bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness
Authors: Meyer Joel N , Pan William K , Ryde Ian T , Alexander Thomas , Klein-Adams Jacquelyn C. , Ndirangu Duncan S. , Falvo Michael J
Published: June 2023

Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit- to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.
Impact of COVID-19 Pandemic on Sleep Including HRV and Physical Activity as Mediators: A Causal ML Approach
Authors: Khatibi Elahe , Abbasian Mahyar , Azimi Iman , Labbaf Sina , Feli Mohammad , Borelli Jessica , Dutt Nikil , Rahmani Amir M.
Published: June 2023

Sleep quality is crucial to both mental and physical well-being. The COVID-19 pandemic, which has notably affected the population’s health worldwide, has been shown to deteriorate people’s sleep quality. Numerous studies have been conducted to evaluate the impact of the COVID-19 pandemic on sleep efficiency, investigating their relationships using correlation-based methods. These methods merely rely on learning spurious correlation rather than the causal relations among variables. Furthermore, they fail to pinpoint potential sources of bias and mediators and envision counterfactual scenarios, leading to a poor estimation. In this paper, we develop a Causal Machine Learning method, which encompasses causal discovery and causal inference components, to extract the causal relations between the COVID-19 pandemic (treatment variable) and sleep quality (outcome) and estimate the causal treatment effect, respectively. We conducted a wearable-based health monitoring study to collect data, including sleep quality, physical activity, and Heart Rate Variability (HRV) from college students before and after the COVID-19 lockdown in March 2020. Our causal discovery component generates a causal graph and pinpoints mediators in the causal model. We incorporate the strongly contributing mediators (i.e., HRV and physical activity) into our causal inference component to estimate the robust, accurate, and explainable causal effect of the pandemic on sleep quality. Finally, we validate our estimation via three refutation analysis techniques. Our experimental results indicate that the pandemic exacerbates college students’ sleep scores by 8%. Our validation results show significant p-values confirming our estimation.
Nothing without connection” – participant perspectives and experiences of mentorship in capacity building in Timor-Leste
Authors: Yan Jennifer , Martins Nelson , Amaral Salvador , Francis Joshua R , Kameniar Barbara , Delany Clare
Published: June 2023

Background

The literature on mentorship approaches to capacity building in global health is limited. Likewise, there are few qualitative studies that describe mentorship in capacity building in global health from the perspective of the mentors and mentees.

Methods

This qualitative study examined the perspectives and experiences of participants involved in a program of health capacity building in Timor-Leste that was based on a side-by-side, in-country mentorship approach. Semi-structured interviews were conducted with 23 participants (including Timorese and Australian mentors, and local Timorese counterparts) from across a range of professional health disciplines, followed by a series of member checking workshops. Findings were reviewed using inductive thematic analysis. Participants were included in review and refinement of themes.

Results

Four major themes were identified: the importance of trust and connection within the mentoring relationship itself; the side-by-side nature of the relationship (akompaña); mentoring in the context of external environmental challenges; and the need for the mentoring relationship to be dynamic and evolving, and aligned to a shared vision and shared goals.

Discussion

The importance of accompaniment (akompaña) as a key element of the mentoring relationship requires further exploration and study. Many activities in global health capacity building remain focused on provision of training, supervision, and supportive supervision of competent task performance. Viewed through a decolonising lens, there is an imperative for global health actors to align with local priorities and goals, and work alongside individuals supporting them in their vision to become independent leaders of their professions. We propose that placing mentoring relationships at the centre of human resource capacity building programs encourages deep and transformative learning, and is more likely to lead to long term, meaningful and sustainable change.
Ventilation heterogeneity is increased in adults exposed to coal mine fire-related PM2.5
Authors: McCrabb Thomas , Borg Brigitte , Gao Caroline X. , Smith Catherine , Brown David , Ikin Jillian , Makar Annie , Lane Tyler , Abramson Michael J. , Thompson Bruce R
Published: June 2023

Background and Objectives

The Hazelwood Health Study was set up to study long term health effects of a mine fire that blanketed residents of the Latrobe Valley with smoke for 45 days in 2014. The Respiratory Stream specifically assessed the impact of fine particulate matter <2.5μm diameter (PM2.5) exposure from mine fire smoke on lung health. The multiple breath nitrogen washout (MBW) test assesses ventilation heterogeneity, which may detect early airways dysfunction not identified using standard tests such as spirometry. This analysis assessed the association of PM2.5exposure with measures of ventilation heterogeneity.

Methods

Exposed (Morwell) and unexposed (Sale) participants were recruited 3.5-4 years after the fire from those who had participated in an Adult Survey. MBW was performed to measure lung clearance index (LCI), functional residual capacity (FRC), acinar (Sacin) and conductive (Scond) ventilation heterogeneity. PM2.5exposure was estimated with emission and chemical transport models. Multivariate linear regression models were fitted controlling for confounders.

Results

We recruited 519 participants. MBW tests were conducted on 504 participants with 479 acceptable test results (40% male; 313 exposed, 166 unexposed). Exposure to mine fire-related PM2.5was associated with increasing Scond (β=2.15/kL, 95%CI: 0.67-3.63, p=0.006), which was comparable to the estimated effect on Scond of 7.9 years of aging. No other MBW outcomes were significant.

Conclusions

Increasing exposure to PM2.5was associated with increased ventilation heterogeneity in the conductive region of the lungs 4 years after the event.
Achieving behavior change at scale: Causal evidence from a national lifestyle intervention program for pre-diabetes in the UK
Authors: Lemp Julia M. , Bommer Christian , Xie Min , Jani Anant , Davies Justine I. , Bärnighausen Till , Vollmer Sebastian , Geldsetzer Pascal
Published: June 2023

There remains widespread doubt among clinicians that mere lifestyle advice and counseling provided in routine care can achieve improvements in health. We aimed to determine the health effects of the largest behavior change program for pre-diabetes globally (the English Diabetes Prevention Programme) when implemented at scale in routine care. We exploited the threshold in glycated hemoglobin (HbA1c) used to decide on program eligibility by applying a regression discontinuity design, one of the most credible quasi-experimental strategies for causal inference, to electronic health data from approximately one-fifth of all primary care practices in England. Program referral led to significant improvements in patients’ HbA1c and body mass index. This analysis provides causal, rather than associational, evidence that lifestyle advice and counseling implemented in a national health system can achieve important health improvements.
Targeting multiphosphorylated tau: technical and clinical validation of a new Simoa® assay for CSF and plasma detection of tau simultaneously phosphorylated at T181 and T231
Authors: Wojdała Anna Lidia , Bellomo Giovanni , Gaetani Lorenzo , Shan Dandan , Parnetti Lucilla , Chiasserini Davide
Published: June 2023

Background and Objectives

Different forms of phosphorylated tau (p-tau) have shown high potential as Alzheimer’s Disease (AD) biomarkers in both cerebrospinal fluid (CSF) and plasma. Hence, we hypothesized that tau peptides showing concomitant phosphorylation at two different sites may provide an increased diagnostic value. We therefore developed and validated a new Simoa® immunoassay detecting tau simultaneously phosphorylated at T181 and T231 (C231D181) in cerebrospinal fluid (CSF) and plasma.

Methods

Technical validation of the C231D181 Simoa® assay included standard curve development, assessment of antibodies cross-reactivity, dilutional linearity, sensitivity, as well as intra- and inter-assay precision. Subsequently, we measured CSF C231D181, p-tau181, and p-tau231 in two cohorts: discovery (MCI-AD n=21, AD dementia n=19, CTRL n=15) and validation (preclinical AD n=19, MCI-AD n=20, AD dementia n=16, frontotemporal dementia n=39, CTRL n=24). Additionally, in the discovery cohort, C231D181, p-tau181, and p-tau231 levels were measured in matched plasma samples.

Results

Specificity of the assay was assessed using a synthetic peptide simultaneously phosphorylated at T181 and T231, while cross-reactivity was excluded with a mix of single-site phosphorylated peptides (T181 or T231). Both in discovery and validation cohorts, CSF C231D181, p-tau181, and p-tau231 levels were significantly elevated in all AD groups vs. CTRL. As assessed in discovery cohort, plasma p-tau231 and p-tau181 levels enabled effective discrimination of AD continuum groups from CTRL (AUC plasma p-tau231: CTRL vs. MCI-AD=0.925, CTRL vs. AD-dem=0.947; AUC plasma p-tau181: CTRL vs. MCI-AD=0.877, CTRL vs. AD-dem=0.943) while plasma C231D181 did not change among clinical groups.

Discussion

A new ultrasensitive immunoassay detecting tau simultaneously phosphorylated at T181 and T231 was developed and validated. While we found this phosphorylated tau form to be significantly elevated across the AD continuum in CSF, in plasma it did not show changes among the diagnostic groups. The differences between CSF and plasma suggest matrix-specific protein processing. Our findings support evidence for qualitative and quantitative importance of tau phosphorylation across AD continuum and warrant further investigation, including assessment of tau simultaneously phosphorylated at multiple sites.
Poor immunogenicity upon SARS-CoV-2 mRNA vaccinations in autoimmune SLE patients is associated with pronounced EF-mediated responses and anti-BAFF/Belimumab treatment
Authors: Faliti Caterina E. , Anam Fabliha A. , Cheedarla Narayanaiah , Woodruff Matthew C. , Usman Sabeena Y. , Runnstrom Martin C. , Van Trinh T.P. , Kyu Shuya , Ahmed Hasan , Morrison-Porter Andrea , Quehl Hannah , Haddad Natalie S. , Chen Weirong , Cheedarla Suneethamma , Neish Andrew S. , Roback John D. , Antia Rustom , Khosroshahi Arezou , Lee F. Eun-Hyung , Sanz Ignacio
Published: June 2023

Novel mRNA vaccines have resulted in a reduced number of SARS-CoV-2 infections and hospitalizations. Yet, there is a paucity of studies regarding their effectiveness on immunocompromised autoimmune subjects. In this study, we enrolled subjects naïve to SARS-CoV-2 infections from two cohorts of healthy donors (HD, n=56) and systemic lupus erythematosus (SLE, n=69). Serological assessments of their circulating antibodies revealed a significant reduction of potency and breadth of neutralization in the SLE group, only partially rescued by a 3rdbooster dose. Immunological memory responses in the SLE cohort were characterized by a reduced magnitude of spike-reactive B and T cell responses that were strongly associated with poor seroconversion.

Vaccinated SLE subjects were defined by a distinct expansion and persistence of a DN2 spike-reactive memory B cell pool and a contraction of spike-specific memory cTfh cells, contrasting with the sustained germinal center (GC)-driven activity mediated by mRNA vaccination in the healthy population. Among the SLE-associated factors that dampened the vaccine responses, treatment with the monoclonal antibody anti-BAFF/Belimumab (a lupus FDA-approved B cell targeting agent) profoundly affected the vaccine responsiveness by restricting thede novoB cell responses and promoting stronger extra-follicular (EF)-mediated responses that were associated with poor immunogenicity and impaired immunological memory.

In summary, this study interrogates antigen-specific responses and characterized the immune cell landscape associated with mRNA vaccination in SLE. The identification of factors associated with reduced vaccine efficacy illustrates the impact of SLE B cell biology on mRNA vaccine responses and provides guidance for the management of boosters and recall vaccinations in SLE patients according to their disease endotype and modality of treatment.
Loneliness Forecasting Using Multi-modal Wearable and Mobile Sensing in Everyday Settings
Authors: Yang Zhongqi , Azimi Iman , Jafarlou Salar , Labbaf Sina , Borelli Jessica , Dutt Nikil , Rahmani Amir M.
Published: June 2023

The adverse effects of loneliness on both physical and mental well-being are profound. Although previous research has utilized mobile sensing techniques to detect mental health issues, few studies have utilized state-of-the-art wearable devices to forecast loneliness and comprehend the physiological manifestations of loneliness and its predictive nature. The primary objective of this study is to examine the feasibility of forecasting loneliness by employing wearable devices, such as smart rings and watches, to monitor early physiological indicators of loneliness. Furthermore, smartphones are employed to capture initial behavioral signs of loneliness. To accomplish this, we employed personalized machine learning techniques, leveraging a comprehensive dataset comprising physiological and behavioral information obtained during our study involving the monitoring of college students. Through the development of personalized models, we achieved a notable accuracy of 0.82 and an F-1 score of 0.82 in forecasting loneliness levels seven days in advance. Additionally, the application of Shapley values facilitated model explainability. The wealth of data provided by this study, coupled with the forecasting methodology employed, possesses the potential to augment interventions and facilitate the early identification of loneliness within populations at risk.
Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos
Authors: Jeon Soyoung , Lo Ying Chu , Morimoto Libby M. , Metayer Catherine , Ma Xiaomei , Wiemels Joseph L. , de Smith Adam J. , Chiang Charleston W.K.
Published: June 2023

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWAS), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study we constructed and evaluated genomic PRS models based on either non-Latino white (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR2= 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR2= 0.116 ± 0.026) or multi-ancestry samples (PseudoR2= 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR2= 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWAS may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligo-genic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.
The Genetic Architecture of Biological Age in Nine Human Organ Systems
Authors: Wen Junhao , Tian Ye Ella , Skampardoni Ioanna , Yang Zhijian , Cui Yuhan , Anagnostakis Filippos , Mamourian Elizabeth , Zhao Bingxin , Toga Arthur W. , Zaleskey Andrew , Davatzikos Christos
Published: June 2023

Understanding the genetic basis of biological aging in multi-organ systems is vital for elucidating age-related disease mechanisms and identifying therapeutic interventions. This study characterized the genetic architecture of the biological age gap (BAG) across nine human organ systems in 377,028 individuals of European ancestry from the UK Biobank. We discovered 393 genomic loci-BAG pairs (P-value<5×10-8) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We observed BAG-organ specificity and inter-organ connections. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system while exerting pleiotropic effects on traits linked to multiple organ systems. A gene-drug-disease network confirmed the involvement of the metabolic BAG-associated genes in drugs targeting various metabolic disorders. Genetic correlation analyses supported Cheverud’s Conjecture1– the genetic correlation between BAGs mirrors their phenotypic correlation. A causal network revealed potential causal effects linking chronic diseases (e.g., Alzheimer’s disease), body weight, and sleep duration to the BAG of multiple organ systems. Our findings shed light on promising therapeutic interventions to enhance human organ health within a complex multi-organ network, including lifestyle modifications and potential drug repositioning strategies for treating chronic diseases. All results are publicly available athttps://labs-laboratory.com/medicine.
Kinematic signature of high-risk labored breathing revealed by novel signal analysis
Authors: Ashe William B. , McNamara Brendan D. , Patel Swet M. , Shanno Julia N. , Innis Sarah E. , Hochheimer Camille J. , Barros Andrew J. , Williams Ronald D. , Ratcliffe Sarah J. , Moorman J. Randall , Gadrey Shrirang M.
Published: June 2023

Breathing patterns (respiratory kinematics) contain vital prognostic information. They report on a dimension of physiology that is not captured by conventional vital signs. But for an informative physiomarker to become clinically valuable, it must be measureable with ease, accuracy, and reproducibility. We sought to enable the quantitative characterization of respiratory kinematics at the bedside. Using inertial sensors, we analyzed upper rib, lower rib, and abdominal motion of 108 patients with respiratory symptoms during a hospital encounter (582 two-minute recordings). We measured the average respiratory rate and 33 other signal characteristics that had an explainable correspondence with clinically significant breathing patterns. K-means clustering revealed that the respiratory kinematic information was optimally represented by adding 3 novel measures to the average respiratory rate. We selected measures representing respiratory rate variability, respiratory alternans (rib-predominant breaths alternating with abdomen-predominant ones), and recruitment of accessory muscles (increased upper rib excursion). Latent profile analysis of these measures revealed a phenotype consistent with labored breathing. Poisson regression showed that the rate at which a patient’s recordings exhibited the labored breathing phenotype was significantly associated (p<0.01) with the severity of illness (discharge home v/s acute-care hospitalization v/s critical-care hospitalization). Notably, labored breathing was frequently detectable (21%) when the respiratory rate was normal, and it improved discrimination for critical illness. These findings validate the feasibility of respiratory kinematic phenotyping in routine healthcare settings, and demonstrate its clinical value. Further research into respiratory kinematic characteristics may reveal novel pathophysiologic mechanisms, advance the efficacy of predictive analytics, and enhance patient safety.
Long-term Air Pollution Exposure are Associated with Higher Incidence of ST-elevation Myocardial Infarction and In-hospital Cardiogenic Shock
Authors: Cha Jinah , Choi Se Yeon , Rha Seung-Woon , Choi Byoung Geol , Byun Jae Kyeong , Hyun Sujin , Lee Min Woo , Kang Jaeho , Chu Wonsang , Park Soohyung , Park Eun Jin , Kang Dong Oh , Choi Cheol Ung , Kim Suhng Wook , Jeong Myung ho ,   the other Korea Acute Myocardial Infarction Registry (KAMIR) investigators
Published: June 2023

Background

Previous studies have reported the association between myocardial infarction (MI) and air pollution (AP). However, limited information is available regarding the long-term effects of AP on the relative incidence rates of ST-elevation MI (STEMI) and Non-ST-elevation MI (NSTEMI).

Methods

Study subjects were enrolled from the Korea Acute MI registry (KAMIR) and KAMIR-National Institutes of Health (NIH). A total of 45,619 eligible patients with AMI were enrolled between January 2006 and December 2015. We investigated the association between long-term exposure to AP and compared the incidence of STEMI with those of NSTEMI. Mixed-effect regression models were used to examine the association between the annual average ambient AP before MI onset and the incidence of STEMI compared with that of NSTEMI, and to evaluate the association of AP with the incidence of in-hospital cardiogenic shock.

Results

After mixed-effect regression model analysis, each 1 μg/m3increase in particulate matter (PM) 10 µm or less in diameter (PM10) was associated with increased incidence of STEMI compared with NSTEMI (odds ratio [OR]:1.009, 95% Confidence Interval [CI]: 1.002–1.016; p = 0.012). For in-hospital cardiogenic shock complication, each 1 μg/m3increase in PM10and 1 part per billion increase in SO2were associated with increased risk, PM10(OR:1.033, 95% CI, 1.018–1.050; p < 0.001), SO2(OR:1.104, 95% CI, 1.006–1.212; p = 0.037), respectively.

Conclusion

A high concentration of air pollutants, particularly PM10,was an environmental risk factor for an increase incidence of development of STEMI. PM10and SO2were found to be risk factors for in-hospital cardiogenic shock complications. Policy-level strategies and clinical efforts to reduce AP exposure are necessary to prevent the incidence of STEMI and severe cardiovascular complications.
Late presenter thrombolysis for ischemic stroke between 4.5-24 hours after last known well: a retrospective cohort study
Authors: Leung Lester Y. , Zebelean Devin , Melkumova Emiliya , Skeels Katelyn , Madan Neel , Thaler David E.
Published: June 2023

Background

Two RCTs demonstrated efficacy and safety of IV alteplase for patients with acute ischemic stroke (AIS) who awaken with symptoms or with last known well (LKW) more than 4.5 hours prior to arrival. However, real world experience using CT perfusion (CTP) or DWI-MRI for patient selection in the U.S. is limited. We developed the Tufts Late Presenter Thrombolysis (LPT) protocol to offer alteplase to patients with wakeup stroke, known LKW more than 4.5 hours, or unknown LKW likely more than 4.5 hours and less than 24 hours, using CTP or DWI-MRI to aid patient selection.

Methods

We reviewed ED stroke codes from our Comprehensive Stroke Center between 1/1/20-12/31/22 to identify patients treated with alteplase. Data were collected on demographics, comorbidities, LKW-to-treatment time (LTT), imaging modality, imaging findings, NIHSS, vessel occlusions, endovascular therapy (EVT), symptomatic ICH, and 90 days mRS. Outcomes for comparative analyses included process times (door to needle, door to CT) and clinical outcomes (90 day mRS, symptomatic ICH).

Results

Forty-three of 118 patients (36%) presenting with AIS and treated with thrombolysis were treated between 4.5-24 hours after LKW. Patients treated in the 4.5 hour window and the later window had similar demographics, comorbidities, NIHSS, and EVT rates. CTP was used in the majority of LPT cases. The median penumbra was 45.04 mL (11.55-83.21), and the median core infarct was 5.92 mL (1.89-16.7). Symptomatic intracranial hemorrhage occurred in one LPT case (2.3%). Favorable mRS (0-1) was achieved by 36% of LPT patients with documented 90 day mRS.

Conclusions

A pragmatic protocol offering thrombolysis to late presenters may be safe and achieve favorable outcomes.
Echocardiographic Evaluation of Spironolactone on Myocardial Remodeling in Atrial Fibrillation with Preserved Ejection Fraction: the INSPIRE-AF randomized controlled trial
Authors: Rujic Dragana , Schou Morten , Madsen Per Lav , Egstrup Kenneth
Published: June 2023

Background

By means of echocardiographic assessment and deformation analysis we sought to evaluate the effect of spironolactone versus placebo in addition to standard treatment in patients with paroxysmal or persistent atrial fibrillation (AF) and preserved ejection fraction regarding the performance of the left atrium (LA) and the left ventricle (LV), and quality of life (QOL).

Methods

Present double-blind, placebo-controlled study enrolled 125 patients with a history of paroxysmal (n=58) and persistent (n=67) non-valvular AF and LVEF ≥45% that were randomized to spironolactone 25 mg (n=63) or placebo (n=62) once daily in addition to optimal standard treatment. Comprehensive echocardiography and QOL were obtained at inclusion and after 12 months. The primary outcome was 12-month change in LA reservoir function as assessed by peak atrial longitudinal strain (PALS) and peak strain rate (SR-s). Secondary outcomes included LA phasic volumes, global longitudinal strain of left ventricle (GLS), E/e’ ratio, QOL, and recurrent documented episodes of AF.

Results

Spironolactone improved the LA reservoir function documented by PALS and SR-s (P =0.03 and P =0.02 for adjusted treatment effect, respectively) but only when adjusting for the parallel changes in blood pressure. Blood pressure significantly reduced in the spironolactone-treated subjects and affected primary outcomes, but not diastolic indices of LV. Transmitral E velocity and E/e’ ratio reduced significantly by spironolactone (P=0.009 for adjusted treatment effect). No differences in secondary outcome parameters were found across treatment groups including volumes, LA geometry, GLS, total number AF recurrences, time-to-first AF recurrence or QOL.

Conclusion

Spironolactone improved left atrial reservoir function by lowering blood pressure and decrease E/e’ ratio but did not affect left atrial volumes or geometry, quality of life or recurrent episodes of atrial fibrillation.

Trial registration:ClinicalTrials.org identifierNCT02764619and EudraCT identifier 2013-000797-30.
Exploring patient-, provider-, and health facility-level determinants of blood pressure among patients with hypertension: A multicenter study in Ghana
Authors: Byiringiro Samuel , Hinneh Thomas , Commodore-Mensah Yvonne , Masteller Jill , Sarfo Fred Stephen , Perrin Nancy , Assibey Shadrack , Himmelfarb Cheryl R.
Published: June 2023

Optimal blood pressure (BP) control is essential in averting cardiovascular disease and associated complications. Multi-level factors influence the achievement of BP targets in hypertension management. We explored patient-, provider-, and health facility-level factors of systolic and diastolic BP and controlled BP status among patients with hypertension in Ghana, where the burden of hypertension and cardiovascular disease is rising. Using a cross-sectional design, we recruited 15 health facilities, and from each facility, four healthcare professionals who managed patients with hypertension and 15 patients diagnosed with hypertension. The primary outcome of interest was systolic and diastolic BP; the secondary outcome was BP control (<140/90 mmHg) in compliance with Ghana’s national standard treatment guidelines. We used mixed-effects regression models to explore the patient- and facility-level predictors of the outcomes. From the 15 health facilities, we recruited 67 healthcare providers with a mean (SD) age of 32 (7) and 224 patients with a mean (SD) age of 60.5 (12.7). Most (182 [81%]) of the patient participants were female, and almost half (109 [49%]) had controlled BP. At the patient level, secondary school education (Coeff.:-7.69, 95% CI: -15.13, -0.26) was associated with lower systolic BP than a lower level of education; and traveling for 30 minutes to 1 hour to the health facility was associated with higher diastolic BP (Coeff.:3.75, 95% CI: 0.12, 7.38) and lower odds of BP control (OR: 0.51, 95% CI: 0.28, 0.92) than traveling less than 30 minutes. Receiving care at government health facilities was associated with less systolic BP (Coeff.: - 19.4; 95% CI: -33.58, -5.22) than private health facilities. A higher patient-to-physician or physician assistant ratio was associated with more elevated systolic BP (Coeff.: 23.06, 95% CI: 10.06, 36.05) and lower odds of controlled BP (OR: 0.18, 95% CI: 0.05, 0.74). Further research is warranted to identify effective strategies to address the multi-level factors influencing hypertension control and to mitigate the rising burden of hypertension in Ghana.
Assessment of relationship between Google Trend search data on clinical symptoms and cases reported during the first wave of COVID-19 outbreak in India
Authors: Vavilala Hariprasad , Mopuri Rajasekhar , Mutheneni Srinivasa Rao
Published: June 2023

Infodemiology and infoveillance approaches have been extensively used in recent years to support traditional epidemiology and disease surveillance. Hence, the present study aimed to explore the association between Google Trends (GTs) search of clinical symptoms and cases reported during the first wave of COVID-19. The GT data from January 30, 2020, to September 30, 2020, and daily COVID-19 cases in India and a few selected states were collected from the Ministry of Health and Family Welfare, Government of India. Correlation analysis was performed between the GT index values and the number of confirmed cases. Followed by, the COVID-19 cases were predicted using Bayesian regression and classical linear regression models. A strong association was observed between the search index of clinical symptoms and reported COVID-19 cases (cold: R=0.41, headache: R=0.46, fever: R=0.66, loss of taste: R=0.78, loss of smell R=0.86) across India. Similarly, lagged correlations were also observed (loss of smell, loss of taste, loss of taste and loss of smell, fever and headache show 3, 9, 1, 9, and 13 days lag periods respectively). Besides this, the Bayesian regression model was outperformed (MAE: 0.331164, RMSE: 0.411087) for predicting the COVID-19 cases in India and regionally than the frequentist linear regression (MAE: 0.33134, RMSE: 0.411316). The study helps health authorities better prepare and planning of health care facility timely to avoid adverse impacts.
Naked-Eye Detection of LAMP-Produced Nucleic Acids in Saliva using Chitosan-capped AuNPs in a Single-Tube Assay
Authors: Grammatikos Stylianos , Svoliantopoulos Ioannis , Gizeli Electra
Published: June 2023

Loop-mediated isothermal amplification (LAMP) is a low-technology molecular assay highly adaptable to point-of-care (POC) applications. However, achieving sensitive naked-eye detection of the amplified target in a crude sample is challenging. Herein, we report a simple, yet highly efficient and sensitive methodology for the colorimetric visualization of a single target copy in saliva, using chitosan-capped gold nanoparticles (Chit-AuNPs) synthesized via a green chemistry approach. The presence or absence of free Chit in the Chit-AuNPs solution was shown to affect LAMP colorimetric detection oppositely: the observed stabilization in the negative samples and aggregation in the positive samples in the presence of free Chit was reversed in the case of neat Chit-AuNPs. The mechanism of the two assays was investigated and attributed to electrostatic and depletion effects exerted between the Chit-AuNPs, free Chit and the solution components. The developed contamination-free, one-tube assay successfully amplified and detected down to 1-5 cfu ofSalmonellaand 10 copies of SARS-CoV-2 per reaction (25 μL) in the presence of 20% saliva, making the method suitable for POC applications. Compared to the commonly used pH sensitive dyes, Chit-AuNPs are shown to have an enhanced sensitivity toward the naked-eye colorimetric observation owing to the direct detection of DNA amplicons. Thus, this is a simple, highly sensitive, fast and versatile naked-eye detection methodology that could be coupled to any LAMP or RT-LAMP assay, avoiding the need of using complicated sample pretreatments and/or AuNPs long and laborious functionalization processes.

Abstract Figure
SARS-CoV-2 seroprevalence in pregnant women during the first three COVID-19 waves in The Gambia
Authors: Janha Ramatoulie E. , Bah Alasana , Jah Hawanatu , Touray Fatima , Idris Yahaya , Keita Saikou , Gaye Yassin , Jallow Samba , Faye-Joof Tisbeh , Njie Baboucarr , Craik Rachel , Mohammed Nuredin I. , von Dadelszen Peter , D’Alessandro Umberto , Roca Anna ,   the PRECISE Network
Published: June 2023

Objectives

SARS-CoV-2 transmission in Sub-Saharan Africa has probably been underestimated. Population-based seroprevalence studies are needed to determine the extent of transmission in the continent.

Methods

Blood samples from a cohort of Gambian pregnant women were tested for SARS-CoV-2 total IgM/IgG before (Pre-pandemic1:October-December 2019 andPre-pandemic2:February-June 2020) and during the pandemic (Post-wave1: October-December 2020,Post-wave2:May-June 2021; andPost-wave3: October-December 2021). Samples positive for total SARS-CoV-2 IgM/IgG were tested for protein-specific antibodies.

Results

SARS-CoV-2 total IgM/IgG seroprevalence was 0.9% 95%CI (0.2, 4.9) inPre-pandemic1; 4.1% (1.4, 11.4) inPre-pandemic2; 31.1% (25.2, 37.7) inPost-wave1; 62.5% (55.8, 68.8) inPost-wave2and 90.0% (85.1, 93.5) inPost-wave3.S-protein IgG and NCP-protein IgG seroprevalence also increased at eachPost-waveperiod. Although S-protein IgG and NCP-protein IgG seroprevalence was similar atPost-wave1, S-protein IgG seroprevalence was higher atPost-wave2andPost-wave3, [prevalence difference (PD) 13.5 (0.1, 26.8) and prevalence ratio (PR) 1.5 (1.0, 2.3) inPost-wave2; and 22.9 (9.2, 36.6) and 1.4 (1.1, 1.8) inPost-wave3respectively, p<0.001].

Conclusion

SARS-CoV-2 transmission in The Gambia during the first three COVID-19 waves was high, differing significantly from official numbers of COVID-19 cases reported. Our findings are important for policy makers in managing the near-endemic COVID-19.

Highlights

High specificity of the IgM/IgG SARS-CoV-2 test using samples collected prepandemic

Very high (>90%) SARS-CoV-2 seroprevalence after third COVID-19 wave in The Gambia

High SARS-CoV-2 transmission contrasts with low number of COVID-19 reported cases
Trends in medication use after the onset of the COVID-19 pandemic in the Republic of Ireland: an interrupted time series study
Authors: Mattsson Molly , Hong Jung Ah , Frazer John Scott , Frazer Glenn Ross , Moriarty Frank
Published: June 2023

The COVID-19 pandemic had a substantial impact on healthcare delivery, particularly in general practice. This study aimed to evaluate how dispensing of medications in primary care in Ireland changed following the COVID-19 pandemic’s onset compared to expected trends. This interrupted time series study used data on medications prescribed in general practice 2016-2022 to patient eligible for state health cover, approximately one third of the population. Dispensing volumes for all therapeutic subgroups (ATC2 codes) and commonly dispensed medications were summarised. Pre-pandemic data was used to forecast expected trends (with 99% prediction intervals) using the Holt-Winters method, and these were compared to observed dispensing from March 2020 onwards. Most (31/77) therapeutic subgroups had dispensing significantly different from forecast in March 2020. Drugs for obstructive airway disease had the largest difference, with dispensing 26.2% (99%CI 19.5%-33.6%) higher than forecasted. Only two subgroups were significantly lower than forecasted, other gynaecologicals (17.7% lower, 99%CI 6.3%-26.6%) and dressings (11.6%, 99%CI 9.4%-41.6%). Dispensing of amoxicillin products and oral prednisolone were lower than forecasted in the months following the pandemic’s onset, particularly during winter 2020/2021. There was a spike in dispensing for many long-term medications in March 2020, while pandemic restrictions likely contributed to reductions for other medications.
Establishing Fully-Automated Fundus-Controlled Dark Adaptometry: A Validation and Retest-Reliability Study
Authors: Oertli Jeannine , Pfau Kristina , Scholl Hendrik P.N. , Jeffrey Brett G. , Pfau Maximilian
Published: June 2023

Purpose

To establish and validate a novel fundus-controlled dark-adaptometry method.

Methods

We developed a custom dark-adaptometry software for the S-MAIA device using the open perimetry interface. In the validation-substudy, participants underwent dark-adaptometry testing with a comparator device (MonCvONE, 59% rhodopsin bleach, cyan and red stimuli centered at 2°, 4°, and 6° eccentricity). Following a brief break (approx. 5 min), the participants were bleached again and underwent dark-adaptometry testing with the S-MAIA device (same loci). In the retest reliability-substudy, participants were tested twice with the S-MAIA device (same loci as above).

Nonlinear curve fitting was applied to extract dark-adaptation curve parameters. Validity and repeatability were summarized in terms of the mean bias and 95% limits of agreement (LoAs).

Results

In the validation-substudy (N=20 participants, median age [IQR] 31.5 years [25.8, 62.0]), measures of rod-mediated dark-adaptation showed little to no between method differences for the cone-rod-break-time (bias [95% CI] of +0.09 min [-0.5, 0.67]), rod-intercept-time (+0.42 min [-0.51, 1.35]), and S2 slope (-0.03 LogUnits/min [-0.04, -0.02]).

In the retest reliability-substudy (N=10 participants, 32.0 years [27.0, 57.5]), the corresponding LoAs were (cone-rod-break-time) -3.01 to 2.02 min, (rod-intercept-time) -3.95 to 2.94min, and (S2 slope) -0.09 to 0.07 LogUnits/min. The LoAs for the steady-state cone and rod thresholds were -0.27 to 0.31 LogUnits and -0.32 to 0.27 LogUnits.

Conclusions

The devised fundus-controlled dark-adaptometry method yields valid and reliable results. Fundus-controlled dark-adaptometry solves the critical need for localized testing of the visual cycle in eyes with unstable fixation (e.g., in the setting of subretinal gene therapy).
Apolipoprotein E moderates the association between Non-APOEPolygenic Risk Score for Alzheimer’s Disease and Aging on Preclinical Cognitive Function
Authors: Xu Yuexuan , Sun Zhongxuan , Jonaitis Erin , Deming Yuetiva , Lu Qiongshi , Johnson Sterling C. , Engelman Corinne D.
Published: June 2023

INTRODUCTION

Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer’s disease (e.g., a non-APOEpolygenic risk scores [PRS]) may interact with theAPOEε4 allele to influence cognitive decline.

METHODS

We tested the PRSξAPOEε4ξage interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1,190 individuals.

RESULTS

We found statistically significant PRSξAPOEε4ξage interactions on immediate learning (P=0.038), delayed recall (P<0.001), and Preclinical Alzheimer’s Cognitive Composite 3 score (P=0.026). PRS-related differences in overall and memory-related cognitive domains between people with and withoutAPOEε4 emerge around age 70, with a much stronger adverse PRS effect amongAPOEε4 carriers. The findings were replicated in a population-based cohort.

DISCUSSION

APOEε4 can modify the association between PRS and cognition decline.

Highlights

APOEε4 can modify the association between PRS and longitudinal cognition decline, with the modifying effects more pronounced when the PRS is constructed using a conservativeP-threshold (e.g.,P< 5e-8).

The adverse genetic effect caused by the combined effect of the currently known genetic variants is more detrimental amongAPOEε4 carriers around age 70.

Individuals who areAPOEε4 carriers with high PRS are the most vulnerable to the harmful effects caused by genetic burden.
Comparison of incidence and prognosis of myocardial injury in patients with COVID-19-related respiratory failure and other pulmonary infections: a contemporary cohort study
Authors: Vivan Manoela Astolfi , Hirakata Vania Naomi , Arteche Maria Antônia Torres , Araujo Débora Marques de , Fuchs Sandra Cristina Pereira Costa , Fuchs Flávio Danni
Published: June 2023

Background

Myocardial injury (MI) is frequent in critically ill patients with COVID-19, but its pathogenesis remains unclear. We hypothesized that MI is not solely due to viral infection by SARS-CoV-2, but rather due to the common pathophysiological mechanisms associated with severe pulmonary infections and respiratory failure.

Methods

Contemporary and comparative cohort study designed to compare the incidence of MI in patients with acute respiratory failure caused by COVID-19 to that of patients with other pulmonary infections. In addition, we aim to investigate whether MI is a distinct risk factor for in-hospital mortality in patients with COVID-19-related respiratory failure compared to those with non-COVID-19 infections.

Results

The study included 1444 patients with COVID-19 [55.5% men; age 58 (46;68) years] and 182 patients with other pulmonary infections [46.9% men; age 62 (44;73) years]. The incidence of MI at ICU admission was lower in COVID-19 patients (36.4%) compared to non-COVID-19 patients (56%), and this difference persisted after adjusting for age, sex, coronary artery disease, heart failure, SOFA score, lactate, and C-reactive protein [RR 0.84 (95% CI, 0.71-0.99)]. MI at ICU admission was associated with a 59% increase in mortality [RR 1.59 (1.36-1.86); P<0.001], and there was no significant difference in the mortality between patients with COVID-19 and those with other pulmonary infections (P=0.271).

Conclusion

Myocardial injury is less frequent in patients with critical COVID-19 pneumonia and respiratory failure compared to those with other types of pneumonia. The occurrence of MI is a significant risk factor for in-hospital mortality, regardless of the etiology of the pulmonary infection.
Photoperiod regulates gonadotrope cell division in medaka via melatonin, Tsh and folliculostellate cells
Authors: Royan Muhammad Rahmad , Hodne Kjetil , Nourizadeh-lillabadi Rasoul , Weltzien Finn-Arne , Henkel Christiaan V. , Fontaine Romain
Published: June 2023

In vertebrates, pituitary gonadotropins (follicle-stimulating and luteinizing hormones: FSH and LH) regulate gonadal development and maturation, therefore playing an essential role in reproduction. The seasonal regulation of gonadotropins has been widely studied in mammals and birds, and in these taxa thyroid-stimulating hormone (TSH) was found to play a critical role. By contrast, the seasonal regulation of gonadotropins remains unclear in teleost fish. In addition, the seasonal regulation of gonadotrope (gonadotropin-producing cell) proliferation has not been elucidated in any vertebrate group. Using the teleost fish medaka as a model, we show for the first time that long photoperiod enables reproduction by stimulating gonadotropin mRNA synthesis and gonadotrope cell proliferation. In female medaka, this proliferation is achieved by gonadotrope mitosis. We then demonstrate that in female medaka, photoperiod stimulates gonadotropin mRNA production and mitosis via an indirect intra-pituitary pathway, involving pituitary Tsh cells. We show that non-endocrine folliculostellate cells in the pituitary mediate the Tsh signal regulating gonadotrope activity and proliferation, as they are the only pituitary cells to express Tsh receptors and send projections to gonadotropes. Finally, we show that melatonin suppresses pituitarytshbaexpression in fish exposed to long photoperiod, suggesting that short photoperiod inhibits gonadotropin synthesis via melatonin in both fish and mammals. This study therefore demonstrates that in fish, photoperiod regulates gonadotrope cell activity and mitosis via a melatonin-Tsh pathway. It also reveals the existence of a novel intra-pituitary pathway for seasonal regulation of gonadotropes, involving folliculostellate cells, which we propose might also exist in other vertebrates.

SIGNIFICANCE

In seasonally breeding mammals and birds, the production of the hormones that regulate reproduction (gonadotropins) by gonadotropes is controlled by the pituitary thyroid-stimulating hormone (TSH) through an indirect pathway via the brain. However, in fish, how seasonal environmental signals influence gonadotropins remains unclear. Here, we show that in a long day seasonally breeding fish, medaka, photoperiod not only regulates the activity (hormone production) of the gonadotropes but also their proliferation. We also reveal a novel intra-pituitary pathway that regulates gonadotrope cell activity and number. This pathway involves melatonin, Tsh, and folliculostellate cells. Interestingly, as all these components are also found in the mammalian pituitary, this study suggests the existence of an alternative regulatory mechanism of seasonal gonadotropin production across vertebrates.