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The effects of healthy aging on the kidney, and how these effects intersect with superimposed diseases, are highly relevant in the context of the population’s increasing longevity. Age-associated changes to podocytes, which are terminally differentiated glomerular epithelial cells, adversely affect kidney health. This review discusses the molecular and cellular mechanisms underlying podocyte aging, how these mechanisms might be augmented by disease in the aged kidney, and approaches to mitigate progressive damage to podocytes. Furthermore, we address how biologic pathways such as those associated with cellular growth confound aging in humans and rodents.

Podocytes undergo defined morphologic changes during development, homeostasis, and aging, and on injury. Quantitative podometric assessments of podocyte endowment provide a powerful tool to interrogate glomerular health. Expanding this approach to a regional assessment demonstrates that the podocytes from cortical, subcortical, and juxtamedullary glomeruli are not only morphologically heterogeneous per se, but respond differently to stressors, such as age and hypertension. This suggests that zonal glomerular changes harbor critical information to understand glomerulopathies.

IMPORTANCE: Multiple interventions are available for the treatment of actinic keratosis (AK). However, most randomized clinical trials and meta-analyses focus on short-term efficacy outcomes. OBJECTIVE: To investigate and synthesize the long-term efficacy (≥12 months) of interventions for AK from parallel-arm randomized clinical trials. DATA SOURCES: Searches in MEDLINE, Embase, and Central were conducted from inception until April 6, 2020. The reference lists of the included studies and pertinent trial registers were hand searched. The study was completed February 27, 2021. STUDY SELECTION: Two reviewers screened the titles and abstracts of 2741 records. Finally, 17 published reports (original studies and follow-up reports) referring to 15 independent randomized clinical trials with an overall sample size of 4252 patients were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data on study, patient, and intervention characteristics. Network meta-analysis (NMA) of each outcome was conducted with a frequentist approach. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidance for NMA was used to assess the certainty of evidence. The revised Cochrane risk-of-bias tool for randomized clinical trials was used to evaluate the methodologic quality. MAIN OUTCOMES AND MEASURES: Participant complete clearance, participant partial clearance, and lesion-specific clearance were the outcomes, with each assessed at least 12 months after the end of treatment. RESULTS: Data from 15 independent randomized clinical trials including 4252 patients were extracted and synthesized. Ten studies were included in an NMA for the outcome of participant complete clearance, with photodynamic therapy with aminolevulinate (ALA-PDT) showing the most favorable risk ratio (RR) compared with placebo (RR, 8.06; 95% CI, 2.07-31.37; GRADE, moderate), followed by imiquimod, 5% (RR, 5.98; 95% CI, 2.26-15.84; GRADE, very low), photodynamic therapy with methyl aminolevulinate (MAL-PDT) (RR, 5.95; 95% CI, 1.21-29.41; GRADE, low), and cryosurgery (RR, 4.67; 95% CI, 1.36-16.66; GRADE, very low). Similarly, ALA-PDT had the highest RR in the NMA for lesion-specific clearance (RR, 5.08; 95% CI, 2.49-10.33; GRADE, moderate). No NMA was possible for participant partial clearance owing to poor reporting of this outcome. CONCLUSIONS AND RELEVANCE: This systematic review and network meta-analysis found that therapy including ALA-PDT, imiquimod, 5%, MAL-PDT, and cryosurgery was associated with significant long-term efficacy in the NMA. This study provides data for a possible use in an evidence-based framework for selecting interventions with sustained lesion clearance.

Das kutane Plattenepithelkarzinom (cSCC) ist der zweithäufigste Hautkrebs und entsteht vor allem in chronisch sonnengeschädigter Haut. Nachgewiesene Hauptrisikofaktoren sind Immunsuppression, genetische Störungen wie Xeroderma pigmentosum (XP), Exposi­tion gegenüber bestimmten Medikamenten und Umweltnoxen. Therapie der Wahl bei cSCC ist die chirurgische Entfernung, die im Frühstadium meist kurativ erfolgt. Einige wenige Patienten entwickeln jedoch lokal fortgeschrittene Tumoren oder Fernmetastasen, die nach wie vor schwierig zu behandeln sind. Die auf CTLA-4, PD-L1 und PD-1 ausgerichtete Immun-Checkpoint-Blockade (ICB) hat die onkologische Therapie und insbesondere die Behandlung von Hautkrebserkrankungen als Tumoren mit hoher Mutationslast sehr stark verändert. In der vorliegenden Übersichtsarbeit liegt der Fokus auf den Unterschieden zwischen dem kutanen Plattenepithelkarzinom und dem kutanen Melanom (CM) sowie den damit verbundenen Implikationen für die Therapie. Darüber hinaus werden die aktuelle Evidenzlage zur ICB für die Behandlung des fortgeschrittenem cSCC zusammengefasst und die Chancen und Risiken dieser therapeutischen Option für diese Krebsentität erörtert. Ferner richten wir das Augenmerk auf spezielle interessierende Subgruppen von Patienten wie etwa Organtransplantatempfänger, Patienten mit malignen hämatologischen Erkrankungen, XP und Feldkanzerisierung.

The mental health of the UK population declined at the onset of the COVID-19 pandemic. Convenience sample surveys indicate that recovery began soon after. Using a probability sample, we tracked mental health during the pandemic to characterise mental health trajectories and identify predictors of deterioration.

ABSTRACTIntroduction:Actinic keratosis (AK) are proliferations of atypical keratinocytes that may eventually progress to cutaneous squamous cell carcinoma. Therefore, AK requires consequent and early treatment. Areas covered:A variety of effective approaches is currently available for the clearance of AK. These interventions may be applied either in a lesion-directed or field-directed mode as AK can occur as single or multiple lesions. Field-directed approaches typically comprise topical drug-mediated interventions which aim at eliminating all visible lesions and also at clearing subclinical changes of the actinically damaged field. However, most treatment options are associated with local adverse events such as erythema, scaling, pain, and rarely with systemic symptoms. This expert review provides a comprehensive and up-to-date overview of the safety considerations of the commonly prescribed topical treatment agents cyclooxygenase inhibitors, 5-fluorouracil, imiquimod, ingenol mebutate, and photodynamic therapy. All these therapies have been proven efficient, yet they differ considerably regarding their safety profile. Expert opinion:In the future, safety concerns will relate to long-term and irreversible adverse drug events instead of application site reactions. In particular, the rate of treatment-associated non-melanoma skin cancers will increasingly come into focus and warrant investigation in postmarketing surveillance trials with a long-term follow-up.

ObjectivesThis study reports preliminary findings on the prevalence of, and factors associated with, mental health and well-being outcomes of healthcare workers during the early months (April–June) of the COVID-19 pandemic in the UK.MethodsPreliminary cross-sectional data were analysed from a cohort study (n=4378). Clinical and non-clinical staff of three London-based NHS Trusts, including acute and mental health Trusts, took part in an online baseline survey. The primary outcome measure used is the presence of probable common mental disorders (CMDs), measured by the General Health Questionnaire. Secondary outcomes are probable anxiety (seven-item Generalised Anxiety Disorder), depression (nine-item Patient Health Questionnaire), post-traumatic stress disorder (PTSD) (six-item Post-Traumatic Stress Disorder checklist), suicidal ideation (Clinical Interview Schedule) and alcohol use (Alcohol Use Disorder Identification Test). Moral injury is measured using the Moray Injury Event Scale.ResultsAnalyses showed substantial levels of probable CMDs (58.9%, 95% CI 58.1 to 60.8) and of PTSD (30.2%, 95% CI 28.1 to 32.5) with lower levels of depression (27.3%, 95% CI 25.3 to 29.4), anxiety (23.2%, 95% CI 21.3 to 25.3) and alcohol misuse (10.5%, 95% CI 9.2 to 11.9). Women, younger staff and nurses tended to have poorer outcomes than other staff, except for alcohol misuse. Higher reported exposure to moral injury (distress resulting from violation of one’s moral code) was strongly associated with increased levels of probable CMDs, anxiety, depression, PTSD symptoms and alcohol misuse.ConclusionsOur findings suggest that mental health support for healthcare workers should consider those demographics and occupations at highest risk. Rigorous longitudinal data are needed in order to respond to the potential long-term mental health impacts of the pandemic.

ObjectivesWhile most UK military personnel transition successfully into civilian life, some experience unemployment and disability, which may be partly attributable to in-service factors. This study aims to determine the degree to which in-service mental health problems impact on postservice benefit claims.MethodsUsing data from a cohort of 5598 recent leavers from regular service in the UK Armed Forces linked with data from the Department for Work and Pensions, we assessed associations between in-service mental health and postservice benefit claims, and the population attributable fraction (PAF) of benefit claims related to in-service mental health. An analysis with postservice mental ill health as mediator was performed to determine the degree to which the observed effects were a consequence of persistent illness, as opposed to remitted.ResultsMental illness occurring in-service predicted both unemployment and disability claims, partly mediated by postservice health (23%–52% total effects mediated), but alcohol misuse did not. Common mental disorder (CMD) (PAF 0.07, 95% CI: 0.02 to 0.11) and probable post-traumatic stress disorder (PTSD) (PAF 0.05, 95% CI 0.01 to 0.09) contributed to unemployment claims. Probable PTSD was the largest contributor to disability claims (PAF 0.25, 95% CI 0.13 to 0.36), with a smaller contribution from CMD (PAF 0.16, 95% CI 0.03 to 0.27).ConclusionsIn-service mental ill health gives rise to benefit claims. These effects are only partly mediated by postservice mental health, implying that in-service (or pre-service) mental issues have carry-over effects into civilian life even if remitted. Better prevention and treatment of in-service PTSD symptoms may well reduce postservice disability claims.

Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.

The potential impact of the COVID-19 pandemic on population mental health is of increasing global concern. We examine changes in adult mental health in the UK population before and during the lockdown.

AbstractAimsPolice employees may experience high levels of stress due to the challenging nature of their work which can then lead to sickness absence. To date, there has been limited research on sickness absence in the police. This exploratory analysis investigated sickness absence in UK police employees.MethodsSecondary data analyses were conducted using data from the Airwave Health Monitoring Study (2006–2015). Past year sickness absence was self-reported and categorised as none, low (1–5 days), moderate (6–19 days) and long-term sickness absence (LTSA, 20 or more days). Descriptive statistics and multinomial logistic regressions were used to examine sickness absence and exploratory associations with sociodemographic factors, occupational stressors, health risk behaviours, and mental health outcomes, controlling for rank, gender and age.ResultsFrom a sample of 40,343 police staff and police officers, forty-six per cent had no sickness absence within the previous year, 33% had a low amount, 13% a moderate amount and 8% were on LTSA. The groups that were more likely to take sick leave were women, non-uniformed police staff, divorced or separated, smokers and those with three or more general practitioner consultations in the past year, poorer mental health, low job satisfaction and high job strain.ConclusionsThe study highlights the groups of police employees who may be more likely to take sick leave and is unique in its use of a large cohort of police employees. The findings emphasise the importance of considering possible modifiable factors that may contribute to sickness absence in UK police forces.

The December, 2019 coronavirus disease outbreak has seen many countries ask people who have potentially come into contact with the infection to isolate themselves at home or in a dedicated quarantine facility. Decisions on how to apply quarantine should be based on the best available evidence. We did a Review of the psychological impact of quarantine using three electronic databases. Of 3166 papers found, 24 are included in this Review. Most reviewed studies reported negative psychological effects including post-traumatic stress symptoms, confusion, and anger. Stressors included longer quarantine duration, infection fears, frustration, boredom, inadequate supplies, inadequate information, financial loss, and stigma. Some researchers have suggested long-lasting effects. In situations where quarantine is deemed necessary, officials should quarantine individuals for no longer than required, provide clear rationale for quarantine and information about protocols, and ensure sufficient supplies are provided. Appeals to altruism by reminding the public about the benefits of quarantine to wider society can be favourable.

Plasmacytoid dendritic cells (pDCs) are key players in the antiviral immune response and type III IFNs such as IL‐29 appear to play a pivotal role in pDC function. Pronounced susceptibility to viral infections in neonates is partly resulting from diminished antiviral immune mechanisms. Accordingly, the aim of the present study was to investigate the impact of IL‐29 in the altered immune response of neonatal pDCs. PBMCs of adult and term newborns were stimulated with CpG‐ODN2216 in the presence or absence of IL‐29 and assessed for IFN‐α production, downstream‐signaling, and activation marker expression. A significantly lower IL‐29 production after TLR9‐specific stimulation was demonstrated in neonatal pDCs. IL‐29 enhanced the IFN‐α production of pDCs in adults compared to newborns. Newborn pDCs displayed a significantly lower surface expression of IL‐10 and IL‐28Rα receptor resulting in diminished STAT1 and IRF7 activation. Interestingly, concomitant stimulation with CpG‐ODN2216/IL‐29 had no impact on the expression of surface activation and maturation markers of pDCs in neither population. The diminished antiviral immune response of neonatal pDCs is associated with reduced production and cellular responses toward IL‐29. Potential therapeutic agents enhancing the IL‐29 response in neonatal pDCs possibly augment viral protection in newborns. Reduced IL‐29 secretion and responsiveness of neonatal plasmacytoid dendritic cells mainly contributes to reduced IFNα response against viral components.