Motor control, movement impairment and postural control recovery targeted in rehabilitation could be affected by pain. The main objective of this comprehensive review is to provide a synthesis of the effect of experimental and chronic pain on postural control throughout the available literature. After presenting the neurophysiological pathways of pain, we demonstrated that pain, preferentially localized at low back or in the leg induced postural control alteration. While proprioceptive and cortical excitability seems modified with pain, spinal modulation assessment might provide new understanding of the pain phenomenon related to postural control. Literature highlight that the motor control of trunk muscles in patient presenting with low back pain could be dichotomized in two populations, where the first one over-activate trunk muscles, the second one under-activate trunk muscles, and both generating increase of tissues loading. Taking account all this findings, will help clinician to provide adapted treatment for managing both pain and postural control.

Abstract Geographic Information System and Remote Sensing played an important role in analyzing environmental and socio-economic drivers that created favorable condition for malaria breeding as well as in identifying hazard and risk areas. This study gives great emphasis on mapping malaria hazard and risk areas in Gedio zone of SNNPs using geospatial technology. The study identifies two major drivers like Environmental (physical) factors: which provide for the endurance of mosquitoes and Socio-economic factors. The above data were presented and analyzed quantitatively. The content analysis shows that Malaria hazard prevalence areas were mapped based on the environmental factors which are potential of providing good environmental conditions for mosquito breeding. The hazard map was produced using elevation, slope, proximity to breeding sites, and soil type as the factors for breeding mosquitoes. The malaria hazard analysis of the Gedio zone revealed that from the total area, 9.83%, 35.29% is mapped as a very high and high-risk area, whereas, the remaining 38.73%, a 16.14%, and 0.01% were mapped as moderate, low, very low level of malaria hazard respectively. The total area of the study area more than 1/3rd of the area is identified as a very high and high malaria risk area while the rest 2/3rd of an area is considered as a moderate to very low hazard risk zone. Accordingly, very high malaria risk area is found around towns because of population density. Finally, I recommend that the concerned body should have to expand health center, creating awareness of society, especially around populated areas where the risk is high and environmental and individual sanitation can reduce the risk of malaria.

Proposal: Pineal region cysts (PCs) may affect the tectum and aqueduct and cause deep central vein congestion and endocrine dysfunction. In addition to headaches, PC often causes a broad range of symptoms, leading to prolonged diagnosis and therapy. The aims of this study are to reveal parameters that might explain the ambiguity of the symptoms and to identify factors association with the respiration driven neurofluid preload system. Methods: This retrospective study included 28 paediatric patients (mean age 11.6 years) who received surgical treatment for pineal region cysts and 18 patients (mean age 11.3 years) who were followed conservatively. Multiple clinical patient characteristics, such as symptoms, time to neuroimaging diagnosis, cyst size, ventricular indices, head circumference and postoperative outcome, were analysed. Four patients were investigated for CSF dynamics with real-time MRI. The mean follow-up time was 1.6 years. Results: The most common early onset symptoms were headaches (92%), blurred vision (42.8%), sleep disturbances (39.3%) and vertigo (32.1%). Tectum contact was observed in 82% of patients, and MRI examinations revealed that imaging flow void signals were absent in 32.1% of patients. The mean cyst diameters were 13.7 mm for the axial axis and 15.6 mm for the longitudinal axis. Together with a postoperative flow void signal, 4 patients recovered their respiration-driven CSF upward flow, which was not detectable before OP. After operation in 92.1% of patients, the leading symptoms improved without any mortality or morbidity. Conclusion: Despite proximity to the tectum and aqueduct with frequently absent aqueductal flow void signals, hydrocephalic ventricular enlargement was never detected. Data from real-time MRI depicted a reduced preoperative filling of the ventricular CSF compartments, indicating a diminished fluid preload, which recovered postoperatively.

Objective: The aim of this study was to identify and characterize the 100 most cited articles on Parkinson's disease (PD) and phenolic compounds (PCs). Methods: Articles were selected in the Web of Science Core Collection up to January 2022 based on predetermined inclusion criteria, and the following bibliometric parameters were extracted: the number of citations, title, keywords, authors, year, study design, tested PC and therapeutic target. MapChart was used to create worldwide networks, and VOSviewer software was used to create bibliometric networks. Descriptive statistical analysis was used to identify the most researched PCs and therapeutic targets in PD. Results: The most cited article was also the oldest. The most recent article was published in 2020. Asia and China were the continent and the country with the most articles in the list (55% and 29%, respectively). In vitro studies were the most common experimental designs among the 100 most cited articles (46%). The most evaluated PC was epigallocatechin. Oxidative stress was the most studied therapeutic target. Conclusion: Despite the demonstrations in laboratorial studies, the results obtained point to the need for clinical studies to better elucidate this association.

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease that increasingly become a global threat for the elder people's health and life. Although there are some drugs in clinic for treating PD, these treatments only can alleviate the symptoms of PD patients but fail in curative therapies. Therefore, seeking other potential mechanisms to develop more effective treatments that can modify the course of PD is still highly desirable. In the last two decades, histone deacetylases as an important group of epigenetic targets in drug discovery have attracted much attention. This review is focused on the current knowledge about histone deacetylases involved in PD pathophysiology and their inhibitors used in PD study. Further perspectives related to small molecules that can inhibit or degrade histone deacetylases to treat PD are also discussed.

As of now, anthropogenic habitat injury via dissemination of manufactured chemicals is injuring the world’s ecosystems, but doctors have yet to recognize its consequences to humans. Recognition of overt toxicity due to chronic low-dose exposure will open the door to diagnosis, sequential elimination studies, and prescriptions for preventive cure that represent a first step in preventing escalating chronic diseases. This paper offers a diagnostic construct for such use: chronic ambient poisoning. Incorporating it into clinical practice can reduce misdiagnosis of gastro- and near-toxicity that doctors and patients presently suppress rather than remove, and reduce patient co-dependence with proton-pump inhibitors, anxiolytics, and antidepressants—and the thriving “alternative” health industry. This diagnostic elephant-in-the-room is presently missed for reasons of habit (when an ailment is not recognized, it cannot be included in the differential diagnosis) and of poor conduct and interpretation of non-clinical research studies that are taken to mean an absence of evidence is evidence of absence. Moreover, modern methods fail when: the exposure comprises a “daily cocktail” of poisons acting additively, interactively, and cumulatively over a lifetime; when there is no normal, unexposed comparison group; and when absence of a robust etiopathogenetic model disallows inapt statistics. Only patient-led, consultant-informed sequential elimination studies can “peel the onion” of toxicity and its recognition and “preventive cure”. Clinical use of the chronic ambient poisoning diagnosis can thus open the door to stemming and reversing anthropogenic epidemics.

This study aimed on evaluating the potential diagnostic value of a novel, sonographic, B-Flow Imaging (BFI)-based sign (“flashlight sign”, FLS) for the detection of wall-adherent, floating arterial structures (WAFAS). The FLS, characterized by a fast moving, very bright, intraluminal signal was detected in 28 patients with WAFAS. We divided this cohort into three subgroups, depending on the affected vascular segments: (1) peripheral arteries (n = 10), (2) native abdominal aorta (n = 8), and (3) abdominal aorta after endovascular aortic repair (EVAR; n = 10). Clinical characteristics were analyzed and BFI-findings were compared with contrast enhanced ultrasound (CEUS) and computed tomography angiography (CTA). Seven patients (25%) suffered from arterial embolism downstream to the FLS (EVAR, n = 4; native abdominal aorta, n = 1; peripheral arteries, n = 2). WAFAS of the abdominal aorta (native or after EVAR), as indicated by the FLS, were visible by CEUS and CTA in 60% and 93.3%, respectively. Based on the so far largest cohort of patients with WAFAS, we propose a clinically useful, BFI-based sonographic sign for detection of these so far underrated arterial pathologies in the abdominal aorta and the peripheral arteries.

Task sharing approaches are challenged by the barriers fundamental to the use of non-specialists who lack specialist mental health training required to triage the candidates who could benefit from task-shared treatments. However, these challenges could be offset by using standardized and easy-to-implement algorithmic devices (e.g., nomograms) to help with the targeted dissemination of interventions. Therefore, the present investigation posits a prognostic model and a nomogram to predict the prognosis of perinatal depression among women in rural Pakistan. This secondary analysis utilizes data based on 903 pregnant women with depression who participated in a cluster randomized controlled trial that tested the effectiveness of the Thinking Healthy Program in rural Rawalpindi, Pakistan. The participants were recruited from 40 union councils in two sub-districts of Rawalpindi and randomly assigned to intervention and enhanced usual care. Sixteen sessions of the THP intervention were delivered by trained community health workers to women with depression over pregnancy and the postnatal period. A trained assessment team used the Structured Clinical Interview for the DSM-4 current major depressive episode module to diagnose depression at the baseline and post-intervention. The intervention received by the participants emerged as the most significant predictor in the model. Among clinical factors, baseline severity of core-emotional symptoms emerged as an essential predictor, followed by atypical symptoms and insomnia. Higher severity of these symptoms was associated with a poorer prognosis. Other important predictors of a favorable prognosis included living with paternal and maternal grandmothers, financial empowerment, higher socioeconomic class, and living in a joint family system. This prognostic model yielded acceptable discrimination (c-statistic =0.75) and calibration to aid in personalized delivery of psychological treatment.

Glioblastoma (GBM) is the most common primary brain tumor. Due to high resistance to treatment, local invasion, and high risk of recurrence, GBM patient prognoses are often dismal, with median survival around 15 months. The current standard of care is threefold: surgery, radiation therapy and chemotherapy with temozolomide (TMZ). However, patient survival has only marginally improved. Radioimmunotherapy (RIT) is a fourth modality under clinical trials and aims at combining immunotherapeutic agents with radiotherapy. Here, we develop in vitro assays for rapid evaluation of RIT strategies. Using a standard cell irradiator and an Electric Cell Impedance Sensor, we quantify cell migration following the combination of radiotherapy and chemotherapy with TMZ and RIT with durvalumab, a PD-L1 immune checkpoint inhibitor. We measure cell survival using a cloud-based clonogenic assay. Irradiated T98G and U87 GBM cells migrate significantly (p < 0.05) more than untreated cells in the first 20-40 hours post-treatment. Addition of TMZ increased migration rates for T98G at the 20 Gy (p < 0.01). Neither TMZ nor durvalumab significantly changed cell survival in 21 days post-treatment. Interestingly, durvalumab abolished the enhanced migration effect, indicating possible potency against local invasion. These results provide parameters for rapid supplementary evaluation of RIT against brain tumors.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease, and organ manifestations, such as lupus nephritis (LN) or skin disease, may be refractory to standard treatment. Therefore, new agents are required to allow for a more personalized therapeutic approach. Recently, several new therapies have been approved internationally, including voclosporine for LN and anifrolumab for moderately to severely active SLE. Here, we report a case of SLE with a predominant and refractory cutaneous manifestation despite treatment with glucocorticoids, hydroxychloroquine, mycophenolate mofetil, and belimumab. Belimumab was switched to anifrolumab, and the patient responded quickly after two infusions (eight weeks) with a reduction of the Cutaneous Lupus Assessment and Severity Index (CLASI) from 17 to 7. In addition, we review the available clinical trial data for anifrolumab with a focus on cutaneous outcomes. Based on phase II and III clinical trials investigating the intravenous administration, a consistent CLASI improvement was observed at 12 weeks. Interestingly, in a phase II trial of subcutaneous anifrolumab application, CLASI response was not different from placebo at 12 weeks but numerically different at 24 and 52 weeks, respectively. Thus, anifrolumab emerges as an attractive new therapeutic option suggesting a possible domain-based approach.

Background: Elevated fasting plasma glucose and visceral fat area (VFA) is highly prevalent in obese adults. This study investigated the associations between systemic arterial hypertension (SAH) and laboratory, anthropometric, heart rate variability (HRV), and obstructive sleep apnea markers. Methods: Cross-sectional study with 95 obese patients treated at Obesity Treatment and Surgery Center, located in Salvador, BA, Brazil. SAH data were obtained from electronic medical records of patients. To evaluate the association of SAH with the predictor variables, the sample was stratified in Normotense Group (NG) and Hypertensive Group (HG), and laboratory markers, body composition, polysomnography data, and HRV were measured. Results: The average age of the NG was 36.3 ± 10.1 and HG 40.4 ± 10.6 years, 73.7% were women in the NG and 57.9% in HG; 82.4% in HG had insulin resistance. In the multivarious logistics regression model with adjustments age, sex, height, and oxyhemoglobin saturation, SAH was inversely associated with fasting plasma glucose mg/dL (odds ratio [OR] = 0.96; 95% interval confidence [CI] = 0.92 - 0.99) and VFA cm² (OR = 0.98; 95% CI = 0.97 - 0.99). The area under curve the VFA was 0.728; CI 95% (0.620 - 0.836) and fasting plasma glucose 0.693; CI 95% (0.582 - 0.804). Conclusions: Lower VFA and fasting plasma glucose concentrations were inversely associated with SAH. These results indicate opportunities to improve the outcome in obese patients through counseling and clinical interventions.

Thyroid hormones, their metabolites and synthetic analogues are potential anti-steatotic drug candidates considering that subclinical and manifest hypothyroidism is associated with hepatic lipid accumulation, non-alcoholic fatty liver disease, and its pandemic sequelae. Thyromimetically active compounds stimulate hepatic lipogenesis, fatty acid beta-oxidation, cholesterol metabolism and metabolic pathways of glucose homeostasis. Many of these effects are mediated by T3 receptor β1-dependent modulation of transcription. However, rapid non-canonical mitochondrial effects have also been reported, especially for the metabolite 3,5-diiodothyronine (3,5-T2), which does not elicit the full spectrum of “thyromimetic” actions inherent to T3. Most preclinical studies in rodent models of obesity and first human clinical trials are promising with respect to the antisteatotic hepatic effects, but potent agents exhibit unwanted thyromimetic effects on the heart and/or suppress feedback regulation of the hypothalamus-pituitary-thyroid-periphery axis and the fine-tuned thyroid hormone system. This review focusses on 3,5-T2 effects on hepatic lipid and glucose metabolism and (non-)canonical mechanisms of action including its mitochondrial targets. Various high fat diet animal models with distinct thyroid hormone status indicate species- and dose-dependent efficiency of 3,5-T2 and its synthetic analogue TRC150094. No convincing evidence has been presented for their clinical use in prevention or treatment of obesity and related metabolic conditions.

Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered. In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents. Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell’s invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+ BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. This study examined the clinical characteristics, genetic basis, and arrhythmic outcomes of CPVT patients from China. Methods: PubMed and EMBASE were systematically searched for case reports or series reporting on CPVT patients from China until February 19th, 2022 using the keyword “Catecholaminergic Polymorphic Ventricular Tachycardia” OR “CPVT”, with the location limited to “China” OR “Hong Kong” or “Macau” in EMBASE, with no language or publication type restriction. Clinical characteristics, genetic findings, and primary outcome of spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) were analyzed. Results: A systematic search of the PubMed and Embase databases yielded 1049 and 47 articles, respectively. After the exclusion of overlapping cohorts, a total of 58 unique cases from 15 studies (median presentation age: 8 [5.0-11.8] years old) were included. All patients except for one presented at or before 19 years of age. 56 patients (96.6%) were initially symptomatic. Premature ventricular complexes (PVCs) were present in 44 of 51 patients (86.3%) and VT in 52 of 58 patients (89.7%). Genetic tests were performed on 54 patients (93.1%) with a yield of 87%. RyR2, CASQ2, TERCL, and SCN10A mutations were found in 35 (71.4%), 12 (24.5%), one (0.02%) patient, and one patient (0.02%) respectively. 54 patients were treated with beta-blockers, eight received flecainide, five received amiodarone, two received verapamil and one received propafenone. Sympathectomy (n=10) and implantable-cardioverter defibrillator implantation (n=8) were performed. On follow-up, 13 patients developed VT/VF. Conclusion: This is the first systematic review of CPVT patients from China. Most patients had symptoms on initial presentation, with syncope as the presenting complaint. RyR2 mutation accounts for more than half of the CPVT cases, followed by CASQ2, TERCL and SCN10A mutations.

Abstract Purpose Since their introduction, intrauterine devices (IUDs) have been associated with various complications. Avery rare complication is the perforation of the cervix by the strings of the IUD. Purpose of the current study is to present a novel case of cervical perforation by the strings of a copper IUD and to perform a systematic review of the literature. Materials and Methods The patient a 43-year-old attended the gynecology clinic in order to remove her copper IUD. Speculum examination revealed that both the strings of the IUD perforated the anterior lip of the cervix. Management options were offered, the patient opted for a hysteroscopic removal. We searched the electronic databases: MEDLINE, Cochrane Library,Google Scholar,EBSCO for similar cases. Results Electronic search yielded 1821 articles; 8 were selected for inclusion. Mean age of the women was 35,37±7,781, range (26-47) years. One woman (12.5%) was nulligravida;3 women were multigravida (37,5%). Seven women (87,5%) were asymptomatic. Three IUDs (37,5%) were LNG-IUS; 5 IUDs (62,5%) contained copper. Conclusions Cervical perforation by the strings of IUD is an extremely rare clinical entity. It is asymptomatic in general and in most cases the strings of the IUD may be returned back to the endocervical canal after surgical maneuvers.

Introduction: The presence of multiple comorbidities increases the risk of all-cause mortality, but the effects of the comorbidity sequence before the baseline date on mortality remained unexplored. This study investigated the relationship between coronary heart disease (CHD), atrial fibrillation (AF) and heart failure (HF) sequence on all-cause mortality risk in type 2 diabetes mellitus. Methods: This study included patients with type 2 diabetes mellitus prescribed antidiabetic/cardiovascular medications in public hospitals of Hong Kong between January 1st, 2009 and December 31st, 2009 with follow-up until death or December 31st, 2019. Cox regression was used to identify comorbidity sequences predicting all-cause mortality in patients with different medication subgroups. Results: A total of 249291 patients (age: 66.0±12.4 years, 47.4% male) were included. At baseline, 7564, 10900 and 25589 patients had AF, HF and CHD, respectively. Over follow-up (3524±1218 days), 85870 patients died (mortality rate: 35.7 per 1000 person-years). Sulphonylurea users with CHD developed later, but insulin users with CHD developing earlier, in the disease course had lower mortality risks. Amongst insulin users with two of the three comorbidities, CHD with preceding AF (hazard ratio [HR]: 3.06, 95% CI: [2.60-3.61], p<0.001) or HF (HR: 3.84 [3.47- 4.24], p<0.001) had a higher mortality. In users of lipid-lowering agents with all three comorbidities, those with preceding AF had higher risk of mortality (AF-CHD-HF: HR: 3.22, [2.24-4.61], p<0.001; AF-HF-CHD: HR: 3.71, [2.66-5.16], p<0.001). Conclusion: The sequence of comorbidity development affects the risk of all-cause mortality to varying degrees in diabetic patients on different antidiabetic/cardiovascular medications.

Glucocorticoid administration is a common clinical practice in attempt to decrease inflammation associated with, and improve resectability of, canine mast cell tumors (MCTs). However, the impact of neoadjuvant glucocorticoids on histological features and proliferation indices of canine MCTs is unknown. The objective of this study was to evaluate changes in tumor grade, mitotic count, Ki67, AgNOR, and AgNORxKi67 scores following short-course, anti-inflammatory neoadjuvant prednisone in canine patients with MCTs. This was a prospective, single-arm pilot study. Client-owned dogs with treatment-naïve, cytologically-confirmed MCTs were enrolled. Patients underwent an initial incisional biopsy followed by a 10-14 day course of anti-inflammatory prednisone, and surgical resection. All histological samples were randomized, masked, and evaluated by a single pathologist. Unstained paired pre- and post-treatment samples were submitted to a commercial laboratory for Ki67 and AgNOR immunohistochemical analysis. There were 11 dogs enrolled with 11 tumors. There were no statistical differences between the pre- and post-treatment histological parameters of mitotic index, Ki67, AgNOR, or Ki67xAgNOR. There were no clinically-significant alterations between pre-treatment and post-treatment in the assignment of tumor grades. A short-course of anti-inflammatory prednisone does not appear to alter the histological parameters that affect grade-determination, nor significantly alter the proliferation indices in canine MCTs.

Diabetes mellitus (DM) is associated with severe COVID-19 infection and complications. This study assessed COVID-19 vaccine acceptance and hesitancy in diabetes and explored reasons for nonvaccinating. A web-based cross-sectional survey using a mixed method approach was distributed to participants aged ≥18 years with self-reported DM in 11 Sub-Saharan African (SSA) countries from March–May 2021 corresponding to the early vaccine roll out period in most SSA countries. Responses to comments were analyzed for reasons for vaccine hesitancy and facilitators for vaccine uptake. Of the 73 participants with DM, 65.8% were males, older than 35 years (86.3%), had a post-secondary education (90%) and a significant proportion were from South Africa (39.7%), Nigeria (28.8%) and Ghana (13.7%). 64.4% had COVID-19 symptoms, 46.6% were tested for COVID-19 of which 19.2% tested positive. Few participants (6.8%) had taken COVID-19 vaccination, 65.8% were willing to take the vaccine, while 26.0% either refused or hesitated to take the vaccines. The main reasons identified for not taking the vaccine were: concerns about the vaccine safety, its effects, and efficacy, mistrust of the pharmaceutical companies, the conspiracy theories around the vaccines, the process of production, and personal belief of the participants. However, participants stated they would take the vaccine if given more education about it, receive positive feedback from those vaccinated, are rewarded for taking the vaccine or if vaccination becomes a condition for travel and employment. The findings of this study showed that uptake of COVID-19 vaccine was very low in this high-risk group. It is imperative that efforts to increase uptake of vaccine such as provision of education and relevant information, are made.

Background: COVID-19 infection has received the attention of the scientific community due its respiratory manifestations and association with evolution to severe acute respiratory syndrome (SARS-CoV-2). There are few studies characterizing SARS-CoV-2 in pediatric immunocompromised patients, such as liver transplanted (LT) patients.The aim of this study was to analyze the outcomes of the larger cohort of pediatric liver transplant recipients (PLTR) from a single center in Brazil who where contaminated with COVID-19 during the pandemic. Methods: Cross-sectional study. Primary outcomes: COVID-19 severity. The Cox regression method was used to determine independent predictors associated with the outcomes. Results: 74 PLTR were included. Patients were divided into two groups according to the severity of COVID-19 disease: moderate-severe COVID and asymptomatic-mild COVID. Patients categorized as moderate-severe COVID were younger (12.6 months vs. 82.1 months, p 0.03), higher prevalence of transplantation with deceased donor (50% vs. 4.3%, p 0.02) and with a higher prevalence of COVID-infected patients before 6 months after LT (75% vs. 5.7%, p 0.002). The independent predictor of COVID-19 severity identified in the multivariate analysis was COVID-19 infection < 6 months after LT (HR=0.001, 95% CI=0.001-0.67, p 0.03). Conclusion: The time interval of less than 6 months between COVID-19 infection and LT was the only predictor of disease severity in pediatric patients.

Background: While several drugs are in the pipeline for treatment of various grades of COVID-19 disease, none of them have shown promise until now. Medicinal plants are crucial in developing and developed countries for their primary and basic health needs owing to better tolerability, superior compatibility with human body and having lesser side effects. AEV01 , a speciality extract of kutki (Picrorhiza kurroa), is one potential medicinal herb which can be effective for mild COVID19 in elderly patients at risk of complications and aging immunity. Purpose: The efficacy and safety of AEV01 for mild COVID-19 in elderly patients at risk of complications was investigated in this study. Study design: A prospective, phase 3, randomized, multicentric, placebo controlled double blinded parallel group interventional trial. Methods: This study was conducted in elderly patients diagnosed as COVID-19 with mild symptoms. 70 patients were randomized into two groups to receive AEV01 capsule (100mg) and placebo respectively thrice daily for 30 days along with standard care of treatment as per national WHO/ICMR guidelines. Clinical improvement timelines and corresponding scores using 8-point ordinal scale and NEWS were assessed for efficacy and safety of AEV01 in COVID-19 patients. Results: AEV01 group showed a significant improvement (P=0.0001) in the normalization of the SpO₂ rate and relief from cough. There was also significant difference in time to recovery, with patients in the AEV01 drugtreated group recovering in 4.5 days as compared to Placebo in 9.1 days. ESR, LDH, serum ferritin, Neutrophil-Lymphocyte ratio (NLR), TNF- alpha, IL-6 and CD4 cell counts, which are considered as prognostic markers in COVID19 infected patients, showed a significant improvement in patients treated with AEV01. The AEV01 drug treated group showed significant clinical improvement in the 8-point ordinal scale severity rating and NEW Score from day 3 onwards which continued up to end of study. Conclusion: AEV01 has shown a significant improvement in clinical and laboratory parameters. There was also reduction in the progression of the COVID-19 disease in unvaccinated elderly patients from mild to moderate when treated at an earlier stage.

Carcinoembriogenic antigen (CEA) is a routine marker for follow-up of colo-rectal cancers. We aimed to determine whether a CEA increase within the normal range can be linked to a recurrence risk. We included 78 consecutive patients with colo-rectal cancer, who underwent curative surgical treatment with or without chemo- or radiotherapy. As reference, we used the smallest value of the CEA during follow-up. A total of 34/78 patients (43.6%) had fluctuations of CEA of at least 1.1 ng/ml, with or without increases above 5 ng/ml. In 27/34 patients (79.4%) increases of CEA were explained either by recurrence (15/34 patients, 44.1%), adjuvant chemotherapy (7/34 patients, 20.6%) or benign pathology (5/34 patients, 14.7%). In 5 of 22 recurrences (23%) a CEA increase of at least 1.1 ng/ml, but below 5 ng/ml preceded the clinical relapse by a median of 8 months (range 3-22 months). The 4-year disease-free survival was 89% in patients with postoperative CEA <2.5 ng/ml, and 55% in patients with CEA >2.5 ng/ml. CEA increase by at least 1.1 ng/ml within the normal range, after curative treatment of colorectal cancer can be either an early sign of relapse or can be usually explained by other pathological processes.

Rising incidences of cutaneous melanoma have fueled the development of statistical models that predict the individual melanoma risk. Our aim was to assess the validity of published prediction models for incident cutaneous melanoma using a standardized procedure based on PROBAST (Prediction model Risk Of Bias ASsessment Tool). We included studies that were identified by a recent systematic review and updated the literature search to ensure that our PROBAST rating included all relevant studies. Six reviewers assessed the risk of bias (ROB) for each study using the published “PROBAST Assessment Form” that consists of four domains and an overall rating of ROB. We further examined a temporal effect regarding changes in overall and domain-specific ROB rating distributions. Altogether 42 studies were assessed, of which a vast majority (n=34; 81%) was rated as having high ROB. Only one study was judged as having low ROB. The main reasons for high ROB ratings were the use of hospital controls in case-control studies and the omission of any validation of prediction models. However, our results of the temporal analysis showed a significant reduction in the number of studies with high ROB for the domain analysis. Nevertheless, the evidence base of high-quality studies that can be used to draw conclusions on the prediction of incident cutaneous melanoma is currently much weaker than the high number of studies on this topic would suggest.

In 2019, the Global Burden of Disease (GBD) estimated that prostate cancer (PC) was the 16th cause of death globally in males. In Mexico, PC epidemiology has been reported for a selected number of metrics and years, although without including the most up-to-date estimates. Herein, we describe and compare the burden and trends of PC in Mexico and its 32 states from 2000 to 2019. For this, we extracted online available data from the GBD 2019 to estimate the crude and age-standardized rate (ASR per 100,000 people) of incidence, mortality, and disability-adjusted life years (DALYs). In Mexico, PC caused 27.1 thousand (95% uncertainty intervals, 20.6-36.0 thousand) incident cases, 9.2 thousand (7.7-12.7 thousand) deaths, and 161.5 thousand (122.7-219.5 thousand) DALYs in males of all ages in 2019. Among states, Sinaloa had the greatest ASR of incidence and Guerrero the highest values of deaths and DALYs. The burden of PC showed an increasing trend, although the magnitude of change differed between metrics and locations. We found both an increasing national trend and subnational variation in the burden of PC. Our results confirm the need for updated and timely estimates to design effective diagnostic and treatment campaigns in locations where the burden of PC is the highest.

Although vaccinating the world is adopted by the WHO to limit COVID-19 transmission, people’s worries about vaccines may suppress their desire for vaccination despite vaccine availability. This study aimed to evaluate the levels of stress and anxiety among 250 Jordanians who received their first vaccine dose at a local community health center. The respondents completed the stress and anxiety subscales of the Depression Anxiety and Stress scale 21 (DASS-21) pre- and post-vaccination. The respondents expressed more moderate-severe levels of stress pre than post vaccination (20.8% and 13.2%, respectively). Meanwhile, 37.2% and 45.2% of the respondents expressed moderate-severe anxiety pre and post vaccination, respectively. Wilcoxon signed-rank test revealed that the drop in the level of stress from pre (median (IQR) = 5 (1-8)) to post vaccination (median (IQR) = 3 (1-7)) was statistically significant (z = -3.81, p = 0.001, r = 0.17) while the increase in anxiety was not. Anxiety median significantly dropped among individuals experiencing mild to severe anxiety pre vaccination. Similarly, stress and anxiety significantly increased among individuals expressing normal anxiety pre vaccination (z = -3.57 and -8.24, p values = 0.001, r = 0.16 and 0.37, respectively). Age positively correlated with post vaccination anxiety among respondents with mild pre vaccination anxiety, and it negatively correlated with pre vaccination level of stress in the normal anxiety group. Gender, marital status, respondents’ level of education, and history of COVID-19 infection had no significant correlation with anxiety or stress at either point of measurement. Overcoming their hesitancy to receive COVID-19 vaccine, individuals with normal levels of anxiety experienced a rise in their distress symptoms following immunization. On the contrary, vaccination seemed to desensitize anxious individuals. Policymakers need to formulate a population-specific plan to increase vaccine preparedness and promote psychological well-being over all during the pandemic.

Objectives: Few studies in literature evaluate the "mean measure" of root divergence. Most of them are linear measurements, they hardly describe the dental furcation conformation. It is left to the subjectivity of the operator deciding whether a furcation is convergent or divergent. The goal of this study is to create a visual evaluation method to overcome these problems giving a conformation of the entire interradicular space. Material and methods: A user-friendly software (Paint®, Windows10®) was used to measure endo-oral radiographs of upper and lower molars. Three kinds of measurements were taken. Three operators used the software to measure 20 radiographs, then the technique was repeated on 250 radiographic images to identify an average measurement. The ratio of these three measurements allowed to develop a new visual evaluation method of the interradicular space. Results: Intra and inter-operator reproducibility was statistically assessed on a sample of 20 anonymous endo-oral radiographs measured by 3 blind operators. Then, a sample of 250 anonymous endo-oral radiographs were measured by a blind operator and were statistically evaluated to identify an average value to define a main conformation of the interradicular space. Measurements made by the 3 operators on the 20 radiographic images showed that the technique is reproducible, and a mean value of the interradicular space was obtained. Conclusions: A new anatomical evaluation of the interradicular space in its entirety, which could help the clinicians in the therapy of furcated molars, can be obtained.

Malnutrition is a serious problem with negative impact on the quality of life and the evolution of our patients, contributing to an increase in morbidity, hospital stay, mortality and health spending. Early identification is fundamental to implement the necessary therapeutic actions involving adequate nutritional support to prevent or reverse malnutrition. This review presents two complementary methods of fighting malnutrition: nutritional screening and nutritional assessment. Nutritional risk screening is conducted using simple, quick-to-perform tools and is the first line of action in detecting at-risk patients. It should be implemented systematically and periodically on admission to hospital or residential care, as well as on an outpatient basis for patients with chronic conditions. Once patients with a nutritional risk have been detected they should undergo a more detailed nutritional assessment to identify and quantify the type and degree of malnutrition. This should include health history and clinical examination, dietary history, anthropometric measurements, evaluation of the degree of aggression determined by the disease, functional assessment and, whenever possible, some method of measuring body composition.

Volatile compounds, abundant in breath, can be used to accurately diagnose and monitor a range of medical conditions. This offers a non-invasive, low-cost approach with screening applications; however, uptake of this diagnostic approach has been limited by conflicting published outcomes. Most published reports rely on large scale screening of the public, at single time points and without reference to ambient air. Here, we present a novel approach to volatile sampling from cellular headspace and mouse breath that incorporates multi-time point analysis and ambient air subtraction revealing compound flux as an effective proxy of active metabolism. This approach to investigating breath volatiles offers a new avenue for disease biomarker discovery and diagnosis. Using gas chromatography mass spectrometry (GC/MS), we focus on low molecular weight, metabolic substrate/by-product compounds and demonstrate that this non-invasive technique is sensitive (reproducible at ~1 µg cellular protein, or ~500,000 cells) and capable of precisely determining cell type, status and treatment. Isolated cellular models represent components of larger mammalian systems and we show that stress- and pathology-indicative compounds are detectable in mice, supporting further investigation using this methodology as a tool to identify volatile targets in human patients.

Chemotherapy-induced peripheral neuropathy (CIPN) develops as a challenging nerve-damaging adverse effect of anticancer drugs used in chemotherapy. The disorder may require a dose reduction of chemo-therapy and its most common sensory symptoms are severe pain, tingling, and numbness in the hands and feet. CIPN affects dramatically the patient's quality of life (QoL). Pain and sensory abnormalities may occur for months, or even years after the termination of chemotherapy. This disease has complicated pathophysiology featured by underlying mechanisms not completely known. Although many pharmaco-logical and non-pharmacological therapeutic approaches have been tested to overcome these symptoms, there is currently no standardized cure to prevent or treat CIPN. According to current guidelines, Duloxe-tine is the only recommended agent for painful neuropathic symptoms. Therefore, finding effective thera-pies for CIPN is mandatory. The purpose of this review is to dissect CIPN, the target and immunothera-py-based approaches to this disorder, as well as to offer new insights for novel therapeutic perspectives.

Tetracyclines are a group of antibiotics whose first representative was discovered over 70 years ago. Since then, they have been of great interest in dermatology. In addition to their antibacterial activity, they are able to inhibit metalloproteinases and exhibit anti-inflammatory, anti-apoptotic and antioxidant effects. The side effects have been thoroughly studied over the years. The most characteristic and important in daily dermatolgical practice are: phototoxicity, hyperpigmentation, onycholysis, photoonycholysis, induced lupus erythematosus, idiopathic intracranial hypertension. In this article, we summarize the use of tetracyclines in infectious diseases and inflammatory dermatoses, and further discuss indications where the efficacy and safety of tetracyclines have been highlighted over the past few years.

The introduction of tenofovir-derived prodrugs has revolutionised the prevention and management of HIV, which has coincided with 23% reduction in new HIV incidences globally. To date, there are two formulations of tenofovir-derived nucleoside reverse transcriptase inhibitor (NRTI): tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and tenofovir alafenamide fumarate/emtricitabine (TAF/FTC). Although these prodrugs have shown favourable safety profile, their effects on cardiovascular health are differ from one another: TDF/FTC exhibits potential lipid-lowering effect, TAF/FTC demonstrates potential lipid-inducing effect, which is a major risk factor for cardiovascular diseases. However, this issue has not been previously elucidated, especially among the marginalised populations [lesbian, gay, bisexual and transgender (LGBT) and men who have sex with men (MSM)] who are likely be the main users of these prodrugs. This is of clinically significance as the cardiovascular health in these populations is often overlooked, in addition to a lack of appropriate cardiovascular risk prediction algorithm. Therefore, this review aims to (1) highlight the cardiovascular risks of tenofovir-derived prodrugs in the marginalized populations, and also to (2) establish the importance of having a cardiovascular risk prediction model that is specific to this particular populations so that their health management could be more comprehensive.

Good child protection systems and processes require reliable and accurate data. A retrospective study of the case records of 452 children referred to a major UK children’s tertiary centre for suspected child maltreatment was undertaken to determine whether routinely collected data on a child’s journey through the child protection system, together with a study of related multidimensional factors, can be used to develop an enhanced dataset to protect children in the UK and in other countries. Child maltreatment was substantiated in 65% of referred cases, with the vast majority of referrals coming from children living in the most deprived neighbourhoods in the country. Domestic violence and abuse, and the child’s previous involvement with statutory bodies was associated with case substantiation. Physical abuse predominated, with soft tissue injuries, including dog bites, and burns. Burns were related almost exclusively to supervisory neglect. There were also cases of medical neglect. Emotional abuse was associated with exposure to domestic violence and abuse, and to self-harm. The strengths and weaknesses for single centre data systems were explored, concluding with a recommendation to establish an agreed national and international minimum data set to protect children from maltreatment.

Background: Biomarker profiles should represent a coherent description of the colorectal cancer (CRC) stage and its evolution. Methods: Using droplet digital PCR, we detected the allelic frequencies (AF) of KRAS, NRAS, BRAF and EGFR mutations from 60 tumors. We employed a pair-wise association approach to estimate the risk involving AF mutations as outcome variables for clinical data and as predicting variables for tumor-staging. We evaluated correlations between mutations AFs and also between the mutations and histopathology features (tumor staging, inflammation, differentiation and invasiveness). Results: KRAS G12/G13 mutations were present in all patients. KRAS Q61 was significantly associated with poor differentiation, high desmoplastic reaction, invasiveness (ypT4) and metastasis (ypM1). NRAS and BRAF were associated with the right-side localization of tumors. Diabetic patients had a higher risk to exhibit NRAS G12/G13 mutations. BRAF’s presence limited the invasiveness in the submucosa, co-existing with NRAS G12/G13 mutations. Conclusions: The associations we found and the mutational AF we reported may help to understand disease processes and may be considered as potential CCR biomarker candidates. In addition, we propose representative mutation panels associated with specific clinical and histopathological features of CRC, as a unique opportunity to refine the degree of personalization of CRC treatment.

A major advance of drug discovery and targeted therapy directed to cancer cells may be achieved by exploitation and immunomodulation of their unique biological property. This re-view summarizes our efforts to develop novel chemo-thermo-immuno-therapy (CTI therapy) by conjugating a melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine), with magnetite nanoparticles (MNP). In our approach, NPrCAP provides a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It also functions as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Moreover, utilization of MNP is a platform to develop thermo-immunotherapy because of heat shock protein (HSP) generation upon exposure to an alternating magnetic field (AMF). The feasibility of our approach was successfully shown in experimental in vivo and in vitro mouse melanoma models and in preliminary clinical trials to a limited number of advanced melanoma patients.

The onset of embryonic heart beating may be regarded as the defining feature for the beginning of personal human life. Clarifying the timing of the 1^st human heartbeat, therefore, has religious, philosophical, ethical, and medicolegal implications. This article reviews the historical and contemporary sources of knowledge on the beginning of human heart activity. Special attention is given to the problem of the determination of the true age of human embryos and to the problem of visualization of the human embryonic heart activity. It is shown that historical and current textbook statements about the onset of blood circulation in man do not derive from observations on living human embryos but derive from the extrapolation of observations on animal embryos to the human species. This fact does not preclude the existence of documented observations on human embryonic heart activity: Modern diagnostic (ultrasound) and therapeutic (IVF) procedures facilitate the visualization of early embryonic heart activity in precisely dated pregnancies. Such studies showed that the human heart started its pumping action during the 4^th post-fertilization week. A small number of direct observations on the heart activity of aborted human embryos were reported since the 19^th century but did not receive much recognition by embryologists.

COVID-19 affects many organs in our body, including the heart and lungs. COVID-19 cases that require hospitalization often exhibit pulmonary hypertension (PH) due to changes in the lung microvasculature in which the blood vessels become stiff, damaged, or narrow, causing increased pulmonary arterial pressure. This review examines the hypothesis that PH can lead to right ventricular hypertrophy (RVH) as a long-lasting aftereffect of COVID-19. Recent studies have shown that significant percentages of hospitalized patients develop right ventricular hypertension and right ventricular dilatation (RVD), which may lead to right ventricular failure and death. Despite recommendations for echocardiogram reports to include right ventricular wall thickness to assess RVH, few published reports have reported this parameter. Relevant studies on animal models of PH in which the timing of PH can be precisely controlled suggest that one to three weeks of PH can cause RVH. Thus, according to the hypothesis proposed here COVID-19 patients who have long-lasting severe disease (e.g., needed to be on a ventilator for one or more weeks) accompanied by PH and RVD may develop RVH as a long-lasting sequela outlasting the infection itself. Echocardiogram studies of recovered COVID-19 patients may determine whether oft-reported cardiovascular sequelae include RVH.

Like 18F-FDG, 99mTc-1-thio-D-glucose (99mTc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of 99mTc-TG. Twelve lym-phoma patients were injected with 729±102 MBq 99mTc-TG. Whole-body planar imaging was per-formed in 10 patients at 2, 4, 6 and 24 h after injection. In all 12 patients SPECT/CT (at 2 h) and SPECT (at 4 and 6 h) imaging was performed. Vital signs and possible side effects were monitored during imaging and up to 7 days after injection. 99mTc-TG injections were well tolerated and no side effects or alterations in blood and urine analyses data were observed. The highest absorbed dose was in the kidneys and urinary bladder wall, followed by the adrenals, prostate, bone mar-row, lungs, myocardium, ovaries, uterus, liver and gall bladder wall. 99mTc-TG SPECT/CT re-vealed foci of high activity uptake in the lymph nodes of all nine patients with known nodal le-sions. Extranodal lesions were detected in all nine cases. In one patient, a lesion in the humerus head, which was not detected by CT, was visualized using 99mTc-TG. Potentially, 99mTc-TG SPECT can be considered as an additional diagnostic method for imaging GLUT receptors in lymphoma patients.

Several clusters and individual cases of acute —often severe— hepatitis have been reported in Europe —mainly in the United Kingdom (U.K.)—, the United States (U.S.) and recently in Asia since October 2021. Laboratory investigation of the common viral hepatitis agents (HAV, HBV, HCV, HDV and HEV) yielded negative results prompting the use of the term “acute non hepA–E hepatitis” to describe this condition. The cases were characterized by the manifestations of acute hepatitis (abdominal pain, vomiting, diarrhea, jaundice and very high levels of liver enzymes) affecting children with a median age of 3–4 years. The exact underlying etiology has not been revealed yet; however, a leading hypothesis is that an infectious agent is the culprit underlying cause or at least a risk factor for acute non hepA–E hepatitis occurrence. So far, laboratory testing has shown the presence of adenovirus serotype 41 (Ad–41) which is classified in group F of adenoviruses in about three-fourths of the reported cases. However, the definitive link between adenoviruses and acute non hepA–E hepatitis has not been fully elucidated, which necessitates further investigation of this possible correlation. As of the end of April 2022, more than 200 cases were reported worldwide, the majority of which were in Europe: the U.K. (n=114), Italy (n=17), Spain (n=13), Israel (n=12), the U.S. (n=9), Denmark (n=6), Netherlands and Ireland (n=4), Japan (n=3), Austria, Belgium, France, and Norway (n=2), Germany, Poland, and Romania (n=1). Possible cases are being evaluated in Illinois, Minnesota, North Carolina, Wisconsin states of the U.S., Canada, Singapore and Slovenia. Vigilant surveillance and epidemiologic investigation to identify further cases are warranted at the global level to delineate the features of this emergent public health issue. The possible role of environmental and toxic agents including foodborne toxins should not be overlooked as well. Specific guidelines for identification of further cases is necessary particularly in low-income settings where testing for adenoviruses is not considered routinely. Genetic analysis of Ad–41 isolates is recommended to assess the potential changes in virus genome with subsequent possible altered virus behavior. Immunopathogenesis is another possibility that should be examined as well considering the absence of virus detection in liver biopsies of the affected children in the U.S.

Platelets are a uniquely mammalian physiologic attribute. As the only non-marine vertebrate class to experience menopause, humans have a substantial post-reproductive lifespan and are believed to have a limited, non-renewable oocyte supply. Ovarian reserve typically declines after about age 35yrs, marking losses which cannot be recovered by available fertility medications. When in vitro fertilization fails due to low or absent ovarian response, gonadotropin adjustments are often ineffectual and if additional oocytes are occasionally harvested, egg quality is usually poor. This problem was confronted by Greek researchers who developed a new surgical method to insert autologous platelet-rich plasma (PRP) into ovaries; the first ovarian PRP success to improve reproductive outcomes was published from Athens in 2016. This innovation influenced later research with condensed platelet-derived growth factors, leading to correction of oocyte ploidy error, normal blastocyst development, and additional term livebirths. Yet women’s health was among the last clinical domains to explore PRP, and its role in ‘ovarian rejuvenation’ remains unsettled. One critical aspect in this procedure is platelet activation, a commonly overlooked step in the cytokine release cascade considered essential for successful transition of undifferentiated ovarian stem cells to an oocyte lineage. Poor activation of platelets thus becomes an unforced error, potentially diminishing or even negating post-treatment ovarian follicular response. To answer this query, relevant theory, current disagreements, and new data on platelet activation are presented, along with clinical challenges for regenerative fertility practice.

Tanning beds have been classified as carcinogenic to humans. As a result, many countries have enacted laws regulating the use of commercial tanning beds, including bans for minors. However, there is no international overview of the current legal status of access restrictions for minors that provides details on their specific design regarding age limits and possible exceptions to the statutory regulation. Therefore, we performed a comprehensive web search of current tanning bed legislation for minors on the three continents North America, Australia, and Europe. Our findings regarding existence and concrete design of access restrictions are presented graphically using maps. We found a wide variety of different legislations. In Australia, a total ban on tanning beds exists, while in New Zealand tanning bed use is banned for minors. In Europe about half of the countries have implemented a strict ban for minors. In North America we found differences in the age limit for access restrictions between the states, provinces and territories for those regions that implemented a ban for minors. In the United States, some states have rather ‘soft bans’ that allow use by minors with different types of parental consent. The patchwork in legislation calls for harmonization. Therefore, our comparison is an important starting point for institutions such as the World Health Organization or the European Commission to advance their goals towards a harmonization of tanning bed legislation in general and for minors in particular.

In the diagnosis of olfactory neuroblastoma (ONB), the presence of S-100–positive sustentacular cells surrounding the tumor is important; however, these are also present in normal nasal sinus epithelium. Although ONB often has a different final diagnosis, complete resection of the tumor has a good prognosis and minimally affects the patient's treatment plan. When the tumor extends around the internal carotid artery (ICA), complete resection is difficult due to the high risk of vascular injury; revascularization using a high-flow bypass can avoid this complication. In the present case, the tumor was located in the left sphenoid sinus and extended around the ICA. Preoperative biopsy tissue was positive for neuroendocrine markers and slightly positive for S-100 protein, leading to a diagnosis of ectopic ONB. High-flow bypass revascularization with trapping of the ICA allowed complete tumor resection. The postoperative histopathological diagnosis was neuroendocrine carcinoma, showing no S-100 protein–positive cells. There was no sign of recurrence two and a half years after surgery without additional treatment. This case demonstrates that the presence of S-100 protein–positive cells in ONB may be misleading. Although misdiagnosis of ectopic ONB should be anticipated, a complete resection of the tumor is an effective treatment strategy.

The urgency of the COVID19 pandemic caused a surge in related scientific literature. This surge made the manual exploration of scientific articles time-consuming and inefficient. Therefore, a range of exploratory search applications have been created to facilitate access to the available literature. In this survey, we give a short description of certain efforts in this direction and explore the different approaches that they used.

Goals: To use visual logistics for interpreting COVID-19 molecular and rapid antigen test (RAgT) performance, determine prevalence boundaries where risk exceeds expectations, and evaluate benefits of recursive testing along home, community, and emergency spatial care paths. Methods: Mathematica/open access software helped graph relationships, compare performance patterns, and perform recursive computations. Results: Tiered sensitivity/specificity comprise: T1) 90%/95%; T2) 95%/97.5%; and T3) 100%/≥99%, respectively. In emergency medicine, median RAgT performance peaks at 13.2% prevalence, then falls below T1, generating risky prevalence boundaries. RAgTs in pediatric ERs/EDs parallel this pattern with asymptomatic worse than symptomatic performance. In communities, RAgTs display large uncertainty with median prevalence boundary of 14.8% for 1/20 missed diagnoses, and at prevalence >33.3-36.9% risk 10% false omissions for symptomatic subjects. Recursive testing improves home RAgT performance. Home molecular tests elevate performance above T1, but lack adequate validation. Conclusions: Widespread RAgT availability encourages self-testing. Asymptomatic RAgT and PCR-based saliva testing present the highest chance of missed diagnoses. Home testing twice, once just before mingling, and molecular-based self-testing help avoid false omissions. Community and ER/ED RAgTs can identify contagiousness in low prevalence (<22%). Real-world trials of performance, cost-effectiveness, and public health impact could identify home molecular diagnostics as the optimal diagnostic portal.

Background: As coronavirus (COVID-19) continues to pose a threat to the entire world, it is critical to developing strategies for containing its spread. The purpose of this study was to assess the demographic characteristics, brain tomography characteristics, and diffusion magnetic resonance findings of COVID-19 positive individuals. Material and Method: Between January 1 and December 31, 2021, 317 patients over the age of 18 were admitted to the emergency department with symptoms consistent with COVID-19. Three groups were formed based on clinical findings in patients, divided into light, medium, and severe, and four groups were formed based on radiological imaging findings. Results: The mean age of the 317 patients included in the study was 67.28±12.06 years, with a range of 28-91 years. The clinical classification of the patients was based on laboratory parameters and radiological imaging, not on their age or gender. Mild cases were classified as CO-RADS 0-4; moderate and severe cases were classified as CO-RADS 5-6 (p=0.001). While 60 (18.9%) of patients were followed outpatient, 144 (45.4%) were admitted to the hospital, 73 (23%) were admitted to the intensive care unit, and 40 (12.7%) died (p=0.001). Direct radiographs revealed bilateral involvement in 224 (70.7%) cases, peripheral involvement in 259 (81.7%) cases, and mid-lower lobe lung involvement in 194 (61.2%) cases (p=0.001). Brain tomography revealed infarction in 42 (13.2%) of the patients who were followed and hospitalized and hemorrhage in 22 (6.9%) of the patients. Magnetic resonance imaging revealed diffusion involvement in 68 (21.5%) of the cases (p=0.001). Conclusion: A standardized reporting system for COVID-19 data is required, and it must be simple to use, quick to understand, and focused on determining the risk of pneumonia. Additionally, the diagnostic role of radiological imaging, prognosis prediction, and severity scoring of lung involvement should be included.

Purpose: To investigate the molecular basis of congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome. Methods: We report ocular features of 3 girls with GAPO syndrome born of consanguineous marriage in a multi- generation consanguineous family. The proband (4year old girl) and her younger sibling (1 year old girl) were operated for bilateral congenital glaucoma in both eyes. The elder sibling (10year old female) had features of GAPO syndrome but did not manifest features of glaucoma. Results: A genetic evaluation using whole exome sequencing revealed a homozygous ANTXR1 mutation in all 3 affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense mutation in TGFBI gene was shared in the two siblings with congenital glaucoma and GAPO syndrome.Conclusions: Mutations in TGFBI gene could have a role in the pathogenesis of congenital glaucoma.

The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to 10e8 CAR T cells/ Kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here we tested CD8/4-1BB compared to CD28-based anti-CAIX CAR PBMCs cells-releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a 10e7 CAR PBMCs cells/ Kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, T cell exhaustion status in peripheral CD4 T cells, additionally to CD8 was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon administration of 10e7 CAR PMBCs cells/Kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.

Transcatheter aortic valve implantation (TAVI) has grown exponentially within the cardiology and cardiac surgical spheres. It has now become a routine approach for treating aortic stenosis. Several uncertainties have been raised about TAVI in comparison to conventional surgical aortic valve replacement (SAVR). The primary concerns are with regards to the longevity of the valves. Several factors have been identified that may predict poor outcomes following TAVI. These include the lesser-used finite element analysis (FEA) to quantify the properties of calcifications that affect TAVI valves. This can also be used in conjunction with other integrated software to ascertain the functionality of these valves. Other imaging modalities are now widely available such as Multi-detector row computed tomography(MDCT) which can accurately size the aortic valve annulus.. This may help reduce the incidence of paravalvular leaks and regurgitation which may necessitate further intervention. Structural valve degeneration (SVD) remains a key factor with varying results from current studies. The true incidence of SVD in TAVI compared to SAVR remains unclear with the lack of long term data. It is now widely accepted that both are part of the armamentarium and are not mutually exclusive. Decision-making for the appropriate intervention should be made via shared decision-making involving the heart team.

Background: Evidence supports a causal relationship between circadian disturbance and impaired glucose homeostasis. Method: To determine the effect of a nursing educational intervention on improving healthy sleep, a parallel, open-label clinical trial in subjects with Impaired Fasting Glucose (IFG) or Type 2 Diabetes Mellitus (T2DM) and 18 and older was performed. Study variables were sex, age, fasting glucose, glycated hemoglobin A1c (HbA1c), Pittsburgh Sleep Quality Index (PSQI), sleep duration and efficiency, BMI, antidiabetic treatment and diet and physical exercise. An individual informative educational intervention was carried out following a bidirectional feedback method. It was intended to develop skills to improve sleep through 9 simple tips. An analysis of covariance was performed on all the mean centered outcome variables controlling for the respective baseline scores. Results: After the intervention, in the experimental group, PSQI dropped, the duration and quality of sleep increased. Further, a decrease in fasting glucose and in HbA1c levels was observed. Conclusion: The proposed intervention has proven to be effective to improve sleep quality, time, and efficiency and in only 3 months, to achieve a decrease in fasting glucose and HbA1c levels. These findings support the importance of sleep and circadian rhythms education focused on improving in T2DM or IFG.

Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A 7–8-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission in approximately 50% of patients for one year or longer, with published culture studies indicating higher doses of dapsone demonstrate efficacy against resistant biofilm forms of Borrelia burgdorferi. The purpose of this study was therefore to evaluate higher doses of dapsone in the treatment of resistant CLD/PTLDS and associated co-infections. Twenty-five patients with a history of Lyme and associated co-infections, most of whom had ongoing symptoms despite several courses of DDDCT, took one or more courses of high dose pulsed dapsone combination therapy (200 mg dapsone X 3-4 days and/or 200 mg BID x 4 days), depending on persistent symptoms. The majority of patients noticed sustained improvement in 8 major Lyme symptoms, including fatigue, pain, headaches, neuropathy, insomnia, cognition, and sweating, where dapsone dosage, not just treatment length, positively affected outcomes. High dose pulsed dapsone combination therapy may represent a novel therapeutic approach for the treatment of resistant CLD/PTLDS, and should be confirmed in randomized, controlled clinical trials.

Epidemiological studies indicate that skipping breakfast as a universal behavior, may have adverse effects on cardiovascular diseases [CVDs}and metabolic diseases. However, eating breakfast regularly, may increase satiety, thereby reducing overeating later in the day which prevents weight gain. Recent studies indicate that skipping breakfast increases the risk of obesity, metabolic syndrome, hypertension, hypercholesterolemia, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), and cardiovascular mortality as well as all-cause mortality. However, many studies also reported that regular taking of breakfast decreases the risk of CVDs and T2DM and all-cause mortality. Previous studies reported that heavy breakfast, in particular eating western diet may increase circadian rhythm of CVDs and sudden cardiac death. It seems that those who do not eat breakfast, they tend to eat refined and sweetened products, possibly, more in the night resulting in to greater risk of CVDs and T2DM. Breakfast skipping and eating in the night, may be associated with circadian misalignment in the central and peripheral clocks, leading to oxidative stress and inflammation. Increased systemic inflammation damages the adipocytes, beta cells of pancreas, endothelial cells and smooth muscle cells as well as neurons, which may produce dysfunction in these cells resulting in to related diseases. The beneficial effects of breakfast, may also be, at least in part, due to nutrient dense foods rather than time of eating. Eating regular breakfast, in particular rich in Indo-Mediterranean foods; vegetables, whole grains, fruits, spices and nuts may be protective against circadian increase in oxidative stress in the morning, resulting in to significant decline in the risk of CVDs and T2DM.

The endothelium plays a key role in blood vessel health. At the interface of the blood, it releases several mediators that regulate local processes and that protect against the development of cardiovascular disease. In this interplay, there is increasing evidence for a role of extracellular nucleotides and endothelial purinergic P2Y receptors (P2Y-R) in vascular protection. Recent advances have revealed that endothelial P2Y1-R and P2Y2-R mediate nitric oxide-dependent vasorelaxation as well as endothelial cell proliferation and migration, which are processes involved in the regeneration of damaged endothelium. However, endothelial P2Y2-R, and possibly P2Y1-R, have also been reported to promote vascular inflammation and atheroma development in mouse models, with endothelial P2Y2-R also being described as promoting vascular remodeling and neointimal hyperplasia. Interestingly, at the interface with lipid metabolism, P2Y12-R has been found to trigger HDL transcytosis through endothelial cells, a process known to be protective against lipid deposition in the vascular wall. Better characterization of the role of purinergic P2Y-R and downstream signaling pathways in determination of the endothelial cell phenotype in healthy and pathological environments has clinical potential for the prevention and treatment of cardiovascular diseases.

Early stroke diagnosis remains a big challenge in healthcare partly due to the lack of reliable diagnostic blood biomarkers, which in turn leads to increased rates of mortality and disability. Current screening methods are optimised to identify patients with a high risk of cardio-vascular disease, especially among the elderly. However, in young adults and children, these methods suffer low sensitivity and specificity and contribute to further delays in their triage and diagnosis. Accordingly, there is an urgent need to develop reliable blood biomarkers for triaging patients suspected of stroke in all age groups, especially children and young adults. This review explores some of the existing blood biomarkers, as single biomarkers, or biomarker panels, and examine their sensitivity and specificity for predicting stroke. A review was performed on PubMed and Web of Science for journal articles published in English during the period 2001 to 2021 which contained information regarding biomarkers of stroke. In this review article, we provide comparative information on the availability, clinical usefulness, and time-window periods of eight single blood biomarkers and six biomarker panels that have been used for predicting stroke in emergency situations. The outcomes of this review can be used in future research for developing more effective stroke biomarkers.

Lethal congenital contracture syndrome 11 (LCCS11) is a form of arthrogryposis multiplex congenita (AMC) which is associated with mutations in the gliomedin gene (GLDN) and has been known to be severely life-shortening, mainly due to respiratory insufficiency. Patients with this condition have been predominantly treated by pediatricians as they usually do not survive beyond childhood. In this case report we present a young adult who developed severe progressive respiratory insufficiency as a teenager due to diaphragmatic hypomotility and was diagnosed with LCCS11 following the finding of compound heterozygous pathogenic variants in GLDN. This case demonstrates the importance of screening for neuromuscular diseases in well-child visits and follow-ups of patients at risk for gross and fine motor function developmental delay. It also underscores the significance of including LCCS11 and other axonopathies in the differential diagnosis of juvenile onset of respiratory insufficiency, highlights that patients with this condition may present to adult practitioners and questions whether the nomenclature of this condition with various phenotypes should be reconsidered due to the stigmatizing term ‘lethal’.

Foot drop is a common disability in post-stroke patients and represents a challenge for the clinician. To date, Ankle Foot Orthosis (AFO) combined with conventional rehabilitation is the gold standard of rehabilitation management. AFO has a palliative mechanical action without actively restoring the associated neural function. Functional Electrical Stimulation (FES), consisting in stimulation of the peroneal nerve pathway, represents an alternative approach. By providing a FES device (Bioness L-300, BIONESS, USA) for 6 months to a post-stroke 22-year-old woman with a foot drop, our goal was to quantify its potential benefit on walking capacity. Gait parameters and the temporal evolution of the speed were collected with a specific connected sole device (Feet Me®) during the 10-meter walking, the Time Up and Go, and the 6-minute walking tests with AFO, FES or without any device (NO). As a result, the walking speed changes on 10-meters were clinically significant with an increase from baseline to 6 months in AFO and FES conditions (+0.14m-1 and +0.36m-1), without any changes in NO condition. In addition, speed decreased at about 4-minutes of the 6-minute walking test in NO and AFO conditions, while speed increased in FES conditions at baseline and after 1, 3 and 6 months. Monitoring gait speed in an endurance test after an ecological rehabilitation training program helps to examine walking performance in post-stroke patients and to propose a specific rehabilitation program depending on a fatigue threshold.

In 1789, the Annonaceae family was cataloged by de Jussieu. It encompasses tropical and subtropical plants which are widespread in distribution across various continents such as Asia, South and Central America, Australia and Africa. The genus of Annona is one of the 120 genera of the Annonaceae family and contains more than 119 species of trees and shrubs. The majority of these species are found in tropical America with more than 105 species (26 of them are endemic). Due to its edible fruits and medicinal properties, Annona is the most important genus of Annonaceae family. Despite Annona having many species, only limited species of this family are economically important such as A. squamosa L. (sugar apple), A. cherimola Mill. (Cherimoya), A. muricata L. (guanabana or soursop), A. atemoya Mabb. (atemoya), a hybrid between A. cherimola and A. squamosa, A. reticulata L. (custard apple), A. glabra L. (pond-apple) and A. macroprophyllata Donn. Sm. (ilama). Phytochemically, several classes of secondary metabolites such as acetogenins, essential oils, alkaloids, terpenoids and flavonoids have been described in this genus. A variety of pharmacological activities have been reported from various parts of Annona species specially leaves and seeds including applications against antibacterial, anticancer, antidiabetic and anti-inflammatory.

Objectives: As institutions modified medical practices to mitigate the spread of the SARS-CoV-2 virus, providers were forced to modify care through the implementation of telemedicine. The objective of this article is to review the current practices of otolaryngology during the COVID-19 pandemic and the limitations of telemedicine in current practice. Methods: A thorough review of the PubMed and MEDLINE databases was performed for publications between 2020 and 2021. Studies discussing telemedicine in otolaryngology during COVID-19 pandemic were selected. Results: As worldwide cases of COVID-19 continue to oscillate, we must continue to be vigilant in our clinical practice, implementing safe techniques to mitigate the spread of the SARS-CoV-2 virus through the continual use of telemedicine in all specialties of otolaryngology. Trends of increased patient acceptance of the use of telemedicine have been seen across subspecialities, including otolaryngology. Conclusion: Currently there are challenges associated with the implementation of telemedicine in the field of otolaryngology that rely heavily on adjunct physical examination, imaging studies, and specialty procedures. However, telemedicine has tremendous potential and can be adapted to include in the otolaryngologist’s toolbelt during public health emergencies such as the COVID-19 pandemic.

The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and plasma ACE levels may allow for the optimization of a preventive intervention to reduce cardiovascular morbidity and mortality in the chronic kidney disease (CKD) population. In this study, we aimed to analyze the association between ACE I/D polymorphism and cardiovascular mortality risk among non-hemodialyzed chronic kidney disease patients. This cross-sectional study examined 70 patients of Javanese ethnic origin with stable CKD who did not receive hemodialysis. ACE I/D polymorphisms, plasma ACE levels, atherosclerotic cardiovascular disease (ASCVD) risk, and cardiovascular mortality risk were investigated. As per our findings, the I allele was found to be more frequent (78.6) than the D allele (21.4), and the DD genotype was less frequent than the II genotype (4.3 vs. 61.4). The ACE I/D polymorphism had a significant direct positive effect on plasma ACE levels (path coefficient = 0.302, p = 0.021). Similarly, plasma ACE levels had a direct and significant positive effect on the risk of atherosclerotic cardiovascular disease (path coefficient = 0.410, p = 0.000). Moreover, atherosclerotic cardiovascular disease risk had a significant positive effect on cardiovascular mortality risk (path coefficient = 0.918, p = 0.000). The ACE I/D polymorphism had no direct effect on ASCVD and cardiovascular mortality risk. However, our findings show that the indirect effects of high plasma ACE levels may be a factor in the increased risk of ASCVD and cardiovascular mortality in Javanese CKD patients.

Purpose: To compare the standard implantation technique of a new ab externo microshunt (PRESERFLO) to a posterior technique with a small incision. The standard anterior approach (A) requires a relatively large, 6-8 mm perilimbal peritomy. In contrast, the posterior approach (P) involves only a 2-3 mm snip incision 2 mm posterior to the limbus. Methods: Charts of 126 PRESERFLO patients (54 A and 72 P) were retrospectively analyzed. Follow-up was 270 days. We compared the surgical time, intraocular pressure (IOP), number of medications, and complications. Results: The preoperative IOP in A was 21.8±8.5 mmHg and 23.9±8.1 mmHg in P (p=0.08). The surgical time for A was 26±0.8 minutes and 10±0.4 minutes for B (p<0.001). Following a low-pressure phase during the first week, A and P had an IOP value of 10.8±5.9 mmHg and 10.6±4.5 mmHg at 30 days, respectively (p=0.62). IOPs remained at this level throughout the study (all intra-group p> 0.08). There were no inter-group differences in IOP at any visit (all p-values > 0.3). Patients in A and P took 3.2 ± 1.3 and 3.3 ± 1.0 pressure-lowering medications at baseline, respectively (p=0.4). These values declined to 0.2 ± 0.6 in A and 0.3 ± 0.7 in P at 270 days. Both groups had a similar number of revisions (13 (10.3%) versus 10 (7.9%, p=0.14)) and complications (26 (20.8%) versus 31 (24.6%, all p>0.25). Conclusion: The posterior PRESERFLO insertion technique was 2.6 times faster than the standard anterior technique and yielded similar results with a large reduction in IOP and medications and a safety profile favorable over traditional filtering surgery.

Abstract: Ambulatory cancer centers face fluctuating patient demand and deploy specialized personnel who have variable availability. This undermines operational stability through misa-lignment of resources to patient needs, resulting in overscheduled clinics, budget deficits, and wait times exceeding provincial targets. We describe deployment of a Learning Health System framework for operational improvements within the entire ambulatory center. Known methods of value stream mapping, operations research and statistical process control were applied to achieve organizational high performance that is data-informed, agile and adaptive. We transitioned from a fixed template model by individual physician to a caseload management by disease site model that is realigned quarterly. We adapted a block schedule model for the ambulatory oncology clinic to align the regional demand for specialized services with optimized human and physical resources. We demonstrated improved utilization of clinical space, increased weekly consistency and im-proved distribution of activity across the workweek. Increased value, represented as the ratio of monthly encounters per nursing worked hours, and increased percentage of services delivered by full-time nurses were benefits realized in our cancer system. The creation of a data-informed demand capacity model enables application of predictive analytics and business intelligence tools that will further enhance clinical responsiveness..

Background The spread of COVID-19 continues, the mutation of SARS-COV-2 is still difficult to control, and the need for antiviral drugs to treat COVID-19 remains urgent. The use of arbidol in the treatment of COVID-19 is limited and controversial. Methods To clarify the efficacy of arbidol on COVID-19, we collected 25 cases and 178 related studies. We analyzed the treatment information of arbidol based on the obtained cases, expanded the scope of the study, and collected current studies on the treatment of COVID-19 in various databases for in-depth analysis. Results History analysis showed that arbidol was effective (76% cure rate) compared with other drugs. However, compared with other antiviral drugs or standard therapy, the arbidol group had no significant advantage in reducing the time to negative virus transformation, length of hospital stays, or improvement in CT (MD=0.22, 95%CI -0.29-0.73; MD = 0.61, 95% CI 1.46 to 2.67; RR=1.15, 95%CI 0.88-1.50); Analysis of adverse events showed no significant difference between the arbidol group and the other groups (RR=0.82, 95%CI 0.25-2.71). Conclusion Our study showed that arbidol had no significant effect on COVID-19, but showed a slight advantage in CT improvement and adverse events. Our study objectively evaluated the efficacy of arbidol in the treatment of COVID-19 and provided some guidance for arbidol in the treatment of COVID-19.

Background: Chronic kidney disease, one of the most common diseases in the world, is characterized by irreversible impairment of the kidney’s metabolic, excretory, and endocrine functions. During end-stage renal disease, patients require renal replacement therapy, such as hemodialysis (HD). Protein-energy wasting is a common health problem among HD patients. However, this study aims to assess the nutritional status of HD patients at two HD centers in Jeddah, Saudi Arabia, and to determine its associated factors. Methods: A cross-sectional study was conducted at two different Dialysis Centers in Jeddah, Saudi Arabia; 211 female and male HD patients. Malnutrition was recognized using the Modified-SGA (M-SGA) comprising two parts: medical history and physical examination. Sociodemographic and health status for all patients were also determined. Patients were classified based on their M-SGA score into two groups: normal and malnourished. Results: Overall, 54.5% of the participants showed malnutrition. Unemployment, low muscle strength and mass, high level of medication use, and high dialysis vintage were positively (P&lt;0.05) associated with malnutrition. Conclusion: The M-SGA score indicates a high prevalence of malnutrition among HD patients. These results show the importance of regular assessment and follow-ups for HD patients ensuring better health and nutritional status.

Drug repurposing is an attractive strategy for developing new antibacterial molecules. Herein, we evaluated the in vitro antibacterial, antibiofilm, and antivirulence activities of eight FDA-approved “non-antibiotic” drugs, comparatively to tobramycin, against selected Pseudomonas aeruginosa strains from cystic fibrosis patients. MIC and MBC values were measured by broth microdilution methods. Time-kill kinetics was studied by the macro dilution method, and synergy studies were performed by checkerboard microdilution assay. The activity against preformed biofilm was measured by crystal violet and viable cell count assays. The effects on gene expression were studied by real-time quantitative PCR, while the cytotoxic potential was evaluated against IB3-1 bronchial CF cells. Ciclopirox, 5-fluorouracil, and actinomycin D showed the best activity against P. aeruginosa planktonic cells and, therefore, underwent further evaluation. Time-kill assays indicated actinomycin D and ciclopirox, contrarily to 5-fluorouracil and tobramycin, have the potential for bacterial eradication, although with strain-dependent efficacy. Ciclopirox was the most effective against the viability of the preformed biofilm. A similar activity was observed for other drugs, although they stimulate EPS production. Ribavirin showed a specific antibiofilm effect, not dependent on bacterial killing. Exposure to drugs and tobramycin generally caused hyperexpression of the virulence traits tested, except for actinomycin D, which downregulated the expression of alkaline protease and alginate polymerization. Ciclopirox and actinomycin D revealed high cytotoxic potential. Ciclopirox and ribavirin might provide chemical scaffolds for anti-P. aeruginosa drugs. Further studies are warranted to decrease ciclopirox cytotoxicity and evaluate the in vivo protective effects.

Numerous studies have firmly established the role of ion channels in essentially all basic cellular functions. Apart from their role in ion transport, they can form macromolecular complexes with adhesion proteins, and signaling molecules. Ion channels are not only responsible for cellular electrogenesis and excitability, but they also regulate the necessary conditions for tissue homeostasis, such as differentiation, proliferation and apoptosis. Although cancer is not officially classified as a channelopathy, it has been increasingly recognized that ion channel aberrations play an important role in virtually all cancer types. Ion channels can exert pro-tumorigenic activities due to genetic or epigenetic alterations, or as a response to molecular signals, such as growth factors, hormones, etc. Prostate cancer is the second leading cause of cancer-related death in men in the United States. Increasing evidence suggests that ion channels and pumps play a critical role in the regulation of prostate cancer cell proliferation, apoptosis evasion, migration, epithelial-to-mesenchymal transition and angiogenesis. There is also evidence suggesting that ion channels might play a role in treatment failure in prostate cancer. Hence, they represent promising targets for diagnosis, staging and treatment. Here, the role of major types of ion channels involved in the development and progression of prostate cancer were reviewed. Identifying the underlying molecular mechanisms of the pro-tumorigenic effects of ion channels, may potentially inform the development of novel therapeutic strategies to counter this malignancy.

SGLT2 inhibitors act to induce glucosuria and have been shown to be efficacious in the treatment of type II diabetes mellitus but have also been shown to positively affect cardiovascular conditions and some benefitting kidney function. SGLT2i have shown to be effective in more advanced conditions but may eventually be a treatment in more general metabolic dysfunction. Metabolic syndrome is a clinical diagnosis for establishing risk for ischemic heart disease and diabetes. The prevalence of type II diabetes mellitus, heart disease, and severe vascular events steadily increased over recent decades. In addition to the established benefits of diet and exercise, SGLT2 inhibitor therapy may be able to aid in the treatment of metabolic syndrome from its proven cardiovascular and anti-hyperglycemic benefits. Pharmacologic modeling in canines is also considered, as they present with similar diagnoses and offer a model that shares many of the characteristics of humans in metabolic dysfunction.

Background: COVID-19 has placed tremendous pressure on the global public health system and has changed daily life. Aim: To examine the relationships between the perceived threat, perceived stress, coping responses and infection control practices towards the COVID-19 pandemic among university students in China. Methods: Using a cross-sectional survey, 4,392 students were recruited from six universities in two regions of China. Methods: Data were collected via an online platform using self-reported questionnaires. Hierarchical multiple regression analyses were performed to predict the variables on COVID-19 infection control practices. Results: Pearson correlation coefficients showed a significant negative relationship between perceived stress and COVID-19 infection control practices. A significant positive relationship was observed between wishful thinking and empathetic responding, and infection control practices. Hierarchical multiple regression analyses revealed that gender, geographical location, perceived stress and emotion-focused and relationship-focused coping responses were predictors of COVID-19 infection control practices. Conclusions: The findings suggest that university students displayed moderate levels of stress, using wishful thinking and empathetic responses as coping strategies. Counselling services should therefore emphasise reassurance and empathy. Male university students tended to be less compliant with social distancing. Both counselling and public health measures should recognise the importance of gender differences. Nurses should integrate these findings into future health program planning and interventions.

We previously described a model of deep intrinsic resistance of breast cancer wherein we used a function-based approach to selection of cancer cells that can survive a variety of challenges in prolonged but reversible quiescence. Our experimental results suggested that resistant cancer cells possess a variety of mechanisms, including modifications of the epigenome and transcriptome, for generating a high degree of cellular heterogeneity. In the present study, we evaluated JIB-04, a small-molecule epigenetic inhibitor initially discovered to inhibit cancer growth, to determine its ability to affect deep intrinsic resistance in our breast cancer model. We found that long pretreatment with JIB-04 sensitized resistant triple-negative inflammatory breast cancer cells and their parental cell line SUM149 to the chemotherapeutic drugs doxorubicin and paclitaxel. Resistant cancer cells derived from another inflammatory breast cancer cell line, FC-IBC02, were considerably more sensitive to JIB-04 than was the parental cell line. Investigating a mechanism of sensitization, we found that JIB-04 exposure increased the expression of PD-L1 in resistant cells, suggesting that JIB-04 may also sensitize resistant breast cancer cells to anti-PD-L1 immune therapy. Finally, these results support the usefulness of our experimental strategy for evaluating anticancer agents such as JIB-04 that may halt cancer evolution and prevent development of cancer resistance to currently used therapies.

Fundamentals of Laparoscopic Surgery (FLS) is a training module designed to provide basic surgical skills. During skill training of the FLS "suturing and intracorporeal knot-tying" task – the most difficult among the five psychomotor FLS tasks, learning from errors is one of the basic principles of motor skill acquisition where appropriate contextual switching of the brain state on error is postulated. This study investigated changes in the brain state following an error event based on the fusion of simultaneously acquired functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) signals. Here, human error processing is postulated to differentiate experts from novices based on the differences in the error-related chain of mental processes. Thirteen right-handed novice medical students and nine expert surgeons participated in this study. Error-related microstate analysis was performed using 32-channel EEG data at a high temporal resolution. Six microstate prototypes were identified from combined EEG data from experts and novices during the FLS task. Analysis of variance (ANOVA) found that the proportion of the total time spent in different microstates during the 10 sec error epoch was significantly affected by the skill level (p<0.01), microstate type (p<0.01), and the interaction between the skill level and the microstate type (p<0.01). Then, the EEG band power (1-40Hz) related to slower oxyhemoglobin (HbO) changes were found using regularized temporally embedded Canonical Correlation Analysis of the fNIRS-EEG signals. The HbO signal from the fNIRS channel overlying ‘Frontal_Inf_Oper_L’, ‘Frontal_Mid_Orb_L’, ‘Postcentral_L’, ‘Temporal_Sup_L’, ‘Frontal_Mid_Orb_R’ cortical areas from Automatic Anatomical Labelling showed significant (p<0.05) difference between experts and novices in the 10-sec error epoch. Here, the frontal/prefrontal cortical areas are postulated to be related to the perception and the activation of the primary somatosensory cortex at the postcentral cortical area is hypothesized to be related to the action underpinning perception-action coupling model for the error-related chain of mental processes. Therefore, our study highlighted the importance of error-related brain states from portable brain imaging when comparing complex surgical skill levels.

About 70% of children and adolescents with cerebral palsy experience gait impairments which affect their autonomy and well-being. Robotic-assisted gait training using the Lokomat is particu-larly promising for rehabilitation as it provides a standardized environment favoring the massive repetition of the movement, in which physical demands are low on the therapist and high training loads can be achieved. As no guidelines exist regarding training protocols and Lokomat settings, the goal of this study was to review the literature on Lokomat-assisted gait therapy and possibly make training recommendations. The twelve studies reviewed reported both positive and null effects of Lokomat training on gait. Half of the studies combined Lokomat with other types of training and only five used a control intervention to assess its benefit. Overall, training was administered 1-5 times per week for 20-60 minutes, over 1-12 weeks. Although Lokomat settings were not always described, progressively decreasing body-weight support and guidance, while increasing treadmill speed appear to be prioritized. The variety of training protocols and settings used did not allow pooling of the studies to assess effects of interventions on gait parameters in children and adoles-cents with cerebral palsy. This review highlights the need for homogenization of interventions so that clear guidelines can emerge and be applied in rehabilitation centers.

Acute kidney injury (AKI), especially if recurring represents a risk factor for future chronic kidney disease. In intensive care units, increased intraabdominal pressure is well-recognized as a significant contributor of AKI. However, the importance of transiently increased intra-abdominal pressures procedures is less commonly appreciated during laparoscopic surgery, the use of which has rapidly increased over the last few decades. Unlike the well-known autoregulation of the renal cortical circulation, medulla perfusion is modulated via partially independent regulatory mechanisms and strongly impacted by changes in venous and lymphatic pressures. In our review paper, we will provide a comprehensive overview of this evolving topic, covering a broad range from basic pathophysiology up to and including current clinical relevance. Key regulators of oxidative stress such as ischemia-reperfusion injury, the activation of inflammatory response and humoral changes interacting with procedural pneumoperitoneum formation and AKI risk will be recounted. Moreover, we present an in-depth review of the interaction of pneumoperitoneum formation with general anesthetic agents and animal models of congestive heart failure. A better understanding of the relationship between pneumoperitoneum formation and renal perfusion will support basic and clinical research, leading to improved clinical care and collaboration among specialists.

Since the detection of the first COVID-19 patient, 2 years have passed, during which more than 287,862,000 people fell ill globally, of which about 1.9% died. Implementation of SARS-CoV-2 control programs required efforts from almost all countries. An important direction in the fight against COVID-19 was the formation of herd immunity, the main tool for managing the pandemic. Study goal: to assess the seroprevalence of antibodies (Abs) to SARS-CoV-2 nucleocapsid (Nc) and receptor binding domain (RBD) in the St. Petersburg population during the COVID-19 pandemic. Materials and methods. A longitudinal cohort randomized monitoring study of Ab seroprevalence (SARS-CoV-2 Nc, RBD) was organized and conducted according to a unified methodology developed by Rospotrebnadzor with the participation of the St. Petersburg Pasteur Institute. For this purpose, a cohort of 1000 volunteers was formed who participated in all five stages of seromonitoring. The cohort was divided into 7 age groups: 1-17; 18-29; 30-39; 40-49; 50-59; 60-69; 70; and older (70+) years. Seropositivity levels (Nc, RBD) were assessed by quantitative and qualitative enzyme immunoassays. During the 2nd year of monitoring, some volunteers were vaccinated with the GamCOVIDVac (84%) or EpiVacCorona (11.6%) vaccines approved in Russia. Statistical processing was carried out using the Excel 2010 software package. Confidence intervals for shares and percentages (95% CI) were calculated using the method of A. Wald and J. Wolfowitz with adjustment (A. Agresti, B.A. Coull). The statistical significance of differences was calculated by z-test, using the appropriate online calculator (p<0.05), unless indicated. Results. There was a trend towards: an increase in Nc seropositivity in stages 1-3 of seromonitoring, with a decrease in stages 4-5 among children and adults. The share of RBD seropositive steadily increased during all 5 stages of seromonitoring. The most frequently found were low anti-RBD Abs levels (22.6-220 BAU/ml). High Ab levels were recorded statistically significantly less frequently. Asymptomatic forms were observed in 84-88% of SARS-CoV-2 seropositive volunteers. By the 5th stage of monitoring, this indicator significantly decreased to 69.8% (95% CI: 66.1-73.4). The monitoring revealed a statistically significant increase in anti-RBD Abs, alongside a statistically significant decrease in the proportion of Nc seropositive. This dynamic was especially characteristic of persons vaccinated with GamCOVIDVac. Conclusion. Prior to the use of specific vaccines, a seroprevalence of anti-Nc Abs was noted. After the introduction of the GamCOVIDVac vaccine in adults, a decrease in the level of anti-Nc Abs was noted due to an increase in the proportion of RBD seropositive persons.

The interleukin 6 (IL-6) receptor blocking antibody tocilizumab was repurposed in the coronavirus pandemic with the intention of blocking the excess inflammatory activation associated with severe disease. We retrospectively evaluated the response to tocilizumab based on measured levels of IL-6 as well as other inflammatory markers. In the sample of 41 patients with measured levels, 16 received tocilizumab. In patients who received tocilizumab, there was a statistically significant relationship between both higher IL-6 levels and measured acute phase reactants with mortality, but not in those who did not. Additionally, an improved mortality after tocilizumab was suggested with those with higher IL-6 measurements, but not in those with lower levels, but this finding failed to achieve statistical significance (p=0.14). Though this study is limited by a small sample size and retrospective design, an association is suggested between higher IL-6 levels and improved mortality after tocilizumab.

Providing healthcare workers with cost information about the medications they prescribe can influence their decisions, particularly when that information is provided at the very moment they are faced with a prescribing decision. The current study aimed to analyse the impact of nudges that presented cost information to prescribers through their organisation's electronic prescribing system. The nudges were co-created by the research team (composed of behavioural scientists) and the lead hospital pharmacist. One nudge provided simple cost information (percentage difference between two brands of Mesalazine – Asacol and Octasa). The second nudge provided the potential annual cost-saving that could result if the cheaper medication was selected across the organisation. While the statistical analyses revealed that these nudges were not effective, several administrative barriers were overcome, which may inform future research. For example, presenting aggregated cost information to the prescribers is possible even when the actual cost of medicine is confidential and can not be displaced. In addition, future research could reveal more behavioural factors that facilitate medication optimisation.

Background: Fluoride toothpaste (FT) has recently been included in the World Health Organization’s (WHO) Model List of Essential Medicines. Whereas it is essential for preventing dental caries, its current affordability around the globe remains unclear. This study aimed to analyse the affordability of FT in as many as possible countries worldwide. Methods: A standardized protocol was developed to collect country-specific information about the characteristics of the cheapest FT at a common point of purchase. 82 members of the WHO Global Oral Health Network of Chief Dental Officers (CDOs), directors of WHO Collaborative Centres and other oral health experts collected data using mobile phone technology. The Fluoride Toothpaste Affordability Ratio (FTAR) was calculated as the price associated with the recommended annual consumption of FT, relative to the daily wage of the lowest-paid unskilled government worker (FTAR >1 = unaffordable spending on fluoride toothpaste). The daily expenditure per capita of the poorest 15% of the income distrubition was used as the main proxy of the daily wage, using World Bank data. Alternatively, we used the daily minimum wage as a proxy of the daily wage. Stratified descriptive statistics were undertaken with respect to different World Bank Income Groups and WHO Regions. Results: There are significant discrepancies in the affordability of FT across 78 countries. FT was strongly affordable in high-income countries, relatively affordable in upper middle-income countries, and strongly unaffordable in lower middle-income and low-income countries. The affordability of FT across WHO Regions was dependent upon the economic mix of WHO Regions’ member states. Conclusion: FT is still unaffordable for many people, particularly in low-resource settings. Health policy members should develop better strategies to address and improve the universal affordability of FTs, for the incidence of dental caries to be reduced at a global level.

The incidence of cutaneous melanoma has been increasing in the last decades among fair-skinned population. Despite etiology is complex and multifactorial, the exposure to ultraviolet radiation (UVR) is the most consistent modifiable risk factor associated with melanoma. Several factors influence the amount of UVR reaching Eart’s surface. The aim of our study is to explore the association between melanoma and altitude in an area characterized by a mixed geographic morphology, such as in the Veneto region. For this purpose, 2752 melanoma patients, who referred to our attention between 1998 and 2014, were included in this study. For each patient we extracted demographic, histological and clinical-survival data. Head/neck and acral melanoma were more common in patients from the hills and the mountains, while the prevalence of limb and trunk melanoma was higher in patients living in plain and coastal areas. With increase of altitude, the Breslow thickness, ulceration and mitotic rate get worse but no significant difference was observed in overall and disease free-survival. Geographical area of origin of melanoma patients and the “coast-plain-hill gradient” could help to estimate the influence of different sun exposure and to explain the importance of vitamin D level in skin-cancer control.

Background: This study aims to set out key clinical features of different Motoric Cognitive Risk (MCR) subtypes based on individual quantitative measures of cognitive impairment and to compare their predictive power on survival over an 8-year observation time. Methods: We analyzed data from a population-based study of 1138 subjects aged 65 years and older in south Italy. These individuals were targeted and allocated to subtypes of the MCR phenotype according to the slowness criterion plus one other different cognitive domain for each characterized phenotype. Clinical evaluation and laboratory assays, along with a comprehensive battery of neuropsychological and physical tests, completed the sample investigation. Results: MCR prevalence was found to be 9.8% (N=112), 3.6% (N=41), 3.4% (N=39), and 1.8% (N=21) for the MCR, MCR-GlobalFunction, MCR-StructuredSCC, and MCR-SCC&amp;GlobalFunction, respectively. Univariate Cox survival analysis showed an association only of the MCR-GlobalFunction subtype with a significant, 1.5-fold increased risk of overall death as compared to the other counterparts (HR 2.53, 95%CI 1.28 to 4.99, P-value&lt;0.01) over an 8-year observation period, even after major adjustment (HR 2.02, 95%CI 1.02 to 4.02). Conclusions: MCR phenotypes assigned to the MMSE cognitive domain are more likely to have an increased risk of overall mortality, 1.5-fold higher than counterparts, over 8-year observation.

Extracorporeal shock wave therapy (ESWT) is a safe and effective treatment option for various pathologies of the musculoskeletal system. Many studies addressed the molecular and cellular mechanisms of action of ESWT. However, no uniform concept could be established in this matter until now. We performed a systematic review of the effects of exposure of musculoskeletal tissue to extracorporeal shock waves (ESWs) reported in the literature. The key results were as follows: (i) compared to the effects of many other forms of therapy, the clinical benefit of ESWT does not appear to be based on a single mechanism; (ii) different tissues respond to the same mechanical stimulus in different ways; (iii) just because a mechanism of action of ESWT was described in a study does not automatically mean that this mechanism was relevant to the observed clinical effect; (iv) focused ESWs and radial ESWs seem to act in a similar way; and (v) even the most sophisticated research into the effects of exposure of musculoskeletal tissue to ESWs cannot substitute clinical research in order to determine the optimum intensity, treatment frequency and localization of ESWT.

Competency frameworks outline the perceived knowledge, skills and other attributes required for professional practice. Competency frameworks have gained in popularity, in part for their ability to inform health professions education, assessment, professional mobility, and other activities. Previous research has shown inadequate reporting within reports describing their development and that may jeopardize their use and application. We aimed to develop a set of minimum criteria that provides guidance to authors (and consumers) in an effort to improve reporting of the development of competency frameworks. The checklist was developed by a 35-member expert panel and a five-member research team following published guidance from the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network. The final checklist contains 20 essential reporting items including guidance on reporting title and abstract, framework development, the development process, testing and funding/conflicts of interest. The intent of the COmpeteNcy FramEwoRk Development in Health Professions (CONFERD-HP) reporting guideline is to help readers (including researchers, educators, regulators, health professionals, and patients) develop a greater understanding of relevant terminology, core concepts, and key items to report for competency framework development in health professions.

Patients with cancer experience insomnia or sleep disturbances. This study aimed to explore whether the discrepancy between a patient's desired time in bed and total sleep time (DBST) index is a measurement tool for insomnia severity or sleep onset latency [SOL] in patients with cancer. This retrospective medical records review study gathered clinical information and rating scale scores including Insomnia Severity Scale (ISI), Cancer-related Dysfunctional Beliefs about Sleep scale (C-DBS), Patient Health Questionnaire-9 items (PHQ-9), State subcategory of State and Trait Anxiety Inventory, and Short form of Fear of Progression Questionnaire. Sleep indices of time variables (bedtime, sleep onset time, and wake-up time), duration variables [SOL, time in bed (TIB), time in bed for 24 hours (TIB/d), and duration from wake-up time to bedtime (WTB)], and the DBST index were calculated. The ISI score was predicted by PHQ-9 (β=0.34, P&lt;0.001), C-DBS (β=0.17, P=0.034), and DBST index (β=0.22, P=0.004) with a significant correlation with the DBST index (r=0.19, p=0.020). The DBST index was significantly correlated with long SOL (r=0.23, P=0.005). Long SOL was predicted by early bedtime (β=0.18, P=0.045), short WTB (β=-0.26, P=0.004), and high DBST index (β=0.19, P=0.013). The DBST index was significantly correlated with a predicting variable each for insomnia severity and SOL in patients with cancer.

This study assesses the secondary metabolites, minerals, antimicrobial, antioxidant, and anticancer properties of Micromeria fruticosa plant different botanical parts (leaf, stem, root, flower) extracted with various solvents. The plant samples were sequentially obtained using different solvents (n-hexane, ethanol and water) through steeping. Then, each of the extracts was further analyzed by using gas chromatography–mass spectrometry (GC-MS). Moreover, the extracts were bio-assayed to test their antioxidant, antibacterial, and anti-cancer activities. Quali-quantitative analysis of M. fruticosa crude extracts revealed the occurrence of 27 secondary metabolites were identified including mainly monoterpenes, sesquterpenes, and fatty acids, with varying quantities. Some of the major bioactive compounds included, Menthone (5.42-30.05%), Oleamide (3.40-32.20%), Pulegone (10.66-64.1%), and Menthol (3.61-100.0%), which were detected mostly in all plant parts with significant quantities. Several antioxidant minerals, mainly, Fe, Zn, and Mn, were detected with the highest amounts in the Micromeria water extracts. Results from antimicrobial assays showed that the water extract of leaves exhibited the highest DPPH scavenging activity (89.73%) followed by the water extract of flowers (80.07%) at a concentration of 100 μg/mL. The water extract of stems showed greater antimicrobial activity against all the tested gram negative and positive bacteria (Methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Escherichia coli, and Shigella sonnie). The leaves ethanolic and stem aqueous extracts had a strong antimicrobial activity against E. coli. and C. albicans. Flower aqueous extract demonstrated the highest cytostatic effect on the colon cell line by reducing viability up to 30.4%, followed by the leaf ethanol extract with 38.6% cell viability reduction at 1000 µg/mL. In conclusion, extraction solvents influenced the recovery of phytocompounds and the highest pharmacological activities of the different extracts could be correlated to the presence of additional bioactive compounds. Our results suggest that M. fruticosa plant is a promising source of natural products with antioxidant, anti-microbial and anti-cancer properties for potential nutraceutical, therapeutic, and functional food applications. , , , , , ,

ABSTRACT Two years after first patients approached the emergency rooms of hospitals in Wuhan becouse of respiratory distress,thousend of SARS-CoV-2 infected persons continue to die every day worldwide.SARS-CoV-2-infected patients undergo a process of dehydration and malnutrition before they develop respiratory problems and approach the emergency room of a hospital.This is,in many cases, the consequence of high fever which causes massive loss of fluids. In addition loss of appetite, is responsible for the deficit of protein intake.Most of the virus-infected patients admitted to the emergency room are therefore hypovolemic and hypoproteinemic and suffer of respiratory distress accompanied by ground grass opacities at CT-scan of the lungs.Critically ill patients are treated following the guidelines for treatment of septic shock but with „conservative“ fluid replacement and administration of diuretics to assure sufficient hourly urine production. The combination of conservative fluid administration with reduced protein content in the enterally administered diet, together with administration of diuretics, has severe hemodynamic consequenses in mostly aged,dehydrated,critically ill patients. Many of them will develop acute kidney injury in the next 24 hours.In most of the cases, patients continue to loose weight by loosing skeletal muscle mass. Ischemic damage in the lung capillaries is responsible for the acute respiratory distreass syndrome (ARDS) and for the hallmark of autoptic findings,diffuse alveolar damage (DAD) characterized by hyaline membrane formation,fluid invasion of the alveoli recruitment of some inflammatory cells and progressive arrest of blood flow in the pulmonary vessels.The consequence is progressive congestion , increase of lung weight and progressive hypoxia (progressive severity of ARDS).Sequestration of blood in the lungs worsen hypovolemia and ischemia in different organs.This is most probably responsible for recruitment of inflammatory cells and for persistance of elevated serum levels of positive acute-phase markers and of hypoalbuminemia. Autoptic studies have been performed mostly in patients who died in the ICU after SARS-CoV-2-infection because of progessive ARDS.In those patients, tubulus epithelium necrosis in the kidney is a frequent finding as it has been the case in the first SARS-CoV-1 pandemic.In the death certification charts, many times weeks after first symptoms have started ,cardiac arrest is the cause of death after respitatory insufficiency.Replacement therapy with sufficient amount of fluid and albumin should be part of the early individualized life-saving supportive measures avoiding mechanical ventilation.

Age estimation in dental radiographs Orthopantomography (OPG) is a medical imaging technique that physicians and pathologists utilise for disease identification and legal matters. For example, for estimating post-mortem interval, detecting child abuse, drug trafficking, and identifying an unknown body. Recent development in automated image processing models improved the age estimation's limited precision to an approximate range of +/- one year. While this estimation is often accepted as accurate measurement, age estimation should be as precise as possible in most serious matters, such as homicide. Current age estimation techniques are highly dependent on manual and time-consuming image processing. Age estimation is often a time-sensitive matter in which the image processing time is vital. Recent development in Machine learning-based data processing methods has decreased the imaging time processing; however, the accuracy of these techniques remains to be further improved. We proposed an ensemble method of image classifiers and transfer learning techniques to enhance the accuracy of age estimation using OPGs from one year to a couple of months (1-3-6). This hybrid model is based on convolutional neural networks (CNN) and K nearest neighbours (KNN). The hybrid (HCNN-KNN) model was used to investigate 1,922 panoramic dental radiographs of patients aged 15 to 23. These OPGs were obtained from the various teaching institutes and private dental clinics in Malaysia. To minimise the chance of overfitting in our model, we used the principal component analysis (PCA) algorithm and eliminated the features with high correlation. To further enhance the performance of our hybrid model, we performed systematic image pre-processing. We applied a series of classifications to train our model. We have successfully demonstrated that combining these innovative approaches has improved the classification and segmentation and thus the age-estimation outcome of the model. Our findings suggest that our innovative model, for the first time, to the best of our knowledge, successfully estimated the age in classified studies of one year old, six months, three months and one-month-old cases with accuracies of 99.98, 99.96, 99.87, and 98.78 respectively.

Gas chromatography-coupled mass spectrometry (GC-MS) has been used in biomedical research to analyze volatile, non-polar, and polar metabolites in a wide array of sample types. Despite advances in technology, missing values are still common in metabolomics datasets and must be properly handled. We evaluated the performance of ten commonly used missing value imputation methods with metabolites analyzed on an HR GC-MS instrument. By introducing missing values into the complete (i.e., data without any missing values) NIST plasma dataset we demonstrate that Random Forest (RF), Glmnet Ridge Regression (GRR), and Bayesian Principal Component Analysis (BPCA) shared the lowest Root Mean Squared Error (RMSE) in technical replicate data. Further examination of these three methods in data from baboon plasma and liver samples demonstrated they all maintained high accuracy. Overall, our analysis suggests that any of the three imputation methods can be applied effectively to untargeted metabolomics datasets with high accuracy. However, it is important to note that imputation will alter the correlation structure of the dataset, and bias downstream regression coefficients and p-values.

Both SARS-CoV-2 and SARS-CoV initially appeared in China and spread to other parts of the world. SARS-CoV-2 has generated a COVID-19 pandemic causing more than 6 million human deaths worldwide while the SARS outbreak quickly ended in six months with a global total of 774 reported deaths. One of the factors contributing to this stunning difference in the outcome between these two outbreaks is the inaccuracy of the RT-qPCR tests for SARS-CoV-2, which generated a large number of false-negative and false-positive test results that have misled patient management and public health policy-makers. This article presented Sanger sequencing evidence to show that the RT-PCR diagnostic protocol established in 2003 for SARS-CoV can in fact detect SARS-CoV-2 accurately due to the well-known nonspecific PCR amplification of DNAs with similar sequences. Using nested RT-PCR followed by Sanger sequencing to retest 50 patient samples collected in January, 2022 and sold as RT-qPCR positive reference confirmed 21 (42%) were false-positive. Although the other 29 positive isolates were categorized as Omicron variant by partial sequencing of the N gene, and the RBD and the NTD of the S gene, 9 (31%) showed focal to complete sequencing failure in the S gene segments due to multi-allelic SNPs. During the course of the study, an Omicron variant isolate containing a BA.1 NTD and a BA.2 RBD in its S gene was also detected. Routine partial S gene sequencing of all PCR-positive samples can timely discover multi-allelic SNPs and viral recombination in the circulating variants for investigation of their impacts on vaccine efficacies, therapeutics and diagnostics.

Lymph node invasion in prostate cancer is a significant prognostic factor indicating worse prognosis. While it affects significantly both survival rates and recurrence, proper management remains a heated issue. Thorough evaluation of risk factors associated with nodal involvement, such as lymph node density or extracapsular extension, is crucial to establish potential expansion of the disease and to substratify patients clinically. There are multiple strategies that may be taken into consideration for patients with positive lymph nodes. Nowadays therapeutic methods are generally based on observation, radiotherapy, and androgen deprivation therapy. However current guidelines are incoherent in terms of indication of the most effective management approach. Future management strategies will be expected to reach for novel diagnostic tools and therapies, such as photodynamic therapy or diagnostic imaging with prostate specific membrane antigen. Nevertheless, this heterogeneous group of men remains a vast therapeutic concern, and both clarification of the guidelines and optimal substratification of patients is required.

Diffuse large B-cell lymphoma (DLBCL) is the most common haematological malignancy in humans and dogs. Several studies disclosed some similarities between the two species, including the constitutive activation of NF- κB pathway as a fundamental underlying pathogenetic mecha-nism. In humans, downregulation of IL-1R8 is implicated in DLBCL development, but its role in dogs has not been explored so far. To gain insight into the pathogenesis of this tumor in dogs, we evaluated the mRNA and protein expression of IL-1R8 in 12 hyperplastic lymph nodes ob-tained from dogs not bearing tumors and from 50 dogs with DLBCL. Moreover, we analysed through qRT-PCR the expression of TLR7, TLR9, MYC, and p52 genes that are known to be in-volved in the IL-1R8 regulatory network. IL-1R8 and p52 were downregulated in DLBCLs com-pared to control lymph nodes (p<0.001), while a higher expression of TLR7, TLR9 and MYC was observed in tumors (p<0.01). Immunohistochemistry confirmed gene expression results, reveal-ing a significantly lower IL-1R8 staining score in DLBCLs compared to control lymph nodes (p<0.0001). Taken together, these results suggest that IL-1R8 downregulation may represent one of the mechanisms driving DLBCL pathogenesis in dogs, mainly through dysregulation of the Toll-like/Interleukin receptors signalling cascade and the aberrant activation of classical NF-κB pathway.

A right frontoparietal neoplastic lesion was found in a young-aged patient with analgesic refractory headache. Surgical resection was performed, and the pathologist analysis turned out a cellular ependymoma with signs of anaplasia. In the follow-up, a MRI showed a suspicious lesion, so a [18F]Fluorocholine PET/CT was performed. An increased uptake was described in the right parietal region on the margin of residual cystic lesion. The patient got a complete resection which was confirmed later by MR. In the pathology analysis, a focally congestive cerebral parenchyma with a central histiocytic reaction to foreign body area was described. Foreign body reaction in brain tissue is a very rare immune response that has not been well studied. Haemostatic material has been reported as a possible trigger of this response in other organs and could be detected by [18F]FDG PET/CT. Following the experience of the current case report, [18F]Fluorocholine PET/CT could also show a false positive related to foreign body reaction.

With arrival of highly transmissible Omicron variants in global pandemic, dentistry is facing another challenge to preserve biosafety of dental care. With a mission to protect both patients and healthcare workers, adaptability to the changing epidemiologic situation is required from dental professionals. This work presents a prospective sustainable biosafety setting for routine orthodontic care. The protocol is composed from combination of available technologies focused on the air-borne part of a virus pathway. Introduced biosafety protocol has been clinically evaluated after 18 months of application in the real clinical environment. The protocol has three fundamental pillars: (1) UVC air disinfection; (2) air saturation with certified virucidal oils through nebulizing diffusers; (3) complementary solutions. As a method of evaluation pseudonymous on-line smart form was used. Protocol operates with premise that everybody as a hypothetical asymptomatic carrier. Results from 115 patient feedbacks imply that with this protocol in place, there was no observed or reported translation of virus from patient to another patient or from patient to doctor or nurse and vice versa, albeit nine patients have retrospectively admitted visiting the clinic as probably infectious. Despite promising results, a larger clinical sample and exposition to current mutated strains is necessary for reliable conclusions about protocol virucidal efficiency.

In kidney transplant recipients, belatacept is usually pursued indefinitely after it has been started. In the setting of the belatacept shortage and after having evaluated the benefit-risk ratio, we established a strategy consisting of time-limited belatacept therapy / transient calcineurin inhibitor withdrawal, whose results are analyzed in that study. We considered all the kidney transplant recipients that had been switched from conventional immunosuppressive therapy to belatacept and then for whom belatacept has been withdrawn intentionally. Furthermore, in the first 8 patients, we assessed changes in peripheral blood mononuclear cells (PBMC) transcriptome using RNAseq before and 3 months after belatacept withdrawal. Over the study period, 28 out of 94 patients had belatacept intentionally withdrawn including 25 (89%) switched to low-dose CNI. One rejection due to poor compliance occurred. The eGFR after 12 months remained stable from 48 ± 19 ml.1.73m^-2 to 46 ±17 ml.1.73m^-2 (p = 0.68). However, patients that resumed belatacept / withdrew CNIs (n=10) had a trend towards a better eGFR comparing with the others (n =15): 54 ± 20 ml.1.73m^-2 vs eGFR 43 ± 16 ml.1.73m^-2 respectively (p = 0.15). The only factor associated with belatacept resumption was when the withdrawal took place during the COVID-19 outbreak. Transcriptome analysis of PBMCs, did not support rebound in alloimmune response. These findings underpin the use of belatacept as part of a time-limited therapy, in selected kidney transplant recipients, possibly as an approach to allow efficient vaccination against SARS-Cov-2.

Coronary optical coherence tomography (OCT) is an intravascular, near-infrared light-based imaging modality capable of reaching axial resolutions of 10-20 µm. This resolution allows for accurate determination of high-risk plaque features, such as thin cap fibroatheroma; however, visualisation of morphological features alone still provides unreliable positive predictive capability for plaque progression or future major adverse cardiovascular events (MACE). Biomechanical simulation could assist in this prediction, but this requires extracting morphological features from intravascular imaging to construct accurate three-dimensional simulations of patients’ arteries. Extracting these features is a laborious process, often carried out manually by trained experts. To address this challenge, numerous techniques have emerged to automate these processes while simultaneously overcoming difficulties associated with OCT imaging, such as its limited penetration depth. This systematic review summarises advances in automated segmentation techniques from the past five years (2016-2021) with a focus on their application to the three-dimensional reconstruction of vessels and their subsequent simulation. We discuss four categories based on the feature being processed, namely: coronary lumen; plaque characteristics and subtypes; artery layers; and stents. Areas for future innovation are also discussed as well as their potential for future translation.

The cannabis plant has been known for millennia for its properties such as textile fiber, food, recreational and medicinal use. Since the origin of its domestication in Asia, cannabis has been transported to the rest of the continents by merchants, nomads, settlers, and slaves, who have also carried with them valuable knowledge about its uses. Its medical use was one of the major contributions of this plant in the various civilizations through which it passed. This article aims to understand its origins, dissemination, and medical use over the years to the present day.

Ciguatera fish poisoning (CFP) is one of the most common causes worldwide of marine poisoning associated with fish consumption from tropical areas. Its incidence is underreported. CFP cases seem to increase with grouped cases reported during summer. Exposure to ciguatoxin, the toxin responsible for CFP with sodium-channel agonistic, cholinergic, and adrenergic activities, may result in a large spectrum of manifestations. We aimed to describe the clinical characteristics, management, and outcome of CFP in Martinique, French West Indies. We conducted an observational retrospective single-center study for six years (October 2012 to September 2018) including all CFP patients managed by the prehospital medical services, admitted to the university hospital emergency department, or declared to the regional health agency. One hundred and forty-nine CFP patients (81females/63males; median age, 46 years [interquartile range, 34-61]) were included. Acute features consisted of general (91%; mainly, myalgia pruritus, and asthenia), gastrointestinal (90%; mainly diarrhea, abdominal pain, and nausea), neurological (72%; mainly, paresthesia, dysgeusia, and impairment of hot/cold feeling), and cardiovascular manifestations (22%; bradycardia, hypotension, and heart conduction disorders). Management was supportive. No patient died but symptoms persisted in 40% of the 77 patients with follow-up on day 15. CFP was mainly attributed to the ingestion of trevallies (59%), snappers (13%), and king mackerels (8%) with collective contaminations (71%). Unusual fish (tuna, salmon, and spider conchs) were suspected in rare cases. Ingestion of trevallies was associated with significantly higher persistent symptoms (odds ratio, 3.00; 95% confidence interval, [1.20-8.00]; p=0.03). CFP incidence was 0.67 cases per 10,000 patient-years in Martinique over the study period. To conclude, CFP represents an increasing public health issue in Martinique like in other Caribbean islands. Patients present usual but possibly life-threatening features. The outcome is excellent despite frequently prolonged manifestations.

The purpose of this work was to evaluate the suitability of recent US Food and Drug Administration (US-FDA) approved and marketed oral liquid, powder, or granule products for children in North America, to identify the next group of Active Pharmaceutical Ingredients (APIs) that have high potential for development as commercially available FDA-approved finished liquid dosage forms , and to propose lists of compounded nonsterile preparations (CNSPs) that should developed as commercially available FDA-approved finished liquid dosage forms as well as those that pharmacists should continue to compound extemporaneously. Through this identification and categorization process, the pharmaceutical industry, government, and the professions are encouraged to continue to work together to improve the likelihood that patients will receive high quality standardized extemporaneous CNSPs and US-FDA-approved products.

Several recent epidemiological studies attempted to identify risk factors for Alzheimer's disease. Age, family history, genetic factors (APOE genotype, Down syndrome), physical activity, and a low level of schooling are significant risk factors. In this review, we summarize the known psychosocial risk factors for the development of Alzheimer's disease in Down syndrome patients and their association with neuroanatomical changes in the brains of people with Down syndrome. We completed a comprehensive review of the literature on PubMed, Google Scholar, and Web of Science about psychosocial risk factors for Alzheimer's disease, for Alzheimer's disease in Down syndrome, and Alzheimer's disease in Down syndrome and their association with neuroanatomical changes in the brains of people with Down syndrome. Alzheimer's disease causes early pathological changes in Down syndrome patients, especially in the hippocampus and corpus callosum. The field needs more data about the neuroanatomical changes during childhood, how they change with increasing age, and the presence or absence of psychosocial risk factors. Further neuroimaging and psychosocial assessment-focused research is needed to understand the mechanisms leading to Alzheimer's disease at an early age and create more sensitive and relevant clinical, memory, and reasoning assessments for people with Down syndrome.

Screen viewing time is the total time spent by a child on any digital/electronic device. The objective of the present study was to determine the incidence and predictors of excessive screen viewing time in children in Ujjain, India. This cross-sectional, community-based study was conducted through house-to-house survey by using the three-stage cluster sampling method in 36 urban wards and 36 villages of Ujjain district, India. Excessive screen viewing time was defined as screen viewing for &gt; 2 h/day. The prevalence of excessive screen viewing time was 17.83%. Risk factors identified using the multivariate logistic regression model were: age (OR: 1.5, P &lt; 0.001); mobile phone use before bedtime (OR: 3.17, P = 0.008); parents’ perception about the child habituated to screen (OR: 14.03, P &lt; 0.001); television in bedroom (OR: 48.69, P &lt; 0.001); morning mobile screen viewing time (OR: 9.27, P &lt; 0.001); not reading books other than textbooks (OR: 9.71, P &lt; 0.001); and lack of outdoor play for &gt;2 h (OR: 4.20, P &lt; 0.001). Presence of eye pain was a protective factor for excessive screen viewing time (OR: 0.12, P = 0.011). The study identified multiple modifiable risk factors for excessive screen viewing time.

Inflammatory bowel disease (IBD) is a chronic and relapsing disease caused by a dysregulated immune response to host intestinal microbiota that occurs in genetically predisposed individuals. IBD encompasses two major clinical entities: ulcerative colitis (UC), which is limited to the colonic mucosa, and Crohn disease (CD), which might affect any segment of the gastrointestinal tract. Despite the prevalence of IBD is increasing worldwide, therapy remains suboptimal, largely because the variability of causative mechanisms, raising the need to develop individualized therapeutic approaches targeted to each individual patient. In this context, patients-derived intestinal organoids represent an effective tool for advancing our understanding on IBD’ s pathogenesis. Organoid 3D culture systems offer a unique model for dissecting epithelial mechanisms involved IBDs and test individualized therapy, although the lack of a functional immune system and a microbiota, two driving components of the IBD pathogenesis, represent a major barrier for their exploitation in clinical medicine. In this review we have examined how to improve the translational utility of intestinal organoids in IBD and how co-coltures of 3D or 2D organoids and immune cells and/or intestinal microbiota might help to overcome these limitations.

Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiot-ropism and high remodeling capacity. Although the expansion of fat mass, by defini-tion, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link between adiposity and its associated metabolic and cardio-vascular complications. The dysfunctional fat displays distinct biological signatures, which include enlarged fat cells (i.e., adipocyte hypertrophy), low-grade inflammation, impaired redox homeostasis, and cellular senescence. While these events are orches-trated in a cell-type, context-dependent and temporal manner, the failure of the adipose precursor cells to form new mature adipocytes appears the main instigator of the adi-pose dysregulation, which, ultimately, poses a deleterious milieu either by promoting ectopic lipid overspill in non-adipose targets (i.e., lipotoxicity) or by inducing an al-tered secretion of different adipose-derived hormones (i.e., adipokines and lipokines). This novel paradigm (“expandability hypothesis”) challenges and extends previous “adipocentric view”, which implies a reduced plasticity of the adipose organ at the nexus between “unhealthy” fat expansion and the development of obesity-associated comorbidities. In this review, we will briefly summarize the potential mechanisms by which adaptive changes to variations of energy balance may impair adipose plasticity and promote fat organ dysfunction. We will also highlight the conundrum with the perturbation of the adipose microenvironment and the development of cardio-metabolic complications by focusing on adipose lipoxidation and cellular senescence. Finally, we discuss the sci-entific rationale for proposing adipose organ plasticity as a target to curb/prevent adi-posity-linked cardio-metabolic complications.

Olfactory Receptors (ORs) are a large family of G protein coupled receptors predominantly expressed by the main olfactory epithelium at nasal level and are responsible for the generation of smelling sense. Microarray and deep sequencing analyses, however, have demonstrated that ORs are ectopically expressed in various human tissues including testis, kidneys, adipose tissue and liver and their biological functions become to be unrevealed. Molecular and pharmacological approaches have shown that some of these ORs modulate glucose and lipid metabolism at multiple interfaces, suggesting that ORs might be part of the large family of nutrient sensors. i.e. molecular/ cellular machines that respond to a specific nutrient component. By using nutrients- derived agonists it has been shown that ORs effectively modulates glucose and lipid metabolism raising interest on their possible therapeutic application in the treatment of metabolic disorders including dyslipidemia, obesity and metabolic syndrome.

The COVID-19 pandemic affects all parameters, especially health care professionals, drugs and medical supplies. The KERRA is a mixed medicinal plant capsule that is used for the treatment of patients with high fever with food and drug administration approved by FDA Thailand. Recently, KERRA showed quicker recovery for COVID-19 patients. Therefore, it is possible that some ingredients in KERRA could inhibit SARS-CoV-2. In this study, two important replication-related enzymes in SARS-CoV-2, a main protease and an RNA-dependent RNA polymerase (RdRp), were used to study the effect of KERRA. The results showed that KERRA inhibited the SARS-CoV-2 main protease and SARS-CoV-2 RdRp with IC50 values of 49.91 ± 1.75 ng/mL and 36.23 ± 5.23 µg/mL, respectively. KERRA displayed no cytotoxic activity on macrophage cells at concentrations lower than 1 mg/mL and exhibited anti-inflammatory activity. Additionally, KERRA was against a feline coronavirus (feline infectious peritonitis [FIP]) infection with an EC50 value of 134.3 g/mL. This study supports the potential use of KERRA as a candidate drug for COVID-19.

Inactivated SARS-CoV-2 vaccine (CoronaVac) is commonly used in national immunization programs. However, the immune response significantly declined within a few months. Our study assessed the immune response against SARS-CoV-2 after receiving booster shots of BNT162b2 or ChAdOx1 among health care workers who previously received CoronaVac as their primary immunization. Fifty-six participants received ChAdOx1 and forty-two participants received BNT162b2 were enrolled into this study which evaluated the immune responses including anti-SARS-CoV-2 spike total antibodies (Elecsys®), surrogated viral neutralization test (sVNT) to ancestral strain (cPass™; GenScript) and five variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) (Luminex; multiplex sVNT) and the ELISpot with spike (S1 and S2) peptide pool against the ancestral SARS-CoV-2 strain. The samples were analyzed at baseline, 4, and 12 weeks after primary immunization as well as 4 and 12 weeks after receiving the booster. This study showed a significantly higher B-cell response among the BNT162b2 than the ChAdOx1 booster group, particularly against the Omicron variant, as well as a trend of good T-cell immune response in the BNT162b2 group. Moreover, the immune response rapidly declined at 12 weeks after the booster. A fourth dose or a second booster should be recommended, especially for reducing Omicron severity.

Osteoporosis is a common metabolic bone disease in patients with diabetes, which can develop simultane-ously with Type 2 diabetes (T2D) in postmenopausal women. Bisphosphonate (BP) is administered to pa-tients with both the conditions and may cause medication-related osteonecrosis of the jaws (MRONJ). It affects the differentiation and function of osteoclasts as well as thickness of cortical bone through bone mineralization. Therefore, this study aimed to investigate the effects of T2D on osteoclast differentiation and activity as well as cortical bone formation in postmenopausal patients with MRONJ. Tissue samples were collected from 10 patients diagnosed with T2D and Stage III MRONJ in the experimental group and from 10 patients without T2D in the control group. Histological examination was conducted, and expres-sion of dendritic cell-specific transmembrane protein (DC-STAMP) and tartrate resistant acid phosphatase (TRAP) was assessed. Cortical bone formation was analyzed using CBCT images. The number of TRAP-positive osteoclasts and DC-STAMP-positive mononuclear cells were significantly less in the experi-mental group (p < 0.05). Furthermore, the thickness and ratio of cortical bone were significantly greater in the experimental group (p < 0.05). In conclusion, T2D decreased the differentiation and function of osteo-clasts, and increased cortical bone formation in postmenopausal patients with MRONJ.

Abstract: (1) Background: tuberculosis presents an epidemiological trend towards inequality, especially among people in social exclusion and situations of vulnerability. To analyze territories where there is a concentration of people diagnosed with tuberculosis, in a street situation, and who make chronic use of alcohol, tobacco, and illicit drugs. We will also analyze trends in this health condition in southern Brazil; (2) Methods: Ecological study, developed in the 399 municipalities of Paraná, Southern Brazil, with all tuberculosis cases in the homeless population registered in the Information System of Notifiable Diseases between 2014 to 2018. For data analysis, we used descriptive statistics, for the time series, the Prais-Winsten autoregression method, whereas for spatial analysis, we used the Getis-Ord Gi technique*; (3) Results: in total, 560 cases were reported. We found a predominance of alcohol, smoking, and illicit drugs users, with an increasing trend in the state and clusters of spatial risk in the East health macro-region; (4) Conclusions: We observed territories with critical levels of highly vulnerable people who use psychoactive substances and are in a street situation. The results highlight the importance of incorporating public policies of social protection to these individuals and resolutive health services that receive and assist in eradicating TB.