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Violence, alcohol use, substance use and poor mental health have been linked with increased HIV acquisition risk, and genital inflammation enhances HIV susceptibility. We examined whether past 6 month experience of these exposures was associated with increased genital inflammation, thereby providing a biological link between these exposures and HIV acquisition risk. The Maisha Fiti study was a longitudinal mixed-methods study of female sex workers in Nairobi, Kenya. Behavioural-biological surveys were conducted at baseline (June-December 2019) and endline (June 2020-March 2021). Analyses were restricted to HIV-negative women (n = 746). Women with raised levels of at least 5 of 9 genital inflammatory cytokines were defined as having genital inflammation. Multivariable logistic regression models were used to estimate (i) baseline associations between genital inflammation and violence, harmful alcohol/substance use, and poor mental health, and (ii) longitudinal associations between these exposures at different survey rounds, and genital inflammation at follow-up. Inflammation data was available for 711 of 746 (95.3%) women at baseline; 351 (50.1%) had genital inflammation, as did 247 (46.7%) at follow-up. At baseline, 67.8% of women had experienced physical and/or sexual violence in the past 6 months, 33.9% had harmful alcohol use, 26.4% had harmful substance use, 25.5% had moderate/severe depression/anxiety, and 13.9% had post-traumatic stress disorder. In adjusted analyses, there was no evidence that these exposures were associated cross-sectionally or longitudinally with genital inflammation. We report no associations between past 6 month experience of violence, harmful alcohol/substance use, or poor mental health, and immune parameters previously associated with HIV risk. This suggests that the well-described epidemiological associations between these exposures and HIV acquisition do not appear to be mediated by genital immune changes, or that any such changes are relatively short-lived. High prevalences of these exposures suggest an urgent need for sex-worker specific violence, alcohol/substance use and mental health interventions.
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Pre-exposure prophylaxis (PrEP) is highly effective at reducing HIV acquisition. We aimed to estimate usage of oral-PrEP, and factors associated with adherence among female sex workers (FSWs) in Nairobi, Kenya, using a novel point-of-care urine tenofovir lateral flow assay (LFA). The Maisha Fiti study randomly selected FSWs from Sex Worker Outreach Program clinics in Nairobi. Data were collected from 1003 FSWs from June-October 2019, including surveys on self-reported oral-PrEP adherence. Adherence was also measured using the LFA for HIV-negative FSWs currently taking oral-PrEP. Informed by a social-ecological theoretical framework, we used hierarchical multivariable logistic regression models to estimate associations between individual, interpersonal/community, and structural/institutional-level factors and either self-reported or LFA-assessed adherence. Overall, 746 HIV-negative FSWs aged 18-40 participated in the study, of whom 180 (24.1%) self-reported currently taking oral-PrEP. Of these, 56 (31.1%) were adherent to oral-PrEP as measured by LFA. In the multivariable analyses, associations with currently taking oral-PrEP included having completed secondary education, high alcohol/substance use, feeling empowered to use PrEP, current intimate partner, no recent intimate partner violence, having support from sex worker organisations, experiencing sex work-related stigma, and seeking healthcare services despite stigma. Associations with oral-PrEP LFA-measured adherence measured included having only primary education, experience of childhood emotional violence, belonging to a higher wealth tertile, and being nulliparous. Oral-PrEP adherence, measured by self-report or objectively, is low among FSWs in Nairobi. Programs to improve oral-PrEP usage among FSWs should work to mitigate social and structural barriers and involve collaboration between FSWs, healthcare providers and policymakers.
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OBJECTIVE: While graphics are commonly used by clinicians to communicate information to patients, the impact of using visual media on surgical patients is not understood. This review seeks to understand the current landscape of research analyzing impact of using visual aids to communicate with patients undergoing surgery, as well as gaps in the present literature. DESIGN: A comprehensive literature search was performed across 4 databases. Search terms included: visual aids, diagrams, graphics, surgery, patient education, informed consent, and decision making. Inclusion criteria were (i) full-text, peer-reviewed articles in English; (ii) evaluation of a nonelectronic visual aid(s); and (iii) surgical patient population. RESULTS: There were 1402 articles identified; 21 met study criteria. Fifteen were randomized control trials and 6 were prospective cohort studies. Visual media assessed comprised of diagrams as informed consent adjuncts (nâ¯=â¯6), graphics for shared decision-making conversations (nâ¯=â¯3), other preoperative educational graphics (nâ¯=â¯8), and postoperative educational materials (nâ¯=â¯4). There was statistically significant improvement in patient comprehension, with an increase in objective knowledge recall (7.8%-29.6%) using illustrated educational materials (nâ¯=â¯10 of 15). Other studies noted increased satisfaction (nâ¯=â¯4 of 6), improvement in shared decision-making (nâ¯=â¯2 of 4), and reduction in patient anxiety (nâ¯=â¯3 of 6). For behavioral outcomes, visual aids improved postoperative medication compliance (nâ¯=â¯2) and lowered postoperative analgesia requirements (nâ¯=â¯2). CONCLUSIONS: The use of visual aids to enhance the surgical patient experience is promising in improving knowledge retention, satisfaction, and reducing anxiety. Future studies ought to consider visual aid format, and readability, as well as patient language, race, and healthcare literacy.
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Recursos Audiovisuais , Educação de Pacientes como Assunto , Humanos , Procedimentos Cirúrgicos Operatórios , Consentimento Livre e EsclarecidoRESUMO
OBJECTIVES: To explore genes in the nuclear factor E2-related factor 2 antioxidative response elements (Nrf2-ARE) signaling pathway using a multiomics approach for associations with variability of cancer-related fatigue (CRF) in postmenopausal women with early-stage hormone receptor-positive breast cancer. SAMPLE & SETTING: Postmenopausal women (N = 116) with early-stage hormone receptor-positive breast cancer were recruited from western Pennsylvania. METHODS & VARIABLES: Candidate genes from the Nrf2-ARE pathway were investigated for associations with CRF occurrence and severity. Associations were evaluated using logistic regression for occurrence and linear regression for severity. RESULTS: The rs2706110 TT genotype in NFE2L2 was associated with a 3.5-fold increase in odds of CRF occurrence. The cytosine-phosphate-guanine (CpG) site cg22820568 in PRDX1 was associated with CRF occurrence and severity. IMPLICATIONS FOR NURSING: Biomarkers based on Nrf2-ARE genes may help to identify women at increased risk for more severe CRF and to develop targeted interventions.
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Neoplasias da Mama , Fadiga , Fator 2 Relacionado a NF-E2 , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/complicações , Fator 2 Relacionado a NF-E2/genética , Fadiga/genética , Pessoa de Meia-Idade , Idoso , Elementos de Resposta Antioxidante/genética , Transdução de Sinais/genética , Pós-Menopausa , Pennsylvania , Estadiamento de NeoplasiasRESUMO
The Challenge Hypothesis is an influential framework for understanding how androgens are involved in the promotion of competitive behavior during mating-related challenges and has been tested extensively in studies across scientific disciplines. Mixed support in psychological research led scholars to develop the Dual Hormone Hypothesis as a potential path forward, which argues that glucocorticoids moderate the relationship between androgens and status-striving. In the current study, we examine the Challenge Hypothesis and the Dual Hormone Hypothesis in wild male mountain gorillas, representing the first time the latter hypothesis has been tested in a non-human primate. In a sample of 30 adult males comprising over 600 days of observation, we find some limited support for the Challenge Hypothesis. Greater daily rates of targeted aggression toward other adult males corresponded to higher fecal androgen metabolites 1-2 days following observations, though this pattern did not fully generalize to dominance rank or other competitive behaviors examined. However, we find no support for the Dual Hormone Hypothesis: neither dominance rank nor any category of competitive behavior was predicted by the interaction between androgens and glucocorticoids. We close by discussing how this initial investigation might be leveraged toward the development of an expanded Dual Hormone Hypothesis that draws on the large evidence base in primate behavioral ecology.
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Agressão , Androgênios , Fezes , Gorilla gorilla , Predomínio Social , Animais , Masculino , Gorilla gorilla/fisiologia , Gorilla gorilla/psicologia , Agressão/fisiologia , Fezes/química , Comportamento Competitivo/fisiologia , Glucocorticoides/metabolismo , Glucocorticoides/análise , Comportamento Sexual Animal/fisiologiaRESUMO
BACKGROUND: Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior. METHODS: This international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC. RESULTS: Overall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P = 0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size. CONCLUSIONS: Despite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies.
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Ampola Hepatopancreática , Carcinoma Ductal Pancreático , Colangiocarcinoma , Neoplasias do Ducto Colédoco , Neoplasias Duodenais , Neoplasias Pancreáticas , Humanos , Masculino , Feminino , Ampola Hepatopancreática/patologia , Ampola Hepatopancreática/cirurgia , Taxa de Sobrevida , Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia , Idoso , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Pessoa de Meia-Idade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Neoplasias do Ducto Colédoco/patologia , Neoplasias do Ducto Colédoco/cirurgia , Neoplasias do Ducto Colédoco/mortalidade , Seguimentos , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Prognóstico , Estudos de Coortes , Estudos RetrospectivosRESUMO
OBJECTIVE: The aim of this study was to examine associations between empirically derived dietary pattern scores and cognition, as well as risk of cognitive decline, over an average of 4.6 (± 0.3) years in older men. MATERIALS AND METHODS: This analysis was conducted as part of the Osteoporotic Fractures in Men (MrOS) prospective cohort study. Diet was assessed at Visit 1 (3/2000-4/2002) by food frequency questionnaire, and dietary patterns (Western and Prudent) were derived by factor analysis. The analytic cohort comprised 4231 community-dwelling American men who were aged 65 years or more. Cognitive function was assessed with the Modified Mini-Mental State exam (3MS) and the Trails B test at Visit 1 and at Visit 2 (3/2005-5/2006). Associations between dietary pattern score and cognition and risk of cognitive decline were estimated using mixed effects regression models. Model 1 was adjusted for age, clinic site and total energy intake (TEI). Model 2 was further adjusted for calcium and vitamin D supplement use, body mass index (BMI), physical activity, smoking, diabetes and hypertension (Western diet group) and education, calcium and vitamin D supplement use, depression, BMI, physical activity, smoking and stroke (Prudent diet group). RESULTS: Adherence to the Western dietary pattern was associated with higher 3MS scores and shorter Trails B test time at Visit 1 in Model 2. Adherence to the Prudent dietary pattern was associated with higher 3MS scores in Model 1 but not Model 2. There were no independent associations between dietary pattern scores and risk of cognitive decline 4.6 (± 0.3) years later at Visit 2. CONCLUSION: The results do not support a robust protective effect of the Prudent dietary pattern on cognition in the MrOS cohort. Associations between the Western dietary pattern and better cognitive scores should be interpreted with caution. Further research is needed to understand the complex interactions between dietary patterns and cognition in older men.
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Cognição , Disfunção Cognitiva , Dieta , Fraturas por Osteoporose , Humanos , Masculino , Idoso , Estudos Prospectivos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/epidemiologia , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/psicologia , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Suplementos Nutricionais , Comportamento Alimentar/psicologia , Fatores de Risco , Estudos de Coortes , Padrões DietéticosRESUMO
OBJECTIVES: This trial examines the impact of the Provider Awareness and Cultural dexterity Toolkit for Surgeons (PACTS) curriculum on surgical residents' knowledge, cross-cultural care, skills, and beliefs. SUMMARY BACKGROUND DATA: Cross-cultural training of providers may reduce healthcare outcome disparities, but its effectiveness in surgical trainees is unknown. METHODS: PACTS focuses on developing skills needed for building trust, working with patients with limited English proficiency, optimizing informed consent, and managing pain. The PACTS trial was a randomized crossover trial of 8 academic general surgery programs in the United States: The Early group ("Early") received PACTS between Periods 1 and 2, while the Delayed group ("Delayed") received PACTS between Periods 2 and 3. Residents were assessed pre- and post-intervention on Knowledge, Cross-Cultural Care, Self-Assessed Skills, and Beliefs. Chi-square and Fisher's exact tests were conducted to evaluate within- and between-intervention group differences. RESULTS: Of 406 residents enrolled, 315 were exposed to the complete PACTS curriculum. Early residents' Cross-Cultural Care (79.6% to 88.2%, P<0.0001), Self-Assessed Skills (74.5% to 85.0%, P<0.0001), and Beliefs (89.6% to 92.4%, P=0.0028) improved after PACTS; Knowledge scores (71.3% to 74.3%, P=0.0661) were unchanged. Delayed resident scores pre- to post-PACTS showed minimal improvements in all domains. When comparing the two groups at Period 2, Early residents had modest improvement in all 4 assessment areas, with statistically significant increase in Beliefs (92.4% vs 89.9%, P=0.0199). CONCLUSION: The PACTS curriculum is a comprehensive tool that improved surgical residents' knowledge, preparedness, skills, and beliefs, which will help with caring for diverse patient populations.
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Amyloid-beta (Aß42) aggregates are characteristic Alzheimer's disease signatures, but probing how their nanoscale architectures influence their growth and decay remains challenging using current technologies. Here, we apply time-lapse single-molecule orientation-localization microscopy (SMOLM) to measure the orientations and rotational "wobble" of Nile blue (NB) molecules transiently binding to Aß42 fibrils. We correlate fibril architectures measured by SMOLM with their growth and decay over the course of 5 to 20 min visualized by single-molecule localization microscopy (SMLM). We discover that stable Aß42 fibrils tend to be well-ordered and signified by well-aligned NB orientations and small wobble. SMOLM also shows that increasing order and disorder are signatures of growing and decaying fibrils, respectively. We also observe SMLM-invisible fibril remodeling, including steady growth and decay patterns that conserve ß-sheet organization. SMOLM reveals that increased fibril architectural heterogeneity is correlated with dynamic remodeling and that large-scale fibril remodeling tends to originate from strongly heterogeneous local regions.
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Corynebacterium glutamicum ATCC 13032 is a promising microbial chassis for industrial production of valuable compounds, including aromatic amino acids derived from the shikimate pathway. In this work, we developed two whole-cell, transcription factor based fluorescent biosensors to track cis,cis-muconic acid (ccMA) and chorismate in C. glutamicum. Chorismate is a key intermediate in the shikimate pathway from which value-added chemicals can be produced, and a shunt from the shikimate pathway can divert carbon to ccMA, a high value chemical. We transferred a ccMA-inducible transcription factor, CatM, from Acinetobacter baylyi ADP1 into C. glutamicum and screened a promoter library to isolate variants with high sensitivity and dynamic range to ccMA by providing benzoate, which is converted to ccMA intracellularly. The biosensor also detected exogenously supplied ccMA, suggesting the presence of a putative ccMA transporter in C. glutamicum, though the external ccMA concentration threshold to elicit a response was 100-fold higher than the concentration of benzoate required to do so through intracellular ccMA production. We then developed a chorismate biosensor, in which a chorismate inducible promoter regulated by natively expressed QsuR was optimized to exhibit a dose-dependent response to exogenously supplemented quinate (a chorismate precursor). A chorismate-pyruvate lyase encoding gene, ubiC, was introduced into C. glutamicum to lower the intracellular chorismate pool, which resulted in loss of dose dependence to quinate. Further, a knockout strain that blocked the conversion of quinate to chorismate also resulted in absence of dose dependence to quinate, validating that the chorismate biosensor is specific to intracellular chorismate pool. The ccMA and chorismate biosensors were dually inserted into C. glutamicum to simultaneously detect intracellularly produced chorismate and ccMA. Biosensors, such as those developed in this study, can be applied in C. glutamicum for multiplex sensing to expedite pathway design and optimization through metabolic engineering in this promising chassis organism. ONE-SENTENCE SUMMARY: High-throughput screening of promoter libraries in Corynebacterium glutamicum to establish transcription factor based biosensors for key metabolic intermediates in shikimate and ß-ketoadipate pathways.
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Técnicas Biossensoriais , Ácido Corísmico , Corynebacterium glutamicum , Ácido Sórbico , Corynebacterium glutamicum/metabolismo , Corynebacterium glutamicum/genética , Técnicas Biossensoriais/métodos , Ácido Sórbico/metabolismo , Ácido Sórbico/análogos & derivados , Ácido Corísmico/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regiões Promotoras Genéticas , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Acinetobacter/metabolismo , Acinetobacter/genéticaRESUMO
BACKGROUND: Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB. PATIENTS AND METHODS: Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS). RESULTS: The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine - cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively). DISCUSSION: Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas.
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Adenocarcinoma , Neoplasias Duodenais , Humanos , Masculino , Feminino , Quimioterapia Adjuvante , Pessoa de Meia-Idade , Idoso , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Neoplasias Duodenais/tratamento farmacológico , Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ampola Hepatopancreática/patologia , Pancreaticoduodenectomia , Estudos de Coortes , Neoplasias do Ducto Colédoco/tratamento farmacológico , Neoplasias do Ducto Colédoco/cirurgia , Neoplasias do Ducto Colédoco/patologia , Neoplasias do Ducto Colédoco/mortalidade , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Estudos Retrospectivos , Capecitabina/uso terapêutico , Capecitabina/administração & dosagemRESUMO
Exposure to early life adversity (ELA) is hypothesized to sensitize threat-responsive neural circuitry. This may lead individuals to overestimate threat in the face of ambiguity, a cognitive-behavioral phenotype linked to poor mental health. The tendency to process ambiguity as threatening may stem from difficulty distinguishing between ambiguous and threatening stimuli. However, it is unknown how exposure to ELA relates to neural representations of ambiguous and threatening stimuli, or how processing of ambiguity following ELA relates to psychosocial functioning. The current fMRI study examined multivariate representations of threatening and ambiguous social cues in 41 emerging adults (aged 18 to 19 years). Using representational similarity analysis, we assessed neural representations of ambiguous and threatening images within affective neural circuitry and tested whether similarity in these representations varied by ELA exposure. Greater exposure to ELA was associated with greater similarity in neural representations of ambiguous and threatening images. Moreover, individual differences in processing ambiguity related to global functioning, an association that varied as a function of ELA. By evidencing reduced neural differentiation between ambiguous and threatening cues in ELA-exposed emerging adults and linking behavioral responses to ambiguity to psychosocial wellbeing, these findings have important implications for future intervention work in at-risk, ELA-exposed populations.
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Amyloid-beta (Aß42) aggregates are characteristic signatures of Alzheimer's disease, but probing how their nanoscale architectures influence their growth and decay remains challenging using current technologies. Here, we apply time-lapse single-molecule orientation-localization microscopy (SMOLM) to measure the orientations and rotational "wobble" of Nile blue (NB) molecules transiently binding to Aß42 fibrils. We quantify correlations between fibril architectures, measured by SMOLM, and their growth and decay visualized by single-molecule localization microscopy (SMLM). We discover that stable Aß42 fibrils tend to be well-ordered, signified by well-aligned NB orientations and small wobble. SMOLM also shows that increasing order and disorder are signatures of growing and decaying Aß42 fibrils, respectively. We also observe SMLM-invisible fibril remodeling, including steady growth and decay patterns that conserve ß-sheet organization. SMOLM reveals that increased heterogeneity in fibril architectures is correlated with more dynamic remodeling and that large-scale fibril remodeling tends to originate from local regions that exhibit strong heterogeneity.
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Background: This study examined clinical characteristics of problematic hair pulling (HP) and skin picking (SP) in infants and young children and their association with self-soothing, sleep, and temperament. Methods: An internet survey of parents/caregivers of 0-5-year-olds (n = 384 with data analyzed, of whom 26 experienced HP, 62 experienced SP, and 302 were controls free of HP and SP) assessed demographics and medical history, HP and SP characteristics, contextual factors, self-soothing, sleep patterns, and temperament. Participants were recruited through both HP and SP advocacy and support webpages and general webpages (e.g., parenting groups). Descriptive statistics, chi-square tests of independence, independent samples t-test clinically characterized HP, SP, and control groups. Logistic regression and one-way analysis of covariance controlled for sex and age in analyses. Results: HP and SP rates were 6.1% (n = 26) and 14.5% (n = 62), respectively. SP presented in 23.1% of children with HP, and HP presented in 9.7% of children with SP. Mean HP and SP onset occurred at 12.2 (SD = 11.2) and 24.1 (SD = 15.8) months, respectively. Contextual factors, including boredom, upset, and awake-in-bed were common in HP and SP. Common caregiver responses included distracting the child, moving the hand away, and telling the child to stop. Few caregivers sought professional help for the child. Children with HP engaged in more hair twirling than controls, and children with SP engaged in more nail biting than controls. Children with HP, but not SP, had more sleep disturbance than controls. In terms of temperament, children with HP displayed sensitivity to stimuli, children with SP exhibited low persistence, and both HP and SP groups displayed serious, observant mood relative to controls. Conclusions: Findings expand clinical understanding of HP and SP in children aged 0-5 and provide targets (contextual factors, sleep, sensory sensitivity, persistence, and mood) for behavioral interventions. Low rates of treatment seeking highlight the need for expansion of clinical guidelines for HP and SP in this age range.
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Understanding intracellular phase separation is crucial for deciphering transcriptional control, cell fate transitions, and disease mechanisms. However, the key residues, which impact phase separation the most for protein phase separation function have remained elusive. We develop PSPHunter, which can precisely predict these key residues based on machine learning scheme. In vivo and in vitro validations demonstrate that truncating just 6 key residues in GATA3 disrupts phase separation, enhancing tumor cell migration and inhibiting growth. Glycine and its motifs are enriched in spacer and key residues, as revealed by our comprehensive analysis. PSPHunter identifies nearly 80% of disease-associated phase-separating proteins, with frequent mutated pathological residues like glycine and proline often residing in these key residues. PSPHunter thus emerges as a crucial tool to uncover key residues, facilitating insights into phase separation mechanisms governing transcriptional control, cell fate transitions, and disease development.
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Aprendizado de Máquina , Proteínas , GlicinaRESUMO
Computational toxicology models have been successfully implemented to prioritize and screen chemicals. There are numerous in silico (quantitative) structure-activity relationship ([Q]SAR) models for the prediction of a range of human-relevant toxicological endpoints, but for a given endpoint and chemical, not all predictions are identical due to differences in their training sets, algorithms, and methodology. This poses an issue for high-throughput screening of a large chemical inventory as it necessitates several models to cover diverse chemistries but will then generate data conflicts. To address this challenge, we developed a consensus modeling strategy to combine predictions obtained from different existing in silico (Q)SAR models into a single predictive value while also expanding chemical space coverage. This study developed consensus models for nine toxicological endpoints relating to estrogen receptor (ER) and androgen receptor (AR) interactions (i.e., binding, agonism, and antagonism) and genotoxicity (i.e., bacterial mutation, in vitro chromosomal aberration, and in vivo micronucleus). Consensus models were created by combining different (Q)SAR models using various weighting schemes. As a multi-objective optimization problem, there is no single best consensus model, and therefore, Pareto fronts were determined for each endpoint to identify the consensus models that optimize the multiple-criterion decisions simultaneously. Accordingly, this work presents sets of solutions for each endpoint that contain the optimal combination, regardless of the trade-off, with the results demonstrating that the consensus models improved both the predictive power and chemical space coverage. These solutions were further analyzed to find trends between the best consensus models and their components. Here, we demonstrate the development of a flexible and adaptable approach for in silico consensus modeling and its application across nine toxicological endpoints related to ER activity, AR activity, and genotoxicity. These consensus models are developed to be integrated into a larger multi-tier NAM-based framework to prioritize chemicals for further investigation and support the transition to a non-animal approach to risk assessment in Canada.
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Pediatric obsessive-compulsive disorder (OCD) can be enormously taxing for affected youth and their families; the distress, impairment, and family upheaval that it brings are well documented.1 Both exposure-based cognitive-behavioral therapy (CBT) and pharmacological interventions are efficacious for reducing symptoms and functional impairment, producing mean effect sizes of g = 1.21 and g = 0.50 respectively.2 These treatments-whether administered alone or in combination-form the backbone of our current suite of interventions. They have helped countless young people to restore functioning and lead healthy, productive lives. Despite this encouraging picture, long-term outcomes for children and adolescents with OCD remain poorly understood. Even for youth who receive high-quality evidence-based care, it is unclear what to expect down the road, and this gap in understanding creates challenges for clinical decision making as well as angst for parents who, quite understandably, want to know what the future holds for their children. Although CBT often is recommended as the frontline intervention for pediatric OCD3 and parents routinely report preferring to begin with nonmedication options,4 data to help patients and families make fully informed treatment decisions are scarce. Most would like to know the long-term outcomes associated with various treatment options, and this is a challenge given that the typical length of follow-up in CBT trials for pediatric OCD is 3 to 6 months-well short of a typical school year. The study by Ivarsson et al.5 is therefore a much-needed advance for the field, offering a first view of long-term outcomes for youth with OCD treated with evidence-based treatments.
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Terapia Cognitivo-Comportamental , Transtorno Obsessivo-Compulsivo , Humanos , Transtorno Obsessivo-Compulsivo/terapia , Adolescente , Criança , Terapia Cognitivo-Comportamental/métodos , Prática Clínica Baseada em Evidências , Medicina Baseada em EvidênciasRESUMO
Typologies serve to organize knowledge and advance theory for many scientific disciplines, including more recently in the social and behavioral sciences. To date, however, no typology exists to categorize an individual's use of emotion regulation strategies. This is surprising given that emotion regulation skills are used daily and that deficits in this area are robustly linked with mental health symptoms. Here, we attempted to identify and validate a working typology of emotion regulation across six samples (collectively comprised of 1,492 participants from multiple populations) by using a combination of computational techniques, psychometric models, and growth curve modeling. We uncovered evidence for three types of regulators: a type that infrequently uses emotion regulation strategies (Lo), a type that uses them frequently but indiscriminately (Hi), and a third type that selectively uses some (cognitive reappraisal and situation selection), but not other (expressive suppression), emotion regulation strategies frequently (Mix). Results showed that membership in the Hi and Mix types is associated with better mental health, with the Mix type being the most adaptive of the three. These differences were stable over time and across different samples. These results carry important implications for both our basic understanding of emotion regulation behavior and for informing future interventions aimed at improving mental health. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Assuntos
Regulação Emocional , Humanos , Regulação Emocional/fisiologia , Masculino , Feminino , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Adolescente , Psicometria , Saúde Mental , Emoções/fisiologiaRESUMO
PURPOSE: Methicillin-resistant Staphylococcus aureus infections are increasing in prevalence in patients with cystic fibrosis (CF) and are associated with worsening lung function and increased mortality. Lefamulin is a pleuromutilin antimicrobial approved to treat community-acquired bacterial pneumonia based on potent in vitro activity and clinical efficacy. This Phase I, open-label, randomized crossover study assessed the safety and pharmacokinetic profile of oral and intravenous (IV) lefamulin in adults with CF. METHODS: The study comprised 2 dosing periods in which adults with CF (N = 13) received a single dose of lefamulin via a 150-mg IV infusion or 600-mg immediate-release orally administered tablet, separated by a 4- to 7-day washout period. Pharmacokinetic and safety parameters were assessed after lefamulin treatment. FINDINGS: Single doses of lefamulin administered via oral tablet or IV infusion resulted in comparable drug exposure, and sputum analysis suggested rapid penetration of lefamulin into the lung. Comparison of the present results with those obtained from prior single-dose studies of healthy volunteers indicate no meaningful difference in the pharmacokinetic properties of lefamulin in patients with CF. Treatment-emergent adverse events were consistent with previous reports, and the majority were mild in severity. IMPLICATIONS: These results show similar lefamulin pharmacokinetic and safety profiles between patients with CF and healthy volunteers receiving the same oral and IV doses, suggesting no need for lefamulin dose adjustment in patients with CF and indicating the potential of lefamulin as therapy for lung infections in patients with CF. CLINICALTRIALS: gov identifier: NCT05225805.
Assuntos
Fibrose Cística , Diterpenos , Staphylococcus aureus Resistente à Meticilina , Pneumonia , Compostos Policíclicos , Tioglicolatos , Adulto , Humanos , Antibacterianos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/induzido quimicamente , Estudos Cross-Over , Pneumonia/tratamento farmacológico , Comprimidos/farmacocinéticaRESUMO
High HIV prevalence among female sex workers (FSWs) is heavily influenced by structural determinants (e.g. criminalisation of sex work; violence) and significant life events (e.g. orphanhood, teenage pregnancy). This study aims to understand the epidemiology of HIV among FSWs in Nairobi, Kenya using a structural determinants and life-course perspective. Baseline cross-sectional survey data were collected June-December 2019 for the Maisha Fiti study with 1003 FSWs (aged 18-45 years). Odds ratios and 95% confidence intervals were estimated using multivariable logistic regression with a hierarchical modelling approach. HIV prevalence was 28.0%, and increased with age (<25 years 5.7%, 25-34 years 19.0%, ≥35 years 40.6%). In adjusted analyses, HIV seroprevalence was associated with childhood and adolescence including violence from militia or soldiers (AOR = 1.60; 95%CI:1.00-2.53), young age at sexual debut (≤15 years old vs. ≥18 years AOR = 0.57; 95%CI:0.39-0.84) and teenage pregnancy (AOR = 1.37; 95%CI:1.00-1.88). For adulthood the factors included lower SES score (lowest vs. highest tertile AOR = 0.63; 95%CI:0.40-0.98); reduced housing insecurity (AOR = 0.52; 95%CI:0.54-0.79); lower alcohol/drug use score (AOR = 0.44; 95%CI:0.31-0.61); and a longer duration of selling sex (0-5 years vs. ≥11 years AOR = 2.35; 95%CI:1.44-3.82). Among HIV-negative FSWs, prevalence of HIV risk factors was high (recent hunger 32.3%; internalised 67.7% and experienced 66.0% sex work stigma; recent police arrest 30.1%; recent physical or sexual violence 65.6%, condomless last sex intimate partner 71.1%; harmful alcohol or substance use 49.1%). Only 24.6% of HIV-negative FSWs reported taking PrEP. Taken together, adverse events in childhood and adolescence were associated with increased odds of living with HIV, and were more strongly associated with HIV serostatus than adulthood structural or behavioural risk factors. HIV-negative FSWs remain at high risk of HIV acquisition. This study highlights the importance of addressing adverse events throughout the life course to reduce HIV risk, and the need to continue multi-level HIV prevention and treatment efforts.