’s w for categorical variables. Adjusted influenza vaccine effectiveness in preventing severity was estimated by multivariate logistic regression where the adjusted VE = (1-adjusted odds ratio) ·100%; adjustment was also made using the propensity score.We analyzed 1414 HLCI aged ≥ 18 years; 465 (33%) were vaccinated, of whom 437 (94%) were aged ≥ 60 years, 269 (57.8%) were male and 295 (63.4%) were positive for influenza type B. ICU admission was required in 214 (15.1%) cases. There were 141/1118 (12.6%) ICU admissions in patients aged ≥ 60 years and 73/296 (24.7%) in those aged < 60 years (p<0.001). The mean LOS and ICU LOS did not differ significantly between vaccinated and unvaccinated patients. There were 52/465 (11.2%) in vaccinated cases) ICU admissions in vaccinated cases vs. 162/949 (17.1%) in unvaccinated cases. Patients admitted to the ICU had a longer hospital LOS (mean: 22.4 [SD 20.3] days) than those who were not (mean: 11.1 [SD14.4] days); p<0.001. Overall, vaccination was associated with a lower risk of ICU admission. Taking virus types A and B together, the estimated adjusted VE in preventing ICU admission was 31% (95% CI 1-52; p=0.04). When stratified by viral type, the aVE was 40% for type A (95% CI -11-68; p = 0.09) and 25% for type B (95% CI -18-52; p = 0.21). Annual influenza vaccination may prevent ICU admission in cases of HLCI. A non-significantly shorter mean hospital stay was observed in vaccinated cases. Our results support the need to increase vaccination uptake and public perception of the benefits of influenza vaccination in groups at a higher risk of hospitalization and severe outcomes.

Current epidemiological data reports that adults aged 65 years and older comprise the most vulnerable age group with the highest proportion of CAP-attributable hospitalizations. Pneumococcal vaccine efficacy (VE) has been shown to decrease over time, contributing to increasing incidence rates of CAP. A holistic evaluation of age, sex, seasonality, and VE are is conducted in this systematic review and meta-analysis of 12 prospective and retrospective cohort studies. The findings suggest that incidence and age are positively associated and that incidence in females is more often reported to be higher in females than in males. In studies that observed seasonality of CAP, high seasons and low seasons were reported to be in winter and summer months, respectively. Lastly, studies that reviewed the effect of vaccination on incidence consistently found decreased observance of CAP in elderly adults following reception of PCV13 or PPSV23. However, one study suggested that such vaccinations may have decreased effectiveness in elderly populations and that research examining potential explanations for this require further investigation. Furthermore, distinct diagnostic and case ascertainment standards, descriptive measures, and methods of prevention and treatment of CAP used across the US are outlined in this review. Public health guidance such as encouraging the reception of pneumococcal vaccinations and mask-wearing during high seasons of CAP, and communicating the risks of not adhering to the aforementioned preventative measures can facilitate an effort to reduce the incidence of CAP and its associated adverse outcomes in the US elderly population.

Nail surgery for the permanent removal of all or part of the nail unit can be performed via incisional or physically ablative techniques for conditions such as ingrown, mycotic, or dystrophic toenails. In the United Kingdom podiatric community, where phenol techniques are the standard of care for ablation of the matrix, there remains confusion about the management of patients undergoing nail surgery who are concurrently taking antithrombotic medication(s). The aim of this paper was to review the literature describing treatment strategies for antithrombosed patients undergoing nail surgery. However, having found limited evidence, the authors considered relevant and associated literature in the field of cutaneous/dermatological surgery and extrapolated those findings for patients undergoing nail avulsion surgery. A case-by-case risk assessment is warranted in all patients but as a general rule, the podiatrist can perform nail surgery without the patientceasing their antithrombotic medication.

The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in Japanese healthy older volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55–73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥ 65 years old) had higher CSF-TP concentration than the younger group (55–64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10–40 mg/dL).

Acute intense exercise causes significant oxidative stress and consequently an increase in total antioxidant capacity; however, the mechanisms and combined effects of intense exercise and smoking on oxidative stress among active and non-active smokers are not clear. The aim of this study was to investigate the effect of acute intense exercise on antioxidant enzyme activity responses in active and non-active individuals exposed to cigarette smoke. The study included 40 subjects who were equally classified as: smokers that did exercise (SE), smokers that did not do exercise (SnE), non-smokers that did exercise (NSE), and non-smokers that did not do exercise (NSnE). The adjusted Astrand test was used to exhaust the subjects. Salivary enzymes of peroxidase (POX), catalase (CAT), and superoxide dismutase (SOD) were measured, by spectrophotometry methods, at 3 different time points: pre-test (TP1), post-test (TP2), and one hour after finishing the test (TP3). Significant (p<0.05) group x time interactions were found for the three enzymes. Salivary POX, CAT and SOD increased in all groups from TP1 to TP2 and decreased from TP2 to TP3. Only the NSE showed a significant difference between TP1 to TP3 in POX and SOD by +0.011 ± 0.007 and +0.075 ± 0.02 (U/ml), respectively. The NSE showed significantly higher levels of POX, CAT and SOD in TP2 compared to the other groups. Furthermore, NSE and NSnE had higher levels of POX, CAT and SOD in TP1 and TP3 (p<0.05) compared with SE and SnE. Only in the NSnE, were no differences observed in CAT compared with SE and SnE in TP3. These results showed that the antioxidant level at rest and in the recovery time after the acute intense exercise was lower in SE and SnE compared with NSE and NSnE, suggesting that smoking habit may reduce the ameliorating effect of regular physical activity on acute exercise-induced oxidative stress.

Globally, over the past several months millions of persons contracted the coronavirus disease 2019 (COVID-19) resulting in significant mortality. Health care systems are negatively impacted including the care of individuals with cancers and other chronic diseases such as chronic active hepatitis, cirrhosis and hepatocellular carcinoma. There are various probable pathogenic mechanisms that have been presented to account for liver injury in COVID-19 patients such as hepatotoxicity cause by therapeutic drugs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the bile duct cells and hepatocytes, hypoxia and systemic inflammatory response. Liver biochemistry tests such as AST, ALT, GGT and ALP are deranged in COVID-19 patients with liver injury. Hepatocellular damage results in the elevation of serum AST and ALT levels in early onset disease while a cholestatic pattern that develops as the disease progress causes higher levels of ALP, GGT, direct and total bilirubin. These liver biochemistry tests are prognostic markers of disease severity and should be carefully monitored in COVID-19 patients. We conducted a systematic review of abnormal liver biochemistry tests in COVID-19 and the possible pathogenesis involved. Significant findings regarding the severity, hepatocellular pattern, incidence and related clinical outcomes in COVID-19 patients are highlighted.

Little is known about family medicine academic staff in Taiwan, and basic data about this workforce may aid healthcare decision makers. We analysed data on Taiwan’s 13 medical schools collected by the Taiwan Association of Family Medicine from June to September 2019. Items included medical school names and total staff, and the gender, age, degree, working title (part-time/full-time), academic level, and sub-specialty of each current family medicine faculty member. A total of 116 family medicine faculty members were reported; most were male (n= 85, 73.3%). Ages ranged between 30 and 69 years, with a mean (SD) age of 43.3 (8.09). Faculty members with a master’s degree were the largest group (n= 49, 42.2%), and most were academic lecturers (n=49, 42.2%). Additionally, only about one-fourth (n=26, 22.4%) of family medicine faculty in medical schools were full-time, while the other three-fourths (n=90, 77.6%) were part-time faculty; most were located in northern Taiwan (n=79, 68.1%) and specialized in gerontology and geriatrics (n=55, 47.4%) and hospice palliative care (n=53, 45.7%). Our research provides the most complete census of family medicine academic physicians in medical schools in Taiwan. The results inform efforts to improve the establishment and development of family medicine departments in Taiwan.

Triple negative breast cancer (TNBC) has a higher mRNA expression of programmed cell death ligand 1 (PD-L1) which is a ligand to programmed cell death protein 1 (PD-1). The binding of the ligand leads to suppressed activity of T-cell-mediated immune response against cancer cells. The approval of anti-PD-L1 drugs including pembrolizumab and atezolizumab in subgroups of TNBC offer potential improvement to the current treatment regimens available for TNBC. We conducted a meta-analysis to review the efficacy of pembrolizumab and atezolizumab for the treatment of TNBC in both adjuvant and neo-adjuvant settings. A systematic strategy was used as per the PRISMA 2020 statement. All statistical analyses were conducted using Review Manager 5.4. Outcome measures included objective response rate, progression free survival, overall survival in adjuvant therapy groups, and pathological complete response rates in neoadjuvant groups. Six clinical trials were included. For adjuvant therapies, the ORR (OR=1.26, P = 0.04) of Atezolizumab/Pembrolizumab plus chemotherapy was higher in intention to treat (ITT) arms than the placebo groups in TNBC. A positive effect size was found for PFS in the ITT arms (Cohen’s d = 1.55, P<0.001). The Atezolizumab plus chemotherapy group had a positive effect size for OS compared to the control groups (Cohen’s d = 0.52, P<0.001). In the neo-adjuvant setting, patients in ITT arms had higher pCR rates as compared to the control groups (OR= 1.61, P = 0.001). Our findings collate evidence of pembrolizumab and atezolizumab as a viable treatment option among patients with TNBC with PDL1+ subgroups deriving benefits.

Background: General Practitioners (GP) have an important role in the prevention of suicidal behavior. The purpose of this study was to explore their views and experiences of identifying and assessing suicidal ideation. Methods: Ten GPs were recruited through convenience sampling, based on accessibility, interest and willingness to participate. In-depth interviews were carried out and results transcribed ver-batim. Aspects of experiences with suicidal patients emerged through the thematic analyses process. Results: The GPs described the varied clinical picture when patients presented in their office. How they identified depressive symptoms apart from originally somatic complaints, formed a trusting relationship and addressed suicide ideation. They described customized interventions as well as obstacles and factors that facilitated communication: time, own personal traits, pa-tient’s disclosure and organizational barriers. Conclusions: The levels of the suicidal process among patients in general practice vary greatly. GPs adjust their appraisals to profundity understand and intervene in order to prevent a crisis to escalate into subsequent suicidal behavior.

Keywords: free radicals; oxidative stress; hepatocellular carcinoma; anti-oxidants; kaempferol

Angiotensin converting enzyme 2 (ACE2) is a key entry point of SARS-CoV-2 virus known to induce COVID-19. We have recently outlined the concept to reduce ACE2 expression by the administration of glycyrrhizin, a component of Glycyrrhiza glabra extract, via its inhibitory activity on 11beta hydroxysteroid dehydrogenase type 2 (11betaHSD2) and resulting activation of mineralocorticoid receptor (MR). We hypothesized that in organs, such as the intestine, which co-express 11betaHSD2, MR and ACE2, the expression of ACE2 would be suppressed. We studied organ tissues from an experiment originally designed to address the effects of Glycyrrhiza glabra extract on the stress response. Male Sprague Dawley rats were left undisturbed or exposed to chronic mild stress for five weeks. For the last two weeks, animals continued with a placebo diet or received a diet containing extract of Glycyrrhiza glabra root at a dose of 150 mg/kg of body weight/day. Quantitative PCR measurements showed a significant decrease in gene expression of ACE2 in the small intestine of rats fed with diet containing Glycyrrhiza glabra extract. This effect was independent of the stress condition and failed to be observed in non-target tissues, namely the heart and the brain cortex. In the small intestine we confirmed the reduction of ACE2 also at the protein level. Present findings provide first evidence to support the hypothesis that Glycyrrhiza glabra extract may reduce an entry point of SARS-CoV-2. Whether this phenomenon, when confirmed in additional studies, is linked to the susceptibility of cells to the virus requires further studies.

In contrast to normal cells, tumor cells of multiple entities overexpress the Heat Shock Protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane-Hsp70 positive tumor cells actively release Hsp70 into lipid microvesicles termed exosomes into the blood. Due to conformational changes of Hsp70 in the lipid environment, most commercially available antibodies fail to detect membrane-bound and exosomal Hsp70. To fill this gap and to assess the role of exosomal Hsp70 in the circulation as a potential tumor biomarker, we established the novel complete Hsp70 (compHsp70) sandwich ELISA using two monoclonal antibodies (mAbs) that are able to recognize both, free and lipid-associated Hsp70 on the cell surface of viable tumor cells and exosomes. The epitopes of the mAbs cmHsp70.1 (aa 451-461) and cmHsp70.2 (aa 614-623) that are conserved among different species reside in the substrate-binding domain of Hsp70, with measured affinities of 0.42 nM and 0.44 nM, respectively. Validation of the compHsp70 ELISA revealed a high intra- and inter-assay precision, linearity in a concentration range of 1.56 to 25 ng/ml, high recovery rates of ‘spiked’ liposomal Hsp70 (>84%), comparable values between human serum and plasma samples, and no interference by food intake or age of the donors. Hsp70 concentrations in the circulation of patients with glioblastoma, squamous cell or adeno non-small cell lung carcinoma (NSCLC) at diagnosis were significantly higher than those of healthy volunteers. Hsp70 concentrations dropped concomitantly with the decrease in viable tumor mass on irradiation of patients with approximately 20 Gy (range 18 – 22.5 Gy) or after completion of radiotherapy (60 - 70 Gy). In summary, the compHsp70 ELISA presented herein provides a highly sensitive and reliable tool for measuring free and exosomal Hsp70 in liquid biopsies of tumor patients, levels of which can be used as a predictive tumor-specific biomarker, risk assessment and for monitoring therapeutic outcome.

We report four allelic variants (3 novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p. Phe 57Leufs * 43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in 3 genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

Type 2 diabetes mellitus (T2DM) is frequently accompanied by affective disorders with a prevalence of comorbid depression of around 25%. Nevertheless, the biomarkers of affective symptoms including depression and anxiety due to T2DM are not well established.Aims: This study was conducted to delineate the serum biomarkers predicting affective symptoms due to T2DM above and beyond the effects of insulin resistance and atherogenicity. Methods: The present study delineated the effects of serum levels of copper, zinc, β-arrestin-1, FBXW7, lactosylceramide (LacCer), serotonin, albumin, calcium, magnesium, IR and atherogenicity on severity of depression and anxiety in 58 men with T2DM and 30 healthy male controls. Severity of affective symptoms was assessed using the Hamilton Depression and Anxiety rating scales.Results: We found that 61.7% of the variance in affective symptoms was explained by the multivariate regression on copper, β-arrestin-1, calcium, and insulin resistance coupled with atherogenicity, while 44.4% of the variance in the latter was explained by copper, β-arrestin-1, LacCer (all positively) and calcium and FBXW7 (both negatively). Copper and LacCer (positive) and calcium and BXW7 (inverse) had significant specific indirect effects on affective symptoms which were mediated by insulin resistance and atherogenicity. Copper, β-arrestin-1, and calcium were associated with affective symptoms above and beyond the effects of insulin resistance and atherogenicity.Discussion: T2DM and affective symptoms share common pathways namely increased atherogenicity, insulin resistance, copper, and β-arrestin-1, and lowered calcium, whereas copper, β-arrestin-1, calcium, LacCer, and FBXW7 may modulate depression and anxiety symptoms by affecting T2DM.

Sport nutrition knowledge has been shown to influence dietary habits of athletes. The purpose of the current study was to examine relationships between sport nutrition knowledge and body composition and examine potential predictors of body weight goal in collegiate athletes. Participants included National Collegiate Athletic Association Division III women (n=42, height: 169.9 ± 6.9 cm; body mass: 67.1 ± 8.6 kg; fat-free mass: 51.3 ± 6.6 kg; body fat %: 24.2 ± 5.3%) and men (n=25, height: 180.8 ± 7.2 cm; body mass: 89.2 ± 20.5 kg; fat-free mass: 75.9 ± 12.2 kg; body fat %: 13.5 ± 8.9%) athletes. Body composition was assessed via air displacement plethysmography. Athletes completed a validated questionnaire designed to assess sport nutrition knowledge and were asked questions about their perceived dietary energy and macronutrient requirements, as well as their body weight goal (i.e. lose, maintain, gain weight). Athletes answered 47.98 ± 11.29 % of questions correctly on the nutrition questionnaire with no differences observed between sexes (men: 49.52 ± 11.76% vs. women: 47.03 ± 11.04%; p=0.40). An inverse relationship between sport nutrition knowledge scores and body fat percentage (r = -0.330; p=0.008), and fat mass (r = -.268; p=0.032) was observed for all athletes. Fat mass (β = 0.224), BF % (β = 0.217), and BMI (β = 0.421) were all significant (p&lt;0.05) predictors of body weight goal in women. All athletes significantly (p&lt;0.001) underestimated daily energy (-1,360 ± 610.2 kcal/d), carbohydrate (-301.6 ± 149.2 g/d), and fat (-41.4 ± 34.5 g/d) requirements. Division III collegiate athletes have a low level of sport nutrition knowledge, which was associated with a higher BF %. Women athletes with a higher body weight, BF % and BMI were more likely to select weight loss as a body weight goal. Athletes also significantly underestimated their energy and carbohydrate requirements based upon the demands of their sport, independent of sex.

Background: HIV is accompanied by production of proinflammatory cytokines which are regarded as critical in neuronal damage, leading to brain dysfunction, hence the need to identify cytokine biomarkers sensitive to brain damage. Methods: We applied MRI volumetric neuroimaging and high throughput Luminex based immunoassays to examine the relationship between cortical white matter, subcortical gray matter and total gray matter brain volumes and plasma cytokines in HIV indviduals using generalised linear models and Partial least square regression model. Results: Higher plasma inflammatory cytokines CCL5/RANTES and MCP-1 were significantly associated with lower cortical white matter volume. Higher IL-6 was associated with both lower subcortical gray matter and lower total gray matter, whereas higher IL-8 and GM-CSF were associated with lower total gray matter only. Higher VEGF, PDGF-BB and IL-9 were associated with higher cortical white matter volumes. After standardisation and adjusting for clinical and demographic variables, IL-6, IL-8, MCP-1 remained associated with lower volumes of the three brain regions whereas IL-9, VEGF and PDGF-BB were associated with higher volumes. Conclusions: Association proinflammatory cytokines RANTES, MCP-1 and IL-6 with lower brain volumes could imply possible involvement in neurodegerative processes in HIV infection while IL-9, VEGF and PDGF may have a neuroprotective or neurotrophic role.

Background: New regional techniques can improve pain management after nephrectomy. Methods: This study was a randomized controlled trial conducted at two teaching hospitals. Patients undergoing elective open and laparoscopic nephrectomy were eligible to participate in the trial. A total of 100 patients were divided into a quadratus lumborum block (QLB) group and a control (CON) group. At the end of surgery, but while still under general anesthesia, unilateral QLB with ropivacaine was performed on the side of nephrectomy for patients in the QLB group. The main measured outcome of this study was oxycodone consumption via a patient-controlled anesthesia (PCA) pump during the first 24 hours following surgery; other measured outcomes included postoperative pain intensity assessment, patient satisfaction with pain management, and persistent pain evaluation. Results: Patients undergoing QLB needed less oxycodone than those in the CON group (34.5 mg [interquartile range 23–40 mg] vs. 47.5 mg [35–50 mg]; p<0.001). No difference between the groups was seen in postoperative pain intensity measured on the visual analog scale, except for the evaluation at hour 2, which was in favor of the QLB group (p=0.03). Patients who received QLB were more satisfied with postoperative pain management than the CON group. Persistent postoperative pain was assessed with the Neuropathic Pain Symptom Inventory (NPSI) at months 1, 3, and 6 and was found to be significantly lower in the QLB group at each evaluation (p<0.001). We also analyzed the impact of the surgery type on persistent pain severity, which was significantly lower after laparoscopic procedures than open procedures at months 1, 3, and 6. Conclusions: QLB reduces oxycodone consumption in patients undergoing open and laparoscopic nephrectomy and decreases persistent pain severity months after hospital discharge.

Background: The aim of our study was to analyze the effect of socioeconomic inequalities, both at the individual and area of residence levels, on the probability of COVID-19 confirmed infection, and its variations across three pandemic waves. Methods: Retrospective cohort study. We included data from all individuals tested by COVID-19 during the three waves of the pandemic, from March to December 2020 (357,989 individuals). We studied the effect of inequalities on the risk of having a COVID-19 confirmed diagnosis after being tested using multilevel analyses with two levels of aggregation: individuals and basic healthcare area (BHA) of residence (deprivation level and type of zone). Results: Patient profile changed through the pandemic, with a predominance of low-paid employees living in deprived BHA. Workers with low salaries, unemployed and people on minimum integration income or who no longer receive the unemployment allowance, had a higher probability of COVID-19 infection than workers with salaries ≥€18,000 per year. Inequalities were higher in women and in the second wave. The deprivation level of BHA of residence influenced the risk of COVID-19 infection, especially in the second wave. Conclusions: There are inequalities in the risk of COVID-19 confirmed infection, both at individual and area level. It is necessary to develop individual and area coordinated measures in the control, diagnosis and treatment of the epidemic, in order to avoid an increase in the already existing inequalities.

Lung cancer represents the most common form of cancer accounting for 1.8 million deaths globally in 2020.The 5-year relative survival rate for lung cancer is lower than many other leading cancer types. Over the last decade the treatment for advanced and metastatic non small cell lung cancer have dramatically improved due to the development of immune checkpoint inhibitors and the identification of targetable driver mutations. Recently, potentially effective inhibitors of a hitherto untargetable oncogenic driver mutation in NSCLC, Kirsten Rat Sarcoma (KRAS) have been developed. KRAS mutations are found in 20-25% of NSCLC and represent the most frequent mutation. The mutation is almost exclusively detected in adenocarcinoma and is found among smokers 90% of the time. Along with the development of new drugs that have been showing promising activity, resistance mechanisms have begun to be clarified. The aim of this review is to unwrap the biology of KRAS in NSCLC with a specific focus on primary and secondary resistance mechanisms and their possible clinical implications.

G-protein-coupled receptors (GPCR) belong to a large family of molecules eliciting different responses to a variety of signaling molecules. These receptors participate in various physiologic pathways such as metabolism, growth, immune responses, inflammation, vision, taste, olfaction, neurotransmission and even and pathologic responses including chronic inflammatory and vascular diseases. Receptors contributing to the biological responses of renin-angiotensin system (RAS) are members of GPCR family. COVID-19-induced inflammatory cascade has been attributed to acute ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/angiotensin (1-7)/Mas axes in favor of the former. Some of the receptors contributing to activities of proteins in RAS including AT1R, AT2R and Mas receptors are members of GPCR family. It is notable that these receptors induce their effects both through G protein and β-arrestin pathway; the former exerts temporary and the latter more sustained effects. In addition to the imbalance of GPCR responses contributing to RAS activities, it has been suggested that SARS-CoV2 pathogenesis might be attributed to the activation of GPCRs or modulating G-proteins involved in adenosine-CFTR regulation system and epithelial Na channel function.This article includes a minireview about the physiological functions of GPCRs and their contribution to COVID-19.

One of the major challenges in the post-genomic era is elucidating the genetic basis of human diseases. In recent years, studies have shown that polygenic risk scores (PRS), based on aggregated information from millions of variants across the human genome, can estimate individual risk for common diseases. In practice, the current medical practice still predominantly relies on physiological and clinical indicators to assess personal disease risk. For example, caregivers mark individuals with high body mass index (BMI) as having an increased risk to develop type 2 diabetes (T2D). An important question is whether combining PRS with clinical metrics can increase the power of disease prediction in particular from early life. In this work we examined this question, focusing on T2D. We show that an integrated approach combining adult BMI and PRS achieves considerably better prediction than each of the measures on unrelated Caucasians in the UK Biobank (UKB, n=290,584). Likewise, integrating PRS with self-reports on birth weight (n=172,239) and comparative body size at age ten (n=287,203) also substantially enhance prediction as compared to each of its components. While the integration of PRS with BMI achieved better results as compared to the other measurements, the latter are early-life measurements that can be integrated already at childhood, to allow preemptive intervention for those at high risk to develop T2D. Our integrated approach can be easily generalized to other diseases, with the relevant early-life measurements.

The development of dosimetry and studies in peptide receptor radionuclide therapy (PRRT) over these two last decades are reviewed. Differences in kidney and bone marrow toxicity reported between ⁹⁰Y, ¹⁷⁷Lu and external beam radiotherapy (EBRT) are discussed with regards to the physical properties of these beta emitter radionuclides. The impact of these properties on the response to small and large tumors is also considered. Capacities of the imaging modalities to assess the dosimetry to target tissues are evaluated. Studies published in the last two years that confirm a red marrow uptake in ¹⁷⁷Lu-DOTATATE therapy, as already observed 20 years ago in ⁸⁶Y-DOTATOC PET studies, are commented and analyzed in the light of the recent knowledges in transferrin transport mechanism. The review enlightens the importance i) of using state of the art imaging modalities, ii) of individualizing the activity to be injected with regards to the huge tissue uptake variability observed between patients, iii) of challenging the currently used but inappropriate blood based red marrow dosimetry and iv) of considering individually tandem therapy. Last, a smart individually optimized tandem therapy taking benefit of the bi-orthogonal toxicity-response pattern of ¹⁷⁷Lu-DOTATATE and of ⁹⁰Y-DOTATOC is proposed.

In this study, we aimed to develop a deep learning model for identifying bacterial keratitis (BK) and fungal keratitis (FK) by using slit-lamp images. We retrospectively collected slit-lamp images of patients with culture-proven microbial keratitis between January 1, 2010, and December 31, 2019, from two medical centers in Taiwan. We constructed a deep learning algorithm, consisting of a segmentation model for cropping cornea images and a classification model that applies convolutional neural networks to differentiate between FK and BK. The model performance was evaluated and presented as the area under the curve (AUC) of the receiver operating characteristic curves. A gradient-weighted class activation mapping technique was used to plot the heatmap of the model. By using 1330 images from 580 patients, the deep learning algorithm achieved an average diagnostic accuracy of 80.00%. The diagnostic accuracy for BK ranged from 79.59% to 95.91% and that for FK ranged from 26.31% to 63.15%. DenseNet169 showed the best model performance, with an AUC of 0.78 for both BK and FK. The heat maps revealed that the model was able to identify the corneal infiltrations. The model showed better diagnostic accuracy than the previously reported diagnostic performance of both general ophthalmologists and corneal specialists.

Fibroblasts are differentiated to myofibroblasts and produce collagen and other extracellular matrix when the heart is exposed to stresses. Myocardial infarction and pressure overload-induced hypertrophy are major stresses to induce differentiation of fibroblasts. Since collagen can compensate the missing tissue due to injury, appropriate production of collagen is beneficial for the injured heart against rupture. However, excessive deposition of collagen is called fibrosis and causes cardiac dysfunction. After fibroblasts are differentiated to myofibroblasts, myofibroblasts can further change their phenotypes. In addition, myofibroblasts are found to have a new function other than collagen production. Myofibroblasts have macrophage-like functions that engulf dead cells and secrete anti-inflammatory cytokines. So far, research on fibroblasts has been delayed due to the lack of available markers for selective isolation of fibroblasts. In recent years, it has become possible to genetically label fibroblasts, sequence the cells at single cell levels, and manipulate function or the number of cells. Based on new technologies, the origin of fibroblasts and myofibroblasts, time-dependent changes of fibroblast states after injury, and heterogeneity have been demonstrated. Here, I will introduce recent advances in fibroblasts and myofibroblasts.

Although automated Acute Lymphoblastic Leukemia (ALL) detection is essential, it is challenging due to the morphological correlation between malignant and normal cells. The traditional ALL classification strategy is arduous, time-consuming, often suffers inter-observer variations, and necessitates experienced pathologists. This article has automated the ALL detection task, employing deep Convolutional Neural Networks (CNNs). We explore the weighted ensemble of deep CNNs to recommend a better ALL cell classifier. The weights are estimated from ensemble candidates' corresponding metrics, such as accuracy, F1-score, AUC, and kappa values. Various data augmentations and pre-processing are incorporated for achieving a better generalization of the network. We train and evaluate the proposed model utilizing the publicly available C-NMC-2019 ALL dataset. Our proposed weighted ensemble model has outputted a weighted F1-score of 88.6%, a balanced accuracy of 86.2%, and an AUC of 0.941 in the preliminary test set. The qualitative results displaying the gradient class activation maps confirm that the introduced model has a concentrated learned region. In contrast, the ensemble candidate models, such as Xception, VGG-16, DenseNet-121, MobileNet, and InceptionResNet-V2, separately produce coarse and scatter learned areas for most example cases. Since the proposed ensemble yields a better result for the aimed task, it can experiment in other domains of medical diagnostic applications.

Total 219 countries and territories globally suffering from the recent pandemic COVID-19 is now in its second wave with more brutality, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . It has several symptoms like as persistent fever; respiratory illnesses; cough; fatigue; shortness of breath; loss of appetite; persistent pain or pressure in the chest; dysgeusia; acute respiratory distress syndrome (ARDS) etc., and here the things to worry about is the development of pulmonary fibrosis after COVID-19 in both peoples who had died of due to acute respiratory distress syndrome (ARDS) or those who survived. Due to COVID-19, dysregulated immune response and wound repair mainly in elderly patients causes this secondary pulmonary fibrosis. Thus using anti-fibrotic agents could be meaningful in these circumstances although their efficacy in treating COVID-19 is subject to more detailed laboratory research works. In this review article you will get to know about the lung fibrosis generation due to COVID-19 infection, about anti-fibrotic agents and the currents challenges of this field.

The development of CRISPR associated proteins, such as Cas9, has led to increased accessibility and ease of use in genome editing. However, additional tools are needed to quantify and identify successful genome editing events in living animals. We developed a method to rapidly and quantitatively monitor gene editing activity non-invasively in living animals that also facilitates confocal microscopy and nucleotide level analyses at the end of study. Here we report a new CRISPR “footprinting” approach to activate luciferase and fluorescent proteins in mice as a function of gene editing. This system is based on experience with our prior Cre-detector system and is designed for Cas editors able to target LoxP including gRNAs including SaCas9 and ErCas12a [1, 2]. These CRISPRs cut specifically within LoxP, an approach that is a departure from previous gene editing in vivo activity detection techniques that targeted adjacent stop sequences. In this sensor paradigm, CRISPR activity was monitored non-invasively in living Cre reporter mice (FVB.129S6(B6)-Gt(ROSA)26Sortm1(Luc)Kael/J and Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/J, which will be referred to as LSL and mT/mG throughout the paper) after intramuscular or intravenous hydrodynamic plasmid injections, demonstrating utility in two diverse organ systems. The same genome-editing event was examined at the cellular level in specific tissues by confocal microscopy to determine the identity and frequency of successfully genome-edited cells. Further, SaCas9 induced targeted editing at efficiencies that were comparable to Cre recombinase demonstrating high effective delivery and activity in a whole animal. This work establishes genome editing tools and models to track CRISPR editing in vivo non-invasively and to fingerprint the identity of targeted cells. This approach also enables similar utility for any of the thousands of previously generated LoxP animal models.

Aims: Spironolactone is a steroidal mineralocoricosteroid receptor antagonist (MRA) used for treatment of resistant hypertension, heart failure and edema. It exerts class specific adverse effects that are shared by other MRAs. Additionally, it exerts unique “off target” steroidal effects that include gynecomastia, impotence and loss of libido in males and menstrual irregularity in females. Together, these have led to a poor tolerability and limited use despite positive results in many randomized, controlled clinical trials. We review the off-target effects of spironolactone that may summate with its MRA action to provide an advantageous profile for prevention or treatment of patients with COVID-19. Methods: Literature review using PubMed Central. Results: The blockade by spironolactone of the androgen receptor should diminish the expression of transmembrane protease serine 2 (TMPRSS2) that has an androgen promoter while its MRA action should enhance the expression of protease nexin1 (PN1) that inhibits furin and plasmin. TMPRSS2, furin and plasmin cooperated to process the SARS-CoV-2 spike protein to increase its high affinity binding to the angiotensin converting enzyme 2 (ACE2) and thereby promote viral cell entry. Its actions as an MRA may reduce inflammation and preserve pulmonary, cardiac and vascular functions. Its anti-plasmin action may combat hemostatic dysfunction. Conclusion: The hypothesis that the off-target effects of spironolactone summate with its MRA actions to provide special benefits for COVID-19 is worthy of direct investigation and clinical trial.

Abstract: COVID-19 in 2020 brought challenges to the Brazilian public health system with an emerging virus with respiratory contagion called SARS-CoV-2. There are few studies in Brazil and in some countries, on the increased incidence of certain viral respiratory infections, includ-ing H1N1 and coronavirus and their association with low levels of vitamin D, zinc and iron. The aim of this study was to demonstrate that the deficit of vitamin D, zinc and iron has an impact on the infectious process of patients with COVID-19 and to establish new forms of prevention for the worsening of COVID-19 in the human body. Data were collected from medical records and test results from patients being followed up during the treatment period for COVID-19. Patients with low blood levels of vitamin D, zinc and iron during the treatment period of COVID-19 had a higher percentage of worsening and complications requiring hospitalization in intensive care beds. The ingestion of vitamin D, zinc and iron in the treatment period of patients with COVID-19 in addition to being an immunological protector against SARS-CoV-2 and alleviating the process of worsening the disease can also act as a biomarker in cases of this disease.

Objectives: To determine the prevalence of controlled systemic hypertension and its associated risk factors among the hypertensive patients who attended the clinic at Mbeya Zonal Referral Hospital in Tanzania. Methods: A descriptive cross-sectional quantitative study was used determine the prevalence of co to 252 hypertensive patients were recruited during clinic visit from September to November 2020 and participant was randomly selected interviews using structured self-administered questionnaires. Data was analyzed using chi square test to find the risk factors associated with controlled hypertension. Results: Among 252 participants, 94(39.7%) individuals with controlled hypertension giving the prevalence of controlled hypertension. The proportion of females with controlled hypertension was slightly higher than male (49 females to 45 males). The prevalence of uncontrolled hypertension was 152(60.3%) participants. The prevalence of controlled hypertension was higher among patients who have regular clinic visit (p< .05) and have daily adherence to their anti-hypertensive medication. A similar trend was observed among participants without financial challenges to attend clinic, short duration of illness, higher level of education and there was no association between age, sex, marital status, smoking, alcohol consumption, having health insurance and having chronic illness. Conclusion: Prevalence of controlled hypertension is higher among patients who have regular clinic visit and have daily adherence to their anti-hypertensive medication. Also, it is higher among participants without financial challenges to attend clinic so they can have regular clinic visit and checkup. Reinforcement on regular drug intake and clinic visit, good nutrition and reduced salt intake and modifying lifestyles of patient with hypertension is important.

Ovarian cancer (OC) represents the most common and lethal gynecologic malignancy, due to its increased incidence and mortality rate. It is usually diagnosed in advanced stages and, even though surgery and platinum-based treatment are initially efficient, recurrences emerge in over 70% of cases. Although there are multiple options of chemotherapy drugs from which to choose, little is known regarding the best strategy for prolonged survival. Thus, the aim of this study was to assess the effect that most frequently used chemotherapeutic regimens have upon time-to-treatment-failure (TTF) from the first line and beyond, considering clinical and biological factors which influence the treatment outcome of platinum-resistant recurrent OC. We retrospectively analyzed data from 78 patients diagnosed with platinum-resistant OC, who underwent chemotherapy-based treatment with or without anti-angiogenic therapy at OncoHelp Oncology Center, Romania (January 2016 - February 2021). Our study identified positive predictive factors for TTF related to anthropometry (age over 60 for patients treated with topotecan with or without bevacizumab), renal function (creatinine levels between 0.65 and 1 mg/dl for patients treated with regimens containing bevacizumab and pegylated liposomal doxorubicin) and treatment choice (bevacizumab in combination with pegylated liposomal doxorubicin or topotecan used from the first line and beyond).

A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein we identify cyclin dependent kinase 1 (CDK1) also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/hypoxia rats were investigated for their expression of CDC2. Protein levels of CDC2 were much higher in PAH than in cells from normal donors. Knocking down FOXM1 or PLK1 protein expression with siRNA or pharmacological inhibitors lowered the cellular expression of CDC2 considerably. However, knockdown of CDC2 with siRNA or inhibiting its activity with RO-3306 did not reduce the protein expression of FOXM1 or PLK1. Expression of CDC2 and FOXM1 reached its maximum at G1/S, while PLK1 reached its maximum at G2/M phase of the cell cycle. The expression of other CDKs such as CDK2, CDK4, CDK6, CDK7 and CDK9 did not change in PAH HPASMC. Moreover, inhibition via Wee1 inhibitor adavosertib or siRNAs targeting Wee1, Myt1, CDC25A, CDC25B, or CDC25C led to dramatic decreases in CDC2 protein expression. Lastly, we found CDC2 expression at the RNA and protein level to be upregulated in pulmonary arteries during disease progression Sugen/hypoxia rats. In sum, our present results illustrate that the increased expression of FOXM1 and PLK1 in PAH leads directly to increased expression of CDC2 resulting in a potentiated growth hyperactivity of PASMC from patients with pulmonary hypertension. Our results further suggest that the regulation of CDC2, or associated regulatory proteins, will prove beneficial in the treatment of this disease.

With rapid advances in gene editing and gene therapy technologies, the development of genetic, cell, or protein-based cures to disease are no longer the realm of science fiction but that of today’s practice. The impact of these technologies are rapidly bringing them to the veterinary market as both enhanced therapeutics and towards modeling their outcomes for translational application. Simply put, gene editing enables scientists to modify an organism’s DNA a priori through the use of site-specific DNA targeting tools like clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). Gene therapy is a broader definition that encompasses the addition of exogenous genetic materials into specific cells to correct a genetic defect. More precisely, the U.S Food and Drug Administration (FDA) defines gene therapy as “a technique that modifies a person’s genes to treat or cure disease” by either (i) replacing a disease-causing gene with a healthy copy of the gene; (ii) inactivating a disease-causing gene that was not functioning properly; or (iii) introducing a new or modified gene into the body to help treat a disease. In some instances, this can be accomplished through direct transfer of DNA or RNA into target cells of interest or more broadly through gene editing. While gene therapy is possible through the simple addition of genetic information into cells of interest, gene editing allows the genome to be reprogrammed intentionally through the deletion of diseased alleles, reconstitution of wild type sequence, or targeted integration of exogenous DNA to impart new function. Cells can be removed from the body, altered, and reinfused, or edited in vivo. Indeed, manufacturing and production efficiencies in gene editing and gene therapy in the 21^st century has brought the therapeutic potential of in vitro and in vivo reprogrammed cells, to the front lines of therapeutic intervention (Brooks et al., 2016). For example, CAR-T cell therapy is revolutionizing hematologic cancer care in humans and is being translated to canines by us and others, and gene therapy trials are ongoing for mitral valve disease in dogs.

Context: Mental and menstrual health, two emerging aspects of health critical to the female population, are bidirectionally linked. But there is limited empirical evidence that establishes the association between these entities. This essay aims to draw the attention of researchers to this healthcare niche. Evidence Acquisition: A systematic review was carried out on literatures sourced from medical databases (e.g. PubMed, Google Scholar, Scopus, Science Direct, and Web of Science), and gray sources—popular and reputable institutional and journalistic websites that publishes mental or menstrual health research. The key words used for the search are “Menstruation, menstrual hygiene, menstrual disorders, premenstrual syndrome, period poverty, menarche, menopause, mental health, mental disorder, mental illness, depression, anxiety, phobia, mania, mood, and affect”. The initial search generated 368 results. But after the duplicates were removed, the exclusion criteria (publication before 2000) was applied, and manual review of abstract (for relevance) was done, 21 publications from the databases and 5 from gray sources were included in this essay. Results: Associations were found between menstrual cycle irregularities and disorders; and mental disorders such as premenstrual syndrome, premenstrual dysphoric disorder, major depressive disorder, major anxiety disorder, psychotic disorder, bipolar disorder, borderline personality disorder, sleep disorder, substance use/abuse, and suicidal ideation and attempts.Few positive associations between mental and menstrual health were recorded, and several research and treatment gaps were identified. Conclusion: Research into the links between mental and menstrual health should not remain a fringe area of scientific curiosity, as it shows tremendous promise in improving healthcare offered to women/girls globally.

The aim of this study was to determine whether a rowing training program improved the quantity and quality of physical activity and quality of life in female breast cancer survivors (stage I - 4.35%; II - 30.43%; III - 52.17%; and IV - 8.7%) diagnosed 6.57 ± 5.02 years previously, who had undergone a subsequent intervention (preservation 53.52%; total mastectomy 39.13% and double mastectomy 4.35%) and had a current mean age of 53.70 ± 7.88 years. The participants (N = 30) engaged in a 12-week training program, each week comprising three sessions and each session lasting 60-90 minutes. An anthropometric evaluation was performed before and after the program. The short form of the International Physical Activity Questionnaire (IPAQ-SF) and the Short Form 36 Health Survey (SF-36) were also administered. The results showed statistically significant improvements in levels of physical activity and in the dimensions of quality of life. We can conclude that a 12-week rowing training program tailored to women who have had breast cancer increases physical activity levels, leading to improved health status and quality of life.

The brain rhythms are essential for information processing in neuronal networks. Oscillations recorded in different brain regions can be synchronized and have a constant phase difference, i.e. be coherent. Coherence between local field potential (LFP) signals from different regions in the brain may be correlated with the performance of cognitive tasks, from which it is concluded that these regions of the brain are involved in the task performance together. In this review, we discuss why coherence occurs and how it is coupled to the information transfer between different regions of the hippocampal formation. Coherence in theta and gamma frequency ranges is described since these rhythms are most pronounced during the hippocampus-dependent attention and memory. We review in vivo studies of interactions between different regions of the hippocampal formation in theta and gamma frequency bands. The kay provisions of the review: 1) coherence emerges from synchronous postsynaptic currents in principal neurons, occurring as a result of synchronization of neuronal spike activity; 2) synchronization of neuronal spike patterns in two regions of the hippocampal formation can be realised through induction or resonance; 3) coherence at a specific time point reflects the transfer of information between regions of the hippocampal formation, in particular, gamma coherence reflects the coupling of active neuronal ensembles. Overall, coherence is not an epiphenomenon, but an important physiological process that has certain generation mechanisms and performs important functions in information processing and transmission across the brain regions.

Guided by the Conceptual Model of Implementation Research, we explored the acceptability, appropriateness, and feasibility of: 1) automated screening approaches utilizing existing health data to identify those who require subsequent diagnostic evaluation for familial hypercholesterolemia (FH) and 2) family communication methods including chatbots and direct contact to communicate information about inherited risk for FH. Focus groups were conducted with 22 individuals with FH (2 groups) and 20 clinicians (3 groups). These were recorded, transcribed, and analyzed using deductive (coded to implementation outcomes) and inductive (themes based on focus group discussions) methods. All stakeholders described these initiatives as: 1) acceptable and appropriate to identify individuals with FH and communicate risk with at-risk relatives; and 2) feasible to implement in current practice. Stakeholders cited current initiatives, outside of FH (e.g., pneumonia protocols, colon cancer and breast cancer screenings), that gave them confidence for successful implementation. Stakeholders described perceived obstacles, such as nonfamiliarity with FH, that could hinder implementation and potential solutions to improve systematic uptake of these initiatives. Automated health data screening, chatbots, and direct contact approaches may be useful for patients and clinicians to improve FH diagnosis and cascade screening.

Background: the devastating outbreak of COVID-19 poses serious challenges for the diagnostics laboratories, which are often facing global shortage of reagents and equipment. With the aim of increasing the diagnostic throughput for SARS-CoV-2 molecular test, the purpose of this study was to validate an additional RNA extraction method respect to those already recommended by WHO and the US Centers for Disease Control and Prevention (CDC). Methods: a new protocol for RNA extraction from nasopharyngeal swab was set up, adapting the Qiagen RNeasy 96 plate and validated on a set of 100 clinical samples analyzed in parallel by Roche-Magnapure method (already recommended by CDC guidelines). Results: the internal control and target genes analysis showed a good agreement between the two extraction methods indicating that the two methods can be considered equivalent and that the RNeasy-adapted method can be applied for the SARS-CoV-2 diagnostics. The addition of this new extraction method resulted in a throughput increase for SARS-CoV-2 molecular test of about 2000 samples/month during the initial months of the pandemic emergency in which the lack of reagents for the extraction led to an insufficient sample processing throughput of the analysis of the swabs.

This review revisits clinical use of antibiotics for most common acute oro-dental conditions; we aim to provide evidence governing antibiotics use when access to oral healthcare is not available, as during the ongoing outbreak of the severe acute respiratory syndrome coronavirus 2. In this rapid review, articles were retrieved after conducting a search on PubMed and Google Scholar. Relevant publications were selected and analyzed. Most recent systematic reviews with/without meta-analyses and societal guidelines were selected. Data were extracted, grouped, and synthesized according to the respective subtopic analysis. There were evidence supporting the use of antibiotics in common oro-dental conditions as temporary measure when immediate care is not accessible, such as in case of localized oral swellings as well as to prevent post-extraction complications. No sufficient evidence could be found in support of antibiotic use for pain resulting from pulpal origin. Consequently, antibiotic use may be justified to defer treatment temporarily or reduce risk of complications in case of localized infection and tooth extraction, when no access to immediate dental care is possible.

Physical symptoms are defined as symptoms for which adequate examination does not reveal a sufficient underlying root cause, e.g., pain and fatigue. The extant literature of the neurobiological underpinnings of physical symptoms has been largely inconsistent and primarily consists of (clinical) case-control studies with relatively small samples sizes. Therefore, we studied the association of brain morphology with physical symptoms in pre-adolescents from two independent and population-based cohorts. This study included 2,683 individuals from the Generation R Study (51% girls, 10.1 ± 0.6 years old) and 10,567 pre-adolescents from the ABCD Study (48% girls, 9.9 ± 0.6 years old). High- resolution structural magnetic resonance imaging (MRI) was collected using 3-Tesla MRI systems. Physical symptoms were evaluated using the somatic complaints syndrome scale from the parent-reported school-age version of the Child Behavior Checklist. Linear regression models were fitted for global brain metrics (i.e., cortical and subcortical grey matter volume and total white matter volume) as well as surface-based vertex-wise measures (surface area and cortical thickness). Analyses were initially conducted separately in each cohort and later meta-analysed. No associations were observed in either cohort separately. In the combined vertex-wise meta-analysis of both cohorts; the right hemisphere surface area, most notably the rostral middle frontal gyrus, superior frontal gyrus and anterior cingulate cortex, were related to physical symptoms after correcting for multiple comparisons (cluster area = 1,882 mm2). The present study, which is the most representative and well-powered to date, suggests that surface area, but not other measures of brain morphology, are modestly related to physical symptoms in pre- adolescents. While these effects are subtle, future longitudinal research is warranted to elucidate whether such associations indicate a cause or a consequence of the physical symptoms.

The World Health Organization has developed the Integrated Care of Older People (ICOPE) strategy, a program based on the measurement of intrinsic capacity (IC) as “the composite of all physical and mental attributes on which an individual can draw”. Multicomponent interventions appear to be the most effective approach to enhance IC and to prevent frailty and disability, since adapted physical activity is the preventive intervention that has shown most evidence in the treatment of frailty and risk of falls. Our paper describes the development of a multi-domain group-based intervention addressed to older people living in the community, aimed at improving and/or maintaining intrinsic capacity by means of promoting physical activity, healthy nutrition, and psychological wellbeing in older people. The process of intervention development is described following the Guidance for reporting intervention development studies in health research (GUIDED. The result of this study is the AMICOPE intervention (Aptitude Multi-domain group-based intervention to improve and/or maintain IC in Older PEople) built upon the ICOPE framework and described following the Template for Intervention Description and Replication (TIDieR) guidelines. This study represents the first stage of the UK Medical Research Council framework for developing and evaluating a complex intervention. The next step should be carrying out a feasibility study for the AMICOPE intervention, and in a later stage, assessing the effectiveness in a randomized controlled trial.

This study analysed trends of first-time patients visiting the paediatric psychiatry clinic in a university hospital. The medical records from 2009 to 2016 of first-time patients visiting the Kyung Hee university hospital were reviewed, focusing on children in grades 1–12. We analysed the prevalence rate of psychiatric disorders per 100,000 general populations by gender and grade, and the characteristics of patients who sought outpatient care more than three times. The study included 1,467 participants, of which 931 were males (63.5%). The number of male patients per 100,000 populations significantly decreased from 4.14 in 2009 to 2.03 in 2016. While hyperkinetic disorders had the highest prevalence in males, neurotic disorders were most frequent in females. Prevalence of disruptive behaviour disorders in males and mental retardations in females decreased significantly during the study period. The factors affecting continuity were being female, studying in grades 7–12, and diagnosis of depressive, hyperkinetic, and tic disorders. Physicians should consider the new paediatric patients’ gender, grade, and expected diagnosis from their first visit to improve treatment compliance.

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer’s disease, anxiety/fear, schizophrenia, and depression, as well as pain.

Introduction: The current generation of 3D printers are lighter, cheaper, and smaller, making them more accessible to the chairside digital dentist than ever before. 3D printers in general in the industrial and chairside setting can work with various types of materials including, metals, ceramics, and polymers. Evidence presented in many studies show that an ideal material used for dental restorations is characterised by several properties related to durability, cost-effectiveness, and high performance. This review is the second part in a 3D Printing series that looks at the literature on material science and applications for these materials in 3D printing as well as a discussion on the potential further development and future evolution in 3D printing materials. Conclusions: Current materials in 3D printing provide a wide range of possibilities for providing more predictable workflows as well as improving efficiency through less wasteful additive manufacturing in CAD/CAM procedures. Incorporating a 3D printer and a digital workflow into a dental practice is challenging but the wide range of manufacturing options and materials available mean that the dentist should be well prepared to treat patients with a more predictable and cost effective treatment pathway. As 3D printing continues to become a commonplace addition to chair side dental clinics, the evolution of these materials, in particular reinforced PMMA, resin incorporating zirconia and glass reinforced polymers offer increased speed and improved aesthetics that will likely replace subtractive manufacturing milling machines for most procedures.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the chief concern of the international community in almost no time. As of May 9th, 2021, more than 150 million cases and 3.2 million deaths have been recorded. Considering the early struggle in treating COVID-19 patients, the researchers and clinicians have decided to try the previously available drugs according to their mechanisms of action. Hence, many antivirals, antibiotics, antiparasitics, and antipyretics have been proposed. Pregnant women, fetuses, and infants are known high-risk populations that are threatened during disease outbreaks. Therefore, this article reviews the safety of potential drugs for COVID-19 patients during pregnancy and breastfeeding.

With the goal of representing common denominators of aging in different organisms López-Otín et al. in 2013 described nine hallmarks of aging. Since then, this representation has become a major reference point for the biogerontology field. The template for the hallmarks of aging account originated from landmark papers by Hanahan and Weinberg (2000, 2011) defining first six and later ten hallmarks of cancer. Here we assess the strengths and weaknesses of the hallmarks of aging account. As a checklist of diverse major foci of current aging research, it has provided a useful shared overview for biogerontology during a time of transition in the field. It also seems useful in applied biogerontology, to identify interventions (e.g. drugs) that impact multiple symptomatic features of aging. However, while the hallmarks of cancer provide a paradigmatic account of the causes of cancer with profound explanatory power, the hallmarks of aging do not. A worry is that as a non-paradigm the hallmarks of aging have obscured the urgent need to define a genuine paradigm, one that can provide a useful basis for understanding the mechanistic causes of the diverse aging pathologies. We argue that biogerontology must look and move beyond the hallmarks to understand the process of aging.

The adverse relationship between viral hepatitis and pregnancy in developing countries was seen as a reflection of retrospective biased hospital-based data collection by the West. However, the discovery of HEV from an epidemic of non-A, non-B hepatitis in Kashmir and documenting increased incidence and severity of hepatitis E in pregnancy from a house-to-house survey unmasked the unholy alliance. Among the family of HEV’s, genotype (gt)-1, with a unique ORF4-encoded protein enhancing viral polymerase activity and viral replication, is the sole HEV that shows this adverse relationship. The epidemics caused by HEV-gt1 and not by HEV-gt2 show adverse relationship with pregnancy. The pathogenesis of the unholy alliance is complex and at present not well understood. Possibly multiple factors play a role in causing severe liver disease in the mother including: infection, replication and damage to the maternal-foetal interface by HEV-gt1; vertical transmission of HEV to foetus causing severe foetal/neonatal hepatitis; and combined viral and hormone related immune dysfunction of diverse nature in the mother promoting viral replication. Management is multidisciplinary and needs a close watch for the development and management of ALF. Preliminary data suggest beneficial maternal outcomes by early termination of pregnancy in patients with lower grades of encephalopathy.

Background: There is ongoing debate regarding the usefulness of laparoscopic pancreaticoduodenectomy. This study aimed to analyze all the randomized control trials published including the most recent one. Material and methods: The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and MOOSE guidelines. Heterogeneity was measured using Q tests and I2. The random-effects models were used to summarise the relative risks, odds ratios, and mean differences as appropriate.Results:4 RCTs were included consisting of 818 patients. 411 patients were in the laparoscopic group and 407 in the open pancreaticoduodenectomy group. Weighted baseline patient characteristics were similar except more patients with pancreatic adenocarcinoma and more males were there in the open pancreaticoduodenectomy group. There was no difference in-hospital stay,90 days complications rate, 90 days mortality, R1 resection, postoperative pancreatic fistula, delayed gastric emptying, post pancreatectomy hemorrhage, bile leak between the two groups. Operative time was more in the laparoscopic group. Blood loss [mean difference -132.12 ml (-172.60,-91.65)] and surgical site infection [Risk ratio 0.41 ( 0.17-1.0)] were significantly lesser in laparoscopic group.Conclusion:There was no benefit in-hospital stay or clinical outcomes after laparoscopic pancreaticoduodenectomy. Blood loss and surgical site infection were lesser in laparoscopic pancreaticoduodenectomy.

Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase implicated in a wide variety of regulatory cellular functions. PP2A is abundant in the mammalian nervous system and dysregulation of its cellular functions are associated with myriad neurodegenerative disorders. Additionally, PP2A has oncologic implications, recently garnering attention and emerging as a therapeutic target because of the antitumor effects of a potent PP2A inhibitor, LB100. LB100 abrogation of PP2A is believed to exert its inhibitory effects on tumor progression through cellular chemo- and radio-sensitization to adjuvant agents. An updated and unifying review of PP2A biology and inhibition with LB100 as a therapeutic strategy for targeting cancers of the nervous system is needed, as other reviews have mainly covered broader applications of LB100. In this review, we discuss the role of PP2A in normal cells and tumor cells of the nervous system. Further, we summarize current evidence regarding the therapeutic potential of LB100 for treating solid tumors of the nervous system.

Extensive limb lengthening (ELL) was completed in 75 patients: 66 achondroplasia and 9 hypochondroplasia. The average lengthening was 27cm for achondroplasia (12-40cm) and 17cm for hypochondroplasia (range 10-25cm). There were 48 females and 27 males. Lengthening was done either by 2-segment (14 patients; both tibias and/or both femurs) or by serial 4-segment lengthenings (64 patients; both femurs and tibias same time). Most patients also had bilateral humeral lengthening. Lengthenings were either juvenile-onset (31), adolescent-onset (38) or adult-onset (6). The average age at final follow-up was 26 years old (range 17-43 years). There were few permanent sequelae of complications. The most serious was one paraparesis. All patients returned to activities of normal living and only one was made worse by the surgery (paraparesis). This is the first study to show that ELL can lead to increase of height into the normal height range. Previous studies showed mean increases of height of up to 20cm, while this study consistently showed an average increase of 30 cm (range 15-40cm) for juvenile-onset and increase of 26cm (range 15-30cm) for adolescent-onset. This results in lower normal height at skeletal maturity for males and females. The adult-onset had a mean increase of 16.8 (range 12-22cm). This long-term follow-up study shows ELL can be done safely even with large lengthenings and that 4-segment lengthening may offer advantages over 2-segment lengthening. While the majority of cases were performed using external fixation, implantable limb lengthening promises to be an excellent alternative and perhaps an improvement.

Background: Research continues to search for blood-based biomarkers sensitive to Alzheimer’s disease (AD) pathology during the initial stages when symptoms of cognitive decline are not yet apparent. A blood-based biomarker candidate is metalloprotein p53, the conformation of which was previously found to be altered in peripheral cells from individuals with mild cognitive impairment (MCI) and AD, presenting as an unfolded p53 (U-p53) conformational variant. Methods: Plasma samples from the well-characterized Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort were used to identify the clinically relevant AZ 284^® peptide, specifically present in samples from individuals with symptomatic AD. The AZ 284^® peptide, which is a marker of the U-p53 conformational variant (U-p53^AZ), was identified by immunoprecipitation (IP) with a novel U-p53 conformational variant-specific antibody followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing. Using IP-LC surface-activated chemical ionization (SACI) MS/MS analysis, the prognostic and diagnostic performance of U-p53^AZ were examined in the longitudinal AIBL cohort, including 252 plasma samples derived from 214 elderly individuals. For the prognostic analyses, U-p53^AZ levels were assessed at 36, 72, and 90 months after baseline assessment. Results: The prognostic performance of U-p53^AZ to predict the progression to AD from preclinical or prodromal AD was high, with area under the receiver operating characteristic curve (AUC) values close to or above 0.90. Furthermore, U-p53^AZ predicted the progression to AD more than 6 years prior to symptom onset with positive and negative predictive values of about 90%. Additionally, the estimated prognostic performance of U-p53^AZ was superior to other main risk factors (i.e., age, sex, and either alone or in combination with amyloid status. Furthermore, U-p53^AZ had high diagnostic performance to differentiate cognitively normal individuals from those with AD (AUC values >0.88). Conclusion: These findings support the use of U-p53^AZ as a prognostic blood-based biomarker accurately predicting the progression to AD dementia during the preclinical and prodromal stages at least 6 years before receiving the clinical diagnosis of AD dementia.

Background Due to the Covid-19 pandemic and the strict national policies regarding social distancing behavior in Europe, America and Australia, people became reliant on social media as a means for gathering information and a tool for staying connected to family, friends and work. This is the first trans-national study exploring the experiences and challenges of using social media while in lockdown or shelter in place during the current pandemic. Methods This study was part of a wider cross-sectional online survey conducted in Norway, UK, USA and Australia during April/May 2020. The research question was to explore the experiences and challenges of social media users during the Covid-19 pandemic. 3810 people took part in the survey and 1991 responses were included in the analysis . Thematic analysis was conducted independently by two researchers. Results Three overarching themes identified were: Emotional/Mental Health, Information and Being Connected. Participants experienced that using social media during the pandemic amplified anxiety, depression, fear, panic, anger, frustration and loneliness. They felt that there was information overload and social media was full of misleading or polarized opinions from which was difficult to switch off. Nonetheless, participants also thought that there was an urge for connection and learning which was positive and stressful and the same time. Conclusion Using social media while in shelter in place or lockdown could have a negative impact on the emotional and mental health of the population. These findings give a clear insight into practical recommendations for policy and practice on the importance of strengthening mental health care in the community and investing in health workers to support the mental health needs of the public.

Histone deacetylase (HDAC) inhibitors are class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic ‘caps’ possessing a central, eight-membered, heterocyclic ring, and investigated the HDAC activity and cytotoxic effect on the cancer and normal cell lines. We found that three out of the 19 compounds, based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds, showed better HDACs inhibition than the referenced Vorinostat. In leukemic cell line MV4-11 and in lymphoma cell line – Daudi three compounds showed lower IC50 values than Vorinostat. These compounds had higher activity and selectivity against MV4-11 and Daudi cell lines than reference Vorinostat. We also observed a strong correlation between HDACs inhibition and the cytotoxic effect. Cell lines derived from solid tumors: A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) as well as reference Balb/3T3 (normal murine fibroblasts) were less susceptible to compounds tested. Developed derivatives show superior properties than Vorinostat, thus they are applicable as selective agents for leukemia and lymphoma treatment.

Despite recent advances in immune-modulatory drugs, pharmacological therapies have been proven ineffective in severe presentations of multiple sclerosis (MS), including secondary progressive MS. At present, therapeutic interventions' performance is primarily focused on ameliorating symptoms to improve the patient's quality of life. Among complementary treatments, nutrition has been considered a decisive factor to control symptoms and enhance the wellness of MS patients. Although no special diets are associated with MS, the impact of diet and dietary supplements on the course of progressive forms of the disease have been studied during the last years. Fatigue is among the most common and disabling symptoms reported by MS patients. Fatigue has been defined in the Multiple Sclerosis Council for Clinical Practice Guidelines (MSCCPG, 1998) as a "subjective lack of physical and/or mental energy that the individual perceives as an interference with habitual and desired activities". This study aimed to compare the psychometric functioning of the "Fatigue Severity Scale" (FSS) and the "Modified Fatigue Impact Scale" (MFIS) in our sample of people with MS. Specifically, during chronic treatment, the change in these two parameters with two vitamin-rich dietary supplements (Citozym® and Ergozym®) was evaluated. The impact of these nutritional supplements revealed differences in antioxidant and anti-inflammatory parameters between treatment groups with subsequent improvement in fatigue. In conclusion, the results obtained have confirmed the effectiveness of complementary nutritional therapies, evaluated essentially based on hematological biomarkers, through which it is possible to act on disability to improve the quality of life of MS patients.

Human milk (HM) is the gold standard for feeding infants but has been associated with slower growth in preterm infants compared with preterm formula. This systematic review and meta-analysis summarises the post-1990 literature to examine the effect of HM feeding on growth during the neonatal admission of preterm infants with birth weight ≤1500g and/or born ≤28 weeks’ gestation. Medline, PubMed, CINAHL and Scopus were searched, and comparisons grouped as: exclusive human milk (EHM) vs exclusive preterm formula (EPTF), any HM vs EPTF and higher vs lower doses of HM. We selected studies that used fortified HM and compared that with a PTF; studies comparing unfortified HM and term formula were excluded. Experimental and observational studies were pooled separately. The GRADE system was used to evaluate risk of bias and certainty of evidence. Forty-four studies were included with 37 (n =9,963 infants) included in the meta-analyses. In general, due to poor quality studies, evidence of the effect of any HM feeds or higher versus lower doses of HM was inconclusive. There was a possible effect that lower doses of HM compared with higher doses of HM improved weight gain during the hospital admission, and separately, a possible effect of increased head circumference growth in infants fed EPTF vs any HM. The clinical significance of this is unclear. There was insufficient evidence to determine the effects of an exclusive HM diet on any outcomes.

Introduction: The aim of the study was to test and validate the performance of the 2012 Briganti nomogram as a predictor for pelvic lymph node invasion (LNI) in men who underwent radical prostatectomy (RP) with extended pelvic lymph node dissection (PLND), to examine their performance and to analyse the therapeutic impact of using different nomogram cut-off . Material and methods: The study group consisted of 222 men with clinically localized prostate cancer (PCa) who underwent RP with ePLND between 01/2012 and 10/2018. Measurements included: preoperative PSA, clinical stage (CS), primary and secondary biopsy Gleason pattern and percentage of positive cores. The area under curve (AUC) of the receiver operator characteristic analysis was appointed to quantify accuracy of the primary nomogram model to predict LNI. The extent of estimation associated with the use of this model was graphically depicted using calibration plots. Results: The median number of removed lymph nodes was 16 (IQR 12-21). A total of 53 of 222 patients (23,9%) had LNI. Preoperative clinical and biopsy characteristics differed significantly (all p&lt;0.005) between men with and without LNI. A nomogram-derived cut-off of 7% could lead to a reduction of 43% (95/222) of lymph node dissection, while missing 19% (10/53) of patients with LNI. The sensitivity, specificity, and negative predictive value associated with the 7% cut-off were 81.1%, 50.3%, and 96.3%, respectively. Conclusions: Analysed nomogram demonstrated high accuracy for LNI prediction. A nomogram-derived cutoff of 7% confirmed good performance characteristics within a first external validation cohort from Poland.

Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English-language publications from 2008 – 2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimizing safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found few, but no serious, adverse events associated with phage therapy. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.

Tailoring extracellular vesicles (EVs) as targeted drug delivery systems to enhance the therapeutic efficacy showed superior advantage over liposomal therapies. Herein, we developed a novel nanotool for targeting B16.F10 murine melanoma, based on EVs stabilized with Polyethylene glycol (PEG) and loaded with doxorubicin (DOX). Nanosized EVs were efficiently enriched from melanoma cells cultured under metabolic stress by ultrafiltration coupled with size exclusion chromatography (UF-SEC) and characterized by size, morphology, and proteome. To reduce their clearance in vivo, EVs were PEGylated and passively loaded with DOX (PEG-EV-DOX). Our data suggested that the low PEG coverage of EVs might still favor EV surface protein interactions with target proteins from intratumor cells, ensuring their use as “Trojan horses” to deliver DOX to the tumor tissue. Moreover, our results showed a superior antitumor activity of PEG-EV-DOX in B16.F10 murine melanoma models in vitro and in vivo compared to that exerted by clinically applied liposomal DOX in the same tumor model. The PEG-EV-DOX administration in vivo reduced NF-κB activation and increased BAX expression, suggesting better prognosis of EV-based therapy than liposomal DOX treatment. Collectively, our results highlight the promising potential of EVs as optimal tools for systemic delivery of DOX to solid tumors.

Introduction: The term 3D printing is commonly used to depict an assembling method whereby the final form of an object is the result of the addition of different layers to build the frame of an object. This procedure is more accurately portrayed as additive manufacturing and is likewise alluded to as fast prototyping. The term 3D printing, in any case, is generally new and has been an active part of current developments in Dentistry. Much publicity encompasses the evolution of 3D printing, which is hailed as an innovation that will perpetually change CAM manufacturing, including in the dental sector. This review is the first part in a 3D Printing series that looks at the history of 3D Printing, the technologies available and reviews the literature relating to the accuracy of these technologies. Conclusions: The recent advancement in digital dentistry to incorporate these tools has modernised dental practices by paving the way for computer-aided design (CAD) technology and rapid prototyping. The use of 3D printing has led to 3D digital models produced with intraoral scanners (IOS), which can be manipulated easily for diagnosis, treatment planning, mockups, and a multitude of other uses. Combining 3D Printing with a 3D intraoral scan eliminates the need for physical storage but makes it to retrieve a 3D models for use within all dental modalities.

Background: Percutaneous coronary intervention (PCI) is known as a very rare possible trigger of pericarditis. Most frequently it develops after a latent period or early in case of periprocedural complications. In this report, we present an atypical early onset of pericarditis after the uncomplicated PCI. Case Summary: A 58-year-old man was admitted to the hospital for the PCI of the chronic total occlusion of left anterior descending (LAD) artery. An initial electrocardiogram (ECG) was unremarkable. PCI attempt was unsuccessful. There were no procedure related complications observed at the end of PCI attempt and patient was symptom free. Six hours after interventional procedure the patient complained of severe chest pain. The ECG demonstrated ST-segment elevation in anterior and lateral leads. Troponin I was mildly elevated but coronary angiogram did not reveal impairment of collateral blood flow to the LAD territory. Because of pericarditic chest pain, typical ECG findings and pericardial effusion with elevated C-reactive protein, the diagnosis of acute pericarditis was established, and a course of nonsteroidal anti-inflammatory drugs (NSAIDs) was initiated. Chest pain was relieved and ST-segment elevation almost completely returned to baseline after three days of treatment. The patient was discharged in stable condition without chest pain on the fourth day after symptom onset. Conclusions: Acute pericarditis is a rare complication of PCI. Despite the lack of specific clinical manifestation, post-traumatic pericarditis should be considered in patients with symptoms and signs of pericarditis and a prior history of iatrogenic injury or thoracic trauma.

The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice. Sources include human fetal retinal stem cells, allogenic cadaveric human cells, adult hippocampal neural stem cells, human CNS stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), human pluripotent stem cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). Of these, RPCs, PSCs and MSCs have already entered early-stage clinical trials since they can all differentiate into RPE, photoreceptors or ganglion cells, and have demonstrated safety, while showing some indicators of efficacy. Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long-term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical translation of cell-based therapy, including (1) the ability to enrich for specific retinal subtypes; (2) cell survival; (3) cell delivery, which may need to incorporate a scaffold to induce correct cell polarization, which increases the size of the retinotomy in surgery and, therefore, the chance of severe complications; (4) the need to induce retinal detachment to perform the subretinal placement of the transplanted cell; and (5) the evaluation of the risk of tumor formation caused by the undifferentiated stem cells and prolific progenitor cells. Despite these challenges, stem/progenitor cells represent the most promising strategy for retinal and optic nerve disease treatment in the near future, and therapeutics assisted by gene techniques, neuroprotective compounds and artificial devices can be applied to fulfil clinical needs.

Background: Colorectal cancer is considered the third most fetal among all type of cancer. Spleen tyrosine kinase (SYK) is a non-receptor type tyrosine-protein that plays crucial role in signaling mediated via immune receptor. We adopted an onco-informatics analysis to evaluate the SYK expression and prognostic value of SYK in colorectal cancer, and identification of potential phytochemicals which may inhibit overexpression of SYK protein as well as minimized colorectal cancer. Materials & Methods: Differential expression of SYK gene was analyzed using the several transcriptomic databases including Oncomine, UALCAN, GENT2 and GEPIA2. The server, cBioPortal was used to analyze mutation and copy number alterations whereas GENT2, GEPIA, OncoLnc and PrognoScan were employed to examine the survival rate. A protein-protein interaction network of SYK and co-expressed genes of SYK was conducted via GeneMANIA. Considering SYK gene encoding protein as drug target, selected phytochemicals were assessed by molecular docking using PyRx 0.8 packages. YASARA molecular dynamics simulators were applied for the post validation of the molecular docking data. Results: We have observed significant overexpression of mRNA expression levels of SYK gene colorectal adenocarcinoma (COAD) samples compared with normal tissues. Significant methylation level and various genetic alterations are assembled in SYK gene which can lead to the development of colorectal cancer. As a result, lower level of SYK expression was related to the more chances of patients’ survival by which all the outcomes from the multiple bioinformatics platforms and web resources have demonstrated the significant evidences that the SYK kinsase can possess as a potential biomarker for the treatment of colorectal cancer. Here, aromatic phytochemicals namely, Kaempferol and Glabridin targeting SYK showed more stability compared to controls and may be useful for the treatment of colorectal cancer. Conclusion: Our study showed dysregulated expression of SYK in colorectal cancer and potentiality to act as a biomarker for the prognosis of CRC. Moreover, we have shown phytochemicals (Kaempferol and Glabridin) target SYK as potential treatment strategies and drug repositioning potentiality in colorectal cancer.

Background: Selection and application of suture materials, has gained more importance especially with the increasing number of patients seeking oral surgeries. Since lying in a bacterial-filled environment, sutures make the tissue prone to infection. Suture material plays an important role in the reduction of the risk of infection. This study aimed to assess the success rate of an antibacterial suture named Vicryl Plus in preventing bacterial growth in the surgical site of the mandibular third molar. Methods: 27 patients were included in this double-blinded randomized clinical trial study. Surgical Extraction of the mandibular wisdom tooth was done and the incision was managed by randomly using Vicryl Plus and Vicryl sutures. After 7 days, sutures were removed and assessed microbiologically. Predominant species of Streptococcus mutans and Lactobacillus were assessed as well as the total number of colonies on each suture. Results: There was a significant difference between two suture materials in colony number-length ratio of lactobacillus (p-value= 0.031) and total bacterial colonies (p-value=0.016); but not for S. mutans species (p-value=0.201). Conclusion: Antibacterial Vicryl suture can be a useful tool for the reduction in the rate of surgical site infection in high-risk cases and situations.

Background: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neo-plasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. Methods: We searched Pubmed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. Results: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors, and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. Conclusions: Further pre-clinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

The authors present a stereotypical case presentation of x-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact Fibroblast Growth Factor 23 (FGF23) which lead to i) low serum phosphate levels, ii) increased fractional excretion of phosphorus, and iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in XLH patients is due to chronic hypophosphatemia. Additionally, XLH patients experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration’s (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

Objective: To investigate social, economic, and environmental contributors to quit or continue smoking and vaping during the COVID-19 pandemic. Methods: A qualitative study design was adopted to identify smokers’ beliefs in a LMIC, using a small community sample. Results: 276 participants were primarily surveyed. Motivation to continue smoking included temporary pleasurable effects, working remotely, stress or anxiety, whereas a motivator to quit smoking was the overlap with COVID-19 symptomatology. There was a rise in social awareness regarding the potential harm of smoking and vaping during the pandemic yet those participants who were younger felt they were immune from its morbid complications. Conclusions: With paradoxical associations of COVID-19 with cigarette and vape usage, it is important to pay attention to biases in data in favor of educating its users of the increased risk of severe disease.

Back pain is a common symptom that affects all age groups across the globe, when left untreated may eventually lead to disability. A convenient sample selection method was used in this study due to the global Covid-19 pandemic lockdown which was effective in Turkey during the investigation period. Thus, virtual data collection and health education including some health risks were employed. A total population of two hundred adult women was involved in the study but one hundred and twenty-one responses were collected. Findings show that, for socio-demographic characteristics, the pain was found highest in women between the ages of 41-50 and obese/overweight individuals. Although, there was no significant difference recorded in the marital status category. Moreover, statistical mean differences were detected between the scales for ODI (4.18) and BPFS (6.09). Also, p<0.05, paired sample t-test was 0.001 ODI and 0.001 BPFS after the training exercise. This suggests that exercise training is inversely correlated with pain severity which implies that training has a significant influence on pain intensity. Thus, it could be concluded that there is a relationship between the training exercise and ODI/BPFS.

The cause and prevention of recurrent aphthous stomatitis (also called aphthous ulcers or canker sores) are still unknown. This may be due in part to ignorance of the risk factors present in susceptible people. In this systematic review (PROSPERO record #CRD42019122214), we show that most of the risk factors for the disease are single nucleotide genetic polymorphisms in genes related to the functioning of immune system (TLR4, MMP9, E-selectin, IL-1 beta and TNF-alpha). Single nucleotide genetic polymorphisms do not constitute a modifiable risk. This indicates that, at least in part, susceptibility to recurrent aphthous stomatitis is hereditary, and that these factors cannot be modified.

Multisystem inflammatory syndrome related to SARS-CoV-2 infection (MIS-C) is a rare severe illness affecting pediatric patients. No data are available in literature about the presence of SARS-CoV-2 RNA in faeces in patients with MIS-C. The SARS-CoV-2 positivity was evaluated in fecal samples obtained in a prospective cohort of pediatric patients admitted to our tertiary Hos-pital and diagnosed with MIS-C or COVID-19 between April 15, 2020, and February 29, 2021. The real-time RT-PCR was performed using a validated kit. The assay measures 3 target genes: SARS-CoV-2 gene E, gene N, gene ORF1ab. Overall, 16/63 (25%) fecal samples revealed the pres-ence of SARS -CoV-2 RNA. No differences were detected about time from presumptive viral ex-posure and the time of stool collection (14 vs 8 days, p> 0,05) as well as about the presence of gas-trointestinal symptoms (p>0.05) between patients with positive (+) stools for SARS-CoV-2 RNA and patients tested negative (-). Among children with MIS-C, stools were collected 27.5 days as median (95% CI 14-34) after presumed contact and the positivity rate was 12.5% (4/32). According to our data, we could suggest contact precautions with all patients with MIS-C. Further sample collection is ongoing to verify our preliminary data.

Abstract Introduction: COVID-19 has a relationship with patients’ demographic characteristics as well as their underlying diseases. This research has been conducted to evaluate factors' effect on Covid-19 patient's hospitalization rate and period in Hormozgan, Iran. Materials and Methods: The inclusion criteria of this retrospective study included all patients diagnosed as COVID-19 Patients after PCR who were referred to Covid-19 hospitals from February 2020 to June 2020 in Hormozgan province, Iran. After the completion of the consent form and observing ethical principles, 3480 patients' information was collected through the interview by Medical care monitoring center unit experts. The checklist was designed according to COVID-19 guidelines and approved by the World Health Organization and Iran Ministry of Health and Medical Education. The studied variables included gender, age, patients’ residence place, smoking history and medications use history, pregnancy, referral type to hospital, contact history with COVID-19 patients, early symptoms, gastrointestinal symptoms, intubation, Po2 level, history of cancer, chronic liver diseases, diabetes, chronic blood diseases, HIV/AIDS, acquired or congenital immunodeficiency, cardiovascular diseases, chronic kidney diseases, dialysis status, asthma and other chronic lung diseases, and chronic neurological disorders. These data were analyzed using descriptive (average-standard deviation-percentage) and analytical (including Chi-square, t-test, and regression tests) statistics with SPSS Ver.23 software. Results: In this study, 3480 COVID-19 patients including 1852 male patients (53.20%) with a median age of 43.11±21.72 and 1628 female patients (46/80%) with a median age of 44.86±22.40. The median age of men was significantly lower than the women's median age (P= 0.02). The duration of hospitalization of male and female patients was reported 2.64±4.14 and 2.76±4.297, respectively which was not statistically significant. The death rate of patients in our study was 6.6%. Conclusion: The results of this study also showed that the hospitalization period of HIV-positive patients and patients with cardiovascular and pulmonary diseases is much longer than other people, which imposes many human and financial costs on the country's health care system. Therefore, to maintain individual health and help improve the critical condition of the virus, it is better to develop and apply stricter protocols to prevent further outbreaks of the disease and check underlying diseases of people suspected to have Covid-19. These results can improve health care system planning and improving medical services presented to covid-19 patients.

Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic) which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs). Aims: To examine whether FF symptoms in schizophrenia are associated with breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial-(BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome. Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods. Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively) and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome. Discussion: The physio-somatic symptoms of schizophrenia are driven by various pathways including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.

An immune-inflammatory response is accompanied by increased nitro-oxidative stress. The aims of this mechanistic review are to review: a) the role of redox sensitive transcription factors and enzymes, ROS/RNS production and the activity of cellular antioxidants on the activation and performance of macrophages, dendritic cells, neutrophils, T cells, B cells and natural killer cells; b) the involvement of high-density lipoprotein (HDL), apolipoprotein (Apo)A1, paraoxonase (PON)-1, and oxidized phospholipids in the regulation of the immune response; and c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor (NF)-κB, HIF1alpha, the mechanistic target of rapamycin (mTor), the phosphatidylinositol 3‑kinase (PI3K) / protein kinase B (AKT) signalling pathway, mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR). The performance and survival of individual immune cells is under redox control and sensitive to intracellular and extracellular levels of ROS/RNS and is heavily influenced by cellular anti-oxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2 (Nrf-2), and the HDL complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, those redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.

Obesity and overweight is a foremost concern around the globe for each group of age. This can be accelerated by the current imposed lockdown. However, excessive weight gain may result in other chronic diseases. This study has been considering the age group of 25 to 55 years as the sample populations and monitoring them from July, 2020 to November, 2020. The lifestyle of this population, food habit, mental health conditions are explored using deep learning based framework. All these parameters need to be monitored as these have close relation with currently imposed constraints due to COVID-19. A predictive model is constructed using deep learning techniques to predict the risk of gaining weight. The predictive model hybridizes the convolutional layer and gated recurrent neural networks as a unified entity for achieving the objective of early weight gain prediction. The result obtained by this model exhibits an encouraging predictive efficiency of 93.7%.

Cordia dichotoma Forst. (F. Boraginaceae) has been traditionally used for the management of a variety of human ailments. In our earlier work, the antidiabetic activity of methanolic bark extract of C. dichotoma (MECD) has been reported. In this paper, two flavonoid molecules were isolated (by column chromatography) and identified (by IR, NMR and Mass spectroscopy/spectrometry) from the MECD with an aim to investigate their antidiabetic effectiveness. Molecular docking and ADMET studies were carried out using AutoDock Vina software and Swiss ADME online tool, respectively. The isolated flavonoids were identified as 3,5,7,3’,4’-tetrahydroxy-4-methoxyflavanone-3-O-L-rhamnopyranoside and 5,7,3’-trihydroxy-4-methoxyflavanone-7-O-L-rhamnopyranoside (quercitrin). Docking and ADMET studies revealed the promising binding affinity of flavonoid molecules for human lysosomal alpha-glucosidase and human pancreatic alpha-amylase with acceptable ADMET properties. Based on computational studies, our study reports the antidiabetic potential of the isolated flavonoids with predictive pharmacokinetics profile.

Optic nerve sheath diameter (ONSD) can help predict the neurologic outcome of patients with post-cardiac arrest (CA) return of spontaneous circulation (ROSC). We aimed to investigate the effect of ONSD changes before and after CA on neurologic outcomes in patients with ROSC after CA using brain computed tomography (CT). The study included patients hospitalized after CA, who had undergone pre- and post-CA brain CT from January 2001 to September 2020. The patients were divided into good and poor neurologic outcome (GNO and PNO, respectively) groups based on the neurologic outcome at hospital discharge. We performed between-group comparisons of the amount and rate of ONSD changes on brain CT and calculated the area under the curve (AUC) to determine their predictive value for neurologic outcomes. Among the 96 enrolled patients, 25 had GNO. Compared to the GNO group, the PNO group showed significantly higher amount (0.30 vs. 0.63 mm; p=0.030) and rate of change (5.26 vs. 12.29 %; p=0.041). The AUC for predicting PNO was 0.64 (95% CI=0.53–0.73; p=0.04) and patients with a rate of ONSD change &gt;27.2% had PNO with 100% specificity and positive predictive value. Hence, ONSD changes may predict neurologic outcomes in patients with post-CA ROSC.

(1) Background: The purpose of this study is to evaluate the full arch scan accuracy (precision and trueness) of nine digital intra-oral scanners and four lab scanners. Previous studies have compared the accuracy of some intra-oral scanners, but as this is a field of quickly developing technologies, a more up-to-date study was needed to assess the capabilities of currently available models.; (2) Methods: The present in vitro study compared nine different intraoral scanners (Omnicam 4.6; Omnicam 5.1; Primescan; CS 3600; Trios 3; Trios 4; Runyes; i500 and DL206) as well as four lab light scanners (Einscan SE; 300e; E2 and Ineos X5) to investigate the accuracy of each scanner by examining the overall trueness and precision. Ten aligned and cut scans from each of the intra-oral and lab scanners in the in vitro study were brought into CloudCompare. A comparison was made with the master STL using the CloudCompare 3D analysis best-fit algorithm. The results were recorded along with individual standard deviation and a colorimetric map of the deviation across the surface of the STL mesh; a comparison was made to the master STL, quantified at specific points. ; (3) Results: In the present study, the Primescan had the best overall trueness (17.3 ± 4.9). Followed by (in order of increasing deviation) the Trios 4 (20.8 ± 6.2), i500 (25.2 ± 7.3), CS3600 (26.9 ± 15.9), Trios 3 (27.7 ± 6.8), Runyes (47.2 ± 5.4), Omnicam 5.1 (55.1 ± 9.5), Omnicam 4.6 (57.5 ± 3.2) and Launca DL206 (58.5 ± 22.0). Regarding the lab light scanners, the Ineos X5 had the best overall trueness with (0.0 ± 1.9). Followed by (in order of increasing deviation) the 3Shape E2 (3.6 ± 2.2), Up3D 300E (12.8 ± 2.7), and Einscan SE (14.9 ± 9.5); (4) Conclusions: This study confirms that all current generations of intra-oral digital scanners can capture a reliable, reproducible full arch scan in dentate patients. Out of the intra-oral scanners tested, no scanner produced results significantly similar in trueness to the Ineos X5. However, the Primescan was the only one to be statistically of a similar level of trueness to the 3Shape E2 lab scanner. All scanners in the study had mean trueness of under 60-micron deviation. While this study can compare the scanning accuracy of this sample in a dentate arch, the scanning of a fully edentulous arch is more challenging. The accuracy of these scanners in edentulous cases should be examined in further studies.

Statistical data extracted from national databases demonstrate a continuous growth in the incidence and prevalence of chronic kidney disease (CKD) and the ineffectiveness of current policies and strategies based on individual risk factors to reduce them, as well as their mortality and costs. Some innovative programs, telemedicine and government interest in the prevention of CKD, did not facilitate timely access to care, continuing the increased demand for dialysis and transplants, high morbidity and long-term disability. In contrast, new forms of kidney disease of unknown etiology affected populations in developing countries and underrepresented minorities, who face socioeconomic and cultural disadvantages. With this background, we analyze in the existing literature the effects of social determinants in CKD, concluding that it is necessary to strengthen current kidney health strategies, designing in a transdisciplinary way, a model that considers demographic characteristics integrated into individual risk factors and risk factors population, incorporating the population health perspective in public health policies to improve results in kidney health care, since CKD continues to be an important and growing contributor to chronic diseases.

Background: Central serous chorioretinopathy (CSC) is a common macular condition characterized by detachment of the neuroretina and is a frequent cause of central vision loss in adults. Among the various therapeutic strategies, subthreshold microsecond pulsed laser (SML) treatment has become a useful option. Despite the suggested involvement of choroidal circulatory disturbances in CSC, effects of this treatment on macular microperfusion have not been fully evaluated yet. Herein, we report the impact of SML on retinal and choroidal microvascular flow using non-invasive optical coherence tomography (OCT) angiography (OCTA). Methods: In this study, CSC patients with persistent subretinal fluid (SRF) with or without secondary choroidal neovascularization (CNV) were included (referred to as pachychoroid neovasculopathy (PNV) group and CSC group, respectively). SML was conducted using a yellow (577 nm) laser with duty cycle of 10%, spot size of 200 µm and duration of 200 ms. Best corrected visual acuity (BCVA) as well as OCT and OCTA images were evaluated at baseline and 4 weeks after SML. OCTA parameters of interest included full retinal perfusion (FRP), choriocapillaris perfusion (CCP), Sattler’s layer perfusion (SLP), and Haller’s layer perfusion (HLP), which were evaluated longitudinally and compared to unaffected fellow eyes. Results: 27 affected eyes and 17 fellow eyes from 27 patients were included. Before treatment, central retinal thickness (CRT) and subfoveal choroidal thickness (SFCT) of affected eyes were significantly larger than in fellow eyes. Four weeks after SML, CRT decreased significantly, whereas perfusion parameters did not change. In subgroup analyses, the CSC group showed a significant decrease of SFCT, whereas the PNV group did not despite the decrease of CRT. Conclusion: Our results suggest that the SML may SFCT of CSC, but not of PNV patients at least within four weeks following treatment. This effect seems to be independent of the change in choroidal perfusion measured with OCTA.

Breast cancer is the most widespread malignancy in women from corner to corner of the world. Nanostructured lipid carrier (NLC) proved its efficacy in the treatment of cancer. NLC loaded with Imatinib (IMA) (NANIMA) was prepared and evaluated for in vitro efficacy in MCF-7 breast cancer cells. Hot homogenization method was used for the preparation of NANIMAs. Aqueous solution of surfactants (hot) was mixed with molten mixture of stearic acid and sesame oil (hot) under homogenization. The prepared NANIMAs were characterized and evaluated for size, polydispersity index, zeta potential, encapsulation efficiency, release studies, stability studies and MTT assay (cytotoxicity studies). The optimized NANIMA revealed particle size of 104.63 ± 9.55 d.nm, PdI of 0.227 ± 0.06 and EE of 99.79 ± 0.03. All NANIMAs revealed slow and sustained release behaviour. The surfactants used in the preparation of NANIMAs exhibited their effects on particle size, zeta potential, encapsulation efficiency, stability studies and release studies. The cytotoxicity studies unveiled 8.75 times increase in cytotoxicity for optimized NANIMA (IC50 = 6 µM) when compared with IMA alone (IC50 = 52.5 µM) on MCF-7 breast cancer cells. After this, NLC containing IMA possibly will be employed for the cure of breast cancer. A lesser amount of IMA loaded NLC will be sufficient than IMA alone for the treatment of breast cancer. Moreover, the patient will exhibit not as much of adverse effects as in case of IMA alone. Consequently, NANIMA could prove to be useful for effective therapeutic outcome in breast cancer treatment.

Objective In this study, we aim to synthesize some evidence on the impacts that COVID-19 is having on the epidemiology of Antimicrobial Resistance (AMR) in Africa since it was declared global pandemic by WHO in March 2020. Methodology A scoping review was undertaken by collecting and curating relevant resources from peer-reviewed articles and also from the gray literature. Mixed approaches of extracting data (qualitative and quantitative) were employed in synthesizing evidence, as suggested by Health Evidence Network (HEN). Findings A model constructed based on the synthesis of early evidences available on the effects of factors linked to COVID-19 in impacting the evolution of AMR in Africa predicted that, in cumulative terms, those factors favoring the evolution of AMR outpace those disfavoring it by no less than three folds. Conclusion COVID-19 is fueling the evolution of AMR almost unhindered in Africa. Due recognition of this crisis, concerted efforts for resource mobilization and global cooperation are needed to tackle it.

Neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR 6.97, 95% CI 1.65-10.55, p= 0.002) and OS (HR 7.79, 95% CI 1.25-15.07, p= 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67≥ 14% were also associated with worse DFS (p= 0.016, p= 0.002, and p= 0.001, respectively). In multivariate analysis, luminal B subtype, post-treatment Ki67≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.

The mechanisms involved in immune responses to cancer have been extensively studied for several decades and, considerable attention has been paid to harnessing the immune system's therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell-cancer therapy and immune test therapy have gained prominence through immunotherapy. However, it remains to be accomplished the full potential of cancer immunotherapy. In spite of having startling aspects, the cancer immunotherapies have some difficulties including the inability to effectively targeting the cancer antigens and the abnormalities in patient response. With the advancement of technology, this system has changed the genome-based immunotherapy process in the human body including generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome-editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR-T cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR-T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against the cancer. In this review, we have broadly focused on the use of CRISPR-Cas9 technology for the modification of the T-cell, which can specifically recognize cancer cells and be used as immune therapeutics against cancer. We have also demonstrated the other potential strategies for the treatment of cancer.

There is a growing need for novel in vitro corneal models to replace animal-based ex vivo test in drug permeability studies. In this study we demonstrate a corneal mimetic that models the stromal and epithelial compartments of human cornea. Human corneal epithelial cells (HCE-T) were grown on top of a self-supporting porcine collagen-based hydrogel. Cross sections of the multilayers were characterized by histological staining and immunocytochemistry of zonula occludens-1 protein (ZO-1) and occludin. Furthermore, water content and elastic properties of the synthetized collagen type I-based hydrogels were measured. The apparent permeability coefficient (Papp) values of a representative set of ophthalmic drugs were measured and correlated to rabbit cornea Papp values found in the literature. Multilayered structure of HCE-T cells and expression of ZO-1 and occludin in full thickness of multilayer were observed. The hydrogel-based corneal model exhibited excellent correlation to rabbit corneal permeability (r=0.96), whereas insert-grown HCE-T multilayer was more permeable and the correlation to the rabbit corneal permeability was lower (r=0.89). The hydrogel-based human corneal model predicts the rabbit corneal permeability more reliably in comparison to HCE-T cells grown in inserts. This in vitro human corneal model can be successfully employed for drug permeability tests whilst avoiding ethical issues and reducing costs.

The Covid-19 pandemic has severely tested the mental health of frontline health care workers. A repeated cross-sectional study can provide information on how their mental health evolved during the various phases of the pandemic. The intensivists of a COVID-19 hub hospital in Rome were investigated with a baseline survey during the first wave of the pandemic in April 2020 and were contacted again in December 2020, during the second wave. 152 of the 205 eligible workers responded to an online questionnaire designed to measure procedural justice, occupational stress (effort/reward imbalance), sleep quality, anxiety, depression, burnout, job satisfaction, happiness, and turnover intention. Workers reported a further increase in workload and compassion fatigue, which had already risen during the first wave, and a marked reduction in the time devoted to meditation and mental activities. A low level of confidence in the adequacy of safety procedures and the need to work in isolation, together with an increased workload and lack of time for meditation were the most significant predictors of occupational stress in a stepwise linear regression model. Occupational stress was, in turn, a significant predictor of insomnia, anxiety, low job satisfaction, burnout, and intention to leave the hospital. The number of workers manifesting symptoms of depression increased significantly to exceed 60%. Action to prevent occupational risks and enhance individual resilience cannot be postponed.

The use of Artificial Neural Networks (ANN) is a great contribution to medical studies since the application of forecasting concepts allows the analysis of future diseases propagations. In this context, this paper presents a study of the new coronavirus SARS-COV-2 with a focus on verifying the virus propagation associated with mitigation procedures and massive vaccination campaigns. There were proposed two methodologies to predict 28 days ahead the number of new cases, deaths, and ICU patients of five European countries: Portugal, France, Italy, United Kingdom, and Germany, and a case study of the results of massive immunization in Israel. The data input of cases, deaths, and daily ICU patients was normalized to reduce discrepant numbers due to the countries size, and the cumulative vaccination values by the percentage of population immunized, at least with one dose of vaccine. As a comparative criterion, the calculation of the mean absolute error (MAE) of all predictions presents the best methodology and targets other possibilities of use for the proposed method. The best architecture achieved a general MAE for the 1 to 28 days ahead forecast lower than 30 cases, 0,6 deaths and 2,5 ICU patients by million people.

Physical distancing and wearing a face mask are key interventions to prevent COVID-19. While this remains difficult to practice for millions of firefighters in fire engines responding to emergencies, the delayed forthcoming of evidence on the physical effectiveness of such safety interventions in this setting presents a major problem. In this field experimental study, we provided initial evidence to close this gap. We examined total aerosol burden in the cabin of a fire engine whilst manipulating crew size, natural ventilation, use of FFP2 respirators and use of SCBA full-face masks during 15-minute driving periods. At the same time, we controlled for crew activity and speaking, vehicle speed, cabin air temperature, pressure and humidity. Limiting the crew size, using FFP2 respirators and not donning SCBA full-face masks was associated with a reduction of the arithmetic mean of total aerosol burden of up to 49%. Natural ventilation as tested in this study was associated with both an increase and a decrease of total aerosol burden. This study provided initial evidence on the physical effectiveness of safety interventions in fire engines to reduce potential airborne transmission of SARS-CoV-2 through aerosols. More research about the physical and clinical effectiveness of such safety interventions is needed.

Glucose is the primary energy fuel used by the brain and is transported across the blood-brain barrier (BBB) by the glucose transporter type 1 and 2.[1] A GLUT1 genetic defect is responsible for glucose transporter type 1 deficiency syndrome (GLUT1DS). Patients with GLUT1DS may present with pharmaco-resistant epilepsy, developmental delay, microcephaly, and/or abnormal movements, with tremendous phenotypic variability. Diagnosis is made by the presence of specific clinical features, hypoglycorrhachia and an SLC2A1 gene mutation. Treatment with a ketogenic diet therapy (KDT) is the standard of care as it results in production of ketone bodies which can readily cross the BBB and provide an alternate energy source to the brain in the absence of glucose. KDTs have been shown to reduce seizures and abnormal movements in children diagnosed with GLUT1DS. However, little is known about the impact of KDT on cognitive function, seizures and movement disorders in adults newly diagnosed with GLUT1DS and started on a KDT in adulthood, or the appropriate ketogenic diet therapy to administer. This case report demonstrates the potential benefits of using a modified Atkins diet (MAD), a less restrictive ketogenic diet therapy on cognition, seizure control and motor function in an adult with newly-diagnosed GLUT1SD.

Excessive alcohol consumption is one of the significant causes of morbidity and mortality worldwide. Alcohol is oxidized to toxic and carcinogenic acetaldehyde by alcohol dehydrogenase (ADH) and further oxidized to a non-toxic acetate by aldehyde dehydrogenase (ALDH). Emerging evidence shows that Lactobacillus and Bifidobacterium species encode alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) mediate alcohol and acetaldehyde metabolism, respectively. This study involves supplementation of Lactobacillus and Bifidobacterium probiotic mixture in humans and assessed their effects on alcohol and acetaldehyde metabolism. Here, twenty-seven wild types (ALDH2*1/*1) and the same number ofheterozygotes (ALDH2*2/*1) were recruited for the study. The enrolled participants were randomly divided into either the probiotic (Duolac ProAP4) or the placebo group. Each group received a probiotic or placebo capsule for 15 days with subsequent crossover. Primary outcomes were measurement of alcohol and acetaldehyde in the blood after the alcohol intake. Blood levels of alcohol and acetaldehyde in the ALDH2 heterozygote group were significantly downregulated in the probiotic-supplemented group with no changes in hangover score symptoms than the placebo group. No clinically significant changes were observed in safety parameters. These results suggest that probiotic has a potential to downregulate the alcohol and acetaldehyde concentrations, and their effects depend on the presence or absence of polymorphism on the ALDH2 gene.

The purpose of this study was to determine the change in overall survival (OS) for patients with de novo metastatic breast cancer (dnMBC) over time. We conducted a retrospective cohort study with 1981 patients with dnMBC diagnosed between January 1995 and December 2017 at The University of Texas MD Anderson Cancer Center. OS was measured from the date of diagnosis of dnMBC. OS was compared between patients diagnosed during different time periods: 5-year periods and periods defined according to when key agents were approved for clinical use. The median OS was 3.4 years. The 5- and 10-year OS rates improved over time across both types of time periods. A subgroup analysis showed that OS improved significantly over time for the estrogen-receptor-positive/HER2-positive (ER+/HER2+) subtype, and exhibited a tendency toward improvement over time for the ER-negative (ER-)/HER2+ subtype. Median OS was significantly longer in patients with non-inflammatory breast cancer (P = .02) and in patients with ER+ disease, progesterone-receptor-positive disease, HER2+ disease, lower nuclear grade, locoregional therapy, and metastasis to a single organ (all P &lt;.0001). These findings showed that OS at 5 and 10 years after diagnosis in patients with dnMBC improved over time. The significant improvements in OS over time for the ER+/HER2+ subtype and the tendency toward improvement for ER-/HER2+ subtype suggest the contribution of HER2-targeted therapy to survival.