Category: Nevin Manimala

Science. 2024 Jul 5;385(6704):eadd8394. doi: 10.1126/science.add8394. Epub 2024 Jul 5.

ABSTRACT

Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5′ single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4⁺ T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.

PMID:38963856 | DOI:10.1126/science.add8394

Aesthet Surg J. 2024 Jul 4:sjae145. doi: 10.1093/asj/sjae145. Online ahead of print.

ABSTRACT

BACKGROUND: Over the past decade, the use of poly-4-hydroxybutyrate (P4HB) in aesthetic breast surgery has grown in popularity. Published data on long-term outcomes, however, is scarce.

OBJECTIVES: The purpose of this study was to assess long-term outcomes when using P4HB in various aesthetic breast procedures.

METHODS: A retrospective review of all patients undergoing breast procedures with P4HB performed by the senior author (WPA) between July 2012 and March 2022. All patients with greater than one year of follow-up were evaluated, including demographics, surgical indications, complications, secondary procedures, and patient satisfaction. A Kruskal-Wallis test was performed to assess the stability of satisfaction over time.

RESULTS: A total of 248 patients were evaluated. The mean follow-up length was 2.9 years (range, 1-9.3y). The most common surgical indication was breast ptosis, which comprised 68 percent (n=167) of patients. The overall complication rate was 8.0 percent (n=20), with an unplanned reoperation rate of 2.8 percent (n=7). Across the entire study population, the mean satisfaction score was 3.42 out of 4. When satisfaction scores were compared to follow-up length, Kruskal-Wallis test demonstrated no statistical differences (H = 18.2, p = 0.89, df = 2), suggesting stability of satisfaction over time.

CONCLUSIONS: This study presents the senior author’s entire experience with P4HB across a wide range of aesthetic breast procedures. With an average follow-up length of almost 3 years, P4HB appears to be both a safe and effective tool to support soft tissue in aesthetic breast surgery. Further, high patient satisfaction appears stable.

PMID:38963821 | DOI:10.1093/asj/sjae145

Neuro Oncol. 2024 Jul 4:noae123. doi: 10.1093/neuonc/noae123. Online ahead of print.

ABSTRACT

BACKGROUND: Brain metastases (BM) are a devastating complication of HER2-positive metastatic breast cancer (BC) and treatment strategies providing optimized local and systemic disease control are urgently required. The antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) over trastuzumab emtansine but data regarding intracranial activity is limited. In the primary outcome analysis of TUXEDO-1, a high intracranial response rate (RR) was reported with T-DXd. Here, we report final PFS and OS results.

PATIENTS AND METHODS: TUXEDO-1 accrued adult patients with HER2-positive BC and active BM (newly diagnosed or progressing) without indication for immediate local therapy. The primary endpoint was intracranial RR; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population.

RESULTS: At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event was fatigue (20%). Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL was maintained over the treatment period.

DISCUSSION: T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive BC BM in line with results from the pivotal trials. These results support the concept of ADCs as systemic therapy for active BM.

PMID:38963808 | DOI:10.1093/neuonc/noae123

Clin Exp Dermatol. 2024 Jul 4:llae252. doi: 10.1093/ced/llae252. Online ahead of print.

ABSTRACT

BACKGROUND: Tissue expression of endothelial cell (EC) markers of microcirculatory changes in CSU is poorly investigated.

OBJECTIVE: to explore the expression of specific EC markers (stem cell factor (SCF), vascular endothelial growth factor (VEGF) and membrane attack complex (MAC)) in CSU-L and CSU-NL skin through immunohistochemistry (IHC) and in serum.

METHODS: Lesional (L) and non-lesional (NL) skin biopsies from CSU patients and HCs were studied for the IHC expression of SCF, VEGF and MAC in CSU patients (n = 23) and healthy controls (HCs, n = 9). In this population, we also investigated blood levels of VEGF and SCF. Patients were also assessed for clinical characteristics, disease activity, and markers of autoimmune CSU (aiCSU).

RESULTS: Epidermal SCF reactivity was significantly higher in CSU-L skin compared to HC skin (p=0.026). In the dermis, SCF immunoreactivity was seen particularly on endothelial, perivascular and epithelial cells. In CSU-L skin, mean perivascular SCF stainings were significantly more intense compared to HCs (p<0.001). Furthermore, CSU-NL skin also showed significantly higher SCF stainings on dermal perivascular cells compared to HCs (p<0.001). CSU patients had the highest SCF immunoreactivity scores in the epidermis and/or on dermal ECs. These patients did not have significantly higher SCF serum levels.

CONCLUSION: This is the first study to show elevated cutaneous expression of SCF in chronic spontaneous urticaria. These findings underline the potential therapeutic possibilities of anti-KIT antibodies in CSU treatment.

PMID:38963799 | DOI:10.1093/ced/llae252

Clin Nutr ESPEN. 2024 May 22;63:197-206. doi: 10.1016/j.clnesp.2024.05.012. Online ahead of print.

ABSTRACT

BACKGROUND: Gut microbiota and obesity are deeply interconnected. However, the causality in the relationship between these factors remains unclear. Therefore, this study aimed to elucidate the genetic relationship between gut microbiota and childhood obesity.

METHODS: Genetic summary statistics for the gut microbiota were obtained from the MiBioGen consortium. Genome-wide association studies (GWAS) summary data for childhood obesity were obtained from North American, Australian, and European collaborative genome-wide meta-analyses. Mendelian randomization (MR) analyses were performed using the inverse variance weighting method. 16 children with obesity and 16 without obesity were included for clinical observation, and their weight, body mass index, blood lipid levels, and gut microbiology were assessed. Paired t-test was the primary method of data analysis, and statistical significance was set at P < 0.05.

RESULTS: MR identified 16 causal relationships between the gut microbiome and childhood obesity. In the case-control study, we found that five gut microorganisms differed between children with and without obesity, whereas three gut microorganisms changed after weight loss in children with obesity.

CONCLUSION: Our study provides new insights into the genetic mechanisms underlying gut microbiota and childhood obesity.

TRIAL REGISTRATION NUMBER: ChiCTR2300072179.

NAME OF REGISTRY: Change of intestinal flora and plasma metabolome in obese children and their weight loss intervention: a randomized controlled tria URL OF REGISTRY: https://www.chictr.org.cn/showproj.html.

DATE OF REGISTRATION: 2023-06-06.

DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 2023-06-07.

PMID:38963766 | DOI:10.1016/j.clnesp.2024.05.012

IEEE J Biomed Health Inform. 2024 Jul 4;PP. doi: 10.1109/JBHI.2024.3423019. Online ahead of print.

ABSTRACT

Transcutaneous auricular vagus nerve stimulation (taVNS) is an emerging neuro modulation technology that has been reported to be beneficial in the treatment of diseases by several studies, but its exact mechanism of action is still unclear. It has been demonstrated that ta VNS can influence interoceptive signals. Notably, the processing of interoceptive signals is directly related to many diseases, such as depression, anxiety, and insomnia. The insula and the medial prefrontal cortex (MPFC) communicate during the bottom-up transmission of taVNS-induced signals, and both play a role in interoceptive signal processing. By focusing on the insula and MPFC, our research pioneers detail the potential interactions between interoceptive signal processing and the neuromodulation effects of taVNS, providing novel insights in to the neurobiological mechanisms of taVNS. Two functional connectivity (FC) analyses (region of interest-based and seed-based) were used in this study. We observed that negative connectivity between the insula and the MPFC was significantly weakened following taVNS, while there were no statistical changes in the sham group. Our findings elucidate potential mechanisms linking vagal activity with intrinsic FC among specific brain regions and networks. Specifically, our results indicate that taVNS may enhance the ability to flexibly balance interoceptive awareness and cognitive experiences by modulating the FC between the insula and MPFC. The modulation effects may impact body-brain interactions, suggesting the mechanism of taVNS in therapeutic applications.

PMID:38963749 | DOI:10.1109/JBHI.2024.3423019

JMIR Mhealth Uhealth. 2024 Jul 4;12:e54669. doi: 10.2196/54669.

ABSTRACT

BACKGROUND: Climate change increasingly impacts health, particularly of rural populations in sub-Saharan Africa due to their limited resources for adaptation. Understanding these impacts remains a challenge, as continuous monitoring of vital signs in such populations is limited. Wearable devices (wearables) present a viable approach to studying these impacts on human health in real time.

OBJECTIVE: The aim of this study was to assess the feasibility and effectiveness of consumer-grade wearables in measuring the health impacts of weather exposure on physiological responses (including activity, heart rate, body shell temperature, and sleep) of rural populations in western Kenya and to identify the health impacts associated with the weather exposures.

METHODS: We conducted an observational case study in western Kenya by utilizing wearables over a 3-week period to continuously monitor various health metrics such as step count, sleep patterns, heart rate, and body shell temperature. Additionally, a local weather station provided detailed data on environmental conditions such as rainfall and heat, with measurements taken every 15 minutes.

RESULTS: Our cohort comprised 83 participants (42 women and 41 men), with an average age of 33 years. We observed a positive correlation between step count and maximum wet bulb globe temperature (estimate 0.06, SE 0.02; P=.008). Although there was a negative correlation between minimum nighttime temperatures and heat index with sleep duration, these were not statistically significant. No significant correlations were found in other applied models. A cautionary heat index level was recorded on 194 (95.1%) of 204 days. Heavy rainfall (>20 mm/day) occurred on 16 (7.8%) out of 204 days. Despite 10 (21%) out of 47 devices failing, data completeness was high for sleep and step count (mean 82.6%, SD 21.3% and mean 86.1%, SD 18.9%, respectively), but low for heart rate (mean 7%, SD 14%), with adult women showing significantly higher data completeness for heart rate than men (2-sided t test: P=.003; Mann-Whitney U test: P=.001). Body shell temperature data achieved 36.2% (SD 24.5%) completeness.

CONCLUSIONS: Our study provides a nuanced understanding of the health impacts of weather exposures in rural Kenya. Our study’s application of wearables reveals a significant correlation between physical activity levels and high temperature stress, contrasting with other studies suggesting decreased activity in hotter conditions. This discrepancy invites further investigation into the unique socioenvironmental dynamics at play, particularly in sub-Saharan African contexts. Moreover, the nonsignificant trends observed in sleep disruption due to heat expose the need for localized climate change mitigation strategies, considering the vital role of sleep in health. These findings emphasize the need for context-specific research to inform policy and practice in regions susceptible to the adverse health effects of climate change.

PMID:38963698 | DOI:10.2196/54669

JMIR Res Protoc. 2024 Jul 4;13:e57103. doi: 10.2196/57103.

ABSTRACT

BACKGROUND: Evidence suggests that having a chronic physical illness (CPI; eg, asthma, diabetes, and epilepsy) is an independent risk factor for suicidality (ie, suicidal ideation or attempts) among youth. Less is known about the mechanisms linking CPI and suicidality. Some evidence suggests that mental illness (eg, depression and anxiety) or neurodevelopmental disorder (eg, attention-deficit/hyperactivity disorder) mediates or moderates the CPI-suicidality association. Missing from the knowledge base is information on the association between having co-occurring CPI and mental illness or neurodevelopmental disorder (MIND) on youth suicidality.

OBJECTIVE: This study uses epidemiological data from the 2019 Canadian Health Survey of Children and Youth (CHSCY) to study the intersection of CPI, MIND, and suicidality in youth. We will estimate prevalence, identify predictors, and investigate psychosocial and service use outcomes for youth with CPI-MIND comorbidity versus other morbidity groups (ie, healthy, CPI only, and MIND only).

METHODS: Conducted by Statistics Canada, the CHSCY collected data from 47,850 children (aged 1-17 years) and their primary caregiving parent. Measures of youth CPI, MIND, family environment, and sociodemographics are available using youth and parent informants. Information on psychiatric services use is available via parent report and linkage to national administrative health data found in the National Ambulatory Care Reporting System and the Discharge Abstract Database, which allow the investigation of hospital-based mental health services (eg, emergency department visits, hospitalizations, and length of stay in hospital). Questions about suicidality were restricted to youths aged 15-17 years (n=6950), which form our analytic sample. Weighted regression-based analyses will account for the complex survey design.

RESULTS: Our study began in November 2023, funded by the American Foundation for Suicide Prevention (SRG-0-008-22). Access to the linked CHSCY microdata file was granted in May 2024. Initial examination of CHSCY data shows that approximately 20% (1390/6950) of youth have CPI, 7% (490/6950) have MIND, 7% (490/6950) seriously considered suicide in the past year, and 3% (210/6950) had attempted suicide anytime during their life.

CONCLUSIONS: Findings will provide estimates of suicidality among youth with CPI-MIND comorbidity, which will inform intervention planning to prevent loss of life in this vulnerable population. Modeling correlates of suicidality will advance understanding of the relative and joint effects of factors at multiple levels-information needed to target prevention efforts and services. Understanding patterns of psychiatric service use is vital to understanding access and barriers to services. This will inform whether use matches need, identifying opportunities to advise policy makers about upstream resources to prevent suicidality. Importantly, findings will provide robust baseline of information on the link between CPI-MIND comorbidity and suicidality in youth, which can be used by future studies to address questions related to the impact of the COVID-19 pandemic and associated countermeasures in this vulnerable population of youth.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57103.

PMID:38963692 | DOI:10.2196/57103

JMIR Aging. 2024 Jul 4;7:e47565. doi: 10.2196/47565.

ABSTRACT

BACKGROUND: Persons living with dementia experience autonomy loss and require caregiver support on a daily basis. Dementia involves a gradual decline in communication skills, leading to fewer interactions and isolation for both people living with dementia and their caregivers, negatively impacting the quality of life for both members of the dyad. The resulting stress and burden on caregivers make them particularly susceptible to burnout.

OBJECTIVE: This study aims to examine the efficacy of Communication Proches Aidants (COMPAs), an app designed following the principles of person-centered and emotional communication, which is intended to improve well-being in persons living with dementia and caregivers and reduce caregiver burden.

METHODS: In this implementation study, volunteer caregivers in 2 long-term care facilities (n=17) were trained in using COMPAs and strategies to improve communication with persons living with dementia. Qualitative and quantitative analyses, semistructured interviews, and questionnaires were completed before and after 8 weeks of intervention with COMPAs.

RESULTS: Semistructured interviews revealed that all caregivers perceived a positive impact following COMPAs interventions, namely, improved quality of communication and quality of life among persons living with dementia and caregivers. Improved quality of life was also supported by a statistically significant reduction in the General Health Questionnaire-12 scores (caregivers who improved: 9/17, 53%; z=2.537; P=.01). COMPAs interventions were also associated with a statistically significant increased feeling of personal accomplishment (caregivers improved: 11/17, 65%; t₁₅=2.430; P=.03; d=0.61 [medium effect size]).

CONCLUSIONS: COMPAs intervention improved well-being in persons living with dementia and their caregivers by developing person-centered communication within the dyad, increasing empathy, and reducing burden in caregivers although most caregivers were unfamiliar with technology. The results hold promise for COMPAs interventions in long-term care settings. Larger group-controlled studies with different populations, in different contexts, and at different stages of dementia will provide a clearer picture of the benefits of COMPAs interventions.

PMID:38963691 | DOI:10.2196/47565

J Occup Rehabil. 2024 Jul 4. doi: 10.1007/s10926-024-10223-w. Online ahead of print.

ABSTRACT

PURPOSE: To develop and validate prediction models for the risk of future work absence and level of presenteeism, in adults seeking primary healthcare with musculoskeletal disorders (MSD).

METHODS: Six studies from the West-Midlands/Northwest regions of England, recruiting adults consulting primary care with MSD were included for model development and internal-external cross-validation (IECV). The primary outcome was any work absence within 6 months of their consultation. Secondary outcomes included 6-month presenteeism and 12-month work absence. Ten candidate predictors were included: age; sex; multisite pain; baseline pain score; pain duration; job type; anxiety/depression; comorbidities; absence in the previous 6 months; and baseline presenteeism.

RESULTS: For the 6-month absence model, 2179 participants (215 absences) were available across five studies. Calibration was promising, although varied across studies, with a pooled calibration slope of 0.93 (95% CI: 0.41-1.46) on IECV. On average, the model discriminated well between those with work absence within 6 months, and those without (IECV-pooled C-statistic 0.76, 95% CI: 0.66-0.86). The 6-month presenteeism model, while well calibrated on average, showed some individual-level variation in predictive accuracy, and the 12-month absence model was poorly calibrated due to the small available size for model development.

CONCLUSIONS: The developed models predict 6-month work absence and presenteeism with reasonable accuracy, on average, in adults consulting with MSD. The model to predict 12-month absence was poorly calibrated and is not yet ready for use in practice. This information may support shared decision-making and targeting occupational health interventions at those with a higher risk of absence or presenteeism in the 6 months following consultation. Further external validation is needed before the models’ use can be recommended or their impact on patients can be fully assessed.

PMID:38963652 | DOI:10.1007/s10926-024-10223-w