Search

BACKGROUND: The 24-h urine protein (24-hUP) excretion is the gold standard for evaluating proteinuria. This study aimed to evaluate the diagnostic efficacy of protein/creatinine ratio (PCR) for estimating 24-hUP at various levels of renal function and proteinuria levels. METHODS: A cross-sectional study was conducted between December 2021 and December 2023 in Salvador, Bahia-Brazil, as an extension of previously published data from the TUNARI study. The study included 217 samples from 152 patients with various levels of renal function and proteinuria. PCR in isolated samples and 24-hUP were determined conventionally within a 24-h timeframe. Patients were classified into three groups according to the level of renal function (Group 1 = 10 to  60 mL/min) and level of proteinuria ( 3.5 g/day). The data were analyzed using the Spearman correlation (rs), coefficient of determination (r2), Bland-Altman plots and receiver operating characteristic (ROC) curve. Likelihood ratios, positive (LR +), and negative (LR-) were derived from the sensitivity and specificity of PCR. RESULTS: Mean age was 41.5 ± 15.7 years, 61.8% were women, 36.8% Black and 52% Mixed-race. Glomerulopathies constituted 80.3%; 46.1% with lupus nephritis. Of the total urine samples, we observed a high correlation between PCR in the total sample of 24-hUP sample (rs = 0.86, p  0.3-3.5 g/day, the sensitivity was 64.1%, the specificity was 84.6%, and the AUC was 0.76 (95% CI = 0.67; 0.84), PCR detected all cases > 3.5 g/day. CONCLUSIONS: PCR is a suitable measure to be used as an indicator of 24-hUP at different levels of renal function, but may have limitations at higher levels of proteinuria. Analysis of PCR by proteinuria level found that agreement as well as sensitivity decreases at higher levels, but it maintains good specificity and is able to identify nephrotic range proteinuria.

Coccidioidomycosis, listed as a priority mycosis by the WHO, is endemic in the United States but often overlooked in Central and South America. Employing a multi-institutional approach, we investigate how disease characteristics, pathogen genetic variation, and environmental factors impact coccidioidomycosis epidemiology and outcomes in South America. We identified 292 cases (1978-2021) and 42 outbreaks in Piauí and Maranhão states, Brazil, the largest series outside the US/Mexico epidemic zone. The male-to-female ratio was 57.4:1 and the most common activity was armadillo hunting (91.1%) 4 to 30 days before symptom onset. Most patients (92.8%) exhibited typical acute pulmonary disease, with cough (93%), fever (90%), and chest pain (77%) as predominant symptoms. The case fatality rate was 8%. Our negative binomial regression model indicates that reduced precipitation levels in the current (p = 0.015) and preceding year (p = 0.001) predict heightened incidence. Unlike other hotspots, acidic soil characterizes this region. Brazilian strains differ genomically from other C. posadasii lineages. Northeastern Brazil presents a distinctive coccidioidomycosis profile, with armadillo hunters facing elevated risks. Low annual rainfall emerges as a key factor in increasing cases. A unique C. posadasii lineage in Brazil suggests potential differences in environmental, virulence, and/or pathogenesis traits compared to other Coccidioides genotypes.

BACKGROUND: Apolipoprotein E ε4 allele (APOE-ε4) is the main genetic risk factor for late-onset Alzheimers disease (AD) and may impact cognitive function also via other neuropathological lesions. However, there is limited evidence available from diverse populations, as APOE associations with dementia seem to differ by race. Therefore, we aimed to evaluate the pathways linking APOE-ε4 to cognitive abilities through AD and non-AD neuropathology in an autopsy study with an admixed sample. METHODS: Neuropathological lesions were evaluated following international criteria using immunohistochemistry. Participants were classified into APOE-ε4 carriers (at least one ε4 allele) and non-carriers. Cognitive abilities were evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the indirect association of APOE-ε4 with cognition through AD-pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA-binding protein 43 (TDP-43). RESULTS: We included 648 participants (mean age 75 ± 12 years old, mean education 4.4 ± 3.7 years, 52% women, 69% White, and 28% APOE-ε4 carriers). The association between APOE-ε4 and cognitive abilities was mediated by neurofibrillary tangles (β = 0.88, 95% CI = 0.45; 1.38, p

The human cerebral cortex is one of the most evolved regions of the brain, responsible for most higher-order neural functions. Since nerve cells (together with synapses) are the processing units underlying cortical physiology and morphology, we studied how the human neocortex is composed regarding the number of cells as a function of sex and age. We used the isotropic fractionator for cell quantification of immunocytochemically labeled nuclei from the cerebral cortex donated by 43 cognitively healthy subjects aged 25-87 years old. In addition to previously reported sexual dimorphism in the medial temporal lobe, we found more neurons in the occipital lobe of men, higher neuronal density in womens frontal lobe, but no sex differences in the number and density of cells in the other lobes and the whole neocortex. On average, the neocortex has ~10.2 billion neurons, 34% in the frontal lobe and the remaining 66% uniformly distributed among the other 3 lobes. Along typical aging, there is a loss of non-neuronal cells in the frontal lobe and the preservation of the number of neurons in the cortex. Our study made possible to determine the different degrees of modulation that sex and age evoke on cortical cellularity.

BACKGROUND: Apolipoprotein E gene (APOE) ε4 allele is associated with a higher risk of carotid atherosclerosis, but less is known about the association of APOE with intracranial atherosclerotic disease (IAD). We aimed to investigate the association of APOE alleles with IAD in a cross-sectional autopsy study. METHODS: We measured the stenosis in the 12 arteries of the Circle of Willis using postmortem morphometric measurements. The APOE polymorphism was determined by real-time polymerase chain reaction. We assessed the association between APOE polymorphism and IAD using regression models adjusted for sociodemographic and clinical variables. We also verified the modifier effect of age, sex, and race on this association. We stratified the analysis by age group to investigate the possibility of attrition bias. RESULTS: In 400 participants (mean age=73.2±12.3 years old, 51% female, and 64% White), IAD was evaluated in 4,504 artery segments. APOE-ε4 was not associated with IAD nor with the number of artery stenosis compared to non-APOE-ε4 carriers. Sociodemographic variables did not modify this relationship. Among participants older than 70 years, there was a trend towards an association between APOE allele ε4 and a lower stenosis index in the middle cerebral artery, suggesting attrition bias related to the APOE-ε4 effect on mortality. CONCLUSIONS: APOE alleles were not associated with IAD in this population-based autopsy study. Lower stenosis in older participants suggests the possibility of attrition bias.

ImportanceRapid vessel density loss during an initial follow-up period may be associated with the rates of visual field loss over time.ObjectivesTo evaluate the association between the rate of vessel density loss during initial follow-up and the rate of visual field loss during an extended follow-up period in patients suspected of having glaucoma and patients with primary open-angle glaucoma.Design, setting, and participantsThis retrospective cohort study assessed 124 eyes (86 with primary open-angle glaucoma and 38 suspected of having glaucoma) of 82 patients who were followed up at a tertiary glaucoma center for a mean of 4.0 years (95% CI, 3.9-4.1 years) from January 1, 2015, to February 29, 2020. Data analysis for the current study was undertaken in March 2021.Main outcomes and measuresThe rate of vessel density loss was derived from macular whole-image vessel density values from 3 optical coherence tomography angiography scans early during the study. The rate of visual field loss was calculated from visual field mean deviation during the entire follow-up period after the first optical coherence tomography angiography visit. Linear mixed-effects models were used to estimate rates of change.ResultsA total of 124 eyes from 82 patients (mean [SD] age, 69.2 [10.9] years; 41 female [50.0%] and 41 male [50.0%]; and 20 African American [24.4%], 10 Asian [12.2%], 50 White [61.0%], and 2 other race or ethnicity [2.4%]) were assessed. The annual rate of vessel density change was -0.80% (95% CI, -0.88% to -0.72%) during a mean initial follow-up of 2.1 years (95% CI, 1.9-2.3 years). Eyes with annual rates of vessel density loss of -0.75% or greater (n = 62) were categorized as fast progressors, and eyes with annual rates of less than -0.75% (n = 62) were categorized as slow progressors. The annual rate of visual field loss was -0.15 dB (95% CI, -0.29 to -0.01 dB) for the slow optical coherence tomography angiography progressors and -0.43 dB (95% CI, -0.58 to -0.29 dB) for the fast optical coherence tomography angiography progressors (difference, -0.28 dB; 95% CI, -0.48 to -0.08 dB; P = .006). The fast optical coherence tomography angiography progressor group was associated with the faster overall rate of visual field loss in a multivariable model after adjusting to include concurrent visual field mean deviation rate (-0.17 dB; 95% CI, -0.33 to -0.01 dB; P = .04).Conclusions and relevanceThe findings of this cohort study suggest that faster vessel density loss during an initial follow-up period was associated with faster concurrent and subsequent rates of visual field loss during an extended period.

BackgroundPesticides and metals may disrupt thyroid function, which is key to fetal brain development.ObjectivesTo evaluate if current-use pesticide exposures, lead and excess manganese alter free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) concentrations in pregnant women from the Infants' Environmental Health Study (ISA).MethodsAt enrollment, we determined women's (n = 400) specific-gravity corrected urinary pesticide (μg/L) metabolite concentrations of mancozeb (ethylene thiourea (ETU)), pyrimethanil, thiabendazole, chlorpyrifos, synthetic pyrethroids, and 2,4-D. We also measured manganese hair (MnH) (μg/g) and blood (MnB) (μg/L), and blood lead (PbB) (μg/L) concentrations. To detect an immediate and late effect on thyroid homeostasis, we determined TSH, FT4 and FT3 in serum obtained at the same visit (n = 400), and about ten weeks afterwards (n = 245). We assessed associations between exposures and outcomes with linear regression and general additive models, Bayesian multivariate linear regression, and Bayesian kernel machine regression.ResultsAbout 80%, 94%, and 100% of the women had TSH, FT4, and FT3 within clinical reference ranges, respectively. Women with higher urinary ETU, and pyrimethanil-metabolites, had lower FT4: β = -0.79 (95%CI = -1.51, -0.08) and β = -0.29 (95%CI = -0.62, -0.03), respectively, for each tenfold increase in exposure. MnB was positively associated with FT4 (β = 0.04 (95%CI = 0.00, 0.07 per 1 μg/L increase), and women with high urinary pyrethroid-metabolite concentrations had decreased TSH (non-linear effects). For the late-effect analysis, metabolites of pyrethroids and chlorpyrifos, as well as MnH, and PbB were associated decreased TSH, or increased FT4 and/or FT3.DiscussionMancozeb (ETU) and pyrimethanil may inhibit FT4 secretion (hypothyroidism-like effect), while chlorpyrifos, pyrethroids, MnB, MnH, PbB and Mn showed hyperthyroidism-like effects. Some effects on thyroid homeostasis seemed to be immediate (mancozeb (ETU), pyrimethanil, MnB), others delayed (chlorpyrifos, MnH, PbB), or both (pyrethroids), possibly reflecting different mechanisms of action.

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed. PATIENTS AND METHODS: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.

PurposeLynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals.Experimental designA retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA.ResultsA total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor-positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response.ConclusionsA subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.

PurposeCyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER+)/HER2- breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.Experimental designParental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.ResultsParental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.ConclusionsAberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Background and objectivesIncidence in first-time and repeat blood donors is an important measure of transfusion-transmitted HIV infection (TT-HIV) risk. This study assessed HIV incidence over time at four large blood centres in Brazil.Materials and methodsDonations were screened and confirmed using serological assays for HIV from 2007 to 2016, and additionally screened by nucleic acid testing from 2011 forward. Limiting antigen (LAg) avidity testing was conducted on HIV seroreactive samples from first-time donors to classify whether an infection was recently acquired. We calculated incidence in first-time donors using the mean duration of recent infection and in repeat donors using classical methods. Time and demographic trends were assessed using Poisson regression.ResultsOver the 10-year period, HIV incidence in first-time donors was highest in Recife (45·1/100 000 person-years (105 py)) followed by São Paulo (32·2/105 py) and then Belo Horizonte (23·3/105 py), and in repeat donors was highest in Recife (33·2/105 py), Belo Horizonte (27·5/105 py) and São Paulo (17·0/105 py). Results from Rio de Janeiro were available from 2013 to 2016 with incidence in first-time donors of 35·9/105 py and repeat donors from 2011 to 2016 of 29·2/105 py. Incidence varied by other donor demographics. When incidence was considered in 2-year intervals, no significant trend was evident. Overall residual risk of TT-HIV was 5·46 and 7·41 per million units of pRBC and FFP transfused, respectively.ConclusionHIV incidence in both first-time and repeat donors varied by region in Brazil. Clear secular trends were not evident.

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.

BackgroundWhile peritoneal dialysis (PD) can offer patients more independence and flexibility compared with in-center hemodialysis, managing the ongoing and technically demanding regimen can impose a burden on patients and caregivers. Patient empowerment can strengthen capacity for self-management and improve treatment outcomes. We aimed to describe patients' and caregivers' perspectives on the meaning and role of patient empowerment in PD.MethodsAdult patients receiving PD (n = 81) and their caregivers (n = 45), purposively sampled from nine dialysis units in Australia, Hong Kong and the USA, participated in 14 focus groups. Transcripts were thematically analyzed.ResultsWe identified six themes: lacking clarity for self-management (limited understanding of rationale behind necessary restrictions, muddled by conflicting information); PD regimen restricting flexibility and freedom (burden in budgeting time, confined to be close to home); strength with supportive relationships (gaining reassurance with practical assistance, comforted by considerate health professionals, supported by family and friends); defying constraints (reclaiming the day, undeterred by treatment, refusing to be defined by illness); regaining lost vitality (enabling physical functioning, restoring energy for life participation); and personal growth through adjustment (building resilience and enabling positive outlook, accepting the dialysis regimen).ConclusionsUnderstanding the rationale behind lifestyle restrictions, practical assistance and family support in managing PD promoted patient empowerment, whereas being constrained in time and capacity for life participation outside the home undermined it. Education, counseling and strategies to minimize the disruption and burden of PD may enhance satisfaction and outcomes in patients requiring PD.

BackgroundAlcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk.MethodsData from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking.ResultsFor all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx).ConclusionsPresent results further encourage the reduction of alcohol intensity to mitigate HNC risk.

Microglial cells play essential volume-related actions in the brain that contribute to the maturation and plasticity of neural circuits that ultimately shape behavior. Microglia can thus be expected to have similar cell sizes and even distribution both across brain structures and across species with different brain sizes. To test this hypothesis, we determined microglial cell densities (the inverse of cell size) using immunocytochemistry to Iba1 in samples of free cell nuclei prepared with the isotropic fractionator from brain structures of 33 mammalian species belonging to males and females of five different clades. We found that microglial cells constitute ∼7% of non-neuronal cells in different brain structures as well as in the whole brain of all mammalian species examined. Further, they vary little in cell density compared with neuronal cell densities within the cerebral cortex, across brain structures, across species within the same clade, and across mammalian clades. As a consequence, we find that one microglial cell services as few as one and as many as 100 neurons in different brain regions and species, depending on the local neuronal density. We thus conclude that the addition of microglial cells to mammalian brains is governed by mechanisms that constrain the size of these cells and have remained conserved over 200 million years of mammalian evolution. We discuss the probable consequences of such constrained size for brain function in health and disease.SIGNIFICANCE STATEMENT Microglial cells are resident macrophages of the CNS, with key functions in recycling synapses and maintaining the local environment in health and disease. We find that microglial cells occur in similar densities in the brains of different species and in the different structures of each individual brain, which indicates that these cells maintain a similar average size in mammalian evolution, suggesting in turn that the volume monitored by each microglial cell remains constant across mammals. Because the density of neurons is highly variable across the same brain structures and species, our finding implies that microglia-dependent functional recovery may be particularly difficult in those brain structures and species with high neuronal densities and therefore fewer microglial cells per neuron.

Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.

Kidney disease is prevalent in low-resource settings worldwide, but tests for its diagnosis are often unavailable. The saliva urea nitrogen (SUN) dipstick is a laboratory and electricity independent tool, which may be used for the detection of kidney disease. We investigated the feasibility and performance of its use in diagnosing kidney disease in community settings in Africa. Adult patients at increased risk of kidney disease presenting to three community health centres, a rural district hospital and a central hospital in Malawi were recruited between October 2016 and September 2017. Patients underwent concurrent SUN and creatinine testing at enrolment, and at 1 week, 1 month, 3 months and 6 months thereafter. Of 710 patients who presented at increased risk of kidney disease, 655 (92.3%) underwent SUN testing at enrolment, and were included (aged 38 (29-52) years, 367 (56%) female and 333 (50.8%) with HIV). Kidney disease was present in 482 (73.6%) patients and 1479 SUN measurements were made overall. Estimated glomerular filtration rate (eGFR) correlated with SUN (r=-0.39; ptest pad #1) compared with patients with non-elevated SUN (p

Sporotrichosis is a subcutaneous infection caused by fungi from the genus Sporothrix. It is transmitted by inoculation of infective particles found in plant-contaminated material or diseased animals, characterizing the classic sapronotic and emerging zoonotic transmission, respectively. Since 1998, southeastern Brazil has experienced a zoonotic sporotrichosis epidemic caused by S. brasiliensis, centred in the state of Rio de Janeiro. Our observation of feline sporotrichosis cases in Brasília (Midwestern Brazil), around 900 km away from Rio de Janeiro, led us to question whether the epidemic caused by S. brasiliensis has spread from the epicentre in Rio de Janeiro, emerged independently in the two locations, or if the disease has been present and unrecognized in Midwestern Brazil. A retrospective analysis of 91 human and 4 animal cases from Brasília, ranging from 1993 to 2018, suggests the occurrence of both sapronotic and zoonotic transmission. Molecular typing of the calmodulin locus identified S. schenckii as the agent in two animals and all seven human patients from which we were able to recover clinical isolates. In two other animals, the disease was caused by S. brasiliensis. Whole-genome sequence typing of seven Sporothrix spp. strains from Brasília and Rio de Janeiro suggests that S. brasiliensis isolates from Brasília are genetically distinct from those obtained at the epicentre of the outbreak in Rio de Janeiro, both in phylogenomic and population genomic analyses. The two S. brasiliensis populations seem to have separated between 2.2 and 3.1 million years ago, indicating independent outbreaks or that the zoonotic S. brasiliensis outbreak might have started earlier and be more widespread in South America than previously recognized.

Carbon (C) footprint of dairy production, expressed in kg C dioxide (CO2) equivalents (CO2e) (kg energy-corrected milk (ECM))-1, encompasses emissions from feed production, diet management and total product output. The proportion of pasture on diets may affect all these factors, mainly in subtropical climate zones, where cows may access tropical and temperate pastures during warm and cold seasons, respectively. The aim of the study was to assess the C footprint of a dairy system with annual tropical and temperate pastures in a subtropical region. The system boundary included all processes up to the animal farm gate. Feed requirement during the entire life of each cow was based on data recorded from Holstein × Jersey cow herds producing an average of 7,000 kg ECM lactation-1. The milk production response as consequence of feed strategies (scenarios) was based on results from two experiments (warm and cold seasons) using lactating cows from the same herd. Three scenarios were evaluated: total mixed ration (TMR) ad libitum intake, 75, and 50% of ad libitum TMR intake with access to grazing either a tropical or temperate pasture during lactation periods. Considering IPCC and international literature values to estimate emissions from urine/dung, feed production and electricity, the C footprint was similar between scenarios, averaging 1.06 kg CO2e (kg ECM)-1. Considering factors from studies conducted in subtropical conditions and actual inputs for on-farm feed production, the C footprint decreased 0.04 kg CO2e (kg ECM)-1 in scenarios including pastures compared to ad libitum TMR. Regardless of factors considered, emissions from feed production decreased as the proportion of pasture went up. In conclusion, decreasing TMR intake and including pastures in dairy cow diets in subtropical conditions have the potential to maintain or reduce the C footprint to a small extent.

Background Macrophages and T lymphocytes in the perivascular adipose tissue (PvAT) were previously linked to coronary artery disease. However, the role of these cells and B lymphocytes in the human PvAT adjacent to unstable atherosclerotic plaques has not been investigated. Moreover, previous studies were inconclusive on whether PvAT inflammation was restricted to the surroundings of the atheroma plaque. Methods and Results Coronary arteries were freshly dissected with the surrounding PvAT. Atherosclerotic plaques were classified according to the internationally accepted anatomopathological criteria. Immune cells in the PvAT were detected using immunohistochemistry and then quantified. We used linear and logistic regressions with robust standard errors, adjusted for possible confounding factors. In 246 atherosclerotic plaques (205 stable and 41 unstable plaques) from 82 participants (mean age=69.0±14.4 years; 50% men), the percentage of arterial obstruction was positively correlated with the densities of CD68+ macrophages (P=0.003) and CD20+ B lymphocytes (P=0.03) in the periplaque PvAT. The number of cells was greater in the periplaque PvAT than in the distal PvAT (macrophages, P

BackgroundTobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk.MethodsWe analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models.ResultsWithout adjusting for tobacco packyears, we observed that younger age at starting tobacco use was associated with an increased HNC risk for ever smokers (OR

ObjectiveTo compare neuropathological correlates of cognitive impairment between very old and younger individuals from a Brazilian clinicopathological study.MethodsWe assessed the frequency of neuropathological lesions and their association with cognitive impairment (Clinical Dementia Rating scale ≥0.5) in the 80 or over age group compared to younger participants, using logistic regression models adjusted for sex, race and education.ResultsExcept for infarcts and siderocalcinosis, all neuropathological lesions were more common in the 80 or over age group (n = 412) compared to 50-79 year olds (n = 677). Very old participants had more than twice the likelihood of having ≥2 neuropathological diagnoses than younger participants (OR = 2.66, 95% CI = 2.03-3.50). Neurofibrillary tangles, infarcts and hyaline arteriolosclerosis were associated with cognitive impairment in the two age groups. Siderocalcinosis was associated with cognitive impairment in the younger participants only, while Lewy body disease was associated with cognitive impairment in the very old only. In addition, we found that the association of infarcts and multiple pathologies with cognitive impairment was attenuated in very old adults (Infarcts: P for interaction = 0.04; and multiple pathologies: P = 0.05). However, the predictive value for the aggregate model with all neuropathological lesions showed similar discrimination in both age groups [Area under Receiver Operating Characteristic curve (AUROC) = 0.778 in younger participants and AUROC = 0.765 in the very old].Conclusion and relevanceDespite a higher frequency of neuropathological findings in the very old group, as found in studies with high-income populations, we found attenuation of the effect of infarcts rather than neurofibrillary tangles and plaques as reported previously.

BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODSAn integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTSCompared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSIONThese observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDINGAdenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).

Shared decision-making about clinical care options in end-stage kidney disease is limited by inconsistencies in the reporting of outcomes and the omission of patient-important outcomes in trials. Here we generated a consensus-based prioritized list of outcomes to be reported during trials in peritoneal dialysis (PD). In an international, online, three-round Delphi survey, patients/caregivers and health professionals rated the importance of outcomes using a 9-point Likert scale (with 7-9 indicating critical importance) and provided comments. Using a Best-Worst Scale (BWS), the relative importance of outcomes was estimated. Comments were analyzed thematically. In total, 873 participants (207 patients/caregivers and 666 health professionals) from 68 countries completed round one, 629 completed round two and 530 completed round three. The top outcomes were PD-related infection, membrane function, peritoneal dialysis failure, cardiovascular disease, death, catheter complications, and the ability to do usual activities. Compared with health professionals, patients/caregivers gave higher priority to six outcomes: blood pressure (mean difference, 0.4), fatigue (0.3), membrane function (0.3), impact on family/friends (0.1), peritoneal thickening (0.1) and usual activities (0.1). Four themes were identified that underpinned the reasons for ratings: contributing to treatment longevity, preserving quality of life, escalating morbidity, and irrelevant and futile information and treatment. Patients/caregivers and health professionals gave highest priority to clinical outcomes. In contrast to health professionals, patients/caregivers gave higher priority to lifestyle-related outcomes including the impact on family/friends and usual activities. Thus, prioritization will inform a core outcome set to improve the consistency and relevance of outcomes for trials in PD.

ObjectivesThis study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures.Materials and methodsWe pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework.ResultsFor oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30  years. In former smokers who quit ≥10  years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers.ConclusionReferring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies.

Main sources of manganese (Mn) in the general population are diet and drinking water. Mn is also found in ethylene bisdithiocarbamate (EBDC) fungicides used in agriculture or emitted into the air by ferromanganese plants and welding fumes, which can be additional environmental and occupational sources of exposure. High occupational Mn exposure has been linked with motor, behavioral, and cognitive impairment, but its effects on neural function remain poorly understood. We conducted a functional neuroimaging study in a sample of 48 farmworkers in Zarcero County, Costa Rica, an agricultural region where EBDC fungicides are sprayed. We measured Mn concentrations in farmworkers' toenails (n = 40 farmworkers) and hair (n = 33 farmworkers), and recorded brain activity in the dorsolateral prefrontal cortex during a letter-retrieval working memory task using functional near-infrared spectroscopy (fNIRS). We estimated exposure-outcome associations using multivariable linear regression models adjusted for age and education level. Geometric mean (geometric standard deviation) toenail and hair Mn concentrations were 0.40 μg/g (3.52) and 0.24 μg/g (3.54), respectively. We did not find strong evidence that Mn concentrations were associated with working memory-related brain activity in this sample of farmworkers; we also found null associations between working memory task accuracy and brain activity. However, our small sample size may have limited our ability to detect small effect sizes with statistical precision. Our study demonstrates that fNIRS can be a useful and feasible tool in environmental epidemiology for examining the effects of toxicants, like Mn, on neural function. This may prove to be important for elucidating neuropathological pathways that underlie previously reported associations of elevated Mn exposure with neurotoxic effects.

BackgroundClinicopathological studies are important in determining the brain lesions underlying dementia. Although almost 60% of individuals with dementia live in developing countries, few clinicopathological studies focus on these individuals. We investigated the frequency of neurodegenerative and vascular-related neuropathological lesions in 1,092 Brazilian admixed older adults, their correlation with cognitive and neuropsychiatric symptoms, and the accuracy of dementia subtype diagnosis.Methods and findingsIn this cross-sectional study, we describe clinical and neuropathological variables related to cognitive impairment in 1,092 participants (mean age = 74 y, 49% male, 69% white, and mean education = 4 y). Cognitive function was investigated using the Clinical Dementia Rating (CDR) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE); neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI). Associations between neuropathological lesions and cognitive impairment were investigated using ordinal logistic regression. We developed a neuropathological comorbidity (NPC) score and compared it to CDR, IQCODE, and NPI scores. We also described and compared the frequency of neuropathological diagnosis to clinical diagnosis of dementia subtype. Forty-four percent of the sample met criteria for neuropathological diagnosis. Among these participants, 50% had neuropathological diagnoses of Alzheimer disease (AD), and 35% of vascular dementia (VaD). Neurofibrillary tangles (NFTs), hippocampal sclerosis, lacunar infarcts, hyaline atherosclerosis, siderocalcinosis, and Lewy body disease were independently associated with cognitive impairment. Higher NPC scores were associated with worse scores in the CDR sum of boxes (β = 1.33, 95% CI 1.20-1.46), IQCODE (β = 0.14, 95% CI 0.13-0.16), and NPI (β = 1.74, 95% CI = 1.33-2.16). Compared to neuropathological diagnoses, clinical diagnosis had high sensitivity to AD and high specificity to dementia with Lewy body/Parkinson dementia. The major limitation of our study is the lack of clinical follow-up of participants during life.ConclusionsNFT deposition, vascular lesions, and high NPC scorewere associated with cognitive impairment in a unique Brazilian sample with low education. Our results confirm the high prevalence of neuropathological diagnosis in older adults and the mismatch between clinical and neuropathological diagnoses.

BackgroundBehavioral and psychological symptoms (BPSD) can be a prodrome of dementia, and the Neuropsychiatric Inventory (NPI) is widely used for BPSD evaluation.ObjectiveTo compare the prevalence of BPSD according to cognitive status, and to determine NPI cutoffs that best discern individuals with mild cognitive impairment (MCI) and dementia from those without dementia.MethodsWe included 1,565 participants (mean age = 72.7±12.2 years, 48% male). BPSD and cognitive status were assessed with the NPI and the Clinical Dementia Rating (CDR). We used multivariable logistic regression models to investigate the association of BPSD with cognitive status. The area under the curve (AUC) was used to assess model discrimination, and to determine the best NPI cutoff for MCI and dementia.ResultsParticipants were cognitively normal (CDR = 0; n = 1,062), MCI (CDR = 0.5; n = 145), or dementia (CDR≥1.0, n = 358). NPI symptoms were more frequent in dementia and MCI when compared to cognitively normal. Higher odds for delusions, hallucinations, disinhibition, and psychomotor alterations were found among participants with dementia and MCI than in those who were cognitively normal. The best NPI cutoff to discern participants with dementia from those cognitively normal was 11 (AUC = 0.755). Poor discrimination (AUC = 0.563) was found for the comparison of MCI and those cognitively normal.ConclusionsWe found an increase in BPSD frequencies across the continuum of cognitive impairment. BPSD severity and frequency in MCI was more similar to individuals cognitively normal than with dementia. NPI scores≥to 11 in individuals with no diagnosis of dementia can support the decision for further investigation of dementia.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessions and/or compulsions. Different striatal subregions belonging to the cortico-striato-thalamic circuitry (CSTC) play an important role in the pathophysiology of OCD. The transcriptomes of 3 separate striatal areas (putamen (PT), caudate nucleus (CN) and accumbens nucleus (NAC)) from postmortem brain tissue were compared between 6 OCD and 8 control cases. In addition to network connectivity deregulation, different biological processes are specific to each striatum region according to the tripartite model of the striatum and contribute in various ways to OCD pathophysiology. Specifically, regulation of neurotransmitter levels and presynaptic processes involved in chemical synaptic transmission were shared between NAC and PT. The Gene Ontology terms cellular response to chemical stimulus, response to external stimulus, response to organic substance, regulation of synaptic plasticity, and modulation of synaptic transmission were shared between CN and PT. Most genes harboring common and/or rare variants previously associated with OCD that were differentially expressed or part of a least preserved coexpression module in our study also suggest striatum subregion specificity. At the transcriptional level, our study supports differences in the 3 circuit CSTC model associated with OCD.

BackgroundThe literature is scarce regarding the prevalence and clinical impact of IgG subclass deficiency in COPD. We investigated the prevalence of IgG subclass deficiencies and their association with exacerbations and hospitalizations using subjects from two COPD cohorts.MethodsWe measured IgG subclass levels using immunonephelometry in serum samples from participants enrolled in two previous COPD trials: Macrolide Azithromycin for Prevention of Exacerbations of COPD (MACRO; n = 976) and Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD (STATCOPE; n = 653). All samples were collected from clinically stable participants upon entry into both studies. IgG subclass deficiency was diagnosed when IgG subclass levels were below their respective lower limit of normal: IgG1

ObjectiveTo evaluate longitudinal cognitive/behavioral change over 12 months in participants enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS).MethodsWe analyzed data from 294 ALS participants, 134 of whom were studied serially. Change over time was evaluated controlling for age, sex, symptom duration, education, race, and ethnicity. Using multiple regression, we evaluated associations among decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and cognitive/behavioral changes. Change in cognitive/behavioral subgroups was assessed using one-way analyses of covariance.ResultsParticipants with follow-up data had fewer baseline behavior problems compared to patients without follow-up data. We found significant worsening of behavior (ALS Cognitive Behavioral Screen (ALS CBS) behavioral scale, p < 0.001; Frontal Behavioral Inventory-ALS (FBI-ALS) disinhibition subscale, p = 0.044). Item analysis suggested change in frustration tolerance, insight, mental rigidity, and interests (p < 0.05). Changes in ALSFRS-R correlated with the ALS CBS. Worsening disinhibition (FBI-ALS) did not correlate with ALSFRS-R, FVC, or disease duration.ConclusionWe did not detect cognitive change. Behavioral change was detected, and increased disinhibition was found among patients with abnormal baseline behavioral scores. Disinhibition changes did not correlate with disease duration or progression. Baseline behavioral problems were associated with advanced, rapidly progressive disease and study attrition.

PurposeTo describe the sequential evolution of outer retinal tubulations (ORTs) in patients diagnosed with choroidal neovascularization and/or retinal pigment epithelium atrophy.MethodsRetrospective evaluation of spectral domain optical coherence tomography of a consecutive cohort of patients with various retinal conditions.ResultsWe reviewed the clinical findings of 238 eyes of 119 consecutive patients (54 men and 65 women) with a mean age of 76.2 ± 14.2 years (range: 57-90) and a mean follow-up of 3 ± 1.6 years (range 1-7). Over the follow-up period, ORTs were diagnosed in 67 of 238 eyes (28.1%), 9 of which were imaged with sequential, eye-tracked spectral domain optical coherence tomography dating from the beginning of ORT formation. The presence of geographic atrophy and subretinal hyperreflective material at baseline were found to be risk factors for ORT development (P < 0.001 and P < 0.001, respectively). Outer retinal tubulations were divided into forming versus formed morphologies. The latter was comprised open and closed ORTs of which the open subtype was the most common. The formation of ORTs was significantly associated with microcystic macular lesions in the inner nuclear layer and the downward displacement of the outer plexiform layer, referred to as the outer plexiform layer subsidence sign (P < 0.001).ConclusionOuter retinal tubulation is a frequent optical coherence tomography finding in eyes with choroidal neovascularization and geographic atrophy. Open ORTs with progressive scrolled edges and shortened diameter were significantly associated with microcystic macular lesions in the inner nuclear layer and the outer plexiform layer subsidence sign.

BackgroundAlthough studies have consistently found an association between childhood leukaemia risk and magnetic fields, the associations between childhood leukaemia and distance to overhead power lines have been inconsistent. We pooled data from multiple studies to assess the association with distance and evaluate whether it is due to magnetic fields or other factors associated with distance from lines.MethodsWe present a pooled analysis combining individual-level data (29,049 cases and 68,231 controls) from 11 record-based studies.ResultsThere was no material association between childhood leukaemia and distance to nearest overhead power line of any voltage. Among children living

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here, the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium presents the largest-ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (n = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

BackgroundAlthough growing evidence suggests that early-life excess manganese (Mn) impairs neurodevelopment, data on the neurodevelopmental effects of mancozeb, a fungicide containing Mn, and its main metabolite ethylenethiourea (ETU) are limited.ObjectiveWe examined whether prenatal mancozeb exposure and excess Mn were associated with neurodevelopment in 355 1-y-old infants living near banana plantations with frequent aerial mancozeb spraying in Costa Rica.MethodsWe measured urinary ETU, hair Mn, and blood Mn concentrations in samples collected 1-3 times during pregnancy from mothers enrolled in the Infants' Environmental Health (ISA) study. We then assessed neurodevelopment in their 1-y-old infants using the Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III). We estimated exposure-outcome associations using linear regression models adjusted for maternal education, parity, gestational age at birth, child age, Home Observation for Measurement of the Environment score, and location of neurodevelopmental assessment.ResultsMedian (P25-P75) urinary ETU, hair Mn, and blood Mn measured during pregnancy were 3.3 μg/L (2.4-4.9; specific gravity-corrected), 1.7 μg/g (0.9-4.1), and 24.0 μg/L (20.3-28.0), respectively. Among girls, higher ETU was associated with lower social-emotional scores [β per 10-fold increase=-7.4 points (95% CI: -15.2, 0.4)], whereas higher hair Mn was associated with lower cognitive scores [-3.0 (-6.1, 0.1)]. Among boys, higher hair Mn was associated with lower social-emotional scores [-4.6 (-8.5, -0.8)]. We observed null associations for blood Mn, language, and motor outcomes.ConclusionsOur findings indicate that maternal exposure to mancozeb and excess Mn during pregnancy may have adverse and sex-specific effects on infant neurodevelopment. https://doi.org/10.1289/EHP1955.

PurposeTo investigate the association between the microstructure of β-zone parapapillary atrophy (βPPA) and parapapillary deep-layer microvasculature dropout assessed by optical coherence tomography angiography (OCT-A).MethodsThirty-seven eyes with βPPA devoid of the Bruch's membrane (BM) (γPPA) ranging between completely absent and discontinuous BM were matched by severity of the visual field (VF) damage with 37 eyes with fully intact BM (βPPA+BM) based on the spectral-domain (SD) OCT imaging. Parapapillary deep-layer microvasculature dropout was defined as a dropout of the microvasculature within choroid or scleral flange in the βPPA on the OCT-A. The widths of βPPA, γPPA, and βPPA+BM were measured on six radial SD-OCT images. Prevalence of the dropout was compared between eyes with and without γPPA. Logistic regression was performed for evaluating association of the dropout with the width of βPPA, γPPA, and βPPA+BM, and the γPPA presence.ResultsEyes with γPPA had significantly higher prevalence of the dropout than did those without γPPA (75.7% versus 40.8%; P = 0.004). In logistic regression, presence and longer width of the γPPA, worse VF mean deviation, and presence of focal lamina cribrosa defects were significantly associated with the dropout (P < 0.05), whereas width of the βPPA and βPPA+BM, axial length, and choroidal thickness were not (P > 0.10).ConclusionsParapapillary deep-layer microvasculature dropout was associated with the presence and larger width of γPPA, but not with the βPPA+BM width. Presence and width of the exposed scleral flange, rather than the retinal pigmented epithelium atrophy, may be associated with deep-layer microvasculature dropout.

PurposeTo characterize OCT angiography (OCT-A) vessel density of patients with primary open-angle glaucoma (POAG) with unilateral visual field (VF) loss.DesignCross-sectional study.ParticipantsA total of 33 patients with POAG with a VF defect in 1 eye (mean VF mean deviation [MD], -3.9±3.1 decibels [dB]) and normal VF in the other eye (mean VF MD, -0.2±0.9 dB) and 33 healthy eyes.MethodsAll subjects underwent OCT-A imaging, spectral-domain (SD)-OCT imaging, and VF testing. OCT-A retinal vascular measurements were summarized as whole image vessel density (wiVD), circumpapillary vessel density (cpVD), and parafoveal vessel density (pfVD). Inter-eye differences in vascular measures, as well as SD OCT retinal nerve fiber layer (RNFL), macular ganglion cell complex (mGCC) thickness, and rim area measurements in glaucoma and healthy eyes were compared. Areas under the receiver operating characteristic curves (AUROCs) were used to evaluate diagnostic accuracy for differentiating between unaffected eyes of patients with POAG and healthy eyes.Main outcome measuresDifference in OCT-A vessel density and SD OCT structural parameters between unaffected eyes of patients with POAG with the fellow affected eyes and healthy controls.ResultsMean wiVD in unaffected eyes of patients with POAG (52.0%) was higher than in their fellow affected eyes (48.8%) but lower than in healthy eyes (55.9%; P < 0.001). Mean circumpapillary RNFL (cpRNFL) thickness, mGCC thickness, and rim area measurement in unaffected eyes of patients with POAG (87.5 μm, 87.7 μm, and 1.0 mm2) were also higher than those measurements in their fellow eyes (76.5 μm, 79.5 μm, and 0.8 mm2; P < 0.001) and lower than in healthy eyes (98.0 μm, 94.5 μm, and 1.4 mm2; P < 0.001). The AUROCs for differentiating unaffected eyes of patients with POAG from healthy eyes were highest for wiVD (0.84), followed by mGCC (0.78), cpRNFL (0.77), and pfVD (0.69).ConclusionsOCT-A measures detect changes in retinal microvasculature before VF damage is detectable in patients with POAG, and these changes may reflect damage to tissues relevant to the pathophysiology of glaucoma. Longitudinal studies are needed to determine whether OCT-A measures can improve the detection or prediction of the onset and progression of glaucoma.

Importance:Individuals of African descent have been reported to be at higher risk for becoming visually impaired from glaucoma compared with individuals of European descent. Objective:To investigate racial differences in longitudinal visual field variability and their impact on time to detect visual field progression. Design, Setting, and Participants:This multicenter prospective observational cohort study included 236 eyes of 173 individuals of European descent and 235 eyes of 171 individuals of African descent followed up for a mean (SD) time of 7.5 (3.4) years. Main Outcomes and Measures:Differences in test-retest variability and simulated time to detect progression in individuals of African descent and of European descent with glaucoma. Standard automated perimetry mean deviation values were regressed over time for each eye, and SD of the residuals was used as a measure of variability. Distributions of residuals were used in computer simulations to reconstruct "real-world" standard automated perimetry mean deviation trajectories under different assumptions about rate of change and frequency of testing. Times to detect progression were obtained for the simulated visual fields. Results:Among the 344 patients, the mean (SD) age at baseline was 60.2 (10.0) and 60.6 (9.0) years for individuals of African descent and of European descent, respectively; 94 (52%) and 86 (48%) of individuals of African descent and of European descent were women, respectively. The mean SD of the residuals was larger in eyes of individuals of African descent vs those of European descent (1.45 [0.83] dB vs 1.12 [0.48] dB; mean difference: 0.33 dB; 95% CI of the difference, 0.21-0.46; P

BACKGROUND AND AIMS:Intracranial (IAD) and extracranial atherosclerotic diseases (EAD) have been mostly investigated using imaging methods. Autopsy studies allow for a direct and complete evaluation of the atherosclerotic disease. We aimed to investigate the frequency of IAD and EAD, their association, and related risk profiles in a large cross-sectional autopsy study. METHODS:We measured the intima-media thickness and stenosis of the common (CCA) and internal carotid arteries (ICA), using morphometric measurements. The main outcome was stenosis (≥50%) in the artery with the largest obstruction among the 12 cerebral arteries. We used multivariable logistic regression models to investigate the association between EAD and IAD. RESULTS:In 661 participants (mean age = 71.3 ± 11.7 y, 51% male), stenosis was more common in IAD than in EAD (59% vs. 51%). EAD was associated with Caucasian race, hypertension, and smoking, while IAD was associated with older age, less years of education, hypertension, diabetes, and a previous history of stroke. Stenosis in CCA and ICA was associated with more than two times the odds of having stenosis in the intracranial arteries (CCA: OR = 2.32, 95% CI = 1.64; 3.28; ICA: OR = 2.51, 95% CI = 1.76; 3.57). CONCLUSIONS:In this population-based autopsy study, IAD was common, even more common than EAD, but correlated with EAD.

Clarifying the relationships between neuropsychiatric symptoms and Alzheimers disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Clarifying the mechanisms connecting neurofibrillary tangle (NFT) neurotoxicity to neuronal dysfunction in humans is likely to be pivotal for developing effective treatments for Alzheimer's disease (AD). To model the temporal progression of AD in humans, we used a collection of brains with controls and individuals from each Braak stage to quantitatively investigate the correlation between intraneuronal caspase activation or macroautophagy markers, NFT burden, and neuronal loss, in the dorsal raphe nucleus and locus coeruleus, the earliest vulnerable areas to NFT accumulation. We fit linear regressions with each count as outcomes, with Braak score and age as the predictors. In progressive Braak stages, intraneuronal active caspase-6 positivity increases both alone and overlapping with NFTs. Likewise, the proportion of NFT-bearing neurons showing autophagosomes increases. Overall, caspases may be involved in upstream cascades in AD and are associated with higher NFTs. Macroautophagy changes correlate with increasing NFT burden from early AD stages.

Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

AimsHyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages.MethodsWe utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-μm-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases.ResultsIn Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9× between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN.ConclusionsLC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.

PurposeWayfinding, the process of determining and following a route between an origin and a destination, is an integral part of everyday tasks. The purpose of this study was to investigate the impact of glaucomatous visual field loss on wayfinding behavior using an immersive virtual reality (VR) environment.MethodsThis cross-sectional study included 31 glaucomatous patients and 20 healthy subjects without evidence of overall cognitive impairment. Wayfinding experiments were modeled after the Morris water maze navigation task and conducted in an immersive VR environment. Two rooms were built varying only in the complexity of the visual scene in order to promote allocentric-based (room A, with multiple visual cues) versus egocentric-based (room B, with single visual cue) spatial representations of the environment. Wayfinding tasks in each room consisted of revisiting previously visible targets that subsequently became invisible.ResultsFor room A, glaucoma patients spent on average 35.0 seconds to perform the wayfinding task, whereas healthy subjects spent an average of 24.4 seconds (P = 0.001). For room B, no statistically significant difference was seen on average time to complete the task (26.2 seconds versus 23.4 seconds, respectively; P = 0.514). For room A, each 1-dB worse binocular mean sensitivity was associated with 3.4% (P = 0.001) increase in time to complete the task.ConclusionsGlaucoma patients performed significantly worse on allocentric-based wayfinding tasks conducted in a VR environment, suggesting visual field loss may affect the construction of spatial cognitive maps relevant to successful wayfinding. VR environments may represent a useful approach for assessing functional vision endpoints for clinical trials of emerging therapies in ophthalmology.

ImportanceThe current assessment of visual field loss in diseases such as glaucoma is affected by the subjectivity of patient responses and the lack of portability of standard perimeters.ObjectiveTo describe the development and initial validation of a portable brain-computer interface (BCI) for objectively assessing visual function loss.Design, setting, and participantsThis case-control study involved 62 eyes of 33 patients with glaucoma and 30 eyes of 17 healthy participants. Glaucoma was diagnosed based on a masked grading of optic disc stereophotographs. All participants underwent testing with a BCI device and standard automated perimetry (SAP) within 3 months. The BCI device integrates wearable, wireless, dry electroencephalogram and electrooculogram systems and a cellphone-based head-mounted display to enable the detection of multifocal steady state visual-evoked potentials associated with visual field stimulation. The performances of global and sectoral multifocal steady state visual-evoked potentials metrics to discriminate glaucomatous from healthy eyes were compared with global and sectoral SAP parameters. The repeatability of the BCI device measurements was assessed by collecting results of repeated testing in 20 eyes of 10 participants with glaucoma for 3 sessions of measurements separated by weekly intervals.Main outcomes and measuresReceiver operating characteristic curves summarizing diagnostic accuracy. Intraclass correlation coefficients and coefficients of variation for assessing repeatability.ResultsAmong the 33 participants with glaucoma, 19 (58%) were white, 12 (36%) were black, and 2 (6%) were Asian, while among the 17 participants with healthy eyes, 9 (53%) were white, 8 (47%) were black, and none were Asian. The receiver operating characteristic curve area for the global BCI multifocal steady state visual-evoked potentials parameter was 0.92 (95% CI, 0.86-0.96), which was larger than for SAP mean deviation (area under the curve, 0.81; 95% CI, 0.72-0.90), SAP mean sensitivity (area under the curve, 0.80; 95% CI, 0.69-0.88; P = .03), and SAP pattern standard deviation (area under the curve, 0.77; 95% CI, 0.66-0.87; P = .01). No statistically significant differences were seen for the sectoral measurements between the BCI and SAP. Intraclass coefficients for global and sectoral parameters ranged from 0.74 to 0.92, and mean coefficients of variation ranged from 3.03% to 7.45%.Conclusions and relevanceThe BCI device may be useful for assessing the electrical brain responses associated with visual field stimulation. The device discriminated eyes with glaucomatous neuropathy from healthy eyes in a clinically based setting. Further studies should investigate the feasibility of the BCI device for home-based testing as well as for detecting visual function loss over time.

PurposeTo compare hemifield differences in the vessel density of the peripapillary and macula in open-angle glaucoma eyes with visual field (VF) defect confined to one hemifield using optical coherence tomography angiography (OCT-A).DesignCross-sectional study.ParticipantsA total of 58 eyes of 58 patients with glaucoma with VF loss confined to a single hemifield and 28 healthy eyes.MethodsRetinal vasculature information was summarized as circumpapillary vessel density (cpVD) and perifoveal vessel density (pfVD). Circumpapillary retinal nerve fiber layer (cpRNFL) and macular ganglion cell complex (mGCC) thickness were calculated using spectral domain optical coherence tomography (SD OCT). Paired and unpaired t tests were used to evaluate differences between the perimetrically affected and intact hemiretinae and healthy hemiretinae. Linear regression analyses were performed to evaluate the associations between VF measures with vascular and structural measurements.Main outcome measuresTotal and hemispheric cpVD, pfVD, cpRNFL, mGCC, and mean sensitivity (MS).ResultsMean cpVD and pfVD in the intact hemiretinae of glaucoma eyes (59.0% and 51.1%, respectively) were higher than in the affected hemiretinae (54.7% and 48.3%, respectively; P < 0.001) but lower than in healthy eyes (62.4% and 53.8%, respectively; P < 0.001). Similar results were noted with cpRNFL and mGCC thickness measurements (P < 0.05 for both). The strongest associations between MS in the affected hemifields were found for cpVD (r = 0.707), followed by pfVD (r = 0.615), cpRNFL (r = 0.496), and mGCC (r = 0.482) in the corresponding hemiretinae (P < 0.001 for all). Moreover, the correlations in the intact hemifields between MS with cpVD and pfVD were higher (r = 0.450 and 0.403) than the correlations between MS and cpRNFL and mGCC thickness measurements (r = 0.340 and 0.290; P values

IntroductionAlzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]).MethodsThe methods include unbiased stereological analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages.ResultsAs the Braak stage increases by 1 unit, the LC volume decreases by 8.4%. Neuronal loss started only midway through AD progression. Age-related changes spare the LC.DiscussionThe long gap between NFT accumulation and neuronal loss suggests that a second trigger may be necessary to induce neuronal death in AD. Imaging studies should determine whether LC volumetry can replicate the stage-wise atrophy observed here and how these changes are specific to AD. LC volumetry may develop into a screening biomarker for selecting high-yield candidates to undergo expensive and less accessible positron emission tomography scans and to monitor AD progression from presymptomatic stages.

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 - 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 - 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.