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Background Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in filaggrin (FLG). Objectives To explore the phenotype of participants (age < 31 years) with atopic eczema of Bangladeshi ancestry from East London and investigate which factors best associate with LoF FLG variants. Methods A cross-sectional study with participants recruited between May 2018 and December 2020. Patterns of palmar linearity were categorized and modelled with the Eczema Area and Severity Index (EASI), transepidermal water loss (TEWL), skin hydration (SH) and LoF FLG variants. Results There were 506 complete cases available. Five palm patterns were noted. The ‘prominent diamond’ pattern associated best with EASI [marginal effects (ME) 2.53, 95% confidence interval (CI) 1.74–3.67], SH (ME 0.85, 95% CI 0.78–0.96) and TEWL (ME 1.32, 95% CI 1.11–1.62). Using five palm patterns had some ability to discriminate LoF FLG variants [area under the receiver operator characteristic (AUROC) 76.32%, 95% CI 71.91–80.73], improving to 77.99% (73.70–82.28) with the addition of SH. In subgroup analysis with only fine perpendicular/prominent diamond patterns the AUROC was 89.11% (95% CI 84.02–94.19). Conclusions This was a single-centre study design with humans classifying clinical patterns. The stability of temperature and humidity was not guaranteed across TEWL and SH measurements despite using a climate-controlled room. Palm patterns associate with EASI and TEWL. The fine perpendicular/prominent diamond patterns are markers to detect the absence/presence of LoF FLG variants, respectively.

To mark the 75th anniversary of the Annals, we look at the evolution of the Lumley Library's service over the past 75 years.

Herd size expansion combined with the seasonal workload on pasture-based dairy farms has led to an increased focus on techniques that can improve farm labor efficiency such as work practices and technologies. The objective of this study was to identify the work practices and technologies associated with labor efficiency of particular tasks, and estimate the time savings that could be made through their implementation during the period of peak labor input on spring-calving dairy farms. Data from an existing labor time-use study, completed from February 1 to June 30, 2019 (150 d), on 76 Irish dairy farms was used in conjunction with a survey on work practice and technology implementation. One hundred ten work practices and technologies were included in the initial survey, and of these, 59 were found to have an association with labor efficiency for their respective tasks. Best practice, regarding labor efficiency, was identified for the 59 work practices and technologies. An accumulation score was compiled for work practice and technology implementation; each farm received one point for each work practice or technology implemented. On average, farms implemented 31 labor-efficient work practices and technologies (ranging from 10-45). The most labor-efficient 25% of farms implemented a greater number of work practices and technologies (n = 37) than the least labor-efficient 25% of farms (n = 25). Multiple regression models estimated that each additional work practice or technology implemented would improve farm labor efficiency by 0.6 h/cow. Additionally, backward-regression models were used to predict the labor-savings associated with the most important work practices and technologies. Labor-savings were estimated for 12 significant individual work practices and technologies, of which 5 were related to milking, 4 to calf care, 2 to cow care, and one to grassland management. The work practices and technologies that offered the largest labor-savings included having one person in the milking pit during the mid-lactation period (-3.04 h/cow), having automatic cluster removers present (-2.55 h/cow) and contracting slurry spreading (-1.78 h/cow). This study focused on the variety of labor-efficient work practices and technologies available and highlighted those that farmers should focus on to improve labor efficiency. The results indicated that there is scope for improvement in the adoption of labor-saving work practices and technologies on many farms. The positive effect of implementing the identified labor-saving techniques on labor efficiency could be used to support future adoption.

One of the most important cytosolic Ca(2+) buffers present in mouse fast-twitch myofibers, but not in human myofibers, is parvalbumin (PV). Previous work using conventional PV gene (PV) knockout (PV-KO) mice suggests that lifelong PV ablation increases fatigue resistance, possibly due to compensations in mitochondrial volume. In this work, PV ablation was induced only in adult mice (PV-KO), and contractile and cytosolic Ca(2+) responses during fatigue were studied in isolated muscle and intact single myofibers. Results were compared with control littermates (PV-Ctr). We hypothesized that the reduced myofiber cytosolic Ca(2+) buffering developed only in adult PV-KO mice leads to a larger cytosolic free Ca(2+) concentration ([Ca(2+)](c)) during repetitive contractions, increasing myofiber fatigue resistance. Extensor digitorum longus (EDL) muscles from PV-KO mice had higher force in unfused stimulations (∼50%, P < 0.05) and slowed relaxation (∼46% higher relaxation time, P < 0.05) versus PV-Ctr, but muscle fatigue resistance or fatigue-induced changes in relaxation were not different between genotypes (P > 0.05). In intact single myofibers from flexor digitorum brevis (FDB) muscles, basal and tetanic [Ca(2+)](c) during fatiguing contractions were higher in PV-KO (P < 0.05), accompanied by a greater slowing in estimated sarcoplasmic reticulum (SR) Ca(2+)-pumping versus PV-Ctr myofibers (∼84% reduction, P < 0.05), but myofiber fatigue resistance was not different between genotypes (P > 0.05). Our results demonstrate that although the estimated SR Ca(2+) uptake was accelerated in PV-KO, the total energy demand by the major energy consumers in myofibers, the cross-bridges, and SR Ca(2+) ATPase were not altered enough to affect the energy supply for contractions, and therefore fatigue resistance remained unaffected. NEW & NOTEWORTHY Parvalbumin (PV) is a cytosolic Ca(2+) buffer that is present in mouse myofibers but not in human muscle. We show that inducible knockout of PV leads to increases in myofiber cytosolic free Ca(2+) concentrations and slowing of Ca(2+) pumping during fatigue versus control mice. However, PV ablation does not interfere with fatigue-induced slowing in relaxation or fatigue resistance. These data support the use of mouse muscle as a suitable model to investigate human muscle fatigue.

Background In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. Methods Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. Results Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1,152 patients have been evaluated with an overall solve rate of 14.1% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. Conclusion Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Background MRNA COVID-19 vaccine is more effective than traditional vaccines due to superior immune activation. However, the impact of mRNA COVID-19 vaccine on triggering de novo/relapsing glomerulonephritis (GN) is limited. We report a case series of patients who developed new or relapsing GN post vaccination. Method We evaluated baseline characteristics, vaccine type and clinical outcomes of 13 patients from our institution who had a new diagnosis or relapse of their GN post mRNA COVID-19 vaccination. Results Of 13 patients, 8 patients were newly diagnosed GNs and 5 patients had relapse. Median age was 62 years (range 19-83 years). Autoimmune disease (38%) was the most prevalent underlying disease followed by cancer (23%). Majority of patients were white male. IgA nephropathy (IgAN) was the most common GN in our series (5 patients, 38%) followed by membranous nephropathy (MN) (3 patients, 23%). One patient with IgAN had evidence of IgA deposits prior to vaccination suggesting that the immune activation following vaccination triggered a flare of the disease. Our case series also included the first case report of tip-variant focal segmental glomerulosclerosis, NELL-1 associated MN, and atypical anti-GBM nephritis. Seventy seven percent developed acute kidney injury with the majority being KDIGO stage 1 (67%). Outcome are favorable with 80% responding to therapy. Conclusions New cases and relapse of GN can present shortly after mRNA COVID-19 vaccination. New cases of IgAN may result from unmasking of undiagnosed IgAN due to robust immune activation rather than development of new deposits.

Objective To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. Patients and Methods Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. Results The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P Conclusion In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.

Recent studies identified underlying genetic causes in a proportion of patients with various forms of kidney disease. In particular, genetic testing reclassified some focal segmental glomerulosclerosis (FSGS) cases into collagen type 4 (COL4)-related nephropathy. This knowledge has major implications for counseling prospective transplant recipients about recurrence risk and screening biologically related donors. We describe our experience incorporating genetic testing in our kidney transplant multidisciplinary practice.Patients' DNA was analyzed using whole exome sequencing for a comprehensive kidney gene panel encompassing 344 genes associated with kidney diseases and candidate genes highly expressed in the kidney. Results were correlated with phenotype by a multidisciplinary committee of nephrologists, renal pathologists, geneticists, and genetic counselors. Between October 2018 and July 2020, 30 recipient and 5 donor candidates completed testing.Among recipient candidates, 24 (80%) carried the diagnosis of FSGS, 2 (6.7%) tubulointerstitial nephritis, and 1 (3.3%) nephrolithiasis, and 3 (10%) had an unknown cause of kidney disease. The yield for pathogenic/likely pathogenic variants was 43.3%, with majority being COL4 variants (53.8%). Among those with FSGS diagnosis, the yield was 10 of 24 (41.6%), with 29% reclassified into a COL4-related nephropathy. Family history of kidney disease was the only clinical characteristic difference between recipients with positive and negative results (76.9 versus 29.4%; P = 0.025). One of 5 donors tested positive for a pathogenic/likely pathogenic variant and was excluded from donation.We conclude that thoughtful use of genetic testing can be valuable for kidney donor selection and transplant recipient management.

Sedation Practice in Intensive Care Evaluation (SPICE-III) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation.to quantify the association of different infusion rates of dexmedetomidine or propofol, given in combination, with mortality and if this is modified by age.We included 1177 patients randomized in SPICE-III to receive dexmedetomidine and given supplemental propofol, stratified by age (65 or ≤65 years). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine, while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression, adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality.Younger patients 598/1177(50.8%) received a significantly higher dose of both sedatives compared with older patients, to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 mcg/kg/h) was associated with reduced adjusted mortality in younger, but not older patients. This was consistent with multivariable regression modelling [hazard ratio: 0.59(95% Confidence Interval 0.43-0.78),P0.0001], adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality [HR:1.30(95%CI 1.03-1.65), P=0.029].In patients ≤ 65 years sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registration available at www.gov, ID: NCT01728558.

In response to a new set of challenges facing universities today—developing the next generation of leaders while integrating existing and emerging technologies to transform learning spaces—a team at Penn State University conducted research that culminated in the Virtual Transformational Leadership Development (VTLD) Experience, a course that addresses these challenges in a virtual format. The research examined the contribution of the arts, in conjunction with immersive technologies, towards promoting student engagement. Student interviews indicated that the creation of high impact practices revolving around the arts ultimately generates a memorable and involved experience that more frequently includes topics of social relevancy such as racial equity. Furthermore, the pairing of these methods with relevant and emerging technologies, such as artificial intelligence (AI) and virtual reality (VR), effectively creates an educational experience that more personally suits a student’s needs in this type of transformational course. Leveraging Research: The VTLD Experience leverages the findings of its associated study, such as the importance of incorporating High Impact Practices (HIPs), to create transformational and interactive learning experiences for undergraduate students. HIPs refer to experiences that more heavily involve students and require them to reflect on their engagement with specific materials, such as being exposed to and attending an arts performance and interacting with artists afterwards. Through the integration of existing and emerging technologies, this learning experience will provide lesson modules that include viewing and reflecting on works of art, such as visual art, performances, and other forms of creative expression. The research demonstrates how the arts engage students in a variety of subjects, such as mindfulness practices to develop mindful leadership skills and lessons about global diversity, equity, inclusion, and belonging. Through exposure to different perspectives to promote cognitive diversity, this learning experience seeks to nurture the whole student – thoughts, feelings, body – by developing skill sets and mindsets to increase their senses of curiosity, empathy, emotional and cultural intelligence, and to develop resilience. Cumulative vision: “Combining teaching and learning with existing and emerging technologies, The VTLD Experience, in conjunction with the human experience, generates a vision for the classroom of the future. These technologies enable learning spaces where students and faculty can take advantage of virtual arts programming to “attend” events around the world that would otherwise be inaccessible, such as museums, works of art, and live performances. This is an example of what the classroom of the future might look like, and we are actively pursuing this vision. We will be offering a pilot of The VTLD Experience fall 2021 and spring 2022 semesters at Penn State. Future enhancements of the experience will incorporate additional technologies and applications.

Next Generation Sequencing (NGS) has become an important tool in the biological sciences and has a growing number of applications across medical fields. Currently, few undergraduate programs provide training in the design and implementation of NGS applications. Here, we describe an inquiry‐based laboratory exercise for a college‐level molecular biology laboratory course that uses real‐time MinION deep sequencing and bioinformatics to investigate characteristic genetic variants found in cancer cell‐lines. The overall goal for students was to identify non‐small cell lung cancer (NSCLC) cell‐lines based on their unique genomic profiles. The units described in this laboratory highlight core principles in multiplex PCR primer design, real‐time deep sequencing, and bioinformatics analysis for genetic variants. We found that the MinION device is an appropriate, feasible tool that provides a comprehensive, hands‐on NGS experience for undergraduates. Student evaluations demonstrated increased confidence in using molecular techniques and enhanced understanding of NGS concepts. Overall, this exercise provides a pedagogical tool for incorporating NGS approaches in the teaching laboratory as way of enhancing students' comprehension of genomic sequence analysis. Further, this NGS lab module can easily be added to a variety of lab‐based courses to help undergraduate students learn current DNA sequencing methods with limited effort and cost.

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR

Introduction Cystic expansion damaging the parenchyma is thought to lead to end-stage kidney disease (ESKD) in autosomal dominant polycystic kidney disease (ADPKD). Here we characterized genotypic and phenotypic attributes of ADPKD at time of ESKD. Methods This is a retrospective cross-sectional study of patients with ADPKD with ESKD evaluated at Mayo Clinic with available abdominal computed tomography (CT) or magnetic resonance imaging (MRI). Kidney volumes were measured (total kidney volume adjusted for height [HtTKV]), Mayo Image Class (MIC) calculated, ADPKD genotype determined, and clinical and laboratory features obtained from medical records. Results Differences in HtTKV at ESKD were associated with patient age and sex; older patients and women had smaller HtTKV at ESKD. HtTKV at ESKD was observed to be 12.3% smaller with each decade of age (P < 0.01); but significant only in women (17.8%, P < 0.01; men 6.9%, P = 0.06). Patients with onset of ESKD at 61 years had different characteristics, with a shift from youngest to oldest in male to female enrichment, MIC from 1D/1E to 1B/1C, likely fully penetrant PKD1 mutations from 95% to 42%, and presence of macrovascular disease from 8% to 40%. Macrovascular disease was associated with smaller kidneys in female patients. Conclusion HtTKV at ESKD was smaller with advancing age in patients with ADPKD, particularly in women. These novel findings provide insight into possible underlying mechanisms leading to ESKD, which differ between younger and older individuals. Cystic growth is the predominant mechanism in younger patients with ESKD, whereas aging-related factors, including vascular disease, becomes potentially important as patients age., Graphical abstract

The present study examined whether teacher–child closeness and conflict across kindergarten and first grade varied by gender and disruptive behavior at kindergarten entry within a sample of 324 predominantly Black children from low-income, urban households. Three main findings emerged from the analyses. First, contrary to findings from previous work that revealed stability in closeness and conflict across the first few years of elementary school, this study identified significant changes in closeness across the kindergarten and first grade years. Second, girls experienced more closeness with teachers than boys across both kindergarten and first grade, and the rate of change in teacher–child closeness differed by child gender across time. Finally, across both school years, associations between gender and teacher–child conflict varied by level of disruptive behavior at the beginning of kindergarten, such that boys with high levels of disruptive behavior experienced more overall conflict with teachers than girls with high levels of disruptive behavior.

The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman's capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman's capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.

We studied sources of variation between countries in per-capita mortality from COVID-19 (caused by the SARS-CoV-2 virus). Potential predictors of per-capita coronavirus-related mortality in 200 countries by May 9, 2020 were examined, including age, gender, obesity prevalence, temperature, urbanization, smoking, duration of the outbreak, lockdowns, viral testing, contact-tracing policies, and public mask-wearing norms and policies. Multivariable linear regression analysis was performed. In univariate analysis, the prevalence of smoking, per-capita gross domestic product, urbanization, and colder average country temperature were positively associated with coronavirus-related mortality. In a multivariable analysis of 196 countries, the duration of the outbreak in the country, and the proportion of the population aged 60 years or older were positively associated with per-capita mortality, whereas duration of mask-wearing by the public was negatively associated with mortality (all P < 0.001). Obesity and less stringent international travel restrictions were independently associated with mortality in a model which controlled for testing policy. Viral testing policies and levels were not associated with mortality. Internal lockdown was associated with a nonsignificant 2.4% reduction in mortality each week (P = 0.83). The association of contact-tracing policy with mortality was not statistically significant (P = 0.06). In countries with cultural norms or government policies supporting public mask-wearing, per-capita coronavirus mortality increased on average by just 16.2% each week, as compared with 61.9% each week in remaining countries. Societal norms and government policies supporting the wearing of masks by the public, as well as international travel controls, are independently associated with lower per-capita mortality from COVID-19.

Introduction Heterogeneity of nephrotic diseases and a lack of validated biomarkers limits interventions and reduces the ability to examine outcomes. Urinary CD80 is a potential biomarker for minimal change disease (MCD) steroid-sensitive nephrotic syndrome (NS). We investigated and validated a CD80 enzyme-linked immunosorbent assay (ELISA) in urine in a large cohort with a variety of nephrotic diseases. Methods A commercial CD80 ELISA was enhanced and analytically validated for urine. Patients were from Mayo Clinic (307) and Nephrotic Syndrome Study Network Consortium (NEPTUNE; 104) as follows: minimal change disease (MCD, 56), focal segmental glomerulosclerosis (FSGS, 92), lupus nephritis (LN, 25), IgA nephropathy (IgAN, 20), membranous nephropathy (MN, 49), autosomal dominant polycystic kidney disease (ADPKD, 10), diabetic nephropathy (DN; 106), pyuria (19), and controls (34). Analysis was by Kruskal−Wallis test, generalized estimating equation (GEE) models, and receiver operating characteristic (AUC) curve. Results Urinary CD80/creatinine values were highest in MCD compared to other glomerular diseases and were increased in DN with proteinuria >2 compared to controls (control = 36 ng/g; MCD = 139 ng/g, P < 0.01; LN = 90 ng/g, P < 0.12; FSGS = 66 ng/g, P = 0.18; DN = 63, P = 0.03; MN = 69 ng/g, P = 0.33; ng/g, P = 0.07; IgA = 19 ng/g, P = 0.09; ADPKD = 42, P = 0.36; and pyuria 31, P = 0.20; GEE, median, P vs. control). In proteinuric patients, CD80 concentration appears to be independent of proteinuria levels, suggesting that it is unrelated to nonspecific passage across the glomeruli. CD80/creatinine values were higher in paired relapse versus remission cases of MCD and FSGS (P < 0.0001, GEE). Conclusion Using a validated ELISA, urinary CD80 levels discriminate MCD from other forms of NS (FSGS, DN, IgA, MN) and primary from secondary FSGS., Graphical abstract

Background Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but remains infrequently and inconsistently measured in clinical trials and poorly managed in clinical settings. A recently completed systematic review of pain in ADPKD identified 26 different outcome measures. None of these measures were considered appropriate as a core outcome measure due to the lack of patient-important dimensions, inadequate content, relatively long duration of completion time and limited evidence to support psychometric robustness. Methods We convened an international Standardized Outcomes in Nephrology–Polycystic Kidney Disease consensus workshop involving 21 patients/caregivers and 40 health professionals (clinicians, nurses, researchers, policy makers and industry representatives) from 18 countries to discuss the identification or development of a core outcome measure for pain. Results Four themes were identified highlighting fundamental issues for the measurement of pain in ADPKD: distressing and disrupting life participation; variability and ambiguity in defining pain; stigma, frustration and adaptation to pain; and ensuring validity and feasibility of pain measures. Conclusions Existing measures were found to be insufficient in capturing pain as a core outcome and there was consensus on the need for a new validated measure that is simple, succinct and addresses the impact of pain on life participation. This measure will facilitate the appropriate prioritization of pain in all trials and guide clinical decision making in people with ADPKD.

A bi-directional relationship exists between obstructive sleep apnoea and obesity. Very low energy diets (VLEDs) have been show to significantly reduce weight in overweight and obese patients. However, they can cause excessive fat free mass (FFM) loss, which adversely impacts health. Concurrent exercise training is a potential method of mitigating FFM loss. This systematic review and meta-analysis aims to assess the impact of exercise on FFM loss during VLED-induced weight loss in the overweight and obese. Medline, Embase, Cochrane Register of Controlled Trials and CINAHL were searched from inception to December 2021 for studies that compared VLED groups with and without concurrent exercise in overweight and obese adults. Studies were included if they reported changes in FFM, VLED was restricted to less than 800kcal/day and exercise programmes were at least low intensity. Following duplicate removal, 6516 studies were screened and 63 full text articles were reviewed, of which 7 were included. The primary outcome is change in FFM between groups and a meta-analysis is planned if deemed appropriate. Results will be available in September. This review will provide evidence regarding the impact of exercise on FFM loss when undertaken concurrently with a VLED. Furthermore, it will help inform practice guidelines around exercise prescription for preserving FFM while undertaking a VLED to ensure better patient health outcomes. It will also help inform translational studies for weight reduction in overweight and obese sleep apnoeics.

Late presentation for care is a major impediment to the prevention and effective treatment of HIV infection. Older individuals are at increased risk of late presentation, represent a growing proportion of people with late presentation, and might require interventions tailored to their age group. We provide a summary of the literature published globally between 2016-21 (reporting data from 1984-2018) and quantify the association of age with delayed presentation. Using the most common definitions of late presentation and older age from these earlier studies, we update this work with data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium, focusing on data from 2000-19, encompassing four continents. Finally, we consider how late presentation among older individuals might be more effectively addressed as electronic medical records become widely adopted.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

ImportanceUnderstanding the severity of postvaccination SARS-CoV-2 (ie, COVID-19) breakthrough illness among people with HIV (PWH) can inform vaccine guidelines and risk-reduction recommendations.ObjectiveTo estimate the rate and risk of severe breakthrough illness among vaccinated PWH and people without HIV (PWoH) who experience a breakthrough infection.Design, Setting, and ParticipantsIn this cohort study, the Corona-Infectious-Virus Epidemiology Team (CIVET-II) collaboration included adults (aged ≥18 years) with HIV who were receiving care and were fully vaccinated by June 30, 2021, along with PWoH matched according to date fully vaccinated, age group, race, ethnicity, and sex from 4 US integrated health systems and academic centers. Those with postvaccination COVID-19 breakthrough before December 31, 2021, were eligible.ExposuresHIV infection.Main Outcomes and MeasuresThe main outcome was severe COVID-19 breakthrough illness, defined as hospitalization within 28 days after a breakthrough SARS-CoV-2 infection with a primary or secondary COVID-19 discharge diagnosis. Discrete time proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% CIs of severe breakthrough illness within 28 days of breakthrough COVID-19 by HIV status adjusting for demographic variables, COVID-19 vaccine type, and clinical factors. The proportion of patients who received mechanical ventilation or died was compared by HIV status.ResultsAmong 3649 patients with breakthrough COVID-19 (1241 PWH and 2408 PWoH), most were aged 55 years or older (2182 patients [59.8%]) and male (3244 patients [88.9%]). The cumulative incidence of severe illness in the first 28 days was low and comparable between PWoH and PWH (7.3% vs 6.7%; risk difference, −0.67%; 95% CI, −2.58% to 1.23%). The risk of severe breakthrough illness was 59% higher in PWH with CD4 cell counts less than 350 cells/μL compared with PWoH (aHR, 1.59; 95% CI, 0.99 to 2.46; P = .049). In multivariable analyses among PWH, being female, older, having a cancer diagnosis, and lower CD4 cell count were associated with increased risk of severe breakthrough illness, whereas previous COVID-19 was associated with reduced risk. Among 249 hospitalized patients, 24 (9.6%) were mechanically ventilated and 20 (8.0%) died, with no difference by HIV status.Conclusions and RelevanceIn this cohort study, the risk of severe COVID-19 breakthrough illness within 28 days of a breakthrough infection was low among vaccinated PWH and PWoH. PWH with moderate or severe immune suppression had a higher risk of severe breakthrough infection and should be included in groups prioritized for additional vaccine doses and risk-reduction strategies.

Dendritic cell (DC) activation is characterized by sustained commitment to glycolysis that is a requirement for survival in DC subsets that express inducible NO synthase (Nos2) due to NO-mediated inhibition of mitochondrial respiration. This phenomenon primarily has been studied in DCs from the classic laboratory inbred mouse strain C57BL/6J (B6) mice, where DCs experience a loss of mitochondrial function due to NO accumulation. To assess the conservation of NO-driven metabolic regulation in DCs, we compared B6 mice to the wild-derived genetically divergent PWD/PhJ (PWD) strain. We show preserved mitochondrial respiration and enhanced postactivation survival due to attenuated NO production in LPS-stimulated PWD DCs phenocopying human monocyte-derived DCs. To genetically map this phenotype, we used a congenic mouse strain (B6.PWD-Chr11.2) that carries a PWD-derived portion of chromosome 11, including Nos2, on a B6 background. B6.PWD-Chr11.2 DCs show preserved mitochondrial function and produce lower NO levels than B6 DCs. We demonstrate that activated B6.PWD-Chr11.2 DCs maintain mitochondrial respiration and TCA cycle carbon flux, compared with B6 DCs. However, reduced NO production by the PWD Nos2 allele results in impaired cellular control of Listeria monocytogenes replication. These studies establish a natural genetic model for restrained endogenous NO production to investigate the contribution of NO in regulating the interplay between DC metabolism and immune function. These findings suggest that reported differences between human and murine DCs may be an artifact of the limited genetic diversity of the mouse models used, underscoring the need for mouse genetic diversity in immunology research.

Background Studies comparing all treatment options for frequently-relapsing/steroid-dependent (FR/SD) minimal change disease (MCD) in adults are lacking. Methods Medical records of 76 adults with FR/SD MCD who were treated with corticosteroids as the first-line therapy were reviewed. Treatment options were compared for the time to relapse, change of therapy and progression (relapse on full-dose treatment). Results Second-line treatments included rituximab (RTX; n = 13), mycophenolate mofetil (MMF; n = 12), calcineurin inhibitors (CNI; n = 26) and cyclophosphamide (CTX; n = 16). During the second-line treatments, 48 (71.6%) patients relapsed at median 17 (range 2–100) months. The majority of relapses occurred during dose tapering or off drug. Twenty of 65 (30.8%) changed therapy after the first relapse. The median time to relapse after the second line was 66 versus 28 months in RTX versus non-RTX groups (P = 0.170). The median time to change of treatment was 66 and 44 months, respectively (P = 0.060). Last-line treatment options included RTX (n = 8), MMF (n = 4), CNI (n = 3) and CTX (n = 2). Seven (41.2%) patients had a relapse during the last-line treatment at median 39 (range 5–112) months. The median time to relapse was 48 versus 34 months in the RTX versus non-RTX groups (P = 0.727). One patient in the RTX group died presumably of heart failure. No major adverse event was observed. During the median follow-up of 81 (range 9–355) months, no patients developed end-stage renal disease. Conclusions Relapse is frequent in MCD in adults. Patients treated with RTX may be less likely to require a change of therapy and more likely to come off immunosuppressive drugs.

BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroup’s molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individual’s specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.

Evidence has implicated oxidative stress (OS) and inflammation as drivers of neurodegenerative pathologies. We previously reported on the beneficial effects of (-)-epicatechin (Epi) treatment on aging-induced OS and its capacity to restore modulators of mitochondrial biogenesis in the prefrontal cortex of 26-month-old male mice. In the present study using the same mouse model of aging, we examined the capacity of Epi to mitigate hippocampus OS, inflammation, hyperphosphorylation of tau protein, soluble β-amyloid protein levels, cell survival, memory, anxiety-like behavior levels and systemic inflammation. Mice were subjected to 4 weeks of Epi treatment (1 mg kg-1 day-1) and samples of the hippocampus were obtained. Assessments of the OS markers, protein carbonyls, and malondialdehyde levels demonstrated their significant increase (∼3 fold) with aging that were partially suppressed by Epi. The protein levels of the glial fibrillary acidic protein, inflammatory factor 1 (Iba1), pro-inflammatory cytokines, interleukins (IL-1β, IL-3, 5, 6 and 15), cyclooxygenase 2, tumor necrosis factor α, nuclear factor-activated B cells and interferon γ increase with aging and were also significantly decreased with Epi treatment. However, anti-inflammatory cytokines, IL-1ra, IL-10 and 11 decrease with aging and were restored with Epi. Epi also reversed the aging effects on the hyperphosphorylation of tau, increased soluble β-amyloid levels (∼2 fold), cellular death (as per caspase 3 and 9 activity), and reduced nerve growth factor and triggering receptor expressed on myeloid cells 2 levels. Measures of anxiety like-behavior and memory demonstrated improvements with Epi treatment. Indicators of systemic inflammation increase with aging and Epi was capable of decreasing blood inflammatory markers. Altogether, the results show a significant capacity of Epi to mitigate hippocampus OS and inflammation leading to improved brain function.

The polycystin–1 (PC1), polycystin–2 (PC2) and fibrocystin proteins, the respective products of the PKD1, PKD2 and PKHD1 genes, are abundant in urinary exosome–like vesicles (ELVs) where they form the polycystin complex (PCC). ELVs are 100 nm diameter membrane vesicles shed into the urine by the cells lining the nephron. Using MS/MS analysis of ELVs from individuals with PKD1 mutations and controls, we show that in addition to the well-described GPS/GAIN cleavage event in PC1 at 3048 aa and the proprotein convertase cleavage (PPC) event in fibrocystin at 3616 aa, there are multiple other cleavage events in these proteins. The C–terminal 11 transmembrane portion of PC1 undergoes three cleavage events in vivo. The absence of peptides from the C–terminal cytoplasmic tail of fibrocystin implies a cleavage event close to its single TM domain prior to loading onto the ELVs. There is also evidence that the C–terminal tail of PC2 is also cleaved in ELVs. Native gel analysis of the PCC shows that the entire complex is > 2 MDa in size and that N–terminal GPS/GAIN cleaved PC1 and PPC cleaved fibrocystin ectodomains can be released under non-reducing conditions and resolve at 300 kDa. This paper shows that the three major human cystogene proteins are detectable in human urinary ELVs and that all three undergo post-translational proteolytic processing. Human urinary ELVs may be a useful source of material in the search for proteins that interact with the PCC.

Dendritic cells (DCs) activated via TLR ligation experience metabolic reprogramming, in which the cells are heavily dependent on glucose and glycolysis for the synthesis of molecular building blocks essential for maturation, cytokine production, and the ability to stimulate T cells. Although the TLR‐driven metabolic reprogramming events are well documented, fungal‐mediated metabolic regulation via C‐type lectin receptors such as Dectin‐1 and Dectin‐2 is not clearly understood. Here, we show that activation of DCs with fungal‐associated β‐glucan ligands induces acute glycolytic reprogramming that supports the production of IL‐1β and its secretion subsequent to NOD‐, LRR‐ and pyrin domain‐containing protein 3 (NLRP3) inflammasome activation. This acute glycolytic induction in response to β‐glucan ligands requires spleen tyrosine kinase signaling in a TLR‐independent manner, suggesting now that different classes of innate immune receptors functionally induce conserved metabolic responses to support immune cell activation. These studies provide new insight into the complexities of metabolic regulation of DCs immune effector function regarding cellular activation associated with protection against fungal microbes., Fungal‐associated Beta‐glucan ligands induce acute glycolytic reprogramming in DCs in a Syk‐dependent TLR‐independent manner that contributes to IL‐1beta production.

Objective: To describe first episodes of bacterial cholangitis complicating autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) and to identify risk factors for cholangitis episodes among patients with ADPKD-associated polycystic liver disease (PLD). Patients and Methods: We searched the electronic medical records at our tertiary referral center for episodes of cholangitis in patients with ADPKD or ADPLD from January 1, 1996, through June 30, 2017. Cases were categorized as suspected or definite cholangitis by expert review. Clinical, laboratory, and radiologic data were manually abstracted. A nested case-control study was conducted to investigate risk factors for cholangitis in patients with ADPKD. Results: We identified 29 cases of definite or suspected cholangitis complicating PLD (24 with ADPKD-associated PLD and 5 with ADPLD). Among patients with definite cholangitis in ADPKD-associated PLD (n=19) vs ADPLD (n=4), the mean ± SD age was 62.4±12.2 vs 55.1±8.6 years, and 9 (47.4%) vs 0 (0%), respectively, were male. The odds of gallstones (odds ratio [OR], 21.6; 95% CI, 3.17-927; P

BACKGROUND: Use of electronic health records (EHRs) in health research may lead to the false assumption of complete event ascertainment. We present a systematic approach to estimate “observation windows” (OWs), defined as time periods within which the assumption of complete ascertainment of events is more likely to hold, as a quality control approach to reducing the likelihood of this false assumption. We demonstrate the impact of observation windows on estimating the rates of type 2 diabetes mellitus (diabetes) using EHR diagnosis, medication, and laboratory data from HIV clinical cohorts. METHODS: Data contributed by 16 HIV clinical cohorts to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were used to identify and evaluate OWs for an operationalized definition of diabetes occurrence as a case study. Procedures included: 1) gathering cohort-level data; 2) visualizing and summarizing gaps in observations; 3) systematically establishing start and stop dates during which complete ascertainment of diabetes events was reasonable; and 4) visualizing the diabetes OWs relative to the cohort open and close dates to identify periods of time during which immortal person time was accumulated and events were not fully ascertained. We estimated diabetes occurrence event rates and 95% confidence intervals ([,]) in the most recent decade that data were available (Jan 1, 2007 to Dec 31, 2016). RESULTS: The number of diabetes events decreased by 17% with the use of the diabetes OWs; immortal person-time was removed decreasing total person-years by 23%. Consequently, the diabetes rate increased from 1.23 (95% confidence interval [1.20, 1.25]) per 100 person-years to 1.32 ([1.29, 1.35] per 100 person-years with the use of diabetes OWs. CONCLUSIONS: As the use of EHR-curated data for event-driven health research continues to expand, OWs have utility as a quality control approach to complete event ascertainment, helping to improve accuracy of estimates by removing immortal person-time when ascertainment is incomplete.

An alumni of the Oral History Program, Wesley Hogan, reflects on ways Goodwyn taught her to interview social movement participants. What makes for a good interview? How do you develop strong rapport? All of these skills are best developed in conversation over a longer period of time than the usual semester format can cover.

Wesley Hogan and Paul Ortiz bring a wealth of experience to the discussion of democracy in the US, through the centering figure of Larry Goodwyn. Contributors have studied slave revolts, popular insurgencies in Latin America, and rural rebellions in the United States. The writers of People Power have also participated in a broad array of struggles including the Chicano movement, women’s liberation, union organizing, consciousness raising, Mississippi Freedom Summer, the Central American solidarity movement of the 1980s, and the 2008 and 2012 Obama presidential campaigns. This book is designed to generate deep discussions on the multiple crises of our time and give everyday people strategies to take back the country in the name of small-d democracy.

Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 monoclonal antibody therapy in KRAS-driven non-small cell lung cancer (NSCLC), but the molecular mechanisms responsible remain unclear. Despite this uncertainty, STK11 functional status is emerging as a reliable biomarker for predicting non-response to anti-PD-1 therapy in NSCLC patients. The clinical utility of this biomarker ultimately depends upon accurate classification of STK11 variants. For nonsense variants occurring early in the STK11 coding region, this assessment is straightforward. However, rigorously demonstrating the functional impact of missense variants remains an unmet challenge. Here we present data characterizing four STK11 splice-site variants by analyzing tumor mRNA, and 28 STK11 missense variants using an in vitro kinase assay combined with a cell-based p53-dependent luciferase reporter assay. The variants we report were identified in primary human NSCLC biopsies in collaboration with the University of Vermont Genomic Medicine group. Additionally, we compare our experimental results with data from 22 in silico predictive algorithms. Our work highlights the power, utility and necessity of functional variant assessment and will aid STK11 variant curation, provide a platform to assess novel STK11 variants and help guide anti-PD-1 therapy utilization in KRAS-driven NSCLCs., Functional assessment of under- and undescribed clinical STK11 variants highlights the limitations of current in silico predictive algorithms. Successful implementation of personalized genomic medicine will rely on rapid and accurate variant classification.

ObjectivesCOVIDTrach is a UK multicentre prospective cohort study project that aims to evaluate the outcomes of tracheostomy in patients with COVID-19 receiving mechanical ventilation and record the incidence of SARS-CoV-2 infection among healthcare workers involved in the procedure.DesignData on patient demographic, clinical history and outcomes were entered prospectively and updated over time via an online database (REDCap). Clinical variables were compared with outcomes, with logistic regression used to develop a model for mortality. Participants recorded whether any operators tested positive for SARS-CoV-2 within 2 weeks of the procedure.SettingUK National Health Service departments involved in treating patients with COVID-19 receiving mechanical ventilation.ParticipantsThe cohort comprised 1605 tracheostomy cases from 126 UK hospitals collected between 6 April and 26 August 2020.Main outcome measuresMortality following tracheostomy, successful wean from mechanical ventilation and length of time from tracheostomy to wean, discharge from hospital, complications from tracheostomy, reported SARS-CoV-2 infection among operators.ResultsThe median time from intubation to tracheostomy was 15 days (IQR 11, 21). 285 (18%) patients died following the procedure. 1229 (93%) of the survivors had been successfully weaned from mechanical ventilation at censoring and 1049 (81%) had been discharged from hospital. Age, inspired oxygen concentration, positive end-expiratory pressure setting, fever, number of days of ventilation before tracheostomy, C reactive protein and the use of anticoagulation and inotropic support independently predicted mortality. Six reports were received of operators testing positive for SARS-CoV-2 within 2 weeks of the procedure.ConclusionsTracheostomy appears to be safe in mechanically ventilated patients with COVID-19 and to operators performing the procedure and we identified clinical parameters that are predictive of mortality.Trial registration numberThe study is registered with ClinicalTrials.Gov (NCT04572438).

Background The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)–specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. Methods Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count Results Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830–.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809–.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. Conclusions Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.

BACKGROUND: Basal cell carcinoma (BCC) is the commonest cancer affecting white‐skinned individuals, and worldwide incidence is increasing. Although rarely fatal, BCC is associated with significant morbidity and costs. First‐line treatment is usually surgical excision, but alternatives are available. New published studies and the development of non‐surgical treatments meant an update of our Cochrane Review (first published in 2003, and previously updated in 2007) was timely. OBJECTIVES: To assess the effects of interventions for BCC in immunocompetent adults. SEARCH METHODS: We updated our searches of the following databases to November 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and LILACS. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions for BCC in immunocompetent adults with histologically‐proven, primary BCC. Eligible comparators were placebo, active treatment, other treatments, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcome measures were recurrence at three years and five years (measured clinically) (we included recurrence data outside of these time points if there was no measurement at three or five years) and participant‐ and observer‐rated good/excellent cosmetic outcome. Secondary outcomes included pain during and after treatment, early treatment failure within six months, and adverse effects (AEs). We used GRADE to assess evidence certainty for each outcome. MAIN RESULTS: We included 52 RCTs (26 new) involving 6690 participants (median 89) in this update. All studies recruited from secondary care outpatient clinics. More males than females were included. Study duration ranged from six weeks to 10 years (average 13 months). Most studies (48/52) included only low‐risk BCC (superficial (sBCC) and nodular (nBCC) histological subtypes). The majority of studies were at low or unclear risk of bias for most domains. Twenty‐two studies were industry‐funded: commercial sponsors conducted most of the studies assessing imiquimod, and just under half of the photodynamic therapy (PDT) studies. Overall, surgical interventions have the lowest recurrence rates. For high‐risk facial BCC (high‐risk histological subtype or located in the facial 'H‐zone' or both), there may be slightly fewer recurrences with Mohs micrographic surgery (MMS) compared to surgical excision (SE) at three years (1.9% versus 2.9%, respectively) (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.16 to 2.64; 1 study, 331 participants; low‐certainty evidence) and at five years (3.2% versus 5.2%, respectively) (RR 0.61, 95% CI 0.18 to 2.04; 1 study, 259 participants; low‐certainty evidence). However, the 95% CI also includes the possibility of increased risk of recurrence and no difference between treatments. There may be little to no difference regarding improvement of cosmetic outcomes between MMS and SE, judged by participants and observers 18 months post‐operatively (one study; low‐certainty evidence); however, no raw data were available for this outcome. When comparing imiquimod and SE for nBCC or sBCC at low‐risk sites, imiquimod probably results in more recurrences than SE at three years (16.4% versus 1.6%, respectively) (RR 10.30, 95% CI 3.22 to 32.94; 1 study, 401 participants; moderate‐certainty evidence) and five years (17.5% versus 2.3%, respectively) (RR 7.73, 95% CI 2.81 to 21.3; 1 study, 383 participants; moderate‐certainty evidence). There may be little to no difference in the number of participant‐rated good/excellent cosmetic outcomes (RR 1.00, 95% CI 0.94 to 1.06; 1 study, 326 participants; low‐certainty evidence). However, imiquimod may result in greater numbers of good/excellent cosmetic outcomes compared to SE when observer‐rated (60.6% versus 35.6%, respectively) (RR 1.70, 95% CI 1.35 to 2.15; 1 study, 344 participants; low‐certainty evidence). Both cosmetic outcomes were measured at three years. Based on one study of 347 participants with high‐ and low‐risk primary BCC of the face, radiotherapy may result in more recurrences compared to SE under frozen section margin control at three years (5.2% versus 0%, respectively) (RR 19.11, 95% CI 1.12 to 325.78; low‐certainty evidence) and at four years (6.4% versus 0.6%, respectively) (RR 11.06, 95% CI 1.44 to 84.77; low‐certainty evidence). Radiotherapy probably results in a smaller number of participant‐ (RR 0.76, 95% CI 0.63 to 0.91; 50.3% versus 66.1%, respectively) or observer‐rated (RR 0.48, 95% CI 0.37 to 0.62; 28.9% versus 60.3%, respectively) good/excellent cosmetic outcomes compared to SE, when measured at four years, where dyspigmentation and telangiectasia can occur (both moderate‐certainty evidence). Methyl‐aminolevulinate (MAL)‐PDT may result in more recurrences compared to SE at three years (36.4% versus 0%, respectively) (RR 26.47, 95% CI 1.63 to 429.92; 1 study; 68 participants with low‐risk nBCC in the head and neck area; low‐certainty evidence). There were no useable data for measurement at five years. MAL‐PDT probably results in greater numbers of participant‐ (RR 1.18, 95% CI 1.09 to 1.27; 97.3% versus 82.5%) or observer‐rated (RR 1.87, 95% CI 1.54 to 2.26; 87.1% versus 46.6%) good/excellent cosmetic outcomes at one year compared to SE (2 studies, 309 participants with low‐risk nBCC and sBCC; moderate‐certainty evidence). Based on moderate‐certainty evidence (single low‐risk sBCC), imiquimod probably results in fewer recurrences at three years compared to MAL‐PDT (22.8% versus 51.6%, respectively) (RR 0.44, 95% CI 0.32 to 0.62; 277 participants) and five years (28.6% versus 68.6%, respectively) (RR 0.42, 95% CI 0.31 to 0.57; 228 participants). There is probably little to no difference in numbers of observer‐rated good/excellent cosmetic outcomes at one year (RR 0.98, 95% CI 0.84 to 1.16; 370 participants). Participant‐rated cosmetic outcomes were not measured for this comparison. AEs with surgical interventions include wound infections, graft necrosis and post‐operative bleeding. Local AEs such as itching, weeping, pain and redness occur frequently with non‐surgical interventions. Treatment‐related AEs resulting in study modification or withdrawal occurred with imiquimod and MAL‐PDT. AUTHORS' CONCLUSIONS: Surgical interventions have the lowest recurrence rates, and there may be slightly fewer recurrences with MMS over SE for high‐risk facial primary BCC (low‐certainty evidence). Non‐surgical treatments, when used for low‐risk BCC, are less effective than surgical treatments, but recurrence rates are acceptable and cosmetic outcomes are probably superior. Of the non‐surgical treatments, imiquimod has the best evidence to support its efficacy. Overall, evidence certainty was low to moderate. Priorities for future research include core outcome measures and studies with longer‐term follow‐up.

Recommendations for additional doses of COVID-19 vaccines for people with HIV (PWH) are restricted to those with advanced disease or unsuppressed HIV viral load. Understanding SARS-CoV-2 infection risk after vaccination among PWH is essential for informing vaccination guidelines.To estimate the rate and risk of breakthrough infections among fully vaccinated PWH and people without HIV (PWoH) in the United States.This cohort study used the Corona-Infectious-Virus Epidemiology Team (CIVET)-II (of the North American AIDS Cohort Collaboration on Research and Design [NA-ACCORD], which is part of the International Epidemiology Databases to Evaluate AIDS [IeDEA]), collaboration of 4 prospective, electronic health record-based cohorts from integrated health systems and academic health centers. Adult PWH who were fully vaccinated prior to June 30, 2021, were matched with PWoH on date of full vaccination, age, race and ethnicity, and sex and followed up through December 31, 2021.HIV infection.COVID-19 breakthrough infections, defined as laboratory evidence of SARS-CoV-2 infection or COVID-19 diagnosis after a patient was fully vaccinated.Among 113 994 patients (33 029 PWH and 80 965 PWoH), most were 55 years or older (80 017 [70%]) and male (104 967 [92%]); 47 098 (41%) were non-Hispanic Black, and 43 218 (38%) were non-Hispanic White. The rate of breakthrough infections was higher in PWH vs PWoH (55 [95% CI, 52-58] cases per 1000 person-years vs 43 [95% CI, 42-45] cases per 1000 person-years). Cumulative incidence of breakthroughs 9 months after full vaccination was low (3.8% [95% CI, 3.7%-3.9%]), albeit higher in PWH vs PWoH (4.4% vs 3.5%; log-rank P .001; risk difference, 0.9% [95% CI, 0.6%-1.2%]) and within each vaccine type. Breakthrough infection risk was 28% higher in PWH vs PWoH (adjusted hazard ratio, 1.28 [95% CI, 1.19-1.37]). Among PWH, younger age (45 y vs 45-54 y), history of COVID-19, and not receiving an additional dose (aHR, 0.71 [95% CI, 0.58-0.88]) were associated with increased risk of breakthrough infections. There was no association of breakthrough with HIV viral load suppression, but high CD4 count (ie, ≥500 cells/mm3) was associated with fewer breakthroughs among PWH.In this study, COVID-19 vaccination, especially with an additional dose, was effective against infection with SARS-CoV-2 strains circulating through December 31, 2021. PWH had an increased risk of breakthrough infections compared with PWoH. Expansion of recommendations for additional vaccine doses to all PWH should be considered.