A two phase survey of epilepsy was conducted in selected villages in Mundri West and East Counties (26 June−8 July, 2021), an onchocerciasis-endemic area in Western Equatoria State in South Sudan. In the first phase, households were visited by a trained research team to identify persons suspected to have epilepsy. In the second phase, persons suspected to have epilepsy were interviewed and examined by a clinician to confirm the diagnosis. A total of 364 households agreed to participate in the survey, amounting to 2,588 individuals. The epilepsy screening questionnaire identified 91 (3.5%) persons suspected to have epilepsy, of whom in 86 (94.5%) the diagnosis of epilepsy was confirmed by a clinician. The overall prevalence of confirmed epilepsy was 3.3% (95% CI: 2.7-4.1%), and of nodding syndrome 0.9% (95% CI: 0.6-1.4%). In 61 (16.8%) households there was at least one person with epilepsy. Only 1,212 (46.9%) of 2,583 people took ivermectin during the last distribution round in 2021. The annual epilepsy incidence was 77.3/100.000 (95% CI: 9.4-278.9/100,000) and the annual epilepsy mortality 251.2/100,000 (95% CI: 133.8-428.7/100,000). In conclusion, a high prevalence and incidence of epilepsy was observed in villages in Mundri. Urgent action is needed to prevent children from developing onchocerciasis-associated epilepsy by strengthening the local onchocerciasis elimination programme.

Background: Immunologic and neuro-inflammatory pathways have been found to play a major role in the pathogenesis of many neurological disorders such as epilepsy, proposing the use of novel therapeutic strategies. In the era of personalized medicine and in the face of the exhaustion of anti-seizure therapeutic resources it is worth looking at the current or future possibilities that neuroimmunomodulator or anti-inflammatory therapy can offer us in the management of patients with epilepsy. Methods: We performed a narrative review on the recent advances on the basic epileptogenic mechanisms related to the activation of immunity or neuroinflammation with special attention to current and future opportunities for novel treatments in epilepsy. Results: Neuroinflammation can be considered a universal phenomenon and occurs in structural, infectious, post-traumatic, autoimmune, or even genetically based epilepsies. The emerging research developed in recent years has allowed us to identify the main molecular pathways in-volved in these processes. These molecular pathways could constitute future therapeutic targets for epilepsy. Conclusions: Different drugs current or in development have demonstrated their capacity to inhibit or modulate molecular pathways involved in the immunologic or neuroinflammatory mechanisms described in epilepsy. Some of them should be tested in the future as possible antiepileptic drugs.

In this report, we describe the course and successful treatment of complicated infective endocarditis (IE). A patient presented with a high-grade irregular fever with chills lasting at least 2 months, dyspnoea, chest pain, fatigue, weight loss, and night sweats during the previous 3 months. Above cardiac congenital disorders, he was found to have Granulicatella adiacens infective aortic valve endocarditis, presumably transmitted from the oral cavity niche. Validated metagenomic 16S rDNA next generation sequencing was used to perform taxonomic identification, allowing for specific adequate antibiotic therapy instead of empiric therapy. This paper highlights the critical role of rapid taxonomic identification of nutritionally variant streptococci crucial and the benefit of proper IE treatment to avoid relapses or fatal complications.

Background: Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous cardiomyopathy characterized by a two-layered myocardium consisting of compacted and noncompacted segments, prominent ventricular trabeculations, and intertrabecular recesses. Patients with LVNC are at increased risk to develop heart failure, atrial and ventricular arrhythmias, and/or systemic thromboembolic events. Familial forms of primary sinus bradycardia have been attributed to mutations in HCN4. There are very few reports about the association between HCN4 mutations and LVNC. The aim of our study was to characterize the clinical phenotype of families with LVNC and sinus bradycardia caused by mutation of the HCN4 gene. Methods: From March 2008 to July 2021 we prospectively enrolled 6 patients from 4 families with diagnosed isolated LVNC based on the clinical presentation, family history and echocardiographic and cardiovascular magnetic resonance (CMR) evidence of LVNC. Next generation sequencing (NGS) analysis was undertaken for evaluation of the molecular basis of the disease in each family. Results: A total of 6 children (median age 11 years) were enrolled and followed prospectively for the median of 12 years. All 6 patients were diagnosed with LVNC by echocardiography and 5 participants additionally by CMR. The presence of LGE was found in 3 children. Sinus bradycardia and dilation of the ascending aorta occurred in 5 studied patients. In 4 patients from 3 families the molecular studies demonstrated the presence of rare heterozygous HCN4 mutations. Conclusion: (1) The HCN4 mutation influences the presence of a complex LVNC phenotype, sinus bradycardia and dilation of the ascending aorta. (2) HCN4 mutation may be associated with the early presentation of clinical symptoms and the severe course of the disease. (3) It is particularly important to assess myocardial fibrosis not only within the ventricles, but also in the atria in patients with LVNC and sinus bradycardia.

Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab were developed. The use of targeted drugs in clinical practice has significantly increased patients’ overall survival. To date, the emergence of several types of targeted drugs has opened new possibilities and revealed new prospects for mCRC treatment. Therapeutic strategies are continually being updated to select the most suitable targeted drugs based on the results of clinical trials that are currently underway. This review discusses the up-to date molecular evidence of targeted therapy for mCRC and summarizes the Food and Drug Administration-approved targeted drugs including the results of clinical trials. We also explain their mechanisms of action and how these affect the choice of a suitable targeted therapy.

Background: Membranous glomerulonephritis (MGN) is one of the most common causes of nephrotic syndrome in non-diabetic adults, accounting for up to one-third of biopsy diagnostics in some regions. A watchful waiting strategy has been adopted to accurately assess the success of MGN. In this study, we predict prognostic risk factors for primary MGN patients for effective intervention and prognosis. Materials and Methods: This is a retrospective study design involving 125 biopsy-proven MGN subjects on follow-up from January 2012 to October 2019 in Hospital Serdang and Hospital Kuala Lumpur, Malaysia. Result and Conclusion: After the median follow-up of 36 (15.0-57.0) months, 26 (20.8%) consisting of 17 (13.6%) primary MGN and 9 (7.2%) secondary MGN subjects achieved complete remission while 17 (13.6%) and 10 (8.0%) of primary and secondary MGN subjects respectively achieved spontaneous remission. Subjects with nephrotic range proteinuria have 2.917 odds more at risk of primary MGN while subjects with hypertension have 2.417 odds risk of primary MGN compared to those with no hypertension at presentation. Multiple logistic regression models retained only factors directly associated with MGN with only nephrotic range proteinuria associated with primary MGN. Those with nephrotic range proteinuria were 3.04 times the odds of primary MGN when compared with those without nephrotic syndrome (95% C. I = 1.089, 8.472). The nephrotic syndrome could be used to determine the prognosis in patients with primary MGN especially those at risk of end-stage kidney disease.

Purpose: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. Method: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e. the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. Results: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (>30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (<30.6%) N30-CTav group (P<0.001, 61.5% at 1 year). Conclusion: The cut-off value of 30.2 HU for CTav (N30-CTav) might be appropriate for identifying post-lenvatinib necrosis in HCC, and an N30-CTav occupancy rate of >30.6% might be a　predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.

Glaucoma is one of the most common causes of irreversible vision loss worldwide. It is an insidious disease with a multifactorial pathogenesis. Despite progress in treatment methods, prevention and lifestyle modifications may be useful in slowing the progression of this disease. This systematic review aimed to evaluate the influence of diet, oxidative stress, and disturbances in blood serum levels of nutrients on the incidence and severity of glaucoma based on scientific reports on the role of nutrition in the pathogenesis and course of glaucoma. This paper presents an analysis of the above issues; however, further research is required to develop this topic. Future clinical trials are needed to assess the influence of nutrition and to develop nutritional management strategies for patients with glaucoma.

We demonstrated the role of natural probiotics 3L, 3 Lactobacilli, in the establishment of a strong and sustainable beneficial healthy gut flora, after chemotherapy through experimental results through in vivo model. Using rat CTX model (immunosuppression induced by cyclophosphamide), we suggested some new adjuvant to chemotherapy as drugs + lactobacillus treament. Further, we proposed a new probiotic formulation (L. acidophilus + L. casei + L. plantarum) to be explored in the prevention of health condition loss by alteration of the general immune system, in numerous studies that reported the use of probiotics involving Lactobacillus in the post-chemo or post-surgical procedures. Here, in our study, Illumina MiSeq sequencing was used to generate sequencing data from microbial genomic DNA libraries, which is appreciable to check for the effects of 3L on bacteria. Microbiome analysis, phylogenetic and classification reports, community data have supported the experiments and the results where 3L had strong beneficial effects on the microbiome. Further, the influence on specific metabolic pathways are assisted in deriving the conclusion of the study (use of 3L for cancer therapy) to the mode of action, mechanistically by correcting microbiota composition and enhancing specific gut metabolic functions.

Objective tools to track medication adherence are lacking. A tool to monitor pill intake that can be implemented in mHealth apps without the need for additional devices was developed. We propose a pill intake detection tool that uses digital image processing to analyze images of a blister to detect the presence of pills. The tool uses the circular Hough transform as a feature extraction technique and is therefore primarily useful for the detection of pills with a round shape. This pill detection tool is composed of two steps. First, the registration of a full blister and storing of reference values in a local database. Second, the detection and classification of taken and remaining pills in similar blisters, to determine the actual number of untaken pills. In the registration of round pills in full blisters, 100% of pills in gray blisters or blisters with a transparent cover were successfully detected. In counting of untaken pills in partially opened blisters, 95.2% of remaining and 95.1% of taken pills were detected in gray blisters, while 88.2% of remaining and 80.8% of taken pills were detected in blisters with a transparent cover. The proposed tool provides promising results for the detection of round pills. However, the classification of taken and remaining pills need to be further improved, in particular for the detection of pills with non-oval shapes.

Improving access to sexual health services is critical in light of rising sexually transmitted infections (STIs). We evaluated a Hub and Spoke model for improving access to sexual health services in three general practices in Victoria, Australia. The primary outcome was the impact on HIV and STI (chlamydia, gonorrhoea, syphilis) testing. Segmented linear regression analysis was conducted to examine the trends in the total HIV/STI tests before (from January 2019 to June 2020) and post-implementation (from July 2020 to July 2021). We evaluated the feasibility and acceptability of integrating this model into the general practices using semi-structured individual interviews. There was a statistically significant rise in testing for HIV and STIs in all general practices: post-implementation, there was an increase of an average of 11.2 chlamydia tests per month (p=0.026), 10.5 gonorrhoea tests per month (p=0.001), 4.3 syphilis tests per month (p=0.010), and 5.6 HIV tests per month (p=0.010). Participants reported increases in knowledge level and confidence in offering STI testing and managing more variety of sexual health cases. This study demonstrated the feasibility of implementing a hub and spoke model to enable GPs to deliver sexual health care with support from a sexual health specialist service.

Background: The burden of resistant fungal infection is rising in patients with pulmonary disease. Options for antifungal therapy are limited, and the only orally-available antifungals, the triazoles, demonstrate inter and intra-patient variability, non-linear kinetics, toxicity, drug interactions and increasing antifungal resistance. Therapeutic drug monitoring (TDM) of itraconazole, voriconazole and posaconazole has been necessary to ensure their safety and efficacy, but is considered unnecessary for the newest triazole isavuconazole, use of which is increasing. Aims: To characterise isavuconazole susceptibility of Aspergillus fumigatus isolates in a tertiary respiratory referral centre to understand prevalence of isavuconazole antimicrobial resistance. To retrospectively review experience of isavuconazole use in this setting, assessing tolerability and therapeutic drug monitoring. Methods: A retrospective observational analysis of adult patients with respiratory disease in a tertiary hospital setting between Sept 2016 and Aug 2021. Clinical cultures were collected and triazole Minimum inhibitory concentration (MIC) were recorded (based on Clinical & Laboratory Standards Institute (CLSI method)). Isavuconazole trough drug levels were carried out as part of the standard of care. Clinical outcomes of treatment were evaluated, along with drug tolerance and TDM. Results: During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp isolates. 80.8% of Aspergillus fumigatus isolates were non-wild type and had isavuconazole MIC > 1mg/L, and 73.0% had MIC above the EUCAST (European Committee on Antimicrobial Susceptibility Testing) epidemiological cut-off (ECOFF) of 2mg/L. There was good correlation between isavuconazole MIC and voriconazole MIC (r =0.7, p=0.0002). 54 patients had isavuconazole therapy over the study period with a median duration of 7.7 months (IQR 0.79 - 16.42). 67% of patients were able to tolerate isavuconazole, despite toxicity with prior azole treatment being the primary indication for use (in 61.8%). Increased age (r=0.29; p=0.03 (95%CI 0.02,0.52)) and gender (r for female sex=-0.31; p=0.027 (95%CI -0.52,0.036) were associated risk factors for development of adverse events (AEs). 127 Isavuconazole TDM levels were performed over the study period with 90% >1mg/L and 72% >2mg/L. Dose change from manufacturer’s dose recommendation, however, was required in 15% of patients to achieve a serum drug concentration above the EUCAST ECOFF or Area of technical uncertainty (ATU) value of 2mg/L. Conclusion: In our study, we show use of Isavuconazole as salvage therapy in chronic pulmonary fungal disease setting with high prevalence of azole resistance. Isavuconazole MICs demonstrated good correlation with voriconazole MICs suggesting the latter could be a useful surrogate marker for isavuconazole susceptibility. Although Isavuconazole achieved excellent serum drug concentrations at standard dose compared to other azole drugs, we highlight the importance of antifungal stewardship and TDM monitoring to optimise therapy in this setting.

Cervical cancer is a public health issue with high disease burden and mortality in Brazil. The objectives of the present study were analyzing age, period, and cohort effects on cervical cancer mortality in women 20 years old or older from 1980 to 2019 in the North, South, and Southeast Regions of Brazil; and evaluating whether the implementation of a national screening program and the expansion of access to public health services caused impacts over the examined period and reduced the risk of death over the past years and among younger cohorts. The effects were estimated by applying Poisson regression models with estimable functions. The highest mortality rate by 100,000 women was found in Amazonas (24.13), and the lowest in São Paulo (10.56). A positive gradient was obtained for death rates as women’s age increased. The states in the most developed regions (South and Southeast) showed a reduction in the risk of death in the period that followed the implementation of the screening program and in cohort from the 1960s onwards. The North Region showed a decreased risk of death only in Amapá (2000–2004) and Tocantins (1995–2004; 2010–2019). The findings indicated that health inequities remain in Brazil and suggested that the health system has limitations regarding decreasing mortality associated with this type of cancer in regions with lower socioeconomic development.

One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways, however, the role of endothelial dysfunction and thrombosis have not been truly explored. This review aims to highlight the pathogenic mechanisms of these inflammatory triggers leading to thrombogenic complications. There are direct and indirect pathogenic pathways of the infection that are examined in detail. We also describe the case of carotid artery thrombosis in a patient following the SARS-CoV-2 infection, while reviewing the literature on the role of ACE2, the endothelium, and the different mechanisms by which SARS-CoV-2 may manifest both acutely and chronically. We also highlight differences from the other coronaviruses that have made this infection pandemic with similarities to the influenza virus.

Resumo: Este estudo teve como objetivo avaliar a Saúde Mental Positiva (SPM) e a sua relação com características sociodemográficas, literacia em saúde mental e escala de vulnerabilidade psicológica (PVS) em estudantes universitários portugueses com idades compreendidas entre os 17 e os 62 anos. Foi realizado um estudo descritivo-correlacional. Uma pesquisa online foi realizada para avaliar variáveis ​​demográficas, e vários questionários foram aplicados para avaliar saúde mental positiva, vulnerabilidade psicológica e alfabetização em saúde mental. Os dados foram coletados de 1º de novembro de 2019 a 1º de setembro de 2020. No geral, 3.405 alunos participaram do estudo. Os resultados mostram que 67,8% dos alunos revelaram um alto nível de PMH, 31,6% apresentaram um nível médio de PMH e 0,6% apresentaram um nível baixo de PMH. Os estudantes do sexo masculino relataram maior satisfação pessoal (t (3170) = -2,39, p=0,017) e autonomia (t (3170) = -3,33, p=0,001), no PMH em relação ao sexo feminino. Alunos sem bolsa pontuaram mais alto (t (3.127) = -2,04, p=0,42) no PMH do que alunos com bolsa. Estudantes que não foram deslocados de casa relataram maior (t (3170) = -1,99, p=0,047) Autocontrole em PMH do que aqueles deslocados de sua casa. Estudantes universitários com resultados de PMH mais altos têm resultados de PVS mais baixos e resultados de Alfabetização mais altos. Os achados deste estudo contribuirão para identificar as necessidades de intervenção dos alunos na PMH. Estudantes universitários com resultados de PMH mais altos têm resultados de PVS mais baixos e resultados de Alfabetização mais altos. Os achados deste estudo contribuirão para identificar as necessidades de intervenção dos alunos na PMH. Estudantes universitários com resultados de PMH mais altos têm resultados de PVS mais baixos e resultados de Alfabetização mais altos. Os achados deste estudo contribuirão para identificar as necessidades de intervenção dos alunos na PMH.

Background A decline in cardiovascular hospitalizations was observed during the initial phases of the COVID-19 pandemic. We examine the continued effect of the pandemic on cardiovascular hospitalizations and the associated mortality rates during the first year of the pandemic in Israel. Methods We conduct a retrospective cohort study using the data of Clalit Health Services, the largest healthcare organization in Israel. We divide the Corona year into six periods (three lockdowns and three post-lockdowns) and compare the incidence rates of cardiovascular hospitalizations and their 30-day mortality during each period to the previous three years. Results The number of non-STEMI hospitalizations during the first year of the pandemic was 13.7% lower than the average of the previous three years (95% CI 11%-17%); STEMI hospitalizations were 15.7% lower (95% CI 13%-19%); and CHF hospitalizations were 23.9% lower (95%, CI 21%-27%). No significant differences in 30-day mortality rates were observed for AMI patients during most of the periods, whereas the annual 30-day all-cause mortality rate of CHF was 23% higher. Conclusions Hospitalizations for AMI and CHF were significantly lower during the first year of the pandemic relative to 2017–9. Mortality rates were higher in the case of CHF patients but not in the case of AMI patients, possibly due a change in the clinical acuity of patients arriving at the hospitals. We conclude that targeted public health messaging should be implemented, together with proactive monitoring in order to identify residual disability in patients that may have received non-optimal treatment during the pandemic.

Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of perspective patients and stakeholders in health care. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions regarding the efficacy of this treatment modality. It is possible that a separate meta-analysis based on an independent, systematic assessment of clinical studies on the management of pkOA with stem cells may reach a different conclusion. Methods: PubMed, Web of Science and the Cochrane library were systematically searched for clinical studies and meta-analyses of clinical studies on the management of pkOA with stem cells. All clinical studies and meta-analyses identified were evaluated in detail, as were all sub-analyses included in the meta-analyses. Results: The inconsistent conclusions regarding the efficacy of treating pkOA with stem cells in the 19 assessed meta-analyses were most probably based on substantial differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the biology of stem cells. An independent, systematic review of the literature yielded a total of 183 studies, of which 33 were randomized clinical trials, including a total of 6860 patients with pkOA. However, it was not possible to perform a scientifically sound meta-analysis. Conclusion: Clinicians should interpret the results of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells with caution, and should be cautious of the conclusions drawn therein. Clinicians and researchers should strive to participate in FDA and/or EMA reviewed and approved clinical trials to provide clinically and statistically valid efficacy.

Background: Objectives were to determine the real-life effectiveness and safety of DT with dolutegravir (50 mg/QD) plus lamivudine (300 mg/QD) in multiple-tablet regimen (MTR) in naïve PLHIV followed up for 48 weeks and to evaluate the compliance and satisfaction of patients. Material and methods: Open, single-arm, multicenter, non-randomized clinical trial from May 2019 through September 2020 with 48-week follow-up. Results: The study included 88 PLHIV (91% male) with mean age of 35.9 years; 76.1% were MSM. Mean baseline CD4 was 516.4 cells/uL, with viral load (VL) of 104,828 cop/mL, and 11.4% were in AIDS stage. DT started within 7 days of first specialist consultation in all patients and the same day in 84.1%; 3.4% had baseline resistance mutations (K103N, V106I+E138A, and V108I); 12.5% were lost to follow-up. At week 48, 86.3% had VL< 50 cop/uL by intention-to-treat analysis and 98.7% by per-protocol (PP) analysis. Virological failure (VF) was recorded in 1.1%, with no resistance mutation. One blip was detected in 5.2%, without VF. Three reported anxiety, dizziness, and cephalgia, respectively, at week 4 and one insomnia at week 24; none reported adverse events at week 48. Mean weight was 4 kg higher at 48 weeks (p=0.0001) and abdominal circumference 3 cm larger at 24 weeks (p=0.022). No forgetfulness occurred in 98.7% of patients. Patient satisfaction was 90/100 at 4, 24, and 48 weeks. Conclusion: Real-world data demonstrate that dolutegravir plus lamivudine in MTR is effective, safe, and satisfactory, moderately increasing weight and abdominal circumference and administrable on a test-and-treat strategy.

Tobacco Free Nicotine (TFN) Electronic Nicotine Delivery Systems (ENDS) are yet to be classified as tobacco products; consequently, there is ambiguity over whether Food and Drug Administration (FDA) regulatory authority can be extended to include TFN e-cigarettes. In recent years, a more significant number of e-cigarette companies have been manufacturing TFN-containing e-cigarettes and e-liquids to circumvent FDA regulations. While studies have shown that aerosols generated from tobacco-derived nicotine-containing e-cigarettes contain significant Reactive Oxygen Species (ROS) levels, no comparison studies have been conducted using TFN e-cigarettes. This study uses a single puff aerosol generator to aerosolize TFN and tobacco-derived nicotine-containing vape-products and subsequently involves semi-quantifying ROS generated by these vape products in H2O2 equivalents. We found that the differences between ROS levels generated from TFN and tobacco-derived nicotine-containing vape products vary by flavor. TFN tobacco flavors and fruit flavors are more toxic in terms of ROS generation than menthol/ice and drink/beverage flavored products using TFN. The type of salt nicotine used in vape products, TFN or tobacco-derived nicotine, impacts the level of ROS generated from flavored vape products. Thus, a better understanding of the type of salt nicotine used in e-cigarettes (tobacco-derived or synthetic), has modulating effect on lung oxidative stress.

Atopic dermatitis (AD) is a chronic and allergic skin disease, however, there is no cure for the disease. Many studies have shown anti-AD potentials of red ginseng, while red ginseng marc (RGM) remained after the ginseng extraction is discarded as industrial waste. However, it is recently reported that RGM, particularly fermented RGM (fRGM), still contains the bioactive properties. Thus, anti-allergic effects of fRGM were examined in 2,4-dinitrochlorobenzene-induced AD-like mice model. The model was topically treated with distilled water (control), dexamethasone, or fRGM for six weeks. The treatments of fRGM alleviated the skin lesions and reduced serum IgE levels, compared with the control. The fRGM also reduced skin levels of lipid peroxidation and superoxide anion, however, increased glutathione contents, with down-regulated gene expressions for inflammatory mediators. The histopathological analyses demonstrated that fRGM suppressed the epidermal thickening, collagen deposition, and inflammatory cell and mast cell infiltration, which involved the anti-inflammatory, anti-oxidant, and anti-apoptotic effects. Further, fRGM suppressed hypertrophic changes and inflammatory responses in the spleen and lymph node. The beneficial effects were observed in the dexamethasone and fRGM groups, however, the antioxidant effects were evident only in the fRGM treatments. These provide useful information for developing fRGM as therapeutic sources for AD.

The aim was to analyze the coping strategies used by primary health care (PHC) professionals. A cross-sectional, descriptive-analytical study was conducted with professionals working in primary health care units in São José do Rio Preto, a large city in the interior of São Paulo, Brazil. For data collection we used an instrument developed by the researchers, containing sociodemographic and professional variables, as well as the Problem Coping Modes Scale (EMEP). We evaluated 333 PHC professionals. A difference was observed between the scores of the four coping strategies (p<0.001), with the highest score for the problem-focused strategy (3.8) and the lowest score for the emotion-focused strategy (2.4). Physicians had the lowest scores in coping strategies focused on religious practices/fantastical thinking (p<0.001) and pursuit of social support (p=0.045), while community health agents had the highest scores in these coping strategies). Professionals working in PHC have different coping strategies for the problems and stressful situations experienced in the work environment. These strategies can involve more positive attitudes focused on confrontation and problem solving, to emotional responses that involve attitudes of avoidance and denial that involve attitudes of avoidance and denial of the problem.

Schistosomiasis is a parasitic disease acquired through contact with contaminated freshwater. The definitive hosts are terrestrial mammals, including humans, with some Schistosoma species crossing the animal-human boundary through zoonotic transmission. An estimated 12 million people live at risk of zoonotic schistosomiasis caused by Schistosoma japonicum and Schistosoma mekongi, largely in the World Health Organization’s Western Pacific Region and in Indonesia. Mathematical models have played a vital role in our understanding of the biology, transmission, and impact of intervention strategies, however, these have mostly focused on non-zoonotic Schistosoma species. Whilst these non-zoonotic-based models capture some aspects of zoonotic schistosomiasis transmission dynamics, the commonly-used frameworks are yet to adequately capture the complex epi-ecology of multi-host zoonotic transmission. However, overcoming these knowledge gaps goes beyond transmission dynamics modelling. To improve model utility and enhance zoonotic schistosomiasis control programmes, we highlight three pillars that we believe are vital to sustainable interventions at the implementation (community) and policy-level, and discuss the pillars in the context of a One-Health approach, recognising the interconnection between humans, animals and their shared environment. These pillars are: (1) human and animal epi-ecological understanding; (2) economic considerations (such as treatment costs and animal losses); and (3) sociological understanding, including inter- and intra-human and animal interactions. These pillars must be built on a strong foundation of trust, support and commitment of stakeholders and involved institutions.

Acetaminophen use during pregnancy and early childhood was accepted in the 1970s, but is now a subject of considerable concern. Careful analysis shows that initial acceptance of the drug was based on false assumptions and ignorance of the impact of the drug on brain development. Fourteen studies now indicate that prenatal exposure to acetaminophen is associated with neurodevelopmental problems. Based on corrections for confounding factors applied to the analyses of available data, it can be concluded that prenatal exposure to acetaminophen causes statistically significant risks of one subtype of autism spectrum disorder (ASD), developmental delays, and attention deficit hyperactivity disorder. In contrast, data regarding postnatal exposure to acetaminophen are limited, and several factors impede a classic multivariate analysis of data to resolve the issue. However, circumstantial evidence regarding postnatal exposure to the drug is abundant, and it can be concluded beyond a reasonable doubt that postnatal exposure to acetaminophen in susceptible children is responsible for many if not most cases of ASD. Circumstantial evidence includes at least three otherwise unexplained temporal relationships, data from laboratory animal studies, several miscellaneous and otherwise unexplained correlations, and the lack of alternative suspects that fit the evidence-derived profile.

Urinary tract infections (UTIs) are very frequent in women and can be caused by a range of pathogens. High recurrence rates and increasing antibiotic resistance of uropathogens make UTIs a severe public health problem. d-mannose is a monosaccharide that can inhibit bacterial adhesion to the urothelium after oral intake. Several clinical studies have shown the efficacy of d-mannose in the prevention of recurrent UTI; these also provided limited evidence for the efficacy of d-mannose in acute therapy. A recent prospective, non-interventional study in female patients with acute cystitis reported good success rates for treatment with d-mannose. Here we present data from a post-hoc analysis of this study to compare the cure rate of d-mannose monotherapy with that of antibiotics. The results show that d-mannose is a promising alternative to antibiotics in the treatment of acute uncomplicated UTIs in women.

The problem of filling the bone cavity remains relevant in maxillofacial and oral surgery. There is a large selection of osteotropic materials of various natures for filling of bone defects of different etiology. The aim of our research was to improve the result of surgical treatment in a patient with a complicated mandibular fracture with the use of collagenic xenograft during osteosynthesis. In this article, we introduce our experience in the treatment of a patient with a complicated mandibular angle fracture in a combination with the follicular cyst. The obligate steps of treatment included stabilization of the bony fragments, a decrease of risk in fracture line malposition along with titan mini- plates, and shortening in the time of bone regeneration due to a filling of bone defect with the osteotropic material. This approach allowed us to reduce the rehabilitation period and further prosthetic treatment after 4-5 months without additional bone grafting manipulations. Though, the use of collagen osteotropic material, possessing osteoconductive properties, can improve the treatment of patients with mandibular fractures.

Resistance to Pyrimethamine, an antimalarial medicine has been reported to be due to mutations in Dihydrofolate reductase-thymidylate synthase (DHFR-TS). Phytochemicals, particularly from plants that been used in ethnomedicine, have been reported to have privileged structures that might bind strongly to the mutants of DHFR-TS. The aim of this study is to identify phytochemicals of Acalypha wilkesiana, Cymbopogon citratus, Azadirachta indica, and Morinda lucida with high binding affinities for the Plasmodium falciparum DHFR-TS. The three-dimensional structures of the phytochemicals, wide type and mutant forms of DHTR-TS were obtained from PubChem and Protein Databank (PDB) respectively. They were appropriately prepared and molecular docking simulations was implemented to predict binding affinities of the phytochemicals to the wildtype and mutant forms of DHTR-TS. Druglikeness assessment was implemented to triage the top binding phytochemicals and molecular dynamics simulations was done to establish the stability of the interaction of the top-ranked phytochemical with one of the mutants of DHFR-TS. Nineteen phytochemicals showed higher binding affinities to both the wild type and mutant forms DHFR-TS than Pyrimethamine. Molecular dynamics revealed that the receptor-ligand binding of luteolin, the top-ranked, drug like phytochemicals, to the quadruple mutant was stable.

Context: Persea Americana is reported to have medicinal value. Calcium Carbide (CaC2), a fruit-ripening agent, has been shown to be toxic to body organs. Objective: To determine the effect of avocado seed extract (ASE) on CaC2-induced hepatotoxicity in rats. Methodology: Four experimental groups, each of 5 adult wistar rats were fed respectively with normal diets (group A); 250mg/kg ASE (group B); 100mg/kg CaC2 (group C); combination of 100mg/kg CaC2 and 250mg/kg ASE – group D. Changes in the rats’ behaviours, body weights, and liver function were assessed over 21 days. Data were analyzed using SPSS. The cumulated rat weights, rat liver weights and serum liver enzyme levels for groups B, C, and D rats were compared to group A. Results: Abnormal behavior was most observed in group C rats. Rats in group A showed a significant increase in weight before and three weeks following administration of feeds while rats in groups B, C, and D showed significant decrease in weight – more marked in group C rats. Only the mean liver weights of rats in group C showed significant decrease compared to that in group A, p = 0.001. Similarly, only the cumulated liver enzyme levels of rats in group C demonstrated significant increase when compared to group A rats - indicating hepatotoxicity. Conclusion In this study, hepatotoxicity occurred in CaC2-administered rats. However, the combination of CaC2 and ASE showed no liver toxicity indicating a mitigating effect of ASE to CaC2-induced hepatotoxicity.

Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare cancers consisting of neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs), which have been increasing in incidence in recent years. Few cell lines and pre-clinical models exist for the study of GEP NECs and NETs, limiting the ability to discover novel imaging and treatment modalities. To address this gap, we isolated tumor cells from cryopreserved patient GEP NECs and NETs and injected them into the flanks of immunocompromised mice to establish patient-derived xenograft (PDX) models. Two of 6 mice developed tumors (NEC913 and NEC1452). Over 90% of NEC913 and NEC1452 tumor cells stained positive for Ki67. NEC913 PDX tumors expressed neuroendocrine markers such as chromogranin A (CgA), synaptophysin (SYP), and somatostatin receptor-2 (SSTR2) whereas NEC1452 PDX tumors do not express SSTR2. Exome sequencing revealed loss of p53 and RB1 in both tumors. To demonstrate an application of these novel NEC PDX models for SSTR2-targeted peptide imaging, the NEC913 and NEC1452 cells were bilaterally injected into mice. Near infrared-labelled octreotide was administered and fluorescent signal was specifically observed for the NEC913 SSTR2 positive tumors. These 2 GEP NEC PDX models serve as valuable resource for GEP NEN therapy testing.

Leisure-time physical activity (LTPA) is associated with access and use of public open spaces. The “President João Goulart Elevated Avenue” and current denominated “Minhocão” is a facility for leisure activities that are open for people during the night/weekends. The aim of this study was to examine if the prevalence of LTPA among individuals living in the surroundings of Minhocão is different according to proximity to, and use of, the facility. We conducted a cross-sectional study with cluster sampling with people aged ≥18 years who lived in households until 500m and between 501m to 1500m of Minhocão. The survey was conducted between December/2017 until March/2019 with an electronic questionnaire self-responded. We conducted bivariate analysis and Poisson regression to examine possible differences in LTPA according to the proximity of residences and use of Minhocão. The analysis used post-stratification weights. A total of 12,030 telephone numbers of people were drawn (≤500m = 6,942; and &gt;500m to ≤1500m = 5,088). The final sample analyzed were of 235 residents who returned the questionnaires. There was a higher prevalence of individuals engaging in at least 150 minutes per week of LTPA among users than non-users (Prevalence Ratio=2.23, IC95%1.72-2.90). People who used the park had higher prevalence of all types of LTPA than non-users. The results can serve to inform government decision-making on the future of Minhocão.

Global malaria epidemiology has changed in the last decade with a substantial increase in cases and death being recorded. Over 90% of global cases and deaths occur in Sub-Saharan Africa (SSA). Tanzania accounts for about 4% of all cases and deaths reported in recent years. It is believed that several factors contribute to the resurgence of malaria, parasite resistance to antimalarials and mosquito resistance to insecticides being at the top of the list. The presence of sub-microscopic infections poses a significant challenge to malaria rapid diagnostic tests (mRDT), particularly in low-endemic areas. Our cross-sectional surveys in Handeni and Moshi, Tanzania assessed the effect of low parasite density on mRDT. A significant difference (P˂0.001) in malaria prevalence by mRDT, light microscopy (LM) and nested polymerase chain reaction (PCR) was found among age groups. In comparison to all other groups, school-age children (5-15 years) had the highest prevalence of malaria. Based on the results of this study, mRDT may miss up to 6% of cases of malaria mainly due to low-density parasitaemia. Routinely used mRDT will likely miss the sub-microscopic parasitemia which will ultimately contribute to the continued spread of malaria and hinder efforts to control and eliminate it.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of cardiotoxicity post-chemotherapeutic exposure, assess how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and discuss its role as a mediator of cardiomyopathy. We highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac re-modeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to plasticity and differential regulation these populations remain difficult to target and persist as a major barrier barring successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through inhibiting cardiomyopathy, cardiac damage and heart failure may be prevented and through CSC targeting, patient prognosis may be improved. Together, both approaches, if successfully implemented would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.

Background: The aim of the present study was to determine the correlation between obesity, serum levels of leptin and proximal gastric cancer. Methods: Sixty-four gastric cancer patients operated on with curative intent were included in the study. We determined the correlation between the preoperative serum levels of leptin and the tumor`s location. Results: Serum leptin levels were correlated significantly with the proximal third location (p = 0.04), gastric outlet obstructing tumors (p < 0.0001), CRP levels (p = 0.03) and BMI (p < 0.0001). Patients with high serum levels of leptin had significantly more intestinal types of gastric cancer (p = 0.033) and better differentiation compared to patients with low serum leptin levels (p = 0.009). The linear regression model determined the proximal tumor location (beta: 0.467; p = 0.045), BMI (beta: 0.657; p = 0.001), high preoperative serum albumin (beta: 0.563; p = 0.016) and the presence of pyloric stenosis (beta: 0.525; p = 0.006) as related significantly to serum leptin levels. The Cox proportional hazard model identified age (HR: 0.003; 95%CI: 0-0.794; p = 0.041), preoperative serum levels of leptin (HR: 0.125; 95%CI: 0.018-0.887; p = 0.037) and the number of extracted LNs (HR: 0.001; 95%CI: 0-0.677; p = 0.038) as independent prognostic factors. Conclusions: Serum levels of leptin were significantly elevated in patients with proximal gastric cancer, suggesting that the leptin`s effect might be due to its systemic secretion. This might explain the higher incidence of proximal gastric cancer in obese patients. Elevated serum leptin levels were an independent prognostic factor.

Background: Continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel infusion (LCIG), and deep brain stimulation of the subthalamic nucleus (STN-DBS) have markedly changed the treatment landscape of advanced Parkinson’s disease (aPD). Despite a similar outcome of all device-aided therapies (DATs), some patients switch or combine DATs. The aim of this retrospective study was to explore the frequency and reasons for switching between or combining DATs in two movement disorders centres in Slovenia and Israel. Methods: We collected and analysed demographic and clinical data from aPD patients who switched between or combined DATs. Motor and non-motor reasons and their frequency for switching/combining were examined, as was the effect of DAT using the Global Improvement subscale of the Clinical Global Impression Scale. Non-parametric tests were used to analyse the data. Results: Of 505 aPD patients treated with DATs at both centres between January 2009 and June 2021, we identified in total 30 patients (6%), who either switched DAT (N=24: 7 LCIG-to-STN-DBS, 1 LCIG-to-CSAI, 5 CSAI-to STN-DBS, 8 CSAI-to-LCIG, 1 STN-DBS-to-LCIG, 1 LCIG-to-CSAI-to-STN-DBS, and 1 STN-DBS-to-CSAI-to-LCIG) or combined DATs (N=6: 5 STN-DBS+LCIG and 1 STN-DBS+CSAI-to-STN-DBS+LCIG). In most of these patients, inadequate control of motor symptoms was the main reason for switching or combining DATs, but non-motor reasons (related to the disease and/or DAT) were also identified. Conclusions: Switching between and combining DATs is uncommon, but in some patients brings substantial clinical improvement and should be considered in those who have either inadequate symptom control on DAT treatment or have developed DAT related complications.

This review of the meaningful data from 2021 on cervical, endometrial, and ovarian cancers aims to provide an update of the most clinically relevant studies presented at important oncologic congresses during the year [the American Society of Clinical Oncology (ASCO) Annual Meeting, the European Society for Medical Oncology (ESMO) Congress and the Society of Gynecologic Oncology (SGO) Annual Meeting]. Despite the underlying existence of the COVID-19 pandemic, the last year has been notable in terms of research, with significant and promising advances in gynecologic malignancies. Several major studies reporting the effects of innovative therapies for patients with cervical, endometrial, and ovarian cancers might change the medical practice in the future.

Abstract—Low-frequency Fahræus–Lindqvist-driven (not blood pressure-driven) oscillations in the small vessels are crucial because oscillations in small vessels support nutrient supply. Understanding of this is critical in type 2 diabetes mellitus (T2DM) to develop therapeutic measures to prevent Alzheimer's Disease Related Dementias: vascular factors contribute to cerebrovascular disease as well as mild cognitive impairment and dementia, which are predicted to affect 152 million people by 2050 (Alzheimer's Disease International London, UK, 2019). In this clinical study, we performed functional near-infrared spectroscopy (fNIRS) of the forehead to investigate the effect of the Mini-Cog with three-item recall test on the prefrontal cortex (PFC) activation and the relative oscillatory power in the 0.01–0.02-Hz (Fahræus–Lindqvist effect) and 0.021–0.052 Hz (smooth muscle autonomic innervation) frequency bands in elderly (60 years and older) T2DM and age-matched controls. We found a significant (p<0.01) difference in the PFC activation between elderly subjects with T2DM and age-matched elderly controls. Moreover, power spectral density (PSD) analysis revealed a significantly lower relative power in 0.021–0.052 Hz (smooth muscle autonomic innervation) frequency band in elderly subjects with T2DM during the Mini-Cog three-item recall test. Furthermore, a drop in the oscillatory power in the 0.01–0.02-Hz frequency band during Mini-Cog three-item recall test was found more pronounced in the elderly subjects with T2DM. Therefore, our study highlighted portable brain imaging to capture cerebrovascular reactivity to cognitive load that may provide a biomarker of cerebrovascular dysfunction in T2DM.Clinical Relevance— Our study establishes forehead portable brain imaging for monitoring cerebrovascular function in T2DM under cognitive load.

Fungi kingdom comprises ubiquitous forms of life with 1.5 billion years, mostly phytopathogenic and commensal for humans and animals. However, in the presence of impaired conditions fungi may cause disease by intoxicating, infecting or sensitizing with allergy. Different genera may be implicated as etiological agents for humans and animals, with Alternaria, Aspergillus, dermatophytes like Microsporum and Trichophyton, and Malassezia as the commonly implicated. Alternaria and Malassezia stand as the most commonly associated to either allergy or infection, immediately followed by Aspergillus, while dermatophytes are usually associated to ring worm skin infection. Research in veterinary field is not much but necessary.

The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this contribution, this recent oncological perspective has been laterally for the first time in order to integrate neurodegeneration within the energetics of the cancer acid-base conceptual frame. At all levels of study, molecular, biochemical, metabolic and clinical, the intimate nature of both processes appears to be opposite mechanisms occurring at the far ends of a physiopathological intracellular pH/extracellular pH (pHi/pHe) spectrum. This wide-ranged original approach now permits an increase in our understanding of these opposite processes, cancer and neurodegeneration, and, as a consequence, allows to propose new avenues of treatment based upon the intracellular and microenvironmental hydrogen ion dynamics regulating and deregulating the biochemistry and metabolism of both cancer and neural cells. Under the same perspective, the etiopathogenesis and special characteristics of multiple sclerosis (MS) becomes an excellent model for the study of neurodegenerative diseases and, utilizing this pioneering approach, we find that MS appears to be a metabolic disease even before an autoimmune one. Also within this paradigm, several important aspects of MS, from mitochondrial failure to microbiota functional abnormalities, are analyzed in depth.

Urinary tract infections (UTIs) remain one of the most important problems of modern urology and medicine. Infections bring great discomfort and significantly reduce the quality of life. UTIs rank second after respiratory tract infections in outpatients. The most common pathogen of UTI are E.coli. The study of the etiology of UTI has great clinical and epidemiological importance in routine practice. Objective: To assess the etiological significance of pathogens in the occurrence of urinary tract infections in the Karaganda region of Kazakhstan. Methods: A total of 2378 patients presenting UTIs were enrolled and each provided a urine sample. The study was carried out in the Clinical Microbiology Laboratory MediTEC-NS between 2 January and 29 December 2018. Identification of isolated microorganisms was carried out on a WalkAway 96 Plus microbiological analyzer, Microscan model manufactured by Beckman Coulter (USA). Statistical Analysis was performed using the STATISTICA-6 package. Results: Out of 2378 patients a total of 1177 (49,5%) urine samples tested positive by culture test. From these samples, 1356 strains of microorganisms were isolated, of which 84.79% were monoculture and 21% were of a mixed culture. Gram-positive bacteria 690 (50, 88%), Gram-negative bacteria 630 (46, 46%), and Candida 36 (2.65%) were identified. Gram-negative rods were represented by Enterobacterales 557 (88.41%) and non-fermenting bacteria 73 (11.59%). In the Enterobacterales group included Escherichia coli 371 (66.61%) of which 108 (29,1%) ESBL strains. The next etiologically significant uropathogens were Klebsiella- 99 (17, 77%), Enterobacter-36 (6,46%) and Proteus-32 (8,09). K.pneumoniae prevailed in comparison with other Klebsiella spp. ESBL producing was 34 (57, 6%) out of 59 K.pneumoniae isolates. Gram-negative non-fermenting rod were represented by Acinetobacter spp-34 (46.57%) and Pseudomonas spp 31 (42.47%). Of 34 Acinetobacter spp. isolates 22 (64.7%) were identified as Acinetobacter lwoffii. Among the gram-positive pathogens of UTI, Staphylococcus spp prevailed - 411 (59.57%), followed by Enterococcus spp 197 (28.55%) and Streptococcus spp 81 (11.73%). Coagulase-negative staphylococci 381 (92,7%) isolates out of total 411 staphylococcal isolates. Staphylococcus epidermidis 245 (59,61%) and Staphylococcus haemolyticus 81 (21,17%) were the most frequent isolated coagulase-negative staphylococci. Of 411 staphylococcal isolates, 182 (44.28%) were MRS Conclusion: We found that UTIs among our study population were predominantly caused by ten opportunistic pathogens. The most common uropathogens with a frequency of 66.9% were E. coli- 30.53%, S. epidermidis -20.16%, and Enterococcus spp. -16.21%. Frequently isolated pathogens included Klebsiella, S. haemolyticus spp., and Streptococcus spp. which amounted to 21.98%. The distribution within the patient group was equable and ranged from 6,67% to 8,15%. Etiologically significant pathogens included Enterobacter spp., Proteus spp., Acinetobacter spp., Pseudomonas spp. These bacteria accounted for 11.11%. The distribution within the group was again equable and ranged within 2,55% to 2,96%.

Amyotrophic lateral sclerosis (ALS) is also called "motor neuron disease”. In this review, we propose that ALS is not just a neuromotor disorder, but begins as a disorder of P53-modulated skeletal muscle metabolism, leading to failures at the energy state of the cells, incorrect redox states, motor denervation, and a loss of muscle fibers. Motoneurons die as a consequence of the lack of muscular feedback, and the oligomeric TDP43 aggregates progressively and relentlessly lead to mistakes in peripheral immune self-tolerance sustained over time. An effective treatment has not been found for this devastating pathology, as for 152 years the target has not been accurately defined. Scientists and doctors should consider new knowledge regarding ALS and consider immunomodulatory therapies that, based on genetic analysis and symptoms, can be combined with compounds that regulate metabolism and promote the elimination of useless organelles and cells. What if ALS could be cured as a result of seeing motor neuron disease differently? This review aims to develop that goal and change the paradigm of our understanding of ALS.

Following the introduction of live-attenuated rotavirus vaccines in many countries, a notable reduction in deaths and hospitalizations associated with diarrhoea in children <5 years of age has been reported. There is growing evidence to suggest that live-attenuated vaccines also provide protection against other infections beyond the vaccine-targeted pathogens. These so called off-target effects of vaccination have been associated with the tuberculosis vaccine Bacille Calmette Guérin (BCG), measles, oral polio and recently salmonella vaccines, and are thought to be mediated by modified innate and possibly adaptive immunity. Indeed, rotavirus vaccines have been reported to provide greater than expected reductions in acute gastroenteritis caused by other enteropathogens, that have mostly been attributed to herd protection and prior underestimation of rotavirus disease. Whether rotavirus vaccines also alter the immune system to reduce non targeted gastrointestinal infections has not been studied directly. Here we review the current understanding of the mechanisms underlying off-target effects of vaccines and propose a mechanism by which the live-attenuated neonatal rotavirus vaccine, RV3-BB, could promote protection beyond the targeted pathogen. Finally, we consider how vaccine developers may leverage these properties to improve health outcomes in children, particularly those in low-income countries where disease burden and mortality is disproportionately high relative to developed countries.

Positron-emission tomography is powerful but costly tool for various medical investigations. In particular, it is used in Parkinson’s disease and essential tremor diagnostics. However, yet there is no standardized figures of the references, for it. We examined the PET efficiency for the analysis of development and degradation of dophaminergic neurons in Parkinson’s disease. The informative indices are determined from the observed PET data. Also, high efficiency of PET for Parkinson’s disease as approved.

Introduction: Urinary tract infections (UTIs) remain one of the most important problems of modern urology and medicine. Infections bring great discomfort and significantly reduce the quality of life. UTIs rank second after respiratory tract infections in outpatients. The most common pathogen of UTI are E.coli. The study of the etiology of UTI has great clinical and epidemiological importance in routine practice.Objective: To assess the etiological significance of pathogens in the occurrence of urinary tract infections in the Karaganda region of Kazakhstan.Methods: A total of 2378 patients presenting UTIs were enrolled and each provided a urine sample. The study was carried out in the Clinical Microbiology Laboratory MediTEC-NS between 2 January and 29 December 2018. Identification of isolated microorganisms was carried out on a WalkAway 96 Plus microbiological analyzer, Microscan model manufactured by Beckman Coulter (USA). Statistical Analysis was performed using the STATISTICA-6 package.Results: Out of 2378 patients a total of 1177 (49,5%) urine samples tested positive by culture test. From these samples, 1356 strains of microorganisms were isolated, of which 84.79% were monoculture and 21% were of a mixed culture. Gram-positive bacteria 690 (50, 88%), Gram-negative bacteria 630 (46, 46%), and Candida 36 (2.65%) were identified. Gram-negative rods were represented by Enterobacterales 557 (88.41%) and non-fermenting bacteria 73 (11.59%). In the Enterobacterales group included Escherichia coli 371 (66.61%) of which 108 (29,1%) ESBL strains. The next etiologically significant uropathogens were Klebsiella- 99 (17, 77%), Enterobacter-36 (6,46%) and Proteus-32 (8,09). K.pneumoniae prevailed in comparison with other Klebsiella spp. ESBL producing was 34 (57, 6%) out of 59 K.pneumoniae isolates. Gram-negative non-fermenting rod were represented by Acinetobacter spp-34 (46.57%) and Pseudomonas spp 31 (42.47%). Of 34 Acinetobacter spp. isolates 22 (64.7%) were identified as Acinetobacter lwoffii. Among the gram-positive pathogens of UTI, Staphylococcus spp prevailed - 411 (59.57%), followed by Enterococcus spp 197 (28.55%) and Streptococcus spp 81 (11.73%). Coagulase-negative staphylococci 381 (92,7%) isolates out of total 411 staphylococcal isolates. Staphylococcus epidermidis 245 (59,61%) and Staphylococcus haemolyticus 81 (21,17%) were the most frequent isolated coagulase-negative staphylococci. Of 411 staphylococcal isolates, 182 (44.28%) were MRSConclusion: We found that UTIs among our study population were predominantly caused by ten opportunistic pathogens. The most common uropathogens with a frequency of 66.9% were E. coli- 30.53%, S. epidermidis -20.16%, and Enterococcus spp. -16.21%. Frequently isolated pathogens included Klebsiella, S. haemolyticus spp., and Streptococcus spp. which amounted to 21.98%. The distribution within the patient group was equable and ranged from 6,67% to 8,15%. Etiologically significant pathogens included Enterobacter spp., Proteus spp., Acinetobacter spp., Pseudomonas spp. These bacteria accounted for 11.11%. The distribution within the group was again equable and ranged within 2,55% to 2,96%.

Abstract Introduction: Urinary tract infections (UTIs) remain one of the most important problems of modern urology and medicine. Infections bring great discomfort and significantly reduce the quality of life. UTIs rank second after respiratory tract infections in outpatients. The most common pathogen of UTI are E.coli. The study of the etiology of UTI has great clinical and epidemiological importance in routine practice. Objective: To assess the etiological significance of pathogens in the occurrence of urinary tract infections in the Karaganda region of Kazakhstan. Methods: A total of 2378 patients presenting UTIs were enrolled and each provided a urine sample. The study was carried out in the Clinical Microbiology Laboratory MediTEC-NS between 2 January and 29 December 2018. Identification of isolated microorganisms was carried out on a WalkAway 96 Plus microbiological analyzer, Microscan model manufactured by Beckman Coulter (USA). Statistical Analysis was performed using the STATISTICA-6 package. Results: Out of 2378 patients a total of 1177 (49,5%) urine samples tested positive by culture test. From these samples, 1356 strains of microorganisms were isolated, of which 84.79% were monoculture and 21% were of a mixed culture. Gram-positive bacteria 690 (50, 88%), Gram-negative bacteria 630 (46, 46%), and Candida 36 (2.65%) were identified. Gram-negative rods were represented by Enterobacterales 557 (88.41%) and non-fermenting bacteria 73 (11.59%). In the Enterobacterales group included Escherichia coli 371 (66.61%) of which 108 (29,1%) ESBL strains. The next etiologically significant uropathogens were Klebsiella- 99 (17, 77%), Enterobacter-36 (6,46%) and Proteus-32 (8,09). K.pneumoniae prevailed in comparison with other Klebsiella spp. ESBL producing was 34 (57, 6%) out of 59 K.pneumoniae isolates. Gram-negative non-fermenting rod were represented by Acinetobacter spp-34 (46.57%) and Pseudomonas spp 31 (42.47%). Of 34 Acinetobacter spp. isolates 22 (64.7%) were identified as Acinetobacter lwoffii. Among the gram-positive pathogens of UTI, Staphylococcus spp prevailed - 411 (59.57%), followed by Enterococcus spp 197 (28.55%) and Streptococcus spp 81 (11.73%). Coagulase-negative staphylococci 381 (92,7%) isolates out of total 411 staphylococcal isolates. Staphylococcus epidermidis 245 (59,61%) and Staphylococcus haemolyticus 81 (21,17%) were the most frequent isolated coagulase-negative staphylococci. Of 411 staphylococcal isolates, 182 (44.28%) were MRS Conclusion: We found that UTIs among our study population were predominantly caused by ten opportunistic pathogens. The most common uropathogens with a frequency of 66.9% were E. coli- 30.53%, S. epidermidis -20.16%, and Enterococcus spp. -16.21%. Frequently isolated pathogens included Klebsiella, S. haemolyticus spp., and Streptococcus spp. which amounted to 21.98%. The distribution within the patient group was equable and ranged from 6,67% to 8,15%. Etiologically significant pathogens included Enterobacter spp., Proteus spp., Acinetobacter spp., Pseudomonas spp. These bacteria accounted for 11.11%. The distribution within the group was again equable and ranged within 2,55% to 2,96%.

Background: Low-dose aspirin (LDA) is the backbone for secondary prevention of coronary artery disease, though limited by gastric toxicity. This study was aimed to identify novel metabolites that could predict LDA-induced gastric toxicity using pharmacometabolomics. Methods: Pre-dosed urine samples were collected from male Sprague-Dawley rats. The rats were treated with either LDA (10 mg/kg) or 1% methylcellulose (10 ml/kg) per oral for 28 days. The rats' stomachs were examined for gastric toxicity using a stereomicroscope. The urine samples were analyzed using a proton nuclear magnetic resonance spectroscopy. Metabolites were systematically identified by exploring established databases and multivariate analyses to identify the spectral pattern of metabolites related to LDA-induced gastric toxicity. Results: Treatment with LDA resulted in gastric toxicity in 20/32 rats (62.5%). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) model displayed a goodness-of-fit (R2Y) value of 0.947, suggesting a near-perfect reproducibility, a goodness-of-prediction (Q2Y) of -0.185 with perfect sensitivity, specificity and accuracy (100%). Furthermore, the area under the receiver operating characteristic (AUROC) displayed was 1. The final OPLS-DA model had an R2Y value of 0.726 and Q2Y of 0.142 with sensitivity (100%), specificity (95.0%) and accuracy (96.9%). Citrate, hippurate, methylamine, trimethylamine N-oxide and alpha-keto-glutarate were identified as the possible metabolites implicated in the LDA-induced gastric toxicity. Conclusion: The study identified metabolic signatures that correlated with the development of a low dose Aspirin-induced gastric toxicity in rats. This pharmacometabolomic approach could further be validated to predict LDA-induced gastric toxicity in patients with coronary artery disease.

Anterior segment dysgenesis (ASD) encompasses a wide spectrum of developmental abnormalities of the anterior ocular segment, including congenital cataract, iris hypoplasia, aniridia, iridocorneal synechiae, as well as Peters, Axenfeld, and Rieger anomalies. Here, we report a large five-generation Caucasian family exhibiting atypical syndromic ASD segregating with a novel truncating variant of FOXC1. The family history is consistent with highly variable autosomal dominant symptoms including isolated glaucoma, iris hypoplasia, aniridia, cataract, hypothyroidism, congenital heart anomalies, and cystic kidney disease. Whole exome sequencing revealed a novel variant [c.313_314insA; p.(Tyr105*)] in FOXC1 that disrupts the alpha-helical region of the DNA-binding forkhead box domain. In vitro studies using a heterologous cell system revealed aberrant cytoplasmic localization of FOXC1 harboring the Tyr105* variant, likely precluding downstream transcription function. Meta-analysis of the literature highlighted the intrafamilial variability related to FOXC1 truncating alleles. This study highlights the clinical variability in ASD and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis.

Biosecurity is a tool used to alleviate the introduction, emergence and spread of diseases caused by infectious agents. It comprises different health-management activities that need to be followed to reduce the passage and dissemination of infectious agents within and among farms, poultry flocks, and humans, as well as within a country, among countries, or the whole globe. In terms of public health measures, biosecurity applies to practices that will reduce contact between poultry and humans and thereby reduce zoonotic disease transmission. Two of the common biosecurity measures are bioexclusion and biocontainment which themselves are further categorized as segregation/isolation, movement control and hygiene/sanitation/disinfection. Isolation is about putting poultry under an exclusively isolated environment where it lives alone without any interference from any source external to the poultry or at least under reduced and controlled interference. Movement/traffic control and sanitation measures are practices to follow the isolation of poultry or preparatory phase as in the case of sanitation of poultry houses before introduction of poultry. These techniques have been effective in controlling poultry diseases like avian influenza, exotic Newcastle, Marek’s disease, and any other diseases. Depending upon the underlying situation either bioexclusion or biocontainment measure will be used to control these infectious diseases of poultry.

The oral route remains one of the most popular and important routes of administration that warrants the development of advanced drug delivery systems such as the polymeric nanoparticles capable of enhancing the absorption and bioavailability of the used drugs. In this work, systematic reviewing through several databases followed by a meta-analysis study were utilized in order to navigate the published studies and reach literature-based evidence about the capability of polymeric nanoparticulate systems of augmenting the absorption and the bioavailability of the orally administered drugs. The pharmacokinetic parameter; area under the curve (AUC) was utilized as the “effect” of the meta-analysis study. The meta-analysis study demonstrated the significant increase AUC as compared to the conventional formulations. Furthermore, comparing the synthetic polymeric nanoparticles versus the naturally-based counterparts, as subgroups of the meta-analysis, revealed no significant differences.

The opioid epidemic is an ongoing public health crisis, and the United States health system is overwhelmed with increasing numbers of opioid-related overdoses. Methocinnamox (MCAM) is a novel mu-opioid receptor antagonist with an extended duration of action and potential to reduce the burden of the opioid epidemic through overdose rescue and could treat opioid use disorder (OUD) long-term. We compared the efficacy and effects of MCAM to the current treatments available to treat OUD including naloxone, naltrexone, methadone, and buprenorphine which have their own limitations including short duration of action, patient non-compliance, and diversion. A literature review was conducted using PubMed and Google Scholar databases covering the history of the opioid epidemic, pain receptors, current OUD treatments and the novel drug MCAM. MCAM could potentially be used as both a rescue and long-term treatment for opioid misuse. This is due to its pseudo-irreversible antagonism of the mu opioid receptor, abnormally long duration of action of nearly two weeks, and the possibility of using kappa or delta opioid receptor agonists for pain management during OUD treatment. MCAM’s novel pharmacokinetic and pharmacodynamic properties open a new avenue for treating the opioid crisis.

We have used Mass Multivariate Method on structural, resting state and task related fMRI data from two groups of patients with schizophrenia and depression, respectively, in order to define several regions of significant relevance to the differential diagnosis between those conditions. The regions included the left Planum polare, Left opercular part of the inferior frontal gyrus (OpIFG), Medial orbital gyrus (MOrG), Posterior Insula (PIns), and Parahippocampal gyrus (PHG). This study delivers evidence that multimodal neuroimaging approach can potentially enhance the validity of psychiatric diagnosis. Either structural, or resting state or task related functional MRI modality cannot provide independent biomarkers. Further studies need to consider and implement a model of incremental validity to combine clinical measures with different neuroimaging modalities to discriminate depressive disorders from schizophrenia. Biological signatures of disease on the level of neuroimaging are more likely to underpin broader nosological entities in psychiatry.

Our bodies produce a host of electrophilic species that can label specific endogenous proteins in cells. The signaling roles of these molecules are underactive debate. However, in our opinion it is becoming increasingly likely that electrophiles can rewire cellular signaling processes at endogenous levels. Attention is turning more to understanding how nuanced electrophile signaling in cells is. In this perspective, we describe recent work from our laboratory that has started to inform on different levels of context-specific regulation of proteins by electrophiles. We discuss the relevance of these data to the field, and to the broader application of electrophile signaling to precision medicine development, beyond the traditional views of their pleiotropic cytotoxic roles.

Background: Sinonasal squamous cell carcinoma (SNSCC) is rare in the general population. No clear and consistent etiologic correlation between human papillomavirus and SNSCC has yet been delineated in literature. p16 is a tumour suppressor protein used as a surrogate marker for HPV. This study aims to evaluate the relationship between p16 overexpression in SNSCC and its role in prognosis and survival. Methods: A population-based retrospective analysis was performed using prospectively collected data from the Northern Alberta Head and Neck Tumour Board, Alberta Cancer Registry, and Alberta Cancer Research Biobank. p16 overexpression was analyzed from pathologic sample of patients meeting study criteria, and participants were dichotomized by status. Subsequently, nonparametric analysis of demographics, initial staging, and initial treatment were performed, and a Kapan-Meier curve was developed to assess differences in survival. Results: 16 patients were included in analysis. p16 overexpression was seen in 68.8% of patients. p16 positive and negative groups were comparable for age, gender, smoking status, stage, and treatment. A statistically significant five-year survival advantage was observed in patients with p16 positive SNSCC (p = 0.013). Conclusions: This is the first Canadian study to demonstrate a high prevalence of p16 positivity in SNSCC and its presence denoting a statistically significant survival advantage. Results demonstrate a previously unconfirmed role of oncogenic HPV in SNSCC.

(1) Background: Loneliness, little studied in Nursing Homes (NHs), can affect physical and mental health. We aimed to verify the prevalence of loneliness in 5 NHs and its associated factors. (2) Methods: Cross-sectional study. Older adults aged 65 or over with preserved cognitive status were included. The De Jong Gierveld Loneliness Scale was used to assess overall, social, and emotional loneliness; sociodemographic and health-related variables were collected. The chi-square (or Fisher’s) test and logistic regression were used for bivariate and multivariate analysis respectively. (3) Results: The final sample consisted of 65 participants (81.5% female) with a mean age of 84±7.13. Prevalence of overall loneliness was 70.7% (95%CI:58.2-81.4), social loneliness 44.6% (95% CI: 33.1-56.6) and emotional loneliness 46.2% (95% CI: 34.5–58.1). Overall loneliness was associated with lower perceived quality of life (Odds Ratio-OR= 5.52, 95% CI:1.25-24.38) and NH with state subsidized places (OR=0.19, 95% CI: 0.05-0.74); social loneliness with having 0-1 children (OR=0.25, 95% CI: 0.08-0.77), and emotional loneliness with depression (OR=4.54, 95% CI: 1.28-16.08) and urinary incontinence (UI) (OR=4.65, 95% CI: 1.23-17.52). (4) Conclusions: Loneliness was present in almost 71% of residents and was associated with the type of NH and poorer quality of life, emotional loneliness with depression and UI and social loneliness with having less than 2 children.

Gut protozoan parasites are neglected and not targeted by specific control initiatives and this have led to a knowledge gap concerning their regional diversity and epidemiology. The present study aims to explore Giardia duodenalis genetic diversity and assess the epidemiologic scenario of subclinical infections in different Brazilian biogeographic regions. Cross-sectional surveys (n=1,334 subjects) were conducted in the Amazon, Cerrado, Semiarid and Atlantic Forest. Microscopy of non-diarrheal feces and nucleotide sequencing of a β-giardin gene fragment were performed. Twenty-seven (52.9%) β-giardin sequences were characterized as assemblage A and 24 (47.1%) as assemblage B. In Amazon, assemblage B was the most frequently detected with 2 novel sub-assemblages. Assemblage A predominated in the extra-Amazon region, with 5 novel sub-assemblages. Prevalence rates reached 17.8% in Amazon, 8.8% in Atlantic Forest, 7.4% in Cerrado and 2.3% in the Semiarid. People living in poverty and extreme poverty presented significantly higher positivity rates, reaching 11.9% and 14.5%, respectively. Giardiasis tended to be more frequent in stunted (21.6%) than in eutrophic children (12.9%). In conclusion, subclinical giardiasis in endemic in Brazilian communities in different biogeographic regions, presenting high genetic diversity and a heterogeneous genotypic distribution.

Obesity has become a rising global health problem affecting adults’ quality of life. The objective of this study was to describe the prevalence of obesity in Indonesian adults based on the cluster of islands. The study was also aimed to identify the risk factors of obesity in each island cluster. This study analysed secondary data of Indonesian Basic Health Research 2018. Our data for analysis comprised 688,638 adults (>=15 years) randomly selected using proportionate to population size throughout Indonesia. We included 20 variables for sociodemographic and obesity-related risk factors for analysis. Obese status was defined using Body Mass Index (BMI) >= 27.5 kg/m2. Our current study defined seven major islands cluster as the unit analysis consisting of 34 provinces in Indonesia. Descriptive analysis was conducted to determine the characteristics of the population and to calculate the prevalence of obesity within provinces in each of the island’s clusters. Multivariate logistic regression analyses to calculate odds ratios (ORs) was performed using R version 3.6.3. The study results showed that all island clusters had at least one province with an obesity prevalence of more than 20%. Six out of twenty variables, comprising four diet factors (consumption of sweet food, high-salt food, meat food, and carbonated drinks) and two other factors (mental health disorders and smoking behaviour), varied across the island clusters. In conclusion, there was a variation of obesity prevalence of the provinces within and between island clusters. Variation of risk factors raised in each cluster island suggested the government rethink and reframe the intervention to address obesity.

The implications of the adult congenital heart disease anatomic and physiological classification (AP-ACHD) for risk assessment have not been adequately studied. A retrospective cohort study was conducted using data from an ongoing national, multicentre registry of patients with ACHD and atrial arrhythmias (AA) receiving apixaban (PROTECT-AR study, NCT03854149). At enrollment, patients were stratified according to Anatomic class (AnatC, range I to III) and physiological stage (PhyS, range B to D). Follow-up was conducted between May 2019 and September 2021. The primary outcome was a composite of death from any cause, any major thromboembolic event, major or clinically relevant non-major bleeding, or hospitalization. Cox proportional-hazards regression modeling was used to evaluate the risks for the outcome among AP-ACHD classes. Over a median 20-month follow-up period, 47 of 157 (29.9%) ACHD patients with AA experienced the composite outcome. Adjusted hazard ratios (aHR) with 95% confidence intervals [CI] for the outcome in PhyS C and PhyS D were 1.84 (95% CI 0.73 to 4.61) and 7.88 (95% CI 1.54 to 40.41) respectively, as compared with PhyS B. The corresponding aHRs in AnatC II and AnatC III were 1.10 (95% CI 0.39 to 3.06) and 0.99 (95% CI 0.24 to 4.10) respectively, as compared with AnatC I. In conclusion, the PhyS component of the AP-ACHD classification was an independent predictor of net adverse clinical events among ACHD patients with AA receiving apixaban.

The combination of interstitial hyperthermia treatment (IHT) with high dose rate brachytherapy (HDR-BT) for prostate cancer treatment and has the potential to improve clinical outcome, since it highly enhances the efficiency of cell kill, especially when applied simultaneously. Therefore, we have developed the ThermoBrachy applicators. To effectively apply optimal targeted IHT, treatment planning is considered essential. However, treatment planning in IHT is rarely applied since it is regarded difficult to accurately calculate the deposited energy in the tissue in a short enough time for clinical practice. In this study, we investigated various time-efficient methods for fast computation of the electromagnetic (EM) energy deposition resulting from the ThermoBrachy applicators. Initially, we investigated the use of an electro-quasistatic solver. Next, we extended our investigation to the application of geometric simplifications. Furthermore, we investigated the validity of the superpositioning principle, which can enable adaptive treatment plan optimization without the need for continuous recomputation of the EM field. Finally, we evaluated the accuracy of the methods by comparing them to the golden standard Finite-Difference Time-Domain calculation method using gamma-index analysis. The simplifications considerably reduced the computation time needed, improving from &gt;12 h to a few seconds. All investigated methods showed excellent agreement with the golden standard by showing a &gt;99% passing rate with 1%/0.5 mm Dose Difference and Distance-to-Agreement criteria. These results allow the proposed electromagnetic simulation method to be used for fast and accurate adaptive treatment planning.

This study compares the efficacy of the two most commonly used surgical methods for pterygium in the Polish population, conjunctival autograft versus amniotic membrane transplantation, and to evaluate the postopera-tive recurrence rate. We retrospectively analysed the medical records of 65 patients who underwent surgery for primary or recurrent pterygium at an ophthalmology clinic in Bialystok, Poland between 2016 and 2020. Surgical success (no regrowth) occurred in almost half of the amniotic membrane patients (44%) and in most of the conjunctival autograft patients (79%); this was a significant relationship. The odds of successful surgery were 79% lower for subjects with amniotic membranes than for those with conjunc-tival autografts (OR with 95% CI = 0.21 (0.05; 0.94]; p = 0.045). Our study confirms that in Polish Caucasian population the success rate of the pro-cedure using conjunctival autograft versus the use of amniotic membrane, is in favoured for the procedure with conjunctival graft.

Liquid biopsies are an integral part of the diagnosis of cancer. Here, we have extended previous validation studies of a new targeted NGS panel to include the detection of copy number amplifications (CNAs), fusions, and exon skipping variants. Detection of these gene classes included specimens from clinical and healthy donors and cell lines (fusions: ROS1, EML4-ALK, NTRK1), (exon skipping: MET exon 14), and (CNAs: HER2, CDK6, EGFR, MYC and MET). The limit of detection (LOD) for fusion/skipping was 42 copies (QC threshold = 3 copies) and was verified using 3 additional fusion/skipping variants. LOD for CNAs was 1.40-fold-change (QC threshold = 1.15-fold change) and was verified with 3 additional CNAs. In precision studies, all fusion/skipping variants were detected in all runs and all days of testing (n=18/18; 100%); average CV for repeatability was 20.5% (range 8.7% - 34.8%), and for reproducibility was 20.8% (range 15.7% - 30.5%). For CNAs, 28/29 (96.6%) copy gains were detected. For CNAs, average CV of 1.85% (range 0% to 5.49%) for repeatability and 6.59% (range 1.65% to 9.22%) for reproducibility. The test panel meets the criteria for being highly sensitive and specific and extends its utility for the detection of clinically relevant variants in cancer.

This study examines the relation between ambient air pollution and emergency department (ED) visits due to certain infectious diseases in Toronto, Canada. The National Ambulatory Care Reporting System database was used to draw the corresponding health cases. Daily data on ED visits, ambient air pollution concentration levels, and weather conditions during the period from April 2004 to December 2015 (4,292 days in total) were linked together and used in statistical models. Six air pollutants (fine particulate matter PM2.5, CO, NO2, SO2, ozone O3 as a daily average, and ozone O3-8 hour ozone, as a maximum eight hour average) were investigated. In addition, the Air Quality Health Index (combining NO2, O3, and PM2.5) was also considered. The time-stratified case-crossover technique was applied in the study design. Conditional Poisson models were created using the daily counts of ED visit data. The considered factors, air pollutants and weather, were lagged by the same number of days, from 0 to 14. In the period of the study 339,644 ED visits were identified; 177,619 for females and 162,025 for males. For each air pollutant 270 models were realized (15 lags x 18 strata). Ambient air pollution concentrations lagged by 2, 3, and 5 days have the highest impact on ED visits, with 34, 32, and 35 positive associations, respectively. For all patients and an increase in a one interquartile range (IQR=1.2 ppb) of sulphur dioxide, the following values of the relative risks (RR) were estimated: RR=1.005 (95% confidence interval: 0.998, 1.013), 1.008 (1.001, 1.016), 1.009 (1.001, 1.016), 1.011 (1.004, 1.019), 1.007 (0.987, 1.028), and 1.009 (1.002, 1.016) for lags from 0 to 5, respectively. The results suggest that exposures for certain air pollutants (mainly CO, O3, and SO2) in urban environment affect the number of ED visits related to infectious diseases.

Biomarker directed selection of targeted anti-neoplastic agents such as immune check-point inhibitors, small molecule inhibitors and monoclonal antibodies form an important aspect of cancer treatment. Immunohistochemistry (IHC) analysis of the tumor tissue is the method of choice to evaluate the presence of these biomarkers. However, a significant barrier to biomarker testing on tissue is the availability of an adequate amount of tissue and need for repetitive sampling due to tumor evolution. Also, tumor tissue testing is not immune to inter- and intra-tumor heterogeneity. We describe the analytical and clinical validation of a Circulating Tumor Cell (CTC) assay to accurately assess the presence of PD-L1 22C3 and PD-L1 28.8, ER, PR and HER2, from patients with solid tumors to guide the choice of suitable targeted therapies. Analytically, the test has high sensitivity, specificity, linearity and precision. Based on a blinded case control study, the clinical sensitivity and specificity for PD-L1 (22C3 and 28.8) was determined to be 90% and 100% respectively. The clinical sensitivity and specificity was 83% and 89% for ER; 80% and 94% for PR; 63% and 89% for HER2 (by ICC); and 100% and 92% for HER2 (by FISH), respectively. The performance characteristics of the test support its suitability and adaptability for routine clinical use.

Background. It is unclear whether the use of clinical prediction rules is sufficient to rule out infective endocarditis (IE) in patients with Staphylococcus aureus bacteremia (SAB) without an echocardiogram evaluation, either transthoracic (TTE) and/or transesophageal (TEE). Our primary purpose was to test the usefulness of PREDICT, POSITIVE and VIRSTA scores to rule out IE without echocardiography. Our secondary purpose was to evaluate whether not performing an echocardiogram evaluation is associated with higher mortality. Methods. We conducted a unicentric retrospective cohort including all patients with a first SAB episode from January 2015 to December 2020. IE was defined according to modified Duke criteria. We predefined threshold cut-off points to consider that IE was ruled out by means of the mentioned scores. To assess 30-day mortality, we used a multivariable regression model considering performing an echocardiogram as covariate. Results. Out of 404 patients, IE was diagnosed in 50 (12.4%). Prevalence of IE within patients with negative PREDICT, POSITIVE and VIRSTA scores was: 3.6% (95% CI 0.1-6.9%), 4.9% (95% CI 2.2-7.7%), and 2.2% (95% CI 0.2-4.3%), respectively. Patients with negative VIRSTA and negative TTE had an IE prevalence of 0.9% (95% CI 0-2.8%). Performing an echocardiogram was independently associated with lower 30-day mortality (OR 0.24 95%CI 0.10-0.54, p=0.001). Conclusion. PREDICT and POSITIVE scores were not sufficient to rule out IE without TEE. In patients with negative VIRSTA score, it was doubtful if IE could be discarded with a negative TTE. Not performing an echocardiogram was associated with worse outcomes, which might be related to presence of occult IE. Further studies are needed to assess the usefulness of clinical prediction rules in avoiding echocardiographic evaluation in SAB patients.

Background: Since the previous study dealing with the case fatality ratio and infection fatality ratio caused by COVID-19, the author has received many comments that prompted the question: "Why did an optimistic prognosis fail?" To answer this question, a more detailed and expanded analysis was carried out in a new study. Objective: To evaluate the dynamics of monthly numbers of cases, deaths, tests and CFR worldwide during three phases of the COVID-19 pandemic. Material and Methods: Twenty three sets of databases, dated the 22nd of each month from January 2020 to November 2021, for 213 countries were collected from the Worldometer website. The number of cases, deaths, tests, CFR, IFR, etc. were counted for various periods of time for each of the 213 countries, then results related to different periods of time were compared. Results: The analysis of the main epidemiological parameters led to the division of three phases of the global pandemic evolution. The first phase (23.01.20-22.07.20), the second phase (23.07.20-22.01.21) and the third phase (23.01.21-22.07.21) were different in terms of the number of tests performed, new cases, and mortality due to COVID-19. By the end of the second phase, the worldwide statistics indicated the imminent end of the pandemic, but the third phase was characterized by a sudden rise in the number of new cases and deaths that could not be explained rationally. The most dramatic evolution of the epidemic curve occurred in the countries where doctors had successfully battled COVID-19 during the first two phases of the pandemic. Conclusions: Despite the decrease in overall death numbers during the latest months analyzed, additional study is necessary to identify the cause for the increase in the number of new cases and deaths during the third phase of the pandemic. Only complete information regarding the positive and negative impact of medical and non-medical methods of diagnostics and prophylaxis of COVID-19 can help to organize effective measures to end the current pandemic and prevent a similar one from occurring in the future. Presumably, there are several causes of the negative evolution of the current pandemic, including the overreliance on PCR tests, application of non-specialized premises for quarantine and treatment, decrease in herd and individual immunity, inadequate change of therapeutic protocols, and ignoring prophylactic treatment. It can be suggested that the use of immunemodulatory drugs, for example, thymus extract or thymic peptides, in groups of people with compromised immunity is necessary, and prophylactic and therapeutic protocols should be changed from the 'standard' types to 'personalized' ones.

The research and development of non-viral gene therapy has been extensive over the past decade and has received a big push thanks to the successful approval of non-viral gene therapy products in recent times. Despite these developments, gene therapy applications in cancer have been limited. One of the main causes of this has been the imbalance in development of delivery vectors as compared to nucleic acid payloads. This paper reviews non-viral vectors that can be used to deliver nucleic acids for cancer treatment. It discusses various types of vectors and highlights their current applications. Additionally, it also discusses perspective on regulatory landscape to facilitate commercial translation of gene therapy.

The study of cell-free DNA (cfDNA) and other peripheral blood components (known as “liquid biopsies”) is promising and has been investigated especially in solid tumors. Nevertheless, it is increasingly showing greater utility in the diagnosis, prognosis, and response to treatment of hematological malignancies; in the future, it could prevent invasive techniques, such as bone marrow (BM) biopsy. Most of the studies about this topic have been focused on B cell lymphoid malignancies; some of them have shown that cfDNA can be used as a novel way for diagnosis and minimal residual monitoring in B cell lymphomas, using techniques such as next-generation sequencing (NGS). In myelodysplastic syndromes, multiple myeloma, or chronic lymphocytic leukemia, liquid biopsies may allow for an interesting genomic representation of the tumor clones affecting different lesions (spatial heterogeneity). In acute leukemias, it can be helpful in the monitoring of early treatment response and the prediction of treatment failure. In chronic lymphocytic leukemia, the evaluation of cfDNA permits the definition of clonal evolution and drug resistance in real-time. However, there are limitations such as the difficulty in obtaining sufficient circulating tumor DNA for achieving a high sensitivity to assess minimal residual disease or the lack of standardization of the method and clinical studies to confirm its prognostic impact. This review focuses on clinical applications of cfDNA on minimal residual disease in hematological malignancies.

Preeclampsia (PE) is associated with an increased risk of cardiovascular disease (CVD) in later life. Postpartum cardiovascular risk screening could identify patients who would benefit most from lifestyle interventions. However, there are no readily available methods to identify these high-risk women. We propose that placental lesions may be useful in this regard. Here, we sought to determine the association between placental lesions and lifetime CVD risk. Placentas from 85 PE women were evaluated for histopathological lesions. At 6 months postpartum, a lifetime cardiovascular risk score was calculated. Placental lesions were compared between CVD risk groups and the association was assessed using odds ratios. Multivariable logistic regression was used to develop prediction models for CVD risk with placental pathology. Placentas from high-risk women had more severe lesions of maternal vascular malperfusion (MVM) and resulted in a 3-fold increased risk of screening high-risk for CVD (OR 3.10[1.20-7.92]) compared to women without these lesions. MVM lesion severity was moderately predictive of high-risk screening (AUC 0.63[0.51,0.75]; sensitivity 71.8%[54.6,84.4]; specificity 54.7%[41.5,67.3]. When clinical parameters were added, the model’s predictive performance improved (AUC 0.73[0.62,0.84]; sensitivity 78.4%[65.4,87.5]; specificity 51.6%[34.8,68.0]. The results suggest that placenta pathology may provide a unique modality to identify women for cardiovascular screening.

Background: Left ventricular noncompaction (LVNC) is a distinct cardiomyopathy characterized by the presence of a two-layer myocardium with prominent trabeculation and deep intertrabecular recesses. The diagnosis of LVNC can be challenging because the diagnostic criteria are not uniform. The aim of our study was to evaluate echocardiographic and CMR findings in a group of children with isolated LVNC. Methods: From February 2008 to July 2021, pediatric patients under 18 years of age at the time of diagnosis with echocardiographic evidence of isolated LVNC were prospectively enrolled. The patients underwent echocardiography and contrast-enhanced cardiovascular magnetic resonance (CMR) with late gadolinium enhancement to assess myocardial noncompaction, ventricular size, and function. Results: A total of 34 patients with a median age of 11.9 years were recruited. Patients were followed prospectively for a median of 5.1 years. Of the 31 patients who met Jenni’s criteria in echocardiography, CMR was performed in 27 (79%). Further comprehensive analysis was performed in the group of 25 patients who met the echocardiographic and CMR criteria for LVNC. In echocardiography, the median NC/C ratio in systole was 2.60 and in diastole 3.40. In 25 out of 27 children (93%), LVNC was confirmed by CMR according to Petersen’s criteria, with a median NC/C ratio of 3.27. Conclusions: 1) Echocardiography precisely identifies patients with LVNC. 2) Echocardiography is a good method for monitoring LV systolic function, but CMR is indicated for the precise assessment of LV remodeling and RV size and function as well as for the detection of myocardial fibrosis.

Precision medicine emphasizes fine-grained diagnostics, taking individual variability into account to enhance treatment effectiveness. Parkinson's Disease (PD) heterogeneity among individuals is a proof that disease subtypes exist, and assigning individuals to subgroups is necessary for a better understanding of disease mechanisms and designing precise treatment approaches. The purpose of this study was to identify PD subtypes using RNA-Seq data in a combined pipeline including unsupervised machine learning, bioinformatics, and network analysis. 210 post mortem brain RNA-Seq samples from PD (n = 115) and Normal Controls (NC, n = 95) were obtained with a systematic data retrieval following PRISMA statements and a fully data-driven clustering pipeline was performed to identify PD subtypes. Bioinformatics and Network analyses were performed to characterize the disease mechanisms of the identified PD subtypes and to identify target genes for drug repurposing. Two PD clusters were identified and 42 DEGs were found (p.adjusted ≤ 0.01). PD clusters had significantly different gene network structures (p &lt; 0.0001) and phenotype-specific disease mechanisms, highlighting the differential involvement of the Wnt/β-catenin pathway regulating adult neurogenesis. NEUROD1 was identified as a key regulator of gene networks and ISX9 and PD98059 were identified as NEUROD1-interacting compounds with disease-modifying potential, reducing the effects of dopaminergic neurodegeneration. This hybrid data analysis approach could enable precision medicine applications by providing insights for the identification and characterization of pathological subtypes. This workflow has proven useful on PD brain RNA-Seq, but its application to other neurodegenerative diseases is encouraged.

Background: LncRNA and pyroptosis play important roles in cancer development and tumor immune microenviroment. However, pyroptosis-related lncRNAs (PRLs) in ovarian cancer have not been identified and its impact on prognosis and immune response are not fully understood. Methods: Using pearson correlation analysis, PRLs were screened. Subsequently, we constructed a prognosis signature by using LASSO cox regression. In addition, the association between risk score and cancer immune environment was analyzed. Results: In TCGA-RNA-seq cohort (n=377), 32 prognostic PRLs were selected and a 7-gene signature were developed and had high accuracy in predicting the OS of ovarian cancer patients. Stratification analysis suggested that it might serve as an independent prognostic indicator. Except to clinical outcome, the signature was significantly associated with tumor immune microenvironment. Patients with high risk score exhibited lower infiltration abundance of MHC class Ⅰ cells, Type Ⅰ IFN response and immunotherapy response. In ovarian cancer, TYMSOS was highly expressed and its high expression was associated with worse OS. TYMSOS deletion in ovarian cancer cell lines inhibited the cell proliferation, invasion and migration, indicating that it might serve as a novel biomarker in ovarian cancer. Conclusions: The prognostic PRLs signature constructed in this work is available for prognostic prediction and immune microenvironment infiltration in ovarian cancer.

Myelodysplastic syndromes (MDS) are diseases that occur when blood-producing cells in the bone marrow are damaged; such damage can affect one or more types of blood cells. Common types of MDS are refractory anemia with ring sideroblasts and refractory anemia with excess blasts (MDS-RS and MDS-EB, respectively). This work analyzed the proteomics of the medullary plasma of 10 patients with MDS-RS and MDS-EB compared to healthy control people. Overexpressed proteins that may be potential candidates for biological markers for the evaluation, study, and diagnosis of these diseases have been identified. These samples were subjected to immunodepleting, concentrated, and digested for further analysis by mass spectrometry. The ratios between selected groups and healthy people were calculated. Seven overexpressed proteins in both syndromes were identified as potential biomarker candidates: vitronectin (VTN), (2) fibrinogen (FGA), (3) pregnancy zone protein (PZP), (4) kininogen (KNG1), (5) immunoglobulin lambda chain (IGLL1), (6) complement factor C4b, and (7) hemopexin (HPX). A modified affinity chromatographic column with lectin frutalin (FTL) was used for non-depleted samples. Immunoglobulin M (IgM) was expressed in the samples from both syndromes. Surprisingly, IgM from patients with syndromes was over retained on the frutalin (FTL) column when compared with the control group. We further hypothesized that over retention of this protein by the FTL is due to the presence of α-galactosidic residues in the IgM of MDS-RS and MDS-EB patients. Differential recognition of proteins on non-depleted samples from the use of FTL appears to be a powerful tool for proteomic analysis.

The tumor microenvironment (TME) surrounding tumor cells is a complex and highly dynamic system that promotes tumorigenesis. Cancer-associated fibroblasts (CAFs) are key elements in TME playing a pivotal role in cancer cells’ proliferation and metastatic spreading. Considering the high expression of the fibroblast activation protein (FAP) on cell membrane, CAFs emerged as appealing TME targets, namely for molecular imaging, leading to a pan-tumoral approach. Therefore, FAP inhibitors (FAPis) have been recently developed for PET imaging and radioligand therapy, exploring the clinical application in different tumor sub-types. The present review aimed to describe recent developments on radiolabeled FAP inhibitors and evaluate the possible translation of this pan-tumoral approach in clinical practice. At present, the application of FAPi-PET has been explored mainly in single-center studies, generally performed in small and heterogeneous cohorts of oncological patients. However, preliminary results were promising, in particular in low FDG-avid tumors such as primary liver and gastro-entero-pancreatic cancer, or in regions with unfavorable tumor-to-background ratio at FDG-PET/CT (i.e. brain), as well as in radiotherapy planning of head and neck tumors. Further promising results have been obtained in the detection of peritoneal carcinomatosis, especially in ovarian and gastric cancer. Data regarding the theranostics approach are still limited at presents, and definitive conclusion about its efficacy cannot be drawn at present. Nevertheless, the use of FAPi-based radio-ligand to treat the TME has been evaluated in first-in-human studies and appears feasible. Although the pan-tumoral approach in molecular imaging showed promising results, its real impact in day-to-day clinical practice has yet to be confirmed, and multi-center, prospective studies powered for efficacy are needed.

(1) Background: Deep hypothermic circulatory arrest (DHCA) with selective antegrade cerebral perfusion (ACP) is an established cerebral protection technique for the conduction of complex surgical procedures involving the aortic arch. It is controversial if the duration of DHCA is associated with adverse outcome in patients with acute type A aortic dissection (AAAD). Our goal was to investigate whether DHCA time was associated with surgical outcome in patients undergoing a surgical treatment of AAAD. (2) Methods: 410 Patients were divided into two groups concerning the DHCA time less than 60 minutes and equal or longer than 60 minutes. (3) Results: Patients with longer DHCA time were significantly younger (p=0.001). Intraoperatively, complex procedures with aortic arch surgery were more common in patients with longer DHCA time (p&lt;0.001). Accordingly, cardiopulmonary bypass (p&lt;0.001), cross-clamping (p&lt;0.001) and DHCA times (p&lt;0.001) were significantly longer in this group. Postoperatively, only the duration of mechanical ventilation (p&lt;0.001) and the rate of tracheotomy were significantly higher in these patients. 30-day mortality was satisfactory for both groups (p=0.746). (4) Conclusions: Our results showed that improvements in perioperative management including ACP allow a successful performance of surgical treatment of AAAD under DHCA with duration of even longer than 60 minutes.

Obturator herniæ are a quite rare type of abdominal hernia, accounting for less then 1% of all abdominal wall hernias and for 0.2-1.6% of patient with a small bowel obstruction. The obturator canal is the only portion of the obturator foramen that is not obliterated by the membrane of the same name and hosts the obturator neurovascular bundle; it is, for this reason, a locus minoris resistentiae, through which obturator hernias are formed, generally in elderly, multiparous women. Despite the fact that Computed Tomography offers the possibility of a quick, correct preoperative diagnosis, often signs and symptoms of obturator herniæ are quite unspecific; considering that, at the same time, patients with an obturator hernia are generally elderly, with concurrent conditions, this might cause delays in the diagnosis and treatment and produces the high postoperative mortality rates that obturator herniæ yield

An ongoing EU Horizon 2020 Project called BionicVEST is investigating the effect of constant electrical stimulation (ES) of the inferior vestibular nerve in patients with bilateral vestibular dysfunction (BVD)[1]. The evidence is that constant ES results in improved postural stability and gait performance and so the question of central importance is how could constant ES of mainly saccular afferents in these BVD patients cause this improved performance? We suggest that the constant ES is substituting for the absent saccular neural input to the vestibular nuclei and the cerebellum in these BVD patients and indirectly via these structures to other structures which have been of great recent interest in motor control. One target area, the anterior midline cerebellum (the uvula) has recently been targeted as a location for deep brain stimulation in human patients to improve postural stability and gait. There are projections from midline cerebellum to basal ganglia including the striatum, structures involved in the initiation of gait. It may be that the effect of this activation of peripheral saccular afferent neurons is analogous to the effect of deep brain stimulation (DBS) by electrodes in basal ganglia acting to help alleviate the symptoms of patients with Parkinson's disease.

The purpose of the current study was directed to investigate the effectiveness of docosahexaenoic acid (DHA) as a chemopreventive agent on experimentally induced hamster buccal pouch (HBP) carcinogenesis; Material and methods: 40 Syrian male hamsters, five weeks old, were divided into 4 groups of 10 animals in each as follows, GI: Topical application of liquid paraffin alone (thrice a week for 14 weeks), GII: Topical application of 7, 12 dimethyl benz[a]anthracene (DMBA) alone (0.5 % in liquid paraffin, thrice a week for 14 weeks), GIII: Topical application of DMBA (0.5 % in liquid paraffin, thrice a week for 14 weeks) + Oral administration of DHA (125 mg/kg b.w. in 1 ml distilled water by oral gavage, thrice a week for 14 weeks on alternative days of DMBA application), GIV : Oral administration of DHA alone (125 mg/kg b.w. in 1 ml distilled water by oral gavage, thrice a week for 14 weeks); Results: Gross observations and histopathological findings revealed a-GI: normal stratified squamous epithelium b- GII: well and moderately differentiated squamous cell carcinoma (SCC) c-: GIII: showed variable results ranges from hyperkeratosis, hyperkeratosis and focal hyperplasia, mild dysplasia, and well differentiated SCC with superficial invasion of tumor cells not extended to deeper areas d: GIV: normal similar to GI. Immunohistochemical results revealed that oral DHA treatment to DMBA treated hamsters restored the normal expression of bcl-2; Conclusion: DHA has the potential to be a dietary chemopreventive agent due to its capacity to improve carcinogen detoxification and to block/suppress the initiation and promotion stages of experimentally produced HBP carcinogenesis.

NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and these efforts continue to be con-troversial. Drug repurposing strategies are a promising alternative to de-novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.

Tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC), but high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with choles-tasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administra-tion. After a 7-months follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets suggesting their potential role in the pathophysiology of the disease.

Introduction: The treatment of peritoneal dialysis in end-stage renal disease is increasing in clinical practice. The main purpose of this study was to evaluate the effect of far-infrared radiation therapy on inflammation and the cellular immunity of patients undergoing peritoneal dialysis. Materials and Methods: We recruited 56 patients undergoing peritoneal dialysis, and we included 32 patients from the experimental group and 24 patients from the control group in the final analysis. The experimental evaluation in our study was as follows: (1) We used abdominal computed tomography to measure the diameter and degree of hardening of the abdominal veins and large blood vessels to explore the changes in abdominal blood vessels. (2) The study compared the effects of peritoneal dialysis using albumin, blood urea nitrogen, creatinine, white blood cell, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, erythrocyte sedimentation rate, Hs-CRP clearance rate, and HBAlC. (3) We compared the cytokine concentration of blood between the two groups while controlling for GM-CSF, IL-2, IFN-γ, IL-6, IL-18, IL-4, IL-5, IL-13, IL-12p70, TNF-α, and IL-1β. Results and Discussion: (1) There was no significant difference in the abdominal blood vessels of the experimental group relative to the control group according to abdominal CT measured over 6 months. (2) Our study demonstrates the statistically significant effect of FIR therapy on the following parameters: albumin (p = 0.048*), creatinine (p = 0.039*), and Hs-CRP (p < 0.001**) decreased significantly, and glomerular filtration rate (eGFR, p = 0.043*) and glucose (p < 0.001**) increased significantly. Our study found that, in the experimental group, albumin and creatinine decreased significantly due to FIR therapy for 6 months. However, our study also found that, in the experimental group, glucose (p < 0.001**) increased significantly due to FIR therapy for 6 months. Peritoneal dialysis combined with FIR can reduce the side effects of glucose in dialysis buffer, which interferes with peritoneal inflammation and peritoneal mesothelial cell fibrosis. In addition, we also found that, in the experimental group, Hs-CRP (p < 0.001**) decreased significantly due to FIR therapy for 6 months. (3) No statistical significance in the inflammatory cytokines related to FIR therapy differences was observed in our study. IFN-γ (p = 0.124), IL-12p70 (p = 0.093), IL-18 (p = 0.213), and TNF-α (p = 0.254) did not exhibit significant improvements in peritoneal dialysis with FIR treatment over 6 months. IFN-γ and IL-18 in the plasma of patients in the experimental group and the control group were higher in the third month than in the first month. Conclusion: We found that the effect of peritoneal dialysis improved significantly with FIR therapy, and significant improvements in the peritoneal permeability and inflammatory response were observed. end-stage renal disease; peritoneal dialysis; far-infrared therapy (FIR)

Objectives: The aim of this study was to compare the performance of the EQ-5D-Y-3L (Y-3L) and the expanded five level version, the EQ-5D-Y-5L (Y-5L). Methods: Children/adolescents with an acute or chronic health condition and from the general population completed the Y-5L and Y-3L self-report questionnaires. Performance of the Y-5L and Y-3L was determined by comparing feasibility, redistribution of dimension responses, discriminatory power, validity, and test-retest reliability. Results. Five hundred and fifty children/adolescents completed baseline measures and 173 completed repeat measures. The ceiling effect decreased by 15% from the Y-3L to Y-5L. Informativity of dimensions improved by 0.094 on the Y-5L. There was a range of 4-9% inconsistent responses moving from the Y-3L to Y-5L. Convergent validity of the Visual Analogue Scale (VAS) and Y-3L, Y-5L dimensions was similar, weak to moderate (r_s range: 0.18 – 0.38) but similar and strong on paired Y-3L and Y-5L dimensions: Kendall Tau B (range 0.69 – 0.80) and Gamma (range 0.92 – 0.98). The Y-5L and Y-3L showed moderate to substantial agreement for test-retest reliability across dimensions and VAS scores in stable chronic health conditions and fair agreement for the general population. Conclusion: The EQ-5D-Y-5L is a valid, reliable extension of the Y-3L for children/adolescents across health conditions and healthy children/adolescents. The expanded levels reduced the ceiling effect. The relative informativity of report across dimensions increased on the Y-5L compared to the Y-3L with retention of the evenness of reporting. The convergent validity and test-retest reliability of the Y-5L was comparable to the Y-3L.

Podoplanin (PDPN) is a cell-surface mucin-like glycoprotein that plays a critical role in tumor development and normal development of the lung, kidney, and lymphatic vascular systems. PDPN is overexpressed in several tumors and is involved in their malignancy. PDPN induces platelet aggregation through binding to platelet receptor C-type lectin-like receptor 2. Furthermore, PDPN modulates signal transductions that regulate cell proliferation, differentiation, migration, invasion, epithelial to mesenchymal transition, and stemness, all of which are crucial for the malignant progression of tumor. In the tumor microenvironment (TME), PDPN expression is up-regulated in the tumor stroma, including cancer-associated fibroblasts (CAFs) and immune cells. CAFs play significant roles in the extracellular matrix remodeling and the development of immunosuppressive TME. Additionally, PDPN functions as a co-inhibitory molecule on T cells, indicating the involvement with immune evasion. In this review, we describe the mechanistic basis and diverse roles of PDPN in malignant progression of tumor and discuss the possibility of the clinical application of PDPN-targeted cancer therapy, including cancer-specific monoclonal antibodies, and chimeric antigen receptor T technologies.

Under the Japanese health insurance system, medicines undergoing therapeutic drug monitoring (TDM) can be billed for medical fees if they meet the specified requirements. In Japan, TDM of vancomycin, teicoplanin, aminoglycosides, and voriconazole, which are used for the treatment of infectious diseases, is common practice. This means the levels of antimicrobial agents are measured in-house using chromatography. This review describes personalized medicine based on the use of chromatography as a result of the current situation in Japan.

Pneumonia is the leading cause of hospitalization in pediatric patients. Disease severity greatly influences pneumonia progression and adverse health outcomes such as hospital readmission. Hospital readmissions have become a measure of healthcare quality to reduce excess expenditures. The aim of this study was to examine 30-day all-cause readmission rates and evaluate the association between pneumonia severity and readmission among pediatric pneumonia hospitalizations. Using 2018 Nationwide Readmissions Database (NRD), we conducted a cross-sectional study of pediatric hospitalizations for pneumonia. Pneumonia severity was defined by the presence of respiratory failure, sepsis, mechanical ventilation, dependence on long-term supplemental oxygen, and/or respiratory intubation. Outcomes of interest were 30-day all-cause readmission, length of stay, and cost. The rate of 30-day readmission for the total sample was 5.9%, 4.7% for non-severe pneumonia, and 8.7% for severe pneumonia (p&lt;0.01). Among those who were readmitted, hospitalizations for severe pneumonia had a longer length of stay (6.5 vs. 5.4 days, p&lt;0.01) and higher daily cost ($3,246 vs. $2,679, p&lt;0.01) than admissions for non-severe pneumonia. Factors associated with 30-day readmission were pneumonia severity, immunosuppressive conditions, length of stay, and hospital case volume. To reduce potentially preventable readmissions, clinical interventions to improve the disease course and hospital system interventions are necessary.

Background: The identification of new cellular receptors has been increasing rapidly. A receptor is called “orphan” if an endogenous ligand has not been identified yet. Methods: Here we review receptors that contribute to prostate cancer and are considered orphan or partially orphan. This means that the full spectrum of their endogenous ligands remains unknown. Results: The orphan receptors are divided into two major families. The first group includes G protein-coupled receptors. Most are orphan olfactory receptors. OR51E1 inhibits cell proliferation and induces senescence in prostate cancer. OR51E2 inhibits prostate cancer growth, but promotes invasiveness and metastasis. GPR158, GPR110 and GPCR-X play significant roles in prostate cancer development and progression. However, GPR160 induces cell cycle arrest and apoptosis. The other major subset of orphan receptors are nuclear receptors. RORα inhibits tumor growth, but RORγ stimulates androgen receptor signaling. PXR contributes to metabolic deactivation of androgens and inhibits cell proliferation. TLX has pro-tumorigenic effects in prostate cancer, while its knockdown triggers cellular senescence and growth arrest. Estrogen-related receptor ERRγ can inhibit tumor growth but ERRα is pro-tumorigenic. Dax1 and Shp are also inhibitory in prostate cancer. Conclusion: There is a “zoo” of relatively underappreciated orphan receptors that play key roles in prostate cancer.

Type 2 Diabetes Mellitus is being increasingly associated with dysfunction of cognition. Dementia, including vascular dementia and Alzheimer’s disease, is being recognized as comorbidities of this metabolic disorder. The progressive hallmarks of this cognitive dysfunction include mild impairment of cognition and cognitive decline. Dementia and mild impairment of cognition appear in older patients primarily. Studies on risk factors, neuropathology, and brain imaging have provided important suggestions for mechanisms that lie behind the development of dementia. It is a significant challenge to understand the disease processes related to diabetes which affect the brain and lead to dementia development. The connection between Diabetes Mellitus and dysfunction of cognition has been observed in many human and animal studies that have noted mechanisms related to Diabetes Mellitus are possibly responsible for aggravating cognitive dysfunction. This article attempts to narrate the possible association between type 2 diabetes and Dementia, reviewing studies that have noted this association in vascular dementia and Alzheimer’s disease and helping to explain the potential mechanisms behind the disease process. The Google search for ‘Diabetes Mellitus and Dementia’ was carried out. Also, the search was done using ‘Diabetes Mellitus,’ ‘Vascular Dementia,’ ‘Alzheimer’s Disease.’ The literature search was done from Google Scholar, Pubmed, Embase, ScienceDirect, and MEDLINE. Keeping in mind the increasing rate of Diabetes Mellitus, it is important to establish the type 2 diabetes effect on the brain and diseases of neurodegeneration. This narrative review aims to build awareness regarding different types of dementia and their relationship with diabetes.

Complex diseases are prevalent medical conditions which are characterized by strong inter-patient differences in symptom profiles, disease trajectory and treatment response. The challenges in understanding and managing these diseases are due to their complex pathophysiology, comprising of a combination of genetic and environmental factors. The traditional model of disease assumes a clear distinction between health and disease, as well as between different diagnoses, but recent findings with regards to diseasomes and network pleiotrophy suggest that this dogma is not useful in understanding complex diseases. This paper presents a novel model, in which the individual disease burden is determined as a function of molecular, physiological and pathological factors simultaneously: disease(symptoms(traits(genes AND environment))). From this a high-dimensional space is defined which includes all individual disease burdens, ranging from healthy (i.e. low disease burden) to multi-morbidity (i.e. high disease burden), termed the disease landscape. This model provides a novel way to conceptualize human physiology and pathophysiology in the context of complex diseases and may present a useful concept to simultaneously address the strong interindividual heterogeneity of diagnose cohorts as well as the lack of clear distinction between diagnoses and health and disease, thus facilitating the progression towards personalized medicine.

Abstract: Appetite loss is common in older patients and an independent risk factor for sarcopenia, which is associated with high mortality. However, few studies have explored the phenomenon of appetite loss after discharge from the intensive care unit (ICU). Therefore, we aimed to describe the prevalence of appetite loss and the relationship between appetite loss and depression in patients living at home 12 months after intensive care. We conducted a post hoc analysis, which was a published ambidirectional study examining post-intensive care syndrome at 12 months after discharge. We included patients aged > 65 years. The Short Nutritional Assessment Questionnaire (SNAQ) and Hospital Anxiety Depression Scale (HADS) were used for the analysis. Descriptive statistics and a multilevel generalized linear model were used to clarify the relationship between appetite loss and depression. Data from 468 patients were analyzed. The defined appetite loss was 25.4% (95%CI, 21.5–29.4). High severity of depression was an independent factor for high probability of appetite loss (OR, 1.2; 95%CI, 1.14–1.28; p=0.00). Poor appetite is common 12 months after intensive care and is associated with the severity of depression.

Patients living with cancer often experience serious adverse events due to their condition or its treatments. Those events may lead to a critical care unit admission or even result in death. One of the most important but challenging part of care is to build a caring plan according to the patient’s wishes, meeting his goals and values. Advance directives (ADs) allow everyone to give their preferences in advance regarding life sustaining treatments, continuation, and withdrawal or withholding of treatments in case one is not able to speak his mind anymore. While the absence of ADs is associated with a greater probability of receiving unwanted intensive care around the end of his life, their existence correlates with the respect of the patient’s desires and his greater satisfaction. Although progress has been made to promote ADs’ completion, they are still scarcely used among cancer patients in many countries. Several limitations to their acceptation and use can be detected. Efforts should be made to provide tailored solutions for the identified hindrances. This narrative review aims to depict the situation of ADs in the oncology context, and to highlight the future areas of improvement.

Role identity theory describes the purpose and meaning in life that comes, in part, from occupying social roles. While robustly linked to health and well-being, this may become, however, when an individual is unable to fulfil the perceived requirements of an especially salient role in the way that they believe they should. Amid high rates of mental illness among public safety personnel, we interviewed a purposely selected sample of 21 paramedics from a single service in Ontario, Canada to explore incongruence between an espoused and able-to-enact paramedic role identity. Situated in an interpretivist epistemology, and using successive rounds of thematic analysis, we developed a framework for role identity dissonance wherein chronic, identity-relevant disruptive events cause emotional and psychological distress. While some participants were able to recalibrate their sense of self and understanding of the role, for others, this dissonance was irreconcilable, contributing to disability and lost time from work. In addition to contributing a novel perspective on paramedic mental health and well-being, our work also offers a modest contribution to the theory in using the paramedic context as an example to consider identity disruption through chronic workplace stress.

Retroaortic left renal veins are an often overlooked, but no so rare anatomic anomaly that might cause a few aspecific symptoms and signs, especially flank or inguinal pain, microscopic or even gross hematuria; in the vast majority of cases it is, thought, totally asymptomatic. The nutcracker syndrome that might arise in the case of RLRV is mainly due to the re- duced space between aorta and the vertebral body and the consequent compression on the venal rein; this might in turn cause upstream hypertension, hematuria, varicocele, pain. The compression of RLRV leads to hematuria because of renal venous hypertension, consequent left renal congestion. This upstream venous congestion might result, in some cases, in left-sided varicocele in men and pelvic congestion syndrome in women. From a radiologic point of view, the presence of RLRV and the precise reporting its subtypes is mandatory.

Urinary incontinence (UI) is a common geriatric syndrome affecting bladder health and is especially prevalent in nursing homes (NHs). The aim of the study was to determine the prevalence of UI and its associated factors in 5 Spanish NHs. UI (measured with Minimum Data Set 3.0.), sociodemographic and health-related variables were collected. Chi- square (or Fisher’s) or Student’s t-test (or Mann Whitney U) for bivariate analysis were used, with Prevalence Ratio (PR) as an association measure. The prevalence of UI was 66.1% (CI:95%, 53.6–77.2) and was significantly associated with frailty (PR 1.84; 95%CI 0.96–3.53), faecal incontinence (FI) (PR 1.65; 95%CI 1.02–2.65), anxiety (PR 1.64; 95%CI 1.01–2.66), physical performance (PR 1.77; 95%CI 1.00–3.11) and cognitive state (PR 1.95; 95%CI 1.05–3.60). Statistically significant differences between incontinent-continent groups were found for activities of daily living (ADL) limitations, mobility, quality of life, sedentary behaviour (SB) and handgrip strength. It can be concluded that 2/3 of the residents experienced UI, and its significant associated factors were mainly physical (SB, frailty, physical performance, ADL limitations, mobility, FI and handgrip strength) followed by psycho-cognitive factors (cognition, anxiety and quality of life).

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn), expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with i) γ-Syn overexpression induced by an adeno-associated viral vector and ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA re-lease/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on SNc/VTA γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.

The aim of this paper was to evaluate the changes in the mean bone density values of the midpalatal suture in 392 young patients treated with the Rapid Palatal Expander appliance according to sex, gender, vertical and sagittal skeletal patterns. Materials and Methods. The evaluations were performed using the low-dose protocol cone-beam computed tomography scans at t0 (preoperatively) and t1 (1 year after the beginning of the therapy). The region of interest was used to calculate bone density in Hounsfield units (HU) in the area between the maxillary incisors. Results. CBCT scan data of 196 females and 196 males (mean age of 11,7 years) showed homogeneous and similar density values of the MPS at T0 (547.59 HU - 565.85 HU) and T1 (542.31 - 554.20 HU). Class III skeletal individuals showed a significant higher BD than the II class group at T0, but not at T1. Females showed significantly higher BD than males at t0 and t1. No significant differences were found between the other groups and between two-time points in terms of bone density values of the MPS. Conclusions. Females and III class groups showed significantly higher bone density values than males and II class, respectively. No statistically significant differences were found from T0 to T1 in any groups, suggesting that a similar rate of suture reorganization occurs after the use of the RPE, following reorganization and bone deposition along with the MPS.

Neoadjuvant systemic therapy has now become the the standard in early breast cancer management. Chemotherapy in combination with trastuzumab +/- pertuzumab targeted therapy can improve rates of pathologic complete response (pCR) in patients with HER2-positive breast cancer. Achieving a pCR is considered a good prognostic factor, in particular in patients with more aggressive breast cancer subtypes such as TNBC or HER2 positive cancers. Furthermore, most studies demonstrate that chemotherapy in combination with trastuzumab and pertuzumab is well tolerated. The retrospective analysis presented here concentrates on neoadjuvant therapy with the TCbH-P regimen, with a particular emphasis on patients over 60 years of age. We analysed the factors affecting the achievement of pCR and presented adverse effects of the applied therapies, which opened a discussion about optimizing the therapy of older patients with HER-2 positive breast cancer.

Hematological malignancies are considered the fifth most common cancer in the world. Several risk factors and probable etiological agents have been suspected in the pathomechanism of those malignancies as infections, chemicals, irradiation, etc., and recently, the contribution of the altered gut flora, dysbiosis, was identified also as a possible additional factor to the existing ones. Host, and external factors, like antibiotics, which were identified as a major disruptor of the "normal" gut flora, influence the composition of the microbiome. Considering the several-fold differences in antibiotic consumption patterns and the incidence of hematological malignancies in European countries, the hypothesis was raised that the dominant consumption of certain antibiotic classes might influence the incidence of different hematological malignancies through the modification of gut flora. Comparisons were performed between the average antibiotic consumption databases reported yearly by ECDC (2009-2019) and the incidence rate of Hodkin lymphoma (HL), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and leukemia (LEU) estimated for 2020 in 30 European countries. Applying Spearman calculations, significant positive correlation has been found between the incidence of HL and tetracycline (J01A) consumption (r = 0.399, p = 0,029), NHL and narrow spectrum, beta-lactamase resistant penicillin (J01CF) (r = 0.580, p = 0,001), MM and tetracycline (r = 0.492, p = 0.006), penicillin (J01C) (r = 0.366, p = 0.047), narrow spectrum, beta-lactamase resistant penicillin (J01CF) (r = 0.574, p = 0.001), while strong, significant negative correlation has been recorded between NHL and cephalosporin (r = -0,460, p = 0,011), and quinolone (r = -0,380, p = 0,038). The incidence of LEU did not show any positive or negative association with any antibiotic classes. It is concluded that certain antibiotic classes, in addition to other putative factors, might promote or inhibit the development of different hematological malignancies.

Low back pain is a common problem in the active population, and the second reason for visiting a physician. In patients with lumbar disc protrusion, the nucleus pulposus bulges against the disc and the latter protrudes into the spinal column, but the annulus fibrosus remains intact. The purpose of this study was to prove that starting an early complex rehabilitation treatment results into pain and disability reduction, and increased muscle strength and mobility in patients with lumbar disc protrusions. We performed a prospective cohort study, enrolling 60 patients (25 men and 35 women) aged between 26 to 76 years, diagnosed with lumbar disc protrusion. Patients in the experimental group registered significant improvements in all studied variables (pain, mobility, muscle strength, disability) after 6 months of treatment. The results of our study suggest that, in the lumbar disc disease, a combined rehabilitation program may be more effective in terms of pain and disability reduction, if it starts early after diagnosis. The current study proves the importance of combining electrotherapy with hydrotherapy and physical therapy. Patients who received this treatment combination showed an extremely significant improvement in pain relief, and reduction of functional disability after 6 months of treatment.

Background: The present study was carried out to evaluate the roles of proliferation and angiogenesis in locally aggressive biologic behavior of ameloblastoma versus ameloblastic fibroma; Methods: 30 formalin-fixed paraffin embedded blocks (15 cases of ameloblastoma & 15 cases of ameloblastic fibroma) were used. To evaluate the proliferation, the tissue sections were stained with AgNORs stain. CD105 was used as immunohistochemical marker of angiogenesis. Quantitative evaluations of AgNORs were performed. The mean vascular density was evaluated as a measure for CD105 protein expression by using image analyzer computer system; Results: The mean number of AgNORs dots per nucleus was significantly higher in ameloblastoma as compared to ameloblastic fibroma. Also, the protein level of CD105 showed positive expression and wide distribution that the mean vascular density was significantly higher in ameloblastoma as compared to ameloblastic fibroma; Conclusion: Quantitative evaluation of AgNORs stain & the mean vascular density utilizing CD105 protein expression may reflect a higher proliferative activity and a more locally aggressive biologic behavior of ameloblastoma when compared to ameloblastic fibroma, that other factors may be involved in biologic behavior of ameloblastic fibroma.

The aims of this study were to assess oral health knowledge, attitudes, and practices among orthodontic patients between the ages of 15 and 17 years old compared to adolescents without orthodontic treatment. This cross-sectional study included 392 adolescents drawn from various French teaching hospitals. A closed-ended questionnaire was used to collect data. Adolescents undergoing orthodontic treatment had a higher knowledge of oral health than adolescents without orthodontic treatment. The majority of adolescents for both groups (69%) claimed to brush their teeth twice a day. Regarding complimentary dental material, 81.9% of adolescents without orthodontic treatment never used an interdental brush and 78.8% never used dental floss. For those undergoing orthodontic treatment, 48.5% never used interdental brush. Only 4% of adolescents without and 3% of adolescents with orthodontic treatment never consumed fizzy drinks, 4.9% and 3% never consumed sweets, 4% and 8.4% never ate fast-food. Adolescents without treatment consumed more sodas (p=0.04) and more fast food (p=0.03). Adolescents had insufficient knowledge of oral health. Health education programmes should be implemented to improve adolescents' knowledge and individual oral prophylaxis with interdental brushes.

Purpose: ETV is indicated for treating obstructions of major CSF pathways. The outcome evaluation often yields success rates of only +- 70% for shunt independency. Hence, compromised CSF absorption seems to occur more often than expected. We searched for parameters suitable to assess the involved CSF dynamics. Material and Methods: This was a prospective study in 58 paediatric patients (7.7 yrs. mean age) between 2000 and 2020 with aqueductal stenosis (11/58), obstruction of the aqueduct due to tumor growth (22/58),and connatal hydrocephalus (9/58). The average follow-up interval was 4.7 years. Head circumferences, Evans- and fronto-occipital horn ratios before and 3 months after ETV were obtained as Delta-indices. Furthermore ETV success score (ETVSS), the patency of the aqueduct pre- and postoperatively as well as of the stoma were assessed by flow void signs on MRI. Evaluation on MRI also included the shape of the floor of the 3^rd ventricle and whether or not the septum pellucidum showed signs of perforation. Four patients were analysed pre- and postoperatively via real-time MRI. At least the educational status regarding protected or unprotected education was analyzed. Results:The prevalence of a bowing of the floor of the 3^rd ventricle was 72%, and the ETVSS was 71.0%. In 26 children a septal perforations or an open aqueduct prior to ETV (19) could be identified. Mean ER and FOHR were reduced by 0.03 and 0.05 , respectively. Maintained open (flow void on postop MRI) or perforation could successfully be carried out during endoscopic surgery in 44 patients (79%). The disproportionate increase of head circumference abated in 79.4% of patients. New shunt insertion occurred in 16 patients (27.5%). Intraoperatively upward CSF flow was detected in all cases. Statistical analyses(ANOVA) showed significant results for unprotected education, postoperative ER and FOHR but not for open stoma. Conclusion: The identification of flow through the stoma on postoperative MRI seems to be a necessary but not sufficient condition for ETV success. In our study, ventricular volumes were used as parameters to determine success rates as well as unprotected education. Furthermore, enabling upward CSF flow driven by inspiration seems crucial for successful ETV.

A better study of the postnatal retinal development is not only essential for the in-depth understanding of the nature of the vision system but also may provide insights for treatment developments of eye conditions, such as retinopathy of premature (ROP). To date, quantitative analysis of postnatal retinal development is primarily limited to endpoint histological examination. This study is to validate in vivo optical coherence tomography (OCT) for longitudinal monitoring of postnatal retinal development in developing mouse eyes. Three-dimensional (3D) frame registration and super averaging were adopted to investigate the fine structure of the retina. Interestingly, a hyporeflective layer (HRL) between the nerve fiber layer (NFL) and inner plexiform layer (IPL) was observed in developing eyes and gradually disappeared with aging. To interpret the observed retinal layer kinetics, a model based on eyeball expansion, cell apoptosis, and retinal structural modification was proposed.

Hematological and biochemical reference values in sickle cell disease (SCD) are crucial for patient management and evaluation of interventions. This study was conducted at Muhimbili National Hospital (MNH) in Dar es Salaam, to establish laboratory reference ranges in SCD at steady-state. Patients were grouped into five age groups with respects to their sex. Aggregate functions were used to handle repeated measures within the indi-vidual level in each age group. A nonparametric approach was used to smooth the curves and a parametric approach was used to determine SCD normal ranges. Comparison between males and females and against the general population was documented. Data from 4,422 patients collected from 2004-2015 were analyzed. The majority of the patients (35.41%) were children aged between 5-11 years. There were no significant differences (p≥0.05) in mean corpuscular hemoglobin concentration (MCHC), lymphocytes, basophils and bilirubin direct observed between males and females. Significant differences (p<0.05) were observed in all selected parameters across age groups except neutrophils and MCHC in adults, as well as platelets and alkaline phosphatase in infants when SCD estimates were compared to the general population. Laboratory reference ranges in SCD at steady-state were different from those of the general population and varied with sex and age. The established reference ranges for SCD at steady-state will be a helpful in the management and monitoring of the progress of SCD.

Basildon and Thurrock University Hospital in the East of England region of the United Kingdom (U.K), witnessed rapidly increasing numbers of pregnant women with diabetes, causing overburdened specialist clinics, poorer patient experience and worsening clinical outcomes. This prompted the multidisciplinary team’s remodelling of care pathways, launching the General ownership of Diabetes (GooD) Pregnancy Network in 2014. Contrary to conventional limitation of care to specialist diabetes antenatal clinics, this novel initiative highlights contemporary necessity to equip and empower all maternity stakeholders to deliver basic care of gestational diabetes (GDM). It strategically connects a Midwife Tele-Clinic “hub” to Educating Gestational diabetics Group Sessions (EGGS) and standard antenatal clinics. Patients were key partners, regularly participating in feedback surveys and promoting public awareness by co-producing local newspaper articles that served up their stories as case studies. Furthermore, the EGGS “faculty” includes a former GDM patient whose video testimony has inspired almost 2000 patients and their families; aiming to foster long term healthy lifestyle changes. Final summative evaluation in November 2019 showed the new culture of wider consciousness has shortened ‘diagnosis to first consultation’ intervals and eliminated overbooked specialist clinics (none since January 2016), without further worsening of clinical outcomes. It also boosted research recruitment and avoided additional running costs to the tune of £66,384 a year.