Assessing the impacts of trace element contamination on the physiological and health of seabirds breeding along the western and southern coasts of Portugal.

Coastal seabirds serve as sentinels of ecosystem health due to their vulnerability to contamination from human activities. However, our understanding on how contaminant burdens affect the physiological and health condition of seabirds is still scarce, raising the uncertainty on the species' vulnerability vs tolerance to environmental contamination. Here, we quantified 15 trace elements (TE) in the blood of gull (yellow-legged gull Larus michahellis and Audouin's gull Ichthyaetus audouinii) and shearwater (Cory's shearwater Calonectris borealis) adults, breeding in five colonies along the Portuguese coastline. Additionally, stable isotopes of carbon (δ13C) and nitrogen (δ15N) were quantified to elucidate foraging habitat and trophic ecology of adults, to identify potential patterns of TE contamination among colonies. We used immuno-haematological parameters as response variables to assess the influence of TE concentrations, stable isotope values, and breeding colony on adults' physiological and health condition. Remarkably, we found blood mercury (Hg) and lead (Pb) concentrations to exceed reported toxicity thresholds in 25% and 13% of individuals, respectively, raising ecotoxicological concerns for these populations. The breeding colony was the primary factor explaining variation in five out of six models, underlining the influence of inherent species needs on immuno-haematological parameters. Model selection indicated a negative relationship between erythrocyte sedimentation rate and both Hg and selenium (Se) concentrations, but a positive relationship with δ13C. The number of immature erythrocyte counts was positively related to Hg and Se, particularly in yellow-legged gulls from one colony, highlighting the colony-site context's influence on haematological parameters. Further research is needed to determine whether essential TE concentrations, particularly copper (Cu) and Se, are falling outside the normal range for seabirds or meet species-specific requirements. Continuous monitoring of non-essential TE concentrations like aluminium (Al), Hg, and Pb, is crucial due to their potential hazardous concentrations, as observed in our study colonies.

PD-L1 and nectin-4 expression and genomic characterization of bladder cancer with divergent differentiation.

BACKGROUND: Bladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin-4 and programmed death ligand-1 (PD-L1) has been reported in BCDD. Importantly, nectin-4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD-L1 expression is associated with responses to immune checkpoint inhibitors (ICIs). METHODS: The authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin-4 and PD-L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole-exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs. RESULTS: The results indicated that nectin-4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD-L1-positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs. CONCLUSIONS: In this study, the authors identified clinically relevant data on nectin-4 and PD-L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis-generating data.

Total Synthesis of a Peptide Diatom Sex Pheromone Bearing a Sulfated Aspartic Acid.

The peptide sex-inducing pheromone SIP+ (1) bearing an unusual sulfated aspartic acid residue induces sexual reproduction in diatom populations. Herein, we report the first total synthesis of SIP+ using both a sulfated building block approach and a solid-phase peptide synthesis (SPPS)-compatible late-stage sulfation strategy to assemble the natural product. The modular approaches provide concise routes to useful quantities of the natural product for future structure activity relationship studies examining the role of SIP+ in diatom biology.

Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.

AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

Perineural Invasion is an Important Prognostic Factor in Patients With Radically Resected (R0) and Node-negative (pN0) Pancreatic Cancer.

OBJECTIVE: To investigate the association between perineural invasion (PNI) and overall survival (OS) in a nationwide cohort of patients with resected pancreatic ductal adenocarcinoma (PDAC), stratified for margin negative (R0) or positive (R1) resection and absence or presence of lymph node metastasis (pN0 or pN1-N2, respectively). BACKGROUND: Patients with R0 and pN0 resected PDAC have a relatively favorable prognosis. As PNI is associated with worse OS, this might be a useful factor to provide further prognostic information for patients counselling. METHODS: A nationwide observational cohort study was performed including all patients who underwent PDAC resection in the Netherlands (2014-2019) with complete information on relevant pathological features (PNI, R status, and N status). OS was assessed using Kaplan-Meier curves, and Cox-proportional hazard analyses were performed to calculate hazard ratio's (HR) with corresponding 95% confidence intervals (CI). RESULTS: In total, 1630 patients were included with a median follow-up of 43 (interquartile range 33-58) months. PNI was independently associated with worse OS in both R0 patients (HR 1.49 [95%CI 1.18-1.88]; P<0.001) and R1 patients (HR 1.39 [95% CI 1.06-1.83]; P=0.02), as well as in pN0 patients (HR 1.75 [95%CI 1.27-2.41]; P<0.001) and pN1-N2 patients (HR 1.35 [95% CI 1.10-1.67]; P<0.01). In 315 patients with R0N0, multivariable analysis showed that PNI was the strongest predictor of OS (HR 2.24 [95% CI 1.52-3.30]; P<0.001). CONCLUSION: PNI is strongly associated with worse survival in patients with resected PDAC, in particular in patients with relatively favorable pathological features. These findings may aid patient stratification and counselling and help guide treatment strategies.

Identifying Risk Factors for Attention-Deficit/Hyperactivity Disorder (ADHD): a Public Health Concern and Opportunity.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant individual and societal negative impacts of the disorder continuing into adulthood (Danielson et al. in Journal of Clinical Child and Adolescent Psychology, in press; Landes and London in Journal of Attention Disorders 25:3-13, 2021). Genetic and environmental risk (e.g., modifiable exposures such as prenatal tobacco exposure and child maltreatment) for ADHD is likely multifactorial (Faraone et al. in Neuroscience & Biobehavioral Reviews 128:789-818, 2021). However, the evidence for potentially modifiable contextual risks is spread across studies with different methodologies and ADHD criteria limiting understanding of the relationship between early risk factors and later childhood ADHD. Using common methodology across six meta-analyses (Bitsko et al. in Prevention Science, 2022; Claussen et al. in Prevention Science 1-23, 2022; Dimitrov et al. in Prevention Science, 2023; Maher et al. in Prevention Science, 2023; Robinson, Bitsko et al. in Prevention Science, 2022; So et al. in Prevention Science, 2022) examining 59 risk factors for childhood ADHD, the papers in this special issue use a public health approach to address prior gaps in the literature. This introductory paper provides examples of comprehensive public health approaches focusing on policy, systems, and environmental changes across socio-ecological contexts to improve health and wellbeing through prevention, early intervention, and support across development using findings from these meta-analyses. Together, the findings from these studies and a commentary by an author independent from the risk studies have the potential to minimize risk conditions, prioritize prevention efforts, and improve the long-term health and wellbeing of children and adults with ADHD.

Clinical Characteristics and Outcomes of Endemic Mycoses After Solid Organ Transplantation: A Comprehensive Review.

Background: Geographically endemic fungi can cause significant disease among solid organ transplant (SOT) recipients. We provide an update on the epidemiology, clinical presentation, and outcomes of 5 endemic mycoses in SOT recipients. Methods: Multiple databases were reviewed from inception through May 2023 using key words for endemic fungi (eg, coccidioidomycosis or Coccidioides, histoplasmosis or Histoplasma, etc). We included adult SOT recipients and publications in English or with English translation. Results: Among 16 cohort studies that reported on blastomycosis (n = 3), coccidioidomycosis (n = 5), histoplasmosis (n = 4), and various endemic mycoses (n = 4), the incidence rates varied, as follows: coccidioidomycosis, 1.2%-5.8%; blastomycosis, 0.14%-0.99%; and histoplasmosis, 0.4%-1.1%. There were 204 reports describing 268 unique cases of endemic mycoses, including 172 histoplasmosis, 31 blastomycosis, 34 coccidioidomycosis, 6 paracoccidioidomycosis, and 25 talaromycosis cases. The majority of patients were male (176 of 261 [67.4%]). Transplanted allografts were mostly kidney (192 of 268 [71.6%]), followed by liver (n = 39 [14.6%]), heart (n = 18 [6.7%]), lung (n = 13 [4.9%]), and combined kidney-liver and kidney-pancreas (n = 6 [2.7%]). In all 5 endemic mycoses, most patients presented with fever (162 of 232 [69.8%]) and disseminated disease (179 of 268 [66.8%]). Cytopenias were frequently reported for histoplasmosis (71 of 91 [78.0%]), coccidioidomycosis (8 of 11 [72.7%]) and talaromycosis (7 of 8 [87.5%]). Graft loss was reported in 12 of 136 patients (8.8%). Death from all-causes was reported in 71 of 267 (26.6%); half of the deaths (n = 34 [50%]) were related to the underlying mycoses. Conclusions: Endemic mycoses commonly present with fever, cytopenias and disseminated disease in SOT recipients. There is a relatively high all-cause mortality rate, including many deaths that were attributed to endemic mycoses.

Multiple genetic loci influence vaccine-induced protection against Mycobacterium tuberculosis in genetically diverse mice.

Mycobacterium tuberculosis (M.tb.) infection leads to over 1.5 million deaths annually, despite widespread vaccination with BCG at birth. Causes for the ongoing tuberculosis endemic are complex and include the failure of BCG to protect many against progressive pulmonary disease. Host genetics is one of the known factors implicated in susceptibility to primary tuberculosis, but less is known about the role that host genetics plays in controlling host responses to vaccination against M.tb. Here, we addressed this gap by utilizing Diversity Outbred (DO) mice as a small animal model to query genetic drivers of vaccine-induced protection against M.tb. DO mice are a highly genetically and phenotypically diverse outbred population that is well suited for fine genetic mapping. Similar to outcomes in people, our previous studies demonstrated that DO mice have a wide range of disease outcomes following BCG vaccination and M.tb. challenge. In the current study, we used a large population of BCG-vaccinated/M.tb.-challenged mice to perform quantitative trait loci mapping of complex infection traits; these included lung and spleen M.tb. burdens, as well as lung cytokines measured at necropsy. We found sixteen chromosomal loci associated with complex infection traits and cytokine production. QTL associated with bacterial burdens included a region encoding major histocompatibility antigens that are known to affect susceptibility to tuberculosis, supporting validity of the approach. Most of the other QTL represent novel associations with immune responses to M.tb. and novel pathways of cytokine regulation. Most importantly, we discovered that protection induced by BCG is a multigenic trait, in which genetic loci harboring functionally-distinct candidate genes influence different aspects of immune responses that are crucial collectively for successful protection. These data provide exciting new avenues to explore and exploit in developing new vaccines against M.tb.

The EORTC QLU-C10D is a valid cancer-specific preference-based measure for cost-utility and health technology assessment in the Netherlands.

BACKGROUND: Cost-utility analysis typically relies on preference-based measures (PBMs). While generic PBMs are widely used, disease-specific PBMs can capture aspects relevant for certain patient populations. Here the EORTC QLU-C10D, a cancer-specific PBM based on the QLQ-C30, is validated using Dutch trial data with the EQ-5D-3L as a generic comparator measure. METHODS: We retrospectively analysed data from four Dutch randomised controlled trials (RCTs) comprising the EORTC QLQ-C30 and the EQ-5D-3L. Respective Dutch value sets were applied. Correlations between the instruments were calculated for domains and index scores. Bland-Altman plots and intra-class correlations (ICC) displayed agreement between the measures. Independent and paired t-tests, effect sizes and relative validity indices were used to determine the instruments' performance in detecting clinically known-group differences and health changes over time. RESULTS: We analysed data from 602 cancer patients from four different trials. In overall, the EORTC QLU-C10D showed good relative validity with the EQ-5D-3L as a comparator (correlations of index scores r = 0.53-0.75, ICCs 0.686-0.808, conceptually similar domains showed higher correlations than dissimilar domains). Most importantly, it detected 63% of expected clinical group differences and 50% of changes over time in patients undergoing treatment. Both instruments showed poor performance in survivors. Detection rate and measurement efficiency were clearly higher for the QLU-C10D than for the EQ-5D-3L. CONCLUSIONS: The Dutch EORTC QLU-C10D showed good comparative validity in patients undergoing treatment. Our results underline the benefit that can be achieved by using a cancer-specific PBM for generating health utilities for cancer patients from a measurement perspective.

Associations between fears related to safety during sleep and self-reported sleep in men and women living in a low-socioeconomic status setting.

South Africans living in low socioeconomic areas have self-reported unusually long sleep durations (approximately 9-10 h). One hypothesis is that these long durations may be a compensatory response to poor sleep quality as a result of stressful environments. This study aimed to investigate whether fear of not being safe during sleep is associated with markers of sleep quality or duration in men and women. South Africans (n = 411, 25-50 y, 57% women) of African-origin living in an urban township, characterised by high crime and poverty rates, participated in this study. Participants are part of a larger longitudinal cohort study: Modelling the Epidemiologic Transition Study (METS)-Microbiome. Customised questions were used to assess the presence or absence of fears related to feeling safe during sleep, and the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index were used to assess daytime sleepiness, sleep quality and insomnia symptom severity respectively. Adjusted logistic regression models indicated that participants who reported fears related to safety during sleep were more likely to report poor sleep quality (PSQI > 5) compared to participants not reporting such fears and that this relationship was stronger among men than women. This is one of the first studies outside American or European populations to suggest that poor quality sleep is associated with fear of personal safety in low-SES South African adults.

Outcomes of Kidney Transplantation Among COVID-19 Recovered Patients in a Single Transplant Center.

BACKGROUND: The COVID-19 pandemic significantly lowered kidney transplantation (KT) rates worldwide, and studies regarding outcomes of patients who developed COVID-19 infection before KT are limited, especially in low to middle-income countries. BACKGROUND: To determine the 1-year graft and patient survival of kidney transplant recipients who recovered from COVID-19 infection before KT. METHODS: We retrospectively reviewed all adult end-stage renal disease patients who underwent KT at the National Kidney and Transplant Institute from June 2020 through October 2021. Transplant parameters, graft and patient survival, pretransplant COVID-19 infection, and post-KT infectious complications were recorded. Data was analyzed using two-tailed descriptive statistical tests. RESULTS: Of the 219 recipients, 23 (11%) had COVID-19 infection within 1 to 16 months before KT. The mean age of KT recipients was 36 years (range, 25-57), and 61.9% had chronic glomerulonephritis as primary renal disease. The mean duration from COVID-19 recovery to KT was 79 days (range, 21-207). There was no significant difference in the 1-year biopsy-proven acute rejection in the 2 groups, at 4.5% vs 12.5% for the COVID-19 and non-COVID-19 group, respectively. Both the 1-year graft and patient survival were similar in the COVID-19 and non-COVID-19 groups at 98.4% vs 100% and 100% vs 98.44%, respectively. CONCLUSION: There was no significant difference in biopsy-proven acute rejection, 1-year graft, and patient survival among patients who had a prior COVID-19 infection vs those who did not. Kidney transplantation appears safe when performed at least 1 month from COVID-19 infection.

The assessment of quality of care of patients with type 2 diabetes mellitus in a population-based cohort in the District of Landeck in Austria.

INTRODUCTION: Structured diabetes care based on evidence-based guidelines is one of the main strategies to improve glycemic control and to reduce long-term complications in diabetes mellitus. METHODS: This study is based on the "Diabetes-Landeck Cohort", a population-based cohort of patients with diabetes mellitus type 2 (T2DM). We assessed the quality of diabetes care and compared it between three groups of care units, that is, general practitioners (GP), diabetes specialists in private practice (DSPP), and hospitals (HOSP). RESULTS: The total study population comprised 1616 patients with T2DM, including 378 patients of GP, 281 of DSPP, and 957 from HOSP. We identified statistically significant differences: DSPP showed the highest percentage of structured training, sufficient training, eye examinations and foot examinations. The group HOSP showed the highest proportion for increased HbA1c≥ 7.5 and almost all long-term complications surveyed, that is, nephropathy (23.2%), neuropathy (14.4%), diabetic foot (5.1%), and cerebrovascular diseases (10.9%). CONCLUSION: This population-based cohort study on patients with T2DM in Austria showed significant differences in important quality-of-care process and outcome parameters across different groups of care units. Future research should also include prediction modeling for early warning and monitoring systems as well as adjustment for patient characteristics and duration and severity of disease.

A model-based approach to estimating the prevalence of disease combinations in South Africa.

BACKGROUND: The development of strategies to better detect and manage patients with multiple long-term conditions requires estimates of the most prevalent condition combinations. However, standard meta-analysis tools are not well suited to synthesising heterogeneous multimorbidity data. METHODS: We developed a statistical model to synthesise data on associations between diseases and nationally representative prevalence estimates and applied the model to South Africa. Published and unpublished data were reviewed, and meta-regression analysis was conducted to assess pairwise associations between 10 conditions: arthritis, asthma, chronic obstructive pulmonary disease (COPD), depression, diabetes, HIV, hypertension, ischaemic heart disease (IHD), stroke and tuberculosis. The national prevalence of each condition in individuals aged 15 and older was then independently estimated, and these estimates were integrated with the ORs from the meta-regressions in a statistical model, to estimate the national prevalence of each condition combination. RESULTS: The strongest disease associations in South Africa are between COPD and asthma (OR 14.6, 95% CI 10.3 to 19.9), COPD and IHD (OR 9.2, 95% CI 8.3 to 10.2) and IHD and stroke (OR 7.2, 95% CI 5.9 to 8.4). The most prevalent condition combinations in individuals aged 15+ are hypertension and arthritis (7.6%, 95% CI 5.8% to 9.5%), hypertension and diabetes (7.5%, 95% CI 6.4% to 8.6%) and hypertension and HIV (4.8%, 95% CI 3.3% to 6.6%). The average numbers of comorbidities are greatest in the case of COPD (2.3, 95% CI 2.1 to 2.6), stroke (2.1, 95% CI 1.8 to 2.4) and IHD (1.9, 95% CI 1.6 to 2.2). CONCLUSION: South Africa has high levels of HIV, hypertension, diabetes and arthritis, by international standards, and these are reflected in the most prevalent condition combinations. However, less prevalent conditions such as COPD, stroke and IHD contribute disproportionately to the multimorbidity burden, with high rates of comorbidity. This modelling approach can be used in other settings to characterise the most important disease combinations and levels of comorbidity.

Measurement of body composition in postpartum South African women living with and without HIV infection.

Background: While several methodologies are available to measure adiposity, few have been validated in sub-Saharan African (SSA) and none in postpartum African women living with HIV (WLHIV). We compared bioelectrical impendence analysis (BIA) and air displacement plethysmography (ADP) against dual x-ray absorptiometry (DXA) in South African women and examined differences by HIV and body mass index (BMI) status. Methods: Lin's concordance correlation coefficient (CCC) test was used to examine fat mass (FM), fat free mass (FFM), and total body fat percent (%BF) difference between BIA vs. DXA, and ADP vs. DXA in women living with HIV (n = 57) and without HIV (n = 25). The Bland Altman test was used to assess mean differences and the direction of bias. Results: The median age was 31 years (IQR, 26-35) and months postpartum were 11 (IQR, 7-16), 44% of the women had obesity. Lin's CCC for BIA and ADP vs. DXA were both 0.80 for %BF and 0.97 for FM, and 0.86 and 0.80 for FFM, respectively. Mean differences (DXA-BIA and ADP estimates) were 0.22 ± 4.54% (p = 0.54) and 3.35 ± 3.27% (p < 0.01) for %BF, -0.82 ± 3.56 kg (p = 0.06) and 1.43 ± 2.68 kg (p = 0.01) for FM, -1.38 ± 3.61 kg (p = 0.01) and - 3.34 ± 2.37 kg (p < 0.01) for FFM, respectively. BIA overestimated %BF in WLHIV and underestimated it in women with obesity. Conclusion: Body composition measurements using BIA and ADP correlated well with DXA, thereby providing alternative, safe tools for measuring postpartum FM and FFM in SSA women, including WLHIV.

Applying the Somatic Symptom Disorder Diagnosis to Individuals with Fibromyalgia: Strengths and Limitations.

Amidst broad changes to the somatic disorder diagnoses, DSM-IV pain disorder was absorbed into DSM-5's somatic symptom disorder (SSD) as a specifier. However, clinical research testing of its use for the chronic pain population has been limited and its utility remains inconclusive. Using the exemplar of fibromyalgia, this article evaluates the validity, reliability, clinical utility, and acceptability of the SSD pain specifier. The diagnosis appears to have moderate validity but low specificity for the fibromyalgia population. The pain specifier has neither undergone sufficient field testing nor been evaluated for use by medical providers, with available data suggesting low reliability. Further research is needed to establish clinical utility via assessment of differential treatment outcomes. Concerns about social, legal, and economic consequences of classifying pain patients with a mental health diagnosis are outstanding. The current SSD criteria should be used with caution among the fibromyalgia patient population until its application for chronic pain has been further researched.

Aerosol source apportionment uncertainty linked to the choice of input chemical components.

For a Positive Matrix Factorization (PMF) aerosol source apportionment (SA) studies there is no standard procedure to select the most appropriate chemical components to be included in the input dataset for a given site typology, nor specific recommendations in this direction. However, these choices are crucial for the final SA outputs not only in terms of number of sources identified but also, and consequently, in the source contributions estimates. In fact, PMF tends to reproduce most of PM mass measured independently and introduced as a total variable in the input data, regardless of the percentage of PM mass which has been chemically characterized, so that the lack of some specific source tracers (e.g. levoglucosan) can potentially affect the results of the whole source apportionment study. The present study elaborates further on the same concept, evaluating quantitatively the impact of lacking specific sources' tracers on the whole source apportionment, both in terms of identified sources and source contributions. This work aims to provide first recommendations on the most suitable and critical components to be included in PMF analyses in order to reduce PMF output uncertainty as much as possible, and better represent the most commons PM sources observed in many sites in Western countries. To this aim, we performed three sensitivity analyses on three different datasets across EU, including extended sets of organic tracers, in order to cover different types of urban conditions (Mediterranean, Continental, and Alpine), source types, and PM fractions. Our findings reveal that the vehicle exhaust source resulted to be less sensitive to the choice of analytes, although source contributions estimates can deviate significantly up to 44 %. On the other hand, for the detection of the non-exhaust one is clearly necessary to analyze specific inorganic elements. The choice of not analysing non-polar organics likely causes the loss of separation of exhaust and non-exhaust factors, thus obtaining a unique road traffic source, which provokes a significant bias of total contribution. Levoglucosan was, in most cases, crucial to identify biomass burning contributions in Milan and in Barcelona, in spite of the presence of PAHs in Barcelona, while for the case of Grenoble, even discarding levoglucosan, the presence of PAHs allowed identifying the BB factor. Modifying the rest of analytes provoke a systematic underestimation of biomass burning source contributions. SIA factors resulted to be generally overestimated with respect to the base case analysis, also in the case that ions were not included in the PMF analysis. Trace elements were crucial to identify shipping emissions (V and Ni) and industrial sources (Pb, Ni, Br, Zn, Mn, Cd and As). When changing the rest of input variables, the uncertainty was narrow for shipping but large for industrial processes. Major and trace elements were also crucial to identify the mineral/soil factor at all cities. Biogenic SOA and Anthropogenic SOA factors were sensitive to the presence of their molecular tracers, since the availability of OC alone is unable to separate a SOA factor. Arabitol and sorbitol were crucial to detecting fungal spores while odd number of higher alkanes (C27 to C31) for plant debris.

Integrated health system intervention aimed at reducing type 2 diabetes risk in women after gestational diabetes in South Africa (IINDIAGO): a randomised controlled trial protocol.

INTRODUCTION: South Africa has a high prevalence of gestational diabetes mellitus (GDM; 15%) and many of these women (48%) progress to type 2 diabetes mellitus (T2DM) within 5 years post partum. A significant proportion (47%) of the women are not aware of their diabetes status after the index pregnancy, which may be in part to low postnatal diabetes screening rates. Therefore, we aim to evaluate a intervention that reduces the subsequent risk of developing T2DM among women with recent GDM. Our objectives are fourfold: (1) compare the completion of the nationally recommended 6-week postpartum oral glucose tolerance test (OGTT) between intervention and control groups; (2) compare the diabetes risk reduction between control and intervention groups at 12 months' post partum; (3) assess the process of implementation; and (4) assess the cost-effectiveness of the proposed intervention package. METHODS AND ANALYSES: Convergent parallel mixed-methods study with the main component being a pragmatic, 2-arm individually randomised controlled trial, which will be carried out at five major referral centres and up to 26 well-baby clinics in the Western Cape and Gauteng provinces of South Africa. Participants (n=370) with GDM (with no prior history of either type 1 or type 2 diabetes) will be recruited into the study at 24-36 weeks' gestational age, at which stage first data collection will take place. Subsequent data collection will take place at 6-8 weeks after delivery and again at 12 months. The primary outcome for the trial is twofold: first, the completion of the recommended 2-hour OGTT at the well-baby clinics 6-8 weeks post partum, and second, a composite diabetes risk reduction indicator at 12 months. Process evaluation will assess fidelity, acceptability, and dose of the intervention. ETHICS AND DISSEMINATION: Ethics approval has been granted from University of Cape Town (829/2016), University of the Witwatersrand, Johannesburg (M170228), University of Stellenbosch (N17/04/032) and the University of Montreal (2019-794). The results of the trial will be disseminated through publication in peer-reviewed journals and presentations to key South African Government stakeholders and health service providers. PROTOCOL VERSION: 1 December 2022 (version #2). Any protocol amendments will be communicated to investigators, Human Ethics Research Committees, trial participants, and trial registries. TRIAL REGISTRATION NUMBER: PAN African Clinical Trials Registry (https://pactr.samrc.ac.za) on 11 June 2018 (identifier PACTR201805003336174).

Body composition is associated with postoperative complications in perihilar cholangiocarcinoma.

BACKGROUND: Perihilar cholangiocarcinoma (pCCA) is a malignant tumor of the hepatobiliary system which is still associated with a challenging prognosis. Postoperative complications play a crucial role in determining the overall prognosis of patients with pCCA. Changes in body composition (BC) have been shown to impact the prognosis of various types of tumors. Therefore, our study aimed to investigate the correlation between BC, postoperative complications and oncological outcome in patients with pCCA. METHODS: All patients with pCCA who underwent curative-intent surgery for pCCA between 2010 and 2022 were included in this analysis. BC was assessed using preoperative computed tomography and analyzed with the assistance of a 3D Slicer software. Univariate and multivariate binary logistic regression analyses were conducted to examine the relationship between BC and clinical characteristics including various measurements of postoperative complications and Cox regressions and Kaplan-Meier analysis to evaluate oncological risk factors in the study cohort. RESULTS: BC was frequently altered in patients undergoing curative-intent liver resection for pCCA (n = 204) with 52.5% of the patients showing obesity, 55.9% sarcopenia, 21.6% sarcopenic obesity, 48.5% myosteatosis, and 69.1% visceral obesity. In multivariate analysis, severe postoperative complications (Clavien-Dindo ≥3b) were associated with body mass index (BMI) (Odds ratio (OR) = 2.001, p = 0.024), sarcopenia (OR = 2.145, p = 0.034), and myosteatosis (OR = 2.097, p = 0.017) as independent predictors. Furthermore, sarcopenia was associated with reduced overall survival (OS) in pCCA patients (sarcopenia vs. no-sarcopenia, 21 months vs. 32 months, p = 0.048 log rank). CONCLUSIONS: BC is highly associated with severe postoperative complications in patients with pCCA and shows tendency to be associated impaired overall survival. Preoperative assessment of BC and interventions to improve BC might therefore be key to improve outcome in pCCA patients undergoing surgical therapy.

Noninvasive Papillary Urothelial Carcinoma of the Bladder: An Institutional Experience Focusing on Tumors With Borderline Features.

CONTEXT.­: Noninvasive papillary urothelial carcinomas (PUCs) comprise most urinary bladder tumors. Distinction between low-grade (LG-PUC) and high-grade (HG-PUC) PUCs is pivotal for determining prognosis and subsequent treatment. OBJECTIVE.­: To investigate the histologic characteristics of tumors with borderline features between LG-PUC and HG-PUC, focusing on the risk of recurrence and progression. DESIGN.­: We reviewed the clinicopathologic parameters of noninvasive PUC. Tumors with borderline features were subcategorized as follows: tumors that look like LG-PUC but have occasional pleomorphic nuclei (1-BORD-NUP) or elevated mitotic count (2-BORD-MIT), and tumors with side-by-side distinct LG-PUC and less than 50% HG-PUC (3-BORD-MIXED). Recurrence-free, total progression-free, and specific invasion-free survival curves were derived from the Kaplan-Meier method, and Cox regression analysis was performed. RESULTS.­: A total of 138 patients with noninvasive PUC were included, with the following distribution: LG-PUC (n = 52; 38%), HG-PUC (n = 34; 25%), BORD-NUP (n = 21; 15%), BORD-MIT (n = 14; 10%), and BORD-MIXED (n = 17; 12%). Median (interquartile range) follow-up was 44.2 months (29.9-73.1 months). Invasion-free survival was different between the 5 groups (P = .004), and pairwise comparison showed that HG-PUC had a worse prognosis compared with LG-PUC (P ≤ .001). On univariate Cox analysis, HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3-48.3; P = .003) and 5.9 times (95% CI, 1.1-31.9; P = .04) more likely to invade, respectively, when compared to LG-PUC. CONCLUSIONS.­: Our findings confirm a continuous spectrum of histologic changes in PUC. Approximately a third of noninvasive PUCs show borderline features between LG-PUC and HG-PUC. Compared with LG-PUC, BORD-NUP and HG-PUC were more likely to invade on follow-up. BORD-MIXED tumors did not statistically behave differently from LG-PUC.

Genetic Profiling of African American Patients With Prostatic Adenocarcinoma Metastatic to the Lymph Nodes: A Pilot Study.

CONTEXT.­: Genetic profiling data of prostatic adenocarcinoma are derived from predominantly White patients. In African Americans, prostatic adenocarcinoma has a poorer prognosis, raising the possibility of distinct genetic alterations. OBJECTIVE.­: To investigate the genomic alterations of prostatic adenocarcinoma metastatic to regional lymph nodes in African American patients, with an emphasis on SPOP mutation. DESIGN.­: We retrospectively reviewed African American patients with pN1 prostatic adenocarcinoma managed with radical prostatectomy and lymph node dissection. Comprehensive molecular profiling was performed, and androgen receptor signaling scores were calculated. RESULTS.­: Nineteen patients were included. The most frequent genetic alteration was SPOP mutations (5 of 17; 29.4% [95% CI: 10.3-56.0]). While most alterations were associated with a high androgen receptor signaling score, mutant SPOP was exclusively associated with a low median and interquartile range (IQR) androgen receptor signaling score (0.788 [IQR 0.765-0.791] versus 0.835 [IQR 0.828-0.842], P = .003). In mutant SPOP, mRNA expression of SPOP inhibitor G3BP1 and SPOP substrates showed a significantly decreased expression of AR (33.40 [IQR 28.45-36.30] versus 59.53 [IQR 53.10-72.83], P = .01), TRIM24 (3.95 [IQR 3.28-5.03] versus 9.80 [IQR 7.39-11.70], P = .008), and NCOA3 (15.19 [IQR 10.59-15.93] versus 21.88 [IQR 18.41-28.33], P = .046). CONCLUSIONS.­: African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.