Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages.

Macrophages are functionally heterogeneous cells essential for apoptotic cell clearance. Apoptotic cells are defined by homogeneous characteristics, ignoring their original cell lineage identity. We found that in an interleukin-4 (IL-4)-enriched environment, the sensing of apoptotic neutrophils by macrophages triggered their tissue remodeling signature. Engulfment of apoptotic hepatocytes promoted a tolerogenic phenotype, whereas phagocytosis of T cells had little effect on IL-4-induced gene expression. In a mouse model of parasite-induced pathology, the transfer of macrophages conditioned with IL-4 and apoptotic neutrophils promoted parasitic egg clearance. Knockout of phagocytic receptors required for the uptake of apoptotic neutrophils and partially T cells, but not hepatocytes, exacerbated helminth infection. These findings suggest that the identity of apoptotic cells may contribute to the development of distinct IL-4-driven immune programs in macrophages.

Retention and Viral Suppression Among Adolescents Newly Initiating Antiretroviral Therapy in Adult HIV Care in Lima, Peru: A Retrospective Cohort Study.

PURPOSE: Published data on outcomes among adolescents newly initiating antiretroviral treatment in the Latin American context are sparse. We estimated the frequency of sustained retention with viral load suppression (i.e., successful transition) and identified predictors of successful transition into adult care among youth (aged 14-21 years) with recently acquired HIV in Lima, Peru. METHODS: A retrospective cohort study was conducted among 184 adolescents and young adults who initiated antiretroviral therapy in an adult public sector HIV clinic between June 2014 and June 2019. Sustained retention (no loss-to-follow-up or death) with viral suppression was calculated for the first 12 and 24 months following treatment initiation. We conducted regression analyses to assess factors associated with successful transition to adult HIV care, including gender, age, occupation, nationality, pregnancy, same-sex sexual behavior, presence of treatment supporter, number of living parents, and social risk factors that may adversely influence health (e.g., lack of social support, economic deprivation). RESULTS: Patients were predominantly male (n = 167, 90.8%). Median age was 19 years (interquartile range: 18-21). Frequency of sustained retention with viral load suppression was 42.4% (78/184) and 35.3% (30/85) at 12 and 24 months following treatment initiation. In multivariable analyses, working and/or studying was inversely associated with successful transition into adult care at 12 months; number of known living parents (relative risk: 2.20; 95% confidence interval: 1.12, 4.34) and absence of social risk factors (relative risk: 1.68; 95% confidence interval: 0.91, 3.11) were positively associated with successful transition at 24 months. DISCUSSION: Sustained retention in HIV care was uncommon. Parental support and interventions targeting social risk factors may contribute to successful transition into adult HIV care in this group.

Adolescent, caregiver and provider perspectives on tuberculosis treatment adherence: a qualitative study from Lima, Peru.

OBJECTIVES: To understand the perspectives of adolescents (10-19 years old), their caregivers and healthcare providers regarding factors that impact adherence to tuberculosis (TB) treatment among adolescents. DESIGN: We conducted in-depth interviews using semistructured interview guides based on the World Health Organization (WHO)'s Five Dimensions of Adherence framework, which conceptualises adherence as being related to the health system, socioeconomic factors, patient, treatment and condition. We applied framework thematic analysis. SETTING: Between August 2018 and May 2019, at 32 public health centres operated by the Ministry of Health in Lima, Peru. PARTICIPANTS: We interviewed 34 adolescents who completed or were lost to follow-up from treatment for drug-susceptible pulmonary TB disease in the preceding 12 months; their primary caregiver during treatment; and 15 nurses or nurse technicians who had ≥6 months' experience supervising TB treatment. RESULTS: Participants reported numerous treatment barriers, the most common of which were the inconvenience of health facility-based directly observed therapy (DOT), long treatment duration, adverse treatment events and symptom resolution. The support of adult caregivers was critical for helping adolescents overcome these barriers and carry out the behavioural skills (eg, coping with the large pill burden, managing adverse treatment events and incorporating treatment into daily routines) needed to adhere to treatment. CONCLUSION: Our findings support a three-pronged approach to improve TB treatment adherence among adolescents: (1) reduce barriers to adherence (eg, home-based or community-based DOT in lieu of facility-based DOT, reducing pill burden and treatment duration when appropriate), (2) teach adolescents the behavioural skills required for treatment adherence and (3) strengthen caregivers' ability to support adolescents.

Expansion-enhanced super-resolution radial fluctuations enable nanoscale molecular profiling of pathology specimens.

Expansion microscopy physically enlarges biological specimens to achieve nanoscale resolution using diffraction-limited microscopy systems1. However, optimal performance is usually reached using laser-based systems (for example, confocal microscopy), restricting its broad applicability in clinical pathology, as most centres have access only to light-emitting diode (LED)-based widefield systems. As a possible alternative, a computational method for image resolution enhancement, namely, super-resolution radial fluctuations (SRRF)2,3, has recently been developed. However, this method has not been explored in pathology specimens to date, because on its own, it does not achieve sufficient resolution for routine clinical use. Here, we report expansion-enhanced super-resolution radial fluctuations (ExSRRF), a simple, robust, scalable and accessible workflow that provides a resolution of up to 25 nm using LED-based widefield microscopy. ExSRRF enables molecular profiling of subcellular structures from archival formalin-fixed paraffin-embedded tissues in complex clinical and experimental specimens, including ischaemic, degenerative, neoplastic, genetic and immune-mediated disorders. Furthermore, as examples of its potential application to experimental and clinical pathology, we show that ExSRRF can be used to identify and quantify classical features of endoplasmic reticulum stress in the murine ischaemic kidney and diagnostic ultrastructural features in human kidney biopsies.

Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy.

Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease, remains unclear. In this study, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9-mediated α-galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified α-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.

The CCR6/CCL20 axis expands RORγt+ Tregs to protect from glomerulonephritis.

Previous studies have identified a unique Treg population, which expresses the Th17 characteristic transcription factor RORγt. These RORγt+ Tregs possess enhanced immunosuppressive capacity, which endows them with great therapeutic potential. However, as a caveat, they are also capable of secreting pro-inflammatory IL-17A. Since the sum function of RORγt+ Tregs in glomerulonephritis (GN) remains unknown, we studied the effects of their absence. Purified CD4+ T cell populations, containing or lacking RORγt+ Tregs, were transferred into immunocompromised RAG1 knockout mice and the nephrotoxic nephritis model of GN was induced. Absence of RORγt+ Tregs significantly aggravated kidney injury, demonstrating overall kidney-protective properties. Analyses of immune responses showed that RORγt+ Tregs were broadly immunosuppressive with no preference for a particular type of T cell response. Further characterization revealed a distinct functional and transcriptional profile, including enhanced production of IL-10. Expression of the chemokine receptor CCR6 marked a particularly potent subset, whose absence significantly worsened GN. As an underlying mechanism, we found that chemokine CCL20 acting through receptor CCR6 signaling mediated expansion and activation of RORγt+ Tregs. Finally, we also detected an increase of CCR6+ Tregs in kidney biopsies, as well as enhanced secretion of chemokine CCL20 in 21 patients with anti-neutrophil cytoplasmic antibody associated GN compared to that of 31 healthy living donors, indicating clinical relevance. Thus, our data characterize RORγt+ Tregs as anti-inflammatory mediators of GN and identify them as promising target for Treg directed therapies.

Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH.

A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.

The Dynamics of Intimate Partner Violence and Its Impact on HIV Care: A Cross-Sectional Study of People of Mixed Gender and Sexual Preference in Lima, Peru.

Intimate partner violence (IPV) is associated with a higher risk of contracting HIV and developing worse HIV outcomes. This cross-sectional, mixed methods study presents data on IPV using the Conflicts Tactics Scale (CTS2-S) among 180 persons with HIV in Lima, Peru, as well as qualitative interviews with 7 of them and 18 of their community caregivers. This study used data collected for a randomized controlled trial (RCT), CASAommunity Based Accompaniment with Supervised Antiretrovirals (CASA) Community-based Accompaniment with Supervised Antiretrovirals (CASA). Physical or sexual IPV was self-reported in 82 (45.6%) of participants reporting having been in a relationship in the last year and 59,8% of those were involved in bidirectional violence. Coping subscales, social support, and stigma were associated with IPV. Intimate partner violence negatively impacted patient adherence to medication and care, particularly during times of severe conflict. In conclusion, profound psychosocial vulnerability-including low social support, substance use as coping, and HIV stigma-contextualize IPV among people with HIV. Bidirectional violence often evolved over time as victims negotiated inter-personal strategies for survival, including retaliation. Interventions should focus on a deeper understanding IPV and facilitating of coping mechanisms to help people with HIV stay in care.

Patient and provider perceptions of a community-based accompaniment intervention for adolescents transitioning to adult HIV care in urban Peru: a qualitative analysis.

INTRODUCTION: Adolescents living with HIV (ALWH) experience higher mortality rates compared to other age groups, exacerbated by the suboptimal transition from paediatric to adult HIV care, during which decreased adherence to antiretroviral therapy (ART) and unsuppressed viremia are frequent. Care transition-a process lasting months or years-ideally prepares ALWH for adult care and can be improved by interventions that are youth-friendly and address psychosocial issues affecting ART adherence; however, such interventions are infrequently operationalized. Community-based accompaniment (CBA), in which laypeople provide individualized support and health system navigation, can improve health outcomes among adults with HIV. Here, we describe patient and provider perceptions of a novel HIV CBA intervention called "PASEO" for ALWH in Lima, Peru. METHODS: PASEO consisted of six core elements designed to support ALWH during and after the transition to adult HIV care. During 2019-2021, community-based health workers provided tailored accompaniment for ALWH aged 15-21 years over 9 months, after which adolescent participants were invited to provide feedback in a focus group or in-depth interview. HIV care personnel were also interviewed to understand their perspectives on PASEO. A semi-structured interview guide probing known acceptability constructs was used. Qualitative data were analysed using a framework analysis approach and emergent themes were summarized with illustrative quotes. RESULTS: We conducted five focus groups and 11 in-depth interviews among N = 26 ALWH and nine key-informant interviews with HIV care personnel. ALWH participants included males, females and one transgender female, and those with both early childhood and recent HIV infection. ALWH praised PASEO, attributing increased ART adherence to the project. Improved mental health, independence, self-acceptance and knowledge on how to manage their HIV were frequently cited. HIV professionals similarly voiced strong support for PASEO. Both ALWH and HIV professionals expressed hope that PASEO would be scaled. HIV professionals voiced concerns regarding financing PASEO in the future. CONCLUSIONS: A multicomponent CBA intervention to increase ART adherence among ALWH in Peru was highly acceptable by ALWH and HIV programme personnel. Future research should determine the efficacy and economic impact of the intervention.

Impact of prolonged isolation on adolescents with drug-susceptible tuberculosis in Lima, Peru: a qualitative study.

OBJECTIVES: Patients with tuberculosis (TB) generally are instructed to isolate at the beginning of treatment in order to prevent disease transmission. The duration of isolation varies and may be prolonged (ie, lasting 1 month or more). Few studies have examined the impact of isolation during TB treatment on adolescents, who may be more vulnerable to its negative effects. METHODS: This study took place from 2018 through 2019 in Lima, Peru, where the Ministry of Health mandates the exclusion of patients with TB from educational institutions for at least 2 months. Using semi-structured guides, we conducted individual in-depth interviews with adolescents who received treatment for drug-susceptible TB, their primary caregivers and health providers. We performed thematic analysis of the transcribed interviews. RESULTS: We interviewed 85 participants: 34 adolescents, 36 caregivers and 15 healthcare workers. At the time of their TB diagnoses, 28 adolescents were in secondary, postsecondary, vocational or military school. Adolescents with drug-susceptible TB were prescribed home isolation usually for 2 (and occasionally for 1) months. Consequently, they could neither attend school nor socialise with family members or friends. Two primary themes emerged from the interviews. First, as a result of their exclusion from school, most adolescents fell behind academically and had to repeat a semester or academic year. Second, absence from school, separation from friends and loved ones, and reinforcement of TB-related stigma (arising from fear of TB transmission) harmed adolescents' mental health. CONCLUSION: Prolonged isolation led to educational setbacks and emotional trauma among adolescents with TB. Prolonged isolation is not supported by current evidence on TB transmission and is problematic from a human rights perspective, as it violates adolescents' rights to education and freedom of movement. Isolation recommendations should be re-evaluated to align with data on TB transmission and the principles of patient-centred care.

Community-based accompaniment for adolescents transitioning to adult HIV care in urban Peru: a pilot study.

We piloted a community-based intervention to improve outcomes among adolescents living with HIV who were transitioning to adult-oriented care in Lima, Peru. We assessed feasibility and potential effectiveness, including within-person changes in self-reported adherence, psychosocial metrics (NIH Toolbox), and transition readiness ("Am I on TRAC" questionnaire, "Got Transition" checklist). From October 2019 to January 2020, we enrolled 30 adolescents (15-21 years). The nine-month intervention consisted of logistical, adherence and social support delivered by entry-level health workers and group sessions to improve health-related knowledge and skills and social support. In transition readiness, we observed within-person improvements relative to baseline. We also observed strong evidence of improvements in adherence, social support, self-efficacy, and stress, which were generally sustained three months post-intervention. All participants remained in treatment after 12 months. The intervention was feasible and potentially effective for bridging the transition to adult HIV care. A large-scale evaluation, including biological endpoints, is warranted.

RESUMEN: Piloteamos una intervención comunitaria para mejorar los resultados de adolescentes viviendo con el VIH que se encontraban en transición a la atención de VIH orientada a adultos en Lima, Perú. Evaluamos la viabilidad y la eficacia potencial, incluidos los cambios personales en la adherencia auto-reportada, criterios psicosociales (NIH Toolbox), y preparación para la transición (cuestionario "Estoy en el TRAC", lista de verificación "Got Transition"). Desde octubre de 2019 hasta enero de 2020, enrolamos a 30 adolescentes (15 a 21 años). La intervención de nueve meses consistió en apoyo logístico, de adherencia y social brindado por técnicos de enfermería y sesiones grupales para mejorar tanto el conocimiento y las habilidades relacionados con la salud, como el apoyo social. En cuanto a la preparación para la transición, observamos mejoras comparada con el basal. También observamos una fuerte evidencia de mejoras en la adherencia, apoyo social, autoeficacia y estrés, que se mantuvieron, generalmente, tres meses después del fin de la intervención. Todos los participantes seguían en tratamiento después de 12 meses. La intervención fue factible y potencialmente efectiva para tender un puente en la transición a la atención del VIH para adultos. Esto amerita una evaluación a mayor escala y que incluya criterios clínicos.

Th17 cell plasticity towards a T-bet-dependent Th1 phenotype is required for bacterial control in Staphylococcus aureus infection.

Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by supporting antibody production and phagocytosis. In particular, Th1 and Th17 cells secreting IFN-γ and IL-17A, are involved in the control of systemic S. aureus infections in humans and mice. To investigate the role of T cells in severe S. aureus infections, we established a mouse sepsis model in which the kidney was identified to be the organ with the highest bacterial load and abundance of Th17 cells. In this model, IL-17A but not IFN-γ was required for bacterial control. Using Il17aCre × R26YFP mice we could show that Th17 fate cells produce Th17 and Th1 cytokines, indicating a high degree of Th17 cell plasticity. Single cell RNA-sequencing of renal Th17 fate cells uncovered their heterogeneity and identified a cluster with a Th1 expression profile within the Th17 cell population, which was absent in mice with T-bet/Tbx21-deficiency in Th17 cells (Il17aCre x R26eYFP x Tbx21-flox). Blocking Th17 to Th1 transdifferentiation in Th17 fate cells in these mice resulted in increased S. aureus tissue loads. In summary, we highlight the impact of Th17 cells in controlling systemic S. aureus infections and show that T-bet expression by Th17 cells is required for bacterial clearance. While targeting the Th17 cell immune response is an important therapeutic option in autoimmunity, silencing Th17 cells might have detrimental effects in bacterial infections.

Molecular consequences of SARS-CoV-2 liver tropism.

Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated2,3. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.

Parietal epithelial cell dysfunction in crescentic glomerulonephritis.

Crescentic glomerulonephritis represents a group of kidney diseases characterized by rapid loss of kidney function and the formation of glomerular crescents. While the role of the immune system has been extensively studied in relation to the development of crescents, recent findings show that parietal epithelial cells play a key role in the pathophysiology of crescent formation, even in the absence of immune modulation. This review highlights our current understanding of parietal epithelial cell biology and the reported physiological and pathological roles that these cells play in glomerular lesion formation, especially in the context of crescentic glomerulonephritis.

Referral Process for Surgical Management of Tuberculosis in Lima: A Qualitative Study.

BACKGROUND: Lung resection surgery can be a complementary therapy for managing tuberculosis (TB) complications, but access is lacking in high-burden areas. The referral process for surgical evaluation is not well described. This study aimed to elucidate the TB surgery referral process in Peru. METHODS: A qualitative study was conducted using focus groups and interviews of health care providers from the Peruvian National TB Program. A semi-structured interview guide was developed with local partners. Focus groups and individual interviews were recorded and transcribed. Thematic analysis was used to reconstruct the referral process and identify barriers as well as areas for improvement. RESULTS: A total of 12 sessions were recorded (7 interviews and 5 focus groups; 36 participants total). The main themes identified were: (1) Surgical referral workflow, (2) Unstandardized selection criteria for surgery, (3) Limited inter-institutional communication, and (4) Material barriers to surgical management. CONCLUSION: Health care providers involved in the referral process of surgical management of tuberculosis in Lima reported a hierarchical referral workflow. Interinstitutional communication may be a critical interventional point to improve a patient's quality of care during the referral process.

A non-specialist depression care pathway for adolescents living with HIV and transitioning into adult care in Peru: a nested, proof of concept pilot study.

BACKGROUND: Adolescents living with HIV (ALWH) are disproportionally impacted by depression, experiencing worse HIV outcomes. Integrated depression and HIV care may support antiretroviral adherence. This study pilot tested for proof of concept a basic depression care pathway for ALWH to inform depression care integration with HIV services in Peru. METHODS: ALWH were screened for depression with the Patient Health Questionnaire-9 (PHQ-9). Participants with PHQ-9 scores of ⩾10 or suicidal ideation (SI) were eligible for Psychological First Aid (PFA) delivered by non-mental health specialists. Participants with PHQ-9 re-assessments of ⩾20 or SI were referred to specialized services. RESULTS: Twenty-eight (11 female, 17 male) ALWH aged 15-21 years participated; n = 20 (71%) identified as heterosexual. Most (18/28) acquired HIV at birth. Baseline PHQ-9 scores were 0-4, n = 3 (11%); 5-9, n = 9 (32%); 10-14, n = 10 (36%); 15-19, n = 4 (14%); and 20-27, n = 2 (7%). Eleven participants (40%) reported SI. Among participants with PHQ-9 > 4, 92% (23/25) were not severe. Of the 21 (75%) of participants eligible for PFA, n = 9 (32%) accepted at least one session, of which n = 3 (33%) were linked to specialized care. CONCLUSIONS: A simple care pathway operationalizing depression screening and non-specialist delivered emotional support is a first step toward integrated depression and HIV care for ALWH.

[Impact of SARS-CoV-2 pandemic on adolescents living with HIV in Lima, Peru]. / Impacto de la pandemia por SARS-CoV-2 en adolescentes que viven con el VIH en Lima, Perú.

Adolescents living with HIV (ALWH) have lower rates of virologic suppression and higher rates of immunologic decline compared to their older counterparts, potentially placing them at high-risk for developing severe SARS-CoV-2 disease. ALWH who are transitioning to adult care face additional challenges to remaining in care and adhering to treatment. In this special section we report the experiences of ALWH in the process of transitioning to adult HIV services during the COVID-19 pandemic. In first place, the government-mandated stay-at-home order has substantially limited access to full HIV care by restricting public transportation, HIV medication stock-outs, and the suspension of routine medical and laboratory appointments. In addition, financial hardship, uncertainty about their future plans, emotional stressors, lifestyle disruptions, and concerns of involuntary disclosure have further challenged continuity in care for this adolescent population.

Los adolescentes que viven con el VIH (AVVIH) tienen tasas más bajas de supresión virológica y tasas más altas de deterioro inmunológico en comparación con sus contrapartes mayores, colocándolos potencialmente en alto riesgo de enfermedad severa por SARS-CoV-2. Los AVVIH que están transicionando hacia el cuidado de adultos enfrentan dificultades adicionales para permanecer en el cuidado y adherirse al tratamiento antirretroviral. En esta sección especial reportamos el impacto observado en AVVIH transicionando al servicio de VIH para adultos durante la pandemia por SARS-CoV-2. En primer lugar, el acceso a la atención del VIH se ha visto perjudicado por la restricción del transporte público, la falta de antirretrovirales, y la suspensión de citas médicas y laboratoriales. Adicionalmente, dificultades financieras, incertidumbre sobre el futuro, estresores emocionales, alteración del estilo de vida y el temor de divulgar el diagnóstico involuntariamente han desafiado aún más la continuidad en la atención de esta población adolescente.

Quality Improvement to Address Surgical Burden of Disease at a Large Tertiary Public Hospital in Peru.

BACKGROUND: In resource-limited settings, there is a unique opportunity for using process improvement strategies to address the lack of access to surgical care. By implementing organizational changes in the surgical admission process, we aimed to decrease wait times, increase surgical volume, and improve patient satisfaction for elective general surgery procedures at a public tertiary hospital in Lima, Peru. METHODS: During the first phase of the intervention, Plan-Do-Study-Act (PDSA) cycles were performed to ensure the surgery waitlist included up-to-date clinical information. In the second phase, Lean Six Sigma methodology was used to adapt the admission and scheduling process for elective general surgery patients. After six months, outcomes were compared to baseline data using Wilcoxon rank-sum test. RESULTS: At the conclusion of phase one, 87.0% (488/561) of patients on the new waitlist had all relevant clinical data documented, improved from 13.3% (2/15) for the pre-existing list. Time from admission to discharge for all surgeries improved from 5 to 4 days (p<0.05) after the intervention. Median wait times from admission to operation for elective surgeries were unchanged at 4 days (p=0.076) pre- and post-intervention. There was a trend toward increased weekly elective surgical volume from a median of 9 to 13 cases (p=0.24) and increased patient satisfaction rates for elective surgery from 80.5 to 83.8% (p=0.62), although these were not statistically significant. CONCLUSION: The process for scheduling and admitting elective surgical patients became more efficient after our intervention. Time from admission to discharge for all surgical patients improved significantly. Other measured outcomes improved, though not with statistical significance. Main challenges included gaining buy-in from all participants and disruptions in surgical services from bed shortages.

Deep learning-based molecular morphometrics for kidney biopsies.

Morphologic examination of tissue biopsies is essential for histopathological diagnosis. However, accurate and scalable cellular quantification in human samples remains challenging. Here, we present a deep learning-based approach for antigen-specific cellular morphometrics in human kidney biopsies, which combines indirect immunofluorescence imaging with U-Net-based architectures for image-to-image translation and dual segmentation tasks, achieving human-level accuracy. In the kidney, podocyte loss represents a hallmark of glomerular injury and can be estimated in diagnostic biopsies. Thus, we profiled over 27,000 podocytes from 110 human samples, including patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN), an immune-mediated disease with aggressive glomerular damage and irreversible loss of kidney function. We identified previously unknown morphometric signatures of podocyte depletion in patients with ANCA-GN, which allowed patient classification and, in combination with routine clinical tools, showed potential for risk stratification. Our approach enables robust and scalable molecular morphometric analysis of human tissues, yielding deeper biological insights into the human kidney pathophysiology.

Incident Tuberculosis Diagnoses in Children at High Risk for Disease.

We followed 35 children meeting a research definition for unconfirmed tuberculosis (TB) but in whom a pediatric pulmonologist did not diagnose or treat TB. After a median follow-up of 16.4 months, most children were not diagnosed with TB following a comprehensive evaluation. However, 2 were diagnosed with TB, demonstrating high TB risk (6%; exact 95% CI, 1%-19%). In some contexts, researchers may wish to supplement these research definitions with clinical decision data and longitudinal follow-up in order to improve specificity.