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BACKGROUND: The physical and the social environment are important predictors of healthy weight, especially in low socioeconomic position (SEP) neighborhoods. Many Dutch municipalities have implemented a healthy weight approach (HWA). Yet, there is room for improvement. This system science study examined what influences the utilization of HWA facilities and activities, and what aspects can help to achieve a desired systems change (also called leverage point themes (LPTs)) in the HWA system as perceived by citizens living in low SEP neighborhoods. METHOD: All research phases were performed with four citizens co-researchers. Forty-seven citizens living in low SEP neighborhoods were semi-structurally interviewed about the neighborhood HWA facilities and municipal HWA activities. A rapid coding qualitative analysis approach was applied per topic. The topics were citizens' healthy living description, personal circumstances, and satisfaction with foot and cycle paths, sports facilities, playgrounds, green spaces, museums and theaters, community centers, churches, healthcare, school, food supplies, contact with neighborhood, unfamiliar and/or unused activities, familiar and used activities, unavailable but desired (lacking) activities, and reaching citizens. RESULTS: The utilization of HWA facilities and activities was influenced by the overarching themes of social cohesion, familiarity, reaching citizens, maintenance, safety, physical accessibility, financial accessibility, social accessibility, fit with personal context, and fit with the neighborhood's specific needs. Different overarching themes stood out across different facilities and activities. LPTs indicated the overarching themes needed in combination with one another for a specific activity or facility to increase utilization. For example, the LPT regarding foot and cycle paths was "accessible, safe, and maintained foot and cycle paths". The LPTs regarding familiar and used activities were "customized activities; information provision (e.g., about possibilities to join without paying); social contact, meeting others, and everyone feels included". CONCLUSION: Conducting inclusive qualitative research from a systems perspective among citizens living in low SEP neighborhoods has contributed valuable insights into their needs. This enables practical implementation of HWAs by providing a deeper understanding of the LPTs within the HWA system. LPTs can help HWA stakeholders to further develop current HWAs toward systems approaches. Future research could study the leverage points that may contribute to LPT implementation.
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Pesquisa Qualitativa , Características de Residência , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Países Baixos , Promoção da Saúde/métodos , Idoso , Meio Social , Análise de Sistemas , Adulto Jovem , Entrevistas como AssuntoRESUMO
Alzheimer's Disease (AD) is characterized by structural and functional dysfunction involving the Default Mode Network (DMN), for which the Precuneus (PC) is a key node. We proposed a randomized double-blind pilot study to determine neurobiological changes after 24 weeks of PC-rTMS in patients with mild-to-moderate AD. Sixteen patients were randomly assigned to SHAM or PC-rTMS, and received an intensive 2-weeks course with daily rTMS sessions, followed by a maintenance phase in which rTMS has been applied once a week. Before and after the treatment structural and functional MRIs were collected. Our results showed macro- and micro-structural preservation in PC-rTMS compared to SHAM-rTMS group after 24 weeks of treatment, correlated to an increase of functional connectivity (FC) within the PC in the PC-rTMS group. Even if preliminary, these results trigger the possibility of using PC-rTMS to arrest atrophy progression by manipulating distributed network connectivity patterns.
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Doença de Alzheimer , Substância Cinzenta , Imageamento por Ressonância Magnética , Estimulação Magnética Transcraniana , Humanos , Doença de Alzheimer/terapia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Projetos Piloto , Masculino , Feminino , Idoso , Método Duplo-Cego , Estimulação Magnética Transcraniana/métodos , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Pessoa de Meia-Idade , Resultado do Tratamento , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/patologiaRESUMO
Background: This study aimed to assess the performance of currently available risk calculators in a cohort of patients with malignant peripheral nerve sheath tumors (MPNST) and to create an MPNST-specific prognostic model including type-specific predictors for overall survival (OS). Methods: This is a retrospective multicenter cohort study of patients with MPNST from 11 secondary or tertiary centers in The Netherlands, Italy and the United States of America. All patients diagnosed with primary MPNST who underwent macroscopically complete surgical resection from 2000 to 2019 were included in this study. A multivariable Cox proportional hazard model for OS was estimated with prespecified predictors (age, grade, size, NF-1 status, triton status, depth, tumor location, and surgical margin). Model performance was assessed for the Sarculator and PERSARC calculators by examining discrimination (C-index) and calibration (calibration plots and observed-expected statistic; O/E-statistic). Internal-external cross-validation by different regions was performed to evaluate the generalizability of the model. Results: A total of 507 patients with primary MPNSTs were included from 11 centers in 7 regions. During follow-up (median 8.7 years), 211 patients died. The C-index was 0.60 (95% CI 0.53-0.67) for both Sarculator and PERSARC. The MPNST-specific model had a pooled C-index of 0.69 (95%CI 0.65-0.73) at validation, with adequate discrimination and calibration across regions. Conclusions: The MPNST-specific MONACO model can be used to predict 3-, 5-, and 10-year OS in patients with primary MPNST who underwent macroscopically complete surgical resection. Further validation may refine the model to inform patients and physicians on prognosis and support them in shared decision-making.
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OBJECTIVE: To investigate cortical microstructural measures from diffusion MRI as "neurodegeneration" markers that could improve prognostic accuracy in mild cognitive impairment (MCI). METHODS: The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non-AD dementia was investigated. Ninety patients underwent clinical evaluation (follow-up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status. T1-structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD+), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices. RESULTS: A progressive increase of whole-brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A-T-. Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A-T- progressing to a mix of AD and non-AD dementias). Adding whole-brain AngleR as an N marker, produced good differentiation between stable and converting MCI A-T- patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%). INTERPRETATION: Results support the clinical utility of cortical microstructure to aid prognosis, especially in A-T- patients. Further work will investigate other complexities of the real-world clinical setting, including A-T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision-making.
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Doença de Alzheimer , Córtex Cerebral , Disfunção Cognitiva , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Humanos , Masculino , Feminino , Idoso , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Pessoa de Meia-Idade , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Doença de Alzheimer/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , PrognósticoRESUMO
Social dysfunction represents one of the most common signs of neuropsychiatric disorders, such as Schizophrenia (SZ) and Alzheimer's disease (AD). Perturbed socioaffective neural processing is crucially implicated in SZ/AD and generally linked to social dysfunction. Yet, transdiagnostic properties of social dysfunction and its neurobiological underpinnings remain unknown. As part of the European PRISM project, we examined whether social dysfunction maps onto shifts within socioaffective brain systems across SZ and AD patients. We probed coupling of social dysfunction with socioaffective neural processing, as indexed by an implicit facial emotional processing fMRI task, across SZ (N = 46), AD (N = 40) and two age-matched healthy control (HC) groups (N = 26 HC-younger and N = 27 HC-older). Behavioural (i.e., social withdrawal, interpersonal dysfunction, diminished prosocial or recreational activity) and subjective (i.e., feelings of loneliness) aspects of social dysfunction were assessed using the Social Functioning Scale and De Jong-Gierveld loneliness questionnaire, respectively. Across SZ/AD/HC participants, more severe behavioural social dysfunction related to hyperactivity within fronto-parieto-limbic brain systems in response to sad emotions (P = 0.0078), along with hypoactivity of these brain systems in response to happy emotions (P = 0.0418). Such relationships were not found for subjective experiences of social dysfunction. These effects were independent of diagnosis, and not confounded by clinical and sociodemographic factors. In conclusion, behavioural aspects of social dysfunction across SZ/AD/HC participants are associated with shifts within fronto-parieto-limbic brain systems. These findings pinpoint altered socioaffective neural processing as a putative marker for social dysfunction, and could aid personalized care initiatives grounded in social behaviour.
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BACKGROUND: A RCT of a novel intervention to detect antidepressant medication response (the PReDicT Test) took place in five European countries, accompanied by a nested study of its acceptability and implementation presented here. The RCT results indicated no effect of the intervention on depression at 8 weeks (primary outcome), although effects on anxiety at 8 weeks and functioning at 24 weeks were found. METHODS: The nested study used mixed methods. The aim was to explore patient experiences of the Test including acceptability and implementation, to inform its use within care. A bespoke survey was completed by trial participants in five countries (n = 778) at week 8. Semi-structured interviews were carried out in two countries soon after week 8 (UK n = 22, Germany n = 20). Quantitative data was analysed descriptively; for qualitative data, thematic analysis was carried out using a framework approach. Results of the two datasets were interrogated together. OUTCOMES: Survey results showed the intervention was well received, with a majority of participants indicating they would use it again, and it gave them helpful extra information; a small minority indicated the Test made them feel worse. Qualitative data showed the Test had unexpected properties, including: instigating a process of reflection, giving participants feedback on progress and new understanding about their illness, and making participants feel supported and more engaged in treatment. INTERPRETATION: The qualitative and quantitative results are generally consistent. The Test's unexpected properties may explain why the RCT showed little effect, as properties were experienced across both trial arms. Beyond the RCT, the qualitative data sheds light on measurement reactivity, i.e., how measurements of depression can impact patients.
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Antidepressivos , Humanos , Antidepressivos/uso terapêutico , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Inquéritos e Questionários , Depressão/tratamento farmacológico , Depressão/psicologia , Depressão/diagnóstico , Idoso , Alemanha , Europa (Continente) , Pesquisa QualitativaRESUMO
Data from the UK suggests 13-55 % of depression patients experience some level of treatment resistance. However, little is known about how physicians manage inadequate response to antidepressants in primary care. This study aimed to explore the incidence of inadequate response to antidepressants in UK primary care. One-hundred-eighty-four medication-free patients with low mood initiated antidepressant treatment and monitored severity of depression symptoms, using the QIDS-SR16, for 48 weeks. Medication changes, visits to healthcare providers, and health-related quality of life were also recorded. Patients were classified into one of four response types based on their QIDS scores at three study timepoints: persistent inadequate responders (<50 % reduction in baseline QIDS at all timepoints), successful responders (≥50 % reduction in baseline QIDS at all timepoints), slow responders (≥50 % reduction in QIDS at week 48, despite earlier inadequate responses), and relapse (initial ≥50 % reduction in baseline QIDS, but inadequate response by week 48). Forty-eight weeks after initiating treatment 47 % of patients continued to experience symptoms of depression (QIDS >5), and 20 % of patients had a persistent inadequate response. Regardless of treatment response, 96 % (n = 176) of patients did not visit their primary care physician over the 40-week follow-up period. These results suggest that despite receiving treatment, a considerable proportion of patients with low mood remain unwell and fail to recover. Monitoring depression symptoms remotely can enable physicians to identify inadequate responders, allowing patients to be reassessed or referred to secondary services, likely improving patients' quality of life and reducing the socioeconomic impacts of chronic mental illness.
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Antidepressivos , Atenção Primária à Saúde , Humanos , Antidepressivos/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Qualidade de Vida , Incidência , Depressão/tratamento farmacológico , Depressão/epidemiologia , Idoso , Reino Unido/epidemiologia , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/epidemiologia , Resultado do TratamentoRESUMO
Objective: To examine the immediate effects of a comprehensive pain course on medical students' pre-existing perceptions and attitudes toward pain patients and opioid management. Methods: First-year medical students at a major academic medical center enrolled in a required pre-clerkship pain course in June 2020 and completed pre- and post-course online surveys with Likert-scale questions about their attitudes toward pain management and opioid-related issues. Additionally, the surveys included a free-text question where the students listed the first five words that came to mind when hearing the word "opioids". These words were categorized as "professional" or "lay" words and further as having "positive", "negative", or "neutral" connotations. Data analyses included descriptive statistics, as well as non-parametric and parametric tests. Results: Fifty-four of the 119 students responded to pretest and posttest surveys and were included in paired analyses. There was a significant difference between the number of professional words used before (M=1.21, SD=0.97) and after the course (M=2.40 SD=1.33); t(52)=-6.39, P<0.001. Students also used more lay-positive words after the course (M=0.81, SD=0.63) than they used pre-course (M=0.23, SD=0.43); t(51)=-5.98, P<0.001. Students' post-course responses to several key Likert-scale questions showed significant shifts toward more positive attitudes about caring for patients with pain. For example, students acknowledged greater comfort in providing opioids for chronic pain (P<0.001) where appropriate, and enhanced interest in handling complex pain cases (P<0.001). Conclusion: Results showed that a comprehensive, multi-disciplinary pain course could greatly enhance first-year medical students' attitudes toward pain management, chronic pain patients, and the complex issues surrounding opioids.
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The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters.
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Doença de Alzheimer , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico , Doença de Alzheimer/diagnósticoRESUMO
INTRODUCTION: The introduction of minimally invasive surgery (MIS) for repair of congenital diaphragmatic hernias (CDH) has reduced postoperative length of stay, postoperative opioid consumption, and provided a more esthetic repair. In adult abdominal surgery, minimally invasive techniques have been associated with decreased long-term rates of small bowel obstruction (SBO), although it is unclear if this benefit carries over into the pediatric population. Our objective was to evaluate the rates of SBO following open versus MIS CDH repair. MATERIAL AND METHODS: Infants who underwent CDH repair between 2010 and 2021 were identified using the PearlDiver Mariner database. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate time to SBO by surgical approach (MIS versus open) while adjusting for mesh use, patient sex, and length of stay. RESULTS: Of 1033 patients that underwent CDH repair, 258 (25.0%) underwent a minimally invasive approach. The overall rate of SBO was 7.5% (n = 77). Rate of SBO following MIS repair was lower than open repair at 1 y (0.8% versus 5.1%), 3 y, (2.3% versus 9.0%), and 5 y (4.4% versus 10.1%, P = 0.004). Following adjustment, the rate of SBO following MIS repair remained significantly lower than open repair (adjusted hazard ratio: 0.37, 95% confidence interval: 0.18, 0.79). CONCLUSIONS: Following CDH repair, long-term rates of SBO are lower among patients treated with MIS approaches. Long-term risk of SBO should be considered when selecting surgical approach for CDH patients.
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Hérnias Diafragmáticas Congênitas , Obstrução Intestinal , Lactente , Humanos , Criança , Resultado do Tratamento , Hérnias Diafragmáticas Congênitas/cirurgia , Herniorrafia/efeitos adversos , Herniorrafia/métodos , Obstrução Intestinal/epidemiologia , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Estudos RetrospectivosRESUMO
Implementing comprehensive health promotion programs in the school setting can be challenging, as schools can be considered complex adaptive systems. As a first step towards understanding what works in improving implementation for which schools and under which conditions, this study aimed to examine the degree of implementation of health promoting school (HPS) programs, in terms of five dimensions of fidelity (adherence, dose, participant responsiveness, quality of delivery and program differentiation), and the dimensions of adaptation and integration. The HPS Implementation Questionnaire was distributed amongâ ±â 2400 primary, secondary, secondary vocational and special needs schools in the Netherlands. Employees of 535 schools (22.3%) filled out the questionnaire. Data were analysed by descriptive statistics and ANOVA tests. The average degree of implementation was 2.55 (SDâ =â 0.58, rangeâ =â 0.68-3.90; scaled 0-4). The lowest scores were achieved for participant responsiveness and adherence, and the highest for integration and adaptation. Schools that identified as HPS reported significantly higher overall degree of implementation, adherence, dose, participant responsiveness, program differentiation and adaptation than schools that didn't. Primary schools achieved a significantly higher degree of implementation, dose, participant responsiveness, quality of delivery and integration than other school types. In conclusion, many schools work on student health and well-being to some extent, but the vast majority have much room for improvement. Higher implementation scores for schools that identified as HPS underline the value of HPS programs. A broader perspective on health and more insight into conditions for effectiveness and implementation in secondary and secondary vocational schools are needed.
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Serviços de Saúde Escolar , Instituições Acadêmicas , Humanos , Estudos Transversais , Promoção da Saúde/métodos , Inquéritos e QuestionáriosRESUMO
Extra temporal lobe epilepsy (eTLE) may involve heterogenous widespread cerebral networks. We investigated the structural network of an eTLE cohort, at the postulated epileptogenic zone later surgically removed, as a network node: the resection zone (RZ). We hypothesized patients with an abnormal connection to/from the RZ to have proportionally increased abnormalities based on topological proximity to the RZ, in addition to poorer post-operative seizure outcome. Structural and diffusion MRI were collected for 22 eTLE patients pre- and post-surgery, and for 29 healthy controls. The structural connectivity of the RZ prior to surgery, measured via generalized fractional anisotropy (gFA), was compared with healthy controls. Abnormal connections were identified as those with substantially reduced gFA (z < -1.96). For patients with one or more abnormal connections to/from the RZ, connections with closer topological distance to the RZ had higher proportion of abnormalities. The minority of the seizure-free patients (3/11) had one or more abnormal connections, while most non-seizure-free patients (8/11) had abnormal connections to the RZ. Our data suggest that eTLE patients with one or more abnormal structural connections to/from the RZ had more proportional abnormal connections based on topological distance to the RZ and associated with reduced chance of seizure freedom post-surgery.
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Diploid A-genome wheat (einkorn wheat) presents a nutrition-rich option as an ancient grain crop and a resource for the improvement of bread wheat against abiotic and biotic stresses. Realizing the importance of this wheat species, reference-level assemblies of two einkorn wheat accessions were generated (wild and domesticated). This work reports an einkorn genome database that provides an interface to the cereals research community to perform comparative genomics, applied genetics and breeding research. It features queries for annotated genes, the use of a recent genome browser release, and the ability to search for sequence alignments using a modern BLAST interface. Other features include a comparison of reference einkorn assemblies with other wheat cultivars through genomic synteny visualization and an alignment visualization tool for BLAST results. Altogether, this resource will help wheat research and breeding. Database URL https://wheat.pw.usda.gov/GG3/pangenome.
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Genoma de Planta , Triticum , Triticum/genética , Genoma de Planta/genética , Melhoramento Vegetal , Genômica/métodos , Estudos de Associação GenéticaRESUMO
Intracranial EEG is the gold standard technique for epileptogenic zone localization but requires a preconceived hypothesis of the location of the epileptogenic tissue. This placement is guided by qualitative interpretations of seizure semiology, MRI, EEG and other imaging modalities, such as magnetoencephalography. Quantitative abnormality mapping using magnetoencephalography has recently been shown to have potential clinical value. We hypothesized that if quantifiable magnetoencephalography abnormalities were sampled by intracranial EEG, then patients' post-resection seizure outcome may be better. Thirty-two individuals with refractory neocortical epilepsy underwent magnetoencephalography and subsequent intracranial EEG recordings as part of presurgical evaluation. Eyes-closed resting-state interictal magnetoencephalography band power abnormality maps were derived from 70 healthy controls as a normative baseline. Magnetoencephalography abnormality maps were compared to intracranial EEG electrode implantation, with the spatial overlap of intracranial EEG electrode placement and cerebral magnetoencephalography abnormalities recorded. Finally, we assessed if the implantation of electrodes in abnormal tissue and subsequent resection of the strongest abnormalities determined by magnetoencephalography and intracranial EEG corresponded to surgical success. We used the area under the receiver operating characteristic curve as a measure of effect size. Intracranial electrodes were implanted in brain tissue with the most abnormal magnetoencephalography findings-in individuals that were seizure-free postoperatively (T = 3.9, P = 0.001) but not in those who did not become seizure-free. The overlap between magnetoencephalography abnormalities and electrode placement distinguished surgical outcome groups moderately well (area under the receiver operating characteristic curve = 0.68). In isolation, the resection of the strongest abnormalities as defined by magnetoencephalography and intracranial EEG separated surgical outcome groups well, area under the receiver operating characteristic curve = 0.71 and area under the receiver operating characteristic curve = 0.74, respectively. A model incorporating all three features separated surgical outcome groups best (area under the receiver operating characteristic curve = 0.80). Intracranial EEG is a key tool to delineate the epileptogenic zone and help render individuals seizure-free postoperatively. We showed that data-driven abnormality maps derived from resting-state magnetoencephalography recordings demonstrate clinical value and may help guide electrode placement in individuals with neocortical epilepsy. Additionally, our predictive model of postoperative seizure freedom, which leverages both magnetoencephalography and intracranial EEG recordings, could aid patient counselling of expected outcome.
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BACKGROUND: There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. METHODS: Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC-the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies-Lewy body disease and TAR DNA-binding protein 43 (TDP-43)-on cortical microstructure was assessed. RESULTS: Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. CONCLUSIONS: Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.
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Doença de Alzheimer , Doença por Corpos de Lewy , Humanos , Doença de Alzheimer/patologia , Doença por Corpos de Lewy/patologia , Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Atrofia/patologiaRESUMO
BACKGROUND: Water, sanitation, and hygiene (WASH) play a pivotal role in controlling typhoid fever, as it is primarily transmitted through oral-fecal pathways. Given our constrained resources, staying current with the most recent research is crucial. This ensures we remain informed about practical insights regarding effective typhoid fever control strategies across various WASH components. We conducted a systematic review and meta-analysis of case-control studies to estimate the associations of water, sanitation, and hygiene exposures with typhoid fever. METHODS: We updated the previous review conducted by Brockett et al. We included new findings published between June 2018 and October 2022 in Web of Science, Embase, and PubMed. We used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for risk of bias (ROB) assessment. We classified WASH exposures according to the classification provided by the WHO/UNICEF Joint Monitoring Programme for Water Supply, Sanitation, and Hygiene (JMP) update in 2015. We conducted the meta-analyses by only including studies that did not have a critical ROB in both Bayesian and frequentist random-effects models. RESULTS: We identified 8 new studies and analyzed 27 studies in total. Our analyses showed that while the general insights on the protective (or harmful) impact of improved (or unimproved) WASH remain the same, the pooled estimates of OR differed. Pooled estimates of limited hygiene (OR = 2.26, 95% CrI: 1.38 to 3.64), untreated water (OR = 1.96, 95% CrI: 1.28 to 3.27) and surface water (OR = 2.14, 95% CrI: 1.03 to 4.06) showed 3% increase, 18% decrease, and 16% increase, respectively, from the existing estimates. On the other hand, improved WASH reduced the odds of typhoid fever with pooled estimates for improved water source (OR = 0.54, 95% CrI: 0.31 to 1.08), basic hygiene (OR = 0.6, 95% CrI: 0.38 to 0.97) and treated water (OR = 0.54, 95% CrI: 0.36 to 0.8) showing 26% decrease, 15% increase, and 8% decrease, respectively, from the existing estimates. CONCLUSIONS: The updated pooled estimates of ORs for the association of WASH with typhoid fever showed clear changes from the existing estimates. Our study affirms that relatively low-cost WASH strategies such as basic hygiene or water treatment can be an effective tool to provide protection against typhoid fever in addition to other resource-intensive ways to improve WASH. TRIAL REGISTRATION: PROSPERO 2021 CRD42021271881.
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Saneamento , Febre Tifoide , Humanos , Teorema de Bayes , Febre Tifoide/epidemiologia , Febre Tifoide/prevenção & controle , Estudos de Casos e Controles , HigieneRESUMO
PURPOSE: Using a high level of mannitol as a diluent in oral formulations can potentially result in tablet defects (e.g., chipping, cracking) during compression. This work aims to scrutinize the linkage between the mechanical properties and material attributes of mannitol and also uncover how variations between vendors and lots can lead to significant changes in the compaction performance of tablet formulations containing mannitol. METHODS: The mechanical properties (Poisson's ratio, fracture energy) and mechanical performance (ejection force, pressure transmission ratio, residual radial die-wall stress, and tensile strength) of mannitol compacts were assessed on a compaction simulator for four lots of mannitol from two different vendors. The variation of material attributes of each lot, including particle size distribution (PSD), crystal form, primary crystal size and morphology, specific surface area (SSA), powder flow, and moisture absorption were investigated. RESULTS: The variability of material attributes in mannitol lots, especially primary crystal size and SSA, can result in significant changes in mechanical properties and mechanical performance such as ejection force and residual radial die-wall stresses, which potentially led to chipping during compression. CONCLUSION: The study elucidated the linkage between fundamental material attributes and mechanical properties of mannitol, highlighting their impact on tablet defects and compaction performance in compression. A comprehensive understanding of the variability in mannitol properties between vendors and lots is crucial for successful formulation development, particularly when high percentages of mannitol are included as a brittle excipient.