Psychiatric morbidity across the life course and provoked vulvodynia: is it dependent upon the presence of non-stress-related immune dysfunction?

BACKGROUND: Vulvodynia impacts up to 8% of women by age 40, and these women may have a more compromised immune system than women with no vulvar pain history. AIM: Given that psychiatric morbidity is associated with vulvodynia and is known to activate immune inflammatory pathways in the brain and systemically, we sought to determine whether the association between psychiatric morbidity and vulvar pain was independent of or dependent upon the presence of immune-related conditions. METHODS: Women born in Sweden between 1973 and 1996 with localized provoked vulvodynia (N76.3) and/or vaginismus (N94.2 or F52.5) diagnosed between 2001 and 2018 were matched to two women from the same birth year with no vulvar pain. International Statistical Classification of Diseases and Related Health Problems (ICD-9 or -10 codes) were used to identify women with a history of depression, anxiety, attempted suicide, neurotic disorders, stress-related disorders, behavioral syndromes, personality disorders, psychotic disorders, or chemical dependencies, as well as a spectrum of immune-related conditions. The Swedish National Prescribed Drug Register was used to identify women with filled prescriptions of antidepressants or anxiolytics. OUTCOMES: Vulvodynia, vaginismus, or both were outcomes assessed in relation to psychiatric morbidity. RESULTS: Women with vulvodynia, vaginismus, or both, relative to those without vulvar pain, had adjusted odds ratios between 1.4 and 2.3, with CIs highly compatible with harmful effects. When we assessed women with and those without a lifetime history of immune-related conditions separately, we also observed elevated odds ratios in both groups for mood, anxiety, and neurotic and stress disorders. CLINICAL IMPLICATIONS: Documenting psychiatric impairment as a cause or consequence of vulvodynia is critical in clinical practice because psychiatric conditions may impact treatment efficacy. STRENGTHS AND LIMITATIONS: Strengths of this study include a data source that represents the entire population of women in Sweden that is known to be highly accurate because Sweden provides universal healthcare. Limitations include difficulty in making an accurate assessment of temporality between psychiatric morbidity and the first onset of vulvar pain. In addition, because Swedish registry data have limited information on lifestyle, behavioral, and anthropomorphic factors such as smoking, diet, physical activity, and obesity, these conditions could not be assessed as confounders of psychiatric morbidity and vulvar pain. CONCLUSIONS: Immune pathways by which women with psychiatric conditions increase their risk of vulvar pain could be independent from other immune pathways.

Single color virtual H&E staining with In-and-Out Net.

Virtual staining streamlines traditional staining procedures by digitally generating stained images from unstained or differently stained images. While conventional staining methods involve time-consuming chemical processes, virtual staining offers an efficient and low infrastructure alternative. Leveraging microscopy-based techniques, such as confocal microscopy, researchers can expedite tissue analysis without the need for physical sectioning. However, interpreting grayscale or pseudo-color microscopic images remains a challenge for pathologists and surgeons accustomed to traditional histologically stained images. To fill this gap, various studies explore digitally simulating staining to mimic targeted histological stains. This paper introduces a novel network, In-and-Out Net, specifically designed for virtual staining tasks. Based on Generative Adversarial Networks (GAN), our model efficiently transforms Reflectance Confocal Microscopy (RCM) images into Hematoxylin and Eosin (H&E) stained images. We enhance nuclei contrast in RCM images using aluminum chloride preprocessing for skin tissues. Training the model with virtual H\&E labels featuring two fluorescence channels eliminates the need for image registration and provides pixel-level ground truth. Our contributions include proposing an optimal training strategy, conducting a comparative analysis demonstrating state-of-the-art performance, validating the model through an ablation study, and collecting perfectly matched input and ground truth images without registration. In-and-Out Net showcases promising results, offering a valuable tool for virtual staining tasks and advancing the field of histological image analysis.

Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography.

Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.

The effect of care interruptions on mortality in adults resuming antiretroviral therapy.

OBJECTIVE: To estimate the relative rate of all-cause mortality amongst those on antiretroviral treatment (ART) with a history of interruptions compared with those with no previous interruptions in care. DESIGN: Retrospective cohort study. METHODS: We used data from four South African cohorts participating in the International epidemiology Databases to Evaluate AIDS Southern Africa collaboration. We included adults who started ART between 2004 and 2019. We defined a care interruption as a gap in contact longer than 180 days. Observation time prior to interruption was allocated to a 'no interruption' group. Observation time after interruption was allocated to one of two groups based on whether the first interruption started before 6 months of ART ('early interruption') or later ('late interruption'). We used Cox regression to estimate hazard ratios. RESULTS: Sixty-three thousand six hundred and ninety-two participants contributed 162 916 person-years of observation. There were 3469 deaths. Most participants were female individuals (67.4%) and the median age at ART initiation was 33.3 years (interquartile range: 27.5-40.7). Seventeen thousand and eleven (26.7%) participants experienced care interruptions. Those resuming ART experienced increased mortality compared with those with no interruptions: early interrupters had a hazard ratio of 4.37 (95% confidence interval (CI) 3.87-4.95) and late interrupters had a hazard ratio of 2.74 (95% CI 2.39-3.15). In sensitivity analyses, effect sizes were found to be proportional to the length of time used to define interruptions. CONCLUSION: Our findings highlight the need to improve retention in care, regardless of treatment duration. Programmes to encourage return to care also need to be strengthened.

It's not all about residual confounding: a plea for QBA for epidemiologic researchers and educators.

We spend a great deal of time on confounding in our teaching, in our methods development and in our assessment of study results. This may give the impression that uncontrolled confounding is the biggest problem that observational epidemiology faces, when in fact, other sources of bias such as selection bias, measurement error, missing data, and misalignment of zero time may often (especially if they are all present in a single study) lead to a stronger deviation from the truth. Compared to the amount of time we spend teaching how to address confounding in a data analysis, we spend relatively little time teaching methods for simulating confounding (and other sources of bias) to learn their impact and develop plans to mitigate or quantify the bias. We review a paper by Desai et al that uses simulation methods to quantify the impact of an unmeasured confounder when it is completely missing or when a proxy of the confounder is measured. We use this article to discuss how we can use simulations of sources of bias to ensure we generate better and more valid study estimates, and we discuss the importance of simulating realistic datasets with plausible bias structures to guide data collection. If an advanced life form exists outside of our current universe and they came to earth with the goal of scouring the published epidemiologic literature to understand what the biggest problem epidemiologists have, they would quickly discover that the limitations section of publications would provide them with all the information they needed. And most likely what they would conclude is that the biggest problem that we face is uncontrolled confounding. It seems to be an obsession of ours.

Paediatric-onset immune-mediated inflammatory disease is associated with an increased mortality risk-A nationwide study.

BACKGROUND: Paediatric-onset immune-mediated inflammatory diseases (pIMID) show more aggressive phenotypes than when diagnosed in adults. However, data on mortality are often extrapolated from adult studies. AIM: To estimate the effect of pIMID on mortality. METHODS: In a population-based cohort study using the nationwide Danish healthcare registers, we included all patients diagnosed with pIMID in Denmark from 1980 to 2018. PIMID were defined as ICD codes indicative of autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, lupus erythematosus, or vasculitis registered before age 18 years. All-cause mortality was the primary outcome; cause-specific mortality was the secondary outcome. We used Cox survival analysis to estimate hazard ratios (HR), and Aalen survival analysis to estimate rate differences. RESULTS: We included 11,581 individuals diagnosed with pIMID and 99,665 reference individuals, accounting for 1,371,994 person-years of follow-up. Median and interquartile (IQR) age at diagnosis was 12.6 (7.9-15.9) years. During follow-up, 152 patients with pIMID and 316 reference individuals died; adjusted HR (aHR) was 3.8 (95% confidence interval [CI] 3.1-4.7). This corresponded to 6.9 (95% CI: 5.3-8.5) additional deaths per 10,000 person-years. The strongest associations were found for gastrointestinal diseases (aHR 22.8; 95% CI 9.6-64.1), gastrointestinal cancers (aHR 19.2; 95% CI 5.0-74.2) and lymphoproliferative disorders (aHR 6.8; 95% CI 2.8-16.8). CONCLUSION: Patients diagnosed with pIMID have a fourfold higher risk of mortality when followed into early adulthood compared with reference individuals. This underlines the severe disease course of pIMID and highlights the need for multidisciplinary care.

Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

Ambulatory Extracorporeal Membrane Oxygenation Use in Patients Listed for Lung Transplant.

There has been an increase in the use of extracorporeal membrane oxygenation (ECMO) to bridge critically ill patients to lung transplant (LTX). This study evaluates how ambulatory status on ECMO affected waitlist and post-LTX outcomes. The United Network of Organ Sharing (UNOS) database was queried for patients aged of greater than or equal to 18 years and between 2016 and 2021 to identify pre-LTX patients supported by ECMO. The patients were classified in venous-arterial (VA) ECMO and veno-venous (VV) ECMO cohorts and further classified as ambulatory (AMB) and non-AMB (nAMB). Each cohort was controlled against the non-ECMO patients. Univariate statistical tests, as well as Kaplan-Meier survival curves, were used for analysis. The 90 day waitlist survival was the highest among the non-ECMO group (96%), but both AMB VV and VA groups had superior survival compared to the nAMB group (85% vs. 75%, 78% vs. 65%, p < 0.01). After adjusting for the median lung allocation score (LAS) (88) in the VV ECMO group, the waitlist survival was superior in the AMB VV ECMO compared to those not on ECMO (86% vs. 78%, p > 0.01). The 1 year post-LTX survival between non-ECMO and AMB VV ECMO was comparable (88% vs. 88%, p = 0.66). Ambulating patients or use of physical therapy while on ECMO can help improve lung transplant outcomes.

Does Engagement in HIV Care Affect Screening, Diagnosis, and Control of Noncommunicable Diseases in Sub-Saharan Africa? A Systematic Review and Meta-analysis.

Low- and middle-income countries are facing a growing burden of noncommunicable diseases (NCDs). Providing HIV treatment may provide opportunities to increase access to NCD services in under-resourced environments. We conducted a systematic review and meta-analysis to evaluate whether use of antiretroviral therapy (ART) was associated with increased screening, diagnosis, treatment, and control of diabetes, hypertension, chronic kidney disease, or cardiovascular disease among people living with HIV in sub-Saharan Africa (SSA). A comprehensive search of electronic literature databases for studies published between 01 January 2011 and 31 December 2022 yielded 26 studies, describing 13,570 PLWH in SSA, 61% of whom were receiving ART. Random effects models were used to calculate summary odds ratios (ORs) of the risk of diagnosis by ART status and corresponding 95% confidence intervals (95% CIs), where appropriate. ART use was associated with a small but imprecise increase in the odds of diabetes diagnosis (OR 1.07; 95% CI 0.71, 1.60) and an increase in the odds of hypertension diagnosis (OR 2.10, 95% CI 1.42, 3.09). We found minimal data on the association between ART use and screening, treatment, or control of NCDs. Despite a potentially higher NCD risk among PLWH and regional efforts to integrate NCD and HIV care, evidence to support effective care integration models is lacking.

CAPABLE: A Scoring System Utilizing Patient-Reported Measures to Evaluate Patient Experience After Mohs Surgery.

BACKGROUND: Patient experience metrics are gaining prominence in health care. We introduce the CAPABLE survey to assess postoperative experiences of Mohs surgery patients. OBJECTIVE: We sought to determine whether CAPABLE scores aligned with overall patient satisfaction in Mohs surgery. METHODS: This was a cross-sectional, survey-based study of patients presenting for their first postoperative visit after Mohs surgery. The CAPABLE survey included questions on postoperative instructions, activity limitations, pain control, provider accessibility, and bleeding, followed by 2 overall satisfaction questions taken from the Outpatient and Ambulatory Surgery Consumer Assessment of Healthcare Providers and Systems survey. The pilot study took place at the University of Texas Dell Medical School (DMS), followed by a validation study ( n = 206) at DMS and Oregon Health and Science University (OHSU). We assessed for correlations between CAPABLE scores and overall satisfaction. RESULTS: In the pilot study ( n = 137), overall CAPABLE scores and scores of individual CAPABLE components correlated positively with overall satisfaction.In the multisite validation study ( n = 206) spanning DMS and OHSU, CAPABLE scores correlated positively with overall satisfaction. CONCLUSION: The CAPABLE survey is a concise tool for assessing specific, actionable components of the postoperative patient experience in Mohs surgery, while correlating with overall patient satisfaction.

Moderate alcohol consumption on the risk of stroke in the Million Veteran Program.

BACKGROUND: There is inconsistent evidence on the association of moderate alcohol consumption and stroke risk in the general population and is not well studied among U.S. Veterans. Furthermore, it is unclear whether primarily drinking beer, wine, or liquor is associated with a difference in stroke risk. METHODS: The study included 185,323 Million Veteran Program participants who self-reported alcohol consumption on the Lifestyle Survey. Moderate consumption was defined as 1-2 drinks/day and beverage preference of beer, wine or liquor was defined if ≥ 50% of total drinks consumed were from a single type of beverage. Strokes were defined using ICD-9 and ICD-10 codes from the participants' electronic health record. RESULTS: The mean (sd) age of the sample was 64 (13) years and 11% were women. We observed 4,339 (94% ischemic; 6% hemorrhagic) strokes over a median follow-up of 5.2 years. In Cox models adjusted for age, sex, race, education, income, body mass index, smoking, exercise, diet, cholesterol, prevalent diabetes, prevalent hypertension, lipid-lowering medication, antihypertensive medication, and diabetes medication, moderate alcohol consumption (1-2 drinks/day) was associated with a 22% lower risk of total stroke compared with never drinking [Hazards ratio (HR) 95% confidence interval (CI): 0.78 (0.67, 0.92)]. When stratifying by stroke type, we observed a similar protective association with moderate consumption and ischemic stroke [HR (95% CI): 0.76 (0.65, 0.90)], but a non-statistically significant higher risk of hemorrhagic stroke [HR (95% CI): 1.29 (0.64, 2.61)]. We did not observe a difference in ischemic or hemorrhagic stroke risk among those who preferred beer, liquor or wine vs. no beverage preference. When stratifying by prior number of hospital visits (≤ 15, 16-33, 34-64, ≥ 65) as a proxy for health status, we observed attenuation of the protective association with greater number of visits [HR (95% CI): 0.87 (0.63, 1.19) for ≥ 65 visits vs. 0.80 (0.59, 1.08) for ≤ 15 visits]. CONCLUSIONS: We observed a lower risk of ischemic stroke, but not hemorrhagic stroke with moderate alcohol consumption and did not observe substantial differences in risk by beverage preference among a sample of U.S. Veterans. Healthy user bias of moderate alcohol consumption may be driving some of the observed protective association.

Deep Learning Approaches for Quantifying Ventilation Defects in Hyperpolarized Gas Magnetic Resonance Imaging of the Lung: A Review.

This paper provides an in-depth overview of Deep Neural Networks and their application in the segmentation and analysis of lung Magnetic Resonance Imaging (MRI) scans, specifically focusing on hyperpolarized gas MRI and the quantification of lung ventilation defects. An in-depth understanding of Deep Neural Networks is presented, laying the groundwork for the exploration of their use in hyperpolarized gas MRI and the quantification of lung ventilation defects. Five distinct studies are examined, each leveraging unique deep learning architectures and data augmentation techniques to optimize model performance. These studies encompass a range of approaches, including the use of 3D Convolutional Neural Networks, cascaded U-Net models, Generative Adversarial Networks, and nnU-net for hyperpolarized gas MRI segmentation. The findings highlight the potential of deep learning methods in the segmentation and analysis of lung MRI scans, emphasizing the need for consensus on lung ventilation segmentation methods.

Gaps in the type 2 diabetes care cascade: a national perspective using South Africa's National Health Laboratory Service (NHLS) database.

BACKGROUND: Research out of South Africa estimates the total unmet need for care for those with type 2 diabetes mellitus (diabetes) at 80%. We evaluated the care cascade using South Africa's National Health Laboratory Service (NHLS) database and assessed if HIV infection impacts progression through its stages. METHODS: The cohort includes patients from government facilities with their first glycated hemoglobin A1c (HbA1c) or plasma glucose (fasting (FPG); random (RPG)) measured between January 2012 to March 2015 in the NHLS. Lab-diagnosed diabetes was defined as HbA1c ≥ 6.5%, FPG ≥ 7.0mmol/l, or RPG ≥ 11.1mmol/l. Cascade stages post diagnosis were retention-in-care and glycaemic control (defined as an HbA1c < 7.0% or FPG < 8.0mmol/l or RPG < 10.0mmol/l) over 24-months. We estimated gaps at each stage nationally and by people living with HIV (PLWH) and without (PLWOH). RESULTS: Of the 373,889 patients tested for diabetes, 43.2% had an HbA1c or blood glucose measure indicating a diabetes diagnosis. Amongst those with lab-diagnosed diabetes, 30.9% were retained-in-care (based on diabetes labs) and 8.7% reached glycaemic control by 24-months. Prevalence of lab-diagnosed diabetes in PLWH was 28.6% versus 47.3% in PLWOH. Among those with lab-diagnosed diabetes, 34.3% of PLWH were retained-in-care versus 30.3% PLWOH. Among people retained-in-care, 33.8% of PLWH reached glycaemic control over 24-months versus 28.6% of PLWOH. CONCLUSIONS: In our analysis of South Africa's NHLS database, we observed that 70% of patients diagnosed with diabetes did not maintain in consistent diabetes care, with fewer than 10% reaching glycemic control within 24 months. We noted a disparity in diabetes prevalence between PLWH and PLWOH, potentially linked to different screening methods. These differences underscore the intricacies in care but also emphasize how HIV care practices could guide better management of chronic diseases like diabetes. Our results underscore the imperative for specialized strategies to bolster diabetes care in South Africa.

Associations of inter-annual rainfall decreases with subsequent HIV outcomes for persons with HIV on antiretroviral therapy in Southern Africa: a collaborative analysis of cohort studies.

BACKGROUND: Periods of droughts can lead to decreased food security, and altered behaviours, potentially affecting outcomes on antiretroviral therapy (ART) among persons with HIV (PWH). We investigated whether decreased rainfall is associated with adverse outcomes among PWH on ART in Southern Africa. METHODS: Data were combined from 11 clinical cohorts of PWH in Lesotho, Malawi, Mozambique, South Africa, Zambia, and Zimbabwe, participating in the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration. Adult PWH who had started ART prior to 01/06/2016 and were in follow-up in the year prior to 01/06/2016 were included. Two-year rainfall from June 2014 to May 2016 at the location of each HIV centre was summed and ranked against historical 2-year rainfall amounts (1981-2016) to give an empirical relative percentile rainfall estimate. The IeDEA-SA and rainfall data were combined using each HIV centre's latitude/longitude. In individual-level analyses, multivariable Cox or generalized estimating equation regression models (GEEs) assessed associations between decreased rainfall versus historical levels and four separate outcomes (mortality, CD4 counts < 200 cells/mm3, viral loads > 400 copies/mL, and > 12-month gaps in follow-up) in the two years following the rainfall period. GEEs were used to investigate the association between relative rainfall and monthly numbers of unique visitors per HIV centre. RESULTS: Among 270,708 PWH across 386 HIV centres (67% female, median age 39 [IQR: 32-46]), lower rainfall than usual was associated with higher mortality (adjusted Hazard Ratio: 1.18 [95%CI: 1.07-1.32] per 10 percentile rainfall rank decrease) and unsuppressed viral loads (adjusted Odds Ratio: 1.05 [1.01-1.09]). Levels of rainfall were not strongly associated with CD4 counts < 200 cell/mm3 or > 12-month gaps in care. HIV centres in areas with less rainfall than usual had lower numbers of PWH visiting them (adjusted Rate Ratio: 0.80 [0.66-0.98] per 10 percentile rainfall rank decrease). CONCLUSIONS: Decreased rainfall could negatively impact on HIV treatment behaviours and outcomes. Further research is needed to explore the reasons for these effects. Interventions to mitigate the health impact of severe weather events are required.