bluuebunny/crossref_metadata_2025 huggingface dataset:
Parastomal Hernia Following Ileal Conduit
Authors: Che Xinyan , Huang Haiwen , Wang Wei , Zhong Lijun , Yu Shuhui , Huang Yanbo , Xi Zhijun
Published: March 2024

PURPOSE:

The purpose of this study was to measure the incidence of parastomal hernia (PH) after radical cystectomy and ileal conduit. Secondary aims were the identification of risk factors for PH and to compare the health-related quality of life (QOL) between patients with and without PH.

DESIGN:

Retrospective review of medical records combined with cross-sectional administration of the QOL instrument and telephone follow-up.

SUBJECTS AND SETTING:

The study sample comprised 219 patients who underwent radical cystectomy and ileal conduit for urothelial cancer between February 2014 and December 2018. The study setting was Peking University First Hospital (Beijing, China).

METHODS:

Demographic and pertinent clinical data, including development of PH, were gathered via the retrospective review of medical records. Participants were also asked to complete the traditional Chinese language version of the City of Hope Quality of Life-Ostomy Questionnaire (C-COH). Multiple linear regression analysis was used to identify the effect of PH on C-COH scores. Logistic regression analysis was used to identify risk factors for PH development.

RESULTS:

At a median follow-up of 34 months (IQR = 21-48), 43 of 219 (19.63%) patients had developed a PH. A body mass index (BMI) indicating overweight (OR = 3.548; 95% CI, 1.562-8.061; P = .002), a prior history of hernia (OR = 5.147; 95% CI, 1.195-22.159; P = .028), and chronic high abdominal pressure postdischarge (CHAP-pd) (OR = 3.197; 95% CI, 1.445-7.075; P = .004) were predictors of PH after operation. There was no significant difference between C-COH scores of patients with or without PH. No significant differences were found when participants with PH were compared to those without PH on 4 factors of the C-COH: physical scores (β= .347, P = .110), psychological scores (β= .316, P = .070), spiritual scores (β=−.125, P = .714), and social scores (β= .054, P = .833).

CONCLUSION:

Parastomal hernia is prevalent in patients undergoing radical cystectomy and ileal conduit urinary diversion. Overweight, hernia history, and CHAP-pd were predictors of PH development. No significant differences in QOL were found when patients with PH were compared to those without PH.
Postoperative Opioid Prescribing via Rule-Based Guidelines Derived from In-Hospital Consumption: An Assessment of Efficacy Based on Postdischarge Opioid Use
Authors: Beaulieu-Jones Brendin R , Berrigan Margaret T , Marwaha Jayson S , Robinson Kortney A , Nathanson Larry A , Fleishman Aaron , Brat Gabriel A
Published: March 2024

BACKGROUND:

Many institutions have developed operation-specific guidelines for opioid prescribing. These guidelines rarely incorporate in-hospital opioid consumption, which is highly correlated with consumption. We compare outcomes of several patient-centered approaches to prescribing that are derived from in-hospital consumption, including several experimental, rule-based prescribing guidelines and our current institutional guideline.

STUDY DESIGN:

We performed a retrospective, cohort study of all adults undergoing surgery at a single-academic medical center. Several rule-based guidelines, derived from in-hospital consumption (quantity of opioids consumed within 24 hours of discharge), were used to specify the theoretical quantity of opioid prescribed on discharge. The efficacy of the experimental guidelines was compared with 3 references: an approximation of our institution’s tailored prescribing guideline; prescribing all patients the typical quantity of opioids consumed for patients undergoing the same operation; and a representative rule-based, tiered framework. For each scenario, we calculated the penalized residual sum of squares (reflecting the composite deviation from actual patient consumption, with 15% penalty for overprescribing) and the proportion of opioids consumed relative to prescribed.

RESULTS:

A total of 1,048 patients met inclusion criteria. Mean (SD) and median (interquartile range [IQR]) quantity of opioids consumed within 24 hours of discharge were 11.2 (26.9) morphine milligram equivalents and 0 (0 to 15) morphine milligram equivalents. Median (IQR) postdischarge consumption was 16 (0 to 150) morphine milligram equivalents. Our institutional guideline and the previously validated rule-based guideline outperform alternate approaches, with median (IQR) differences in prescribed vs consumed opioids of 0 (−60 to 27.25) and 37.5 (−37.5 to 37.5), respectively, corresponding to penalized residual sum of squares of 39,817,602 and 38,336,895, respectively.

CONCLUSIONS:

Rather than relying on fixed quantities for defined operations, rule-based guidelines offer a simple yet effective method for tailoring opioid prescribing to in-hospital consumption.
Longitudinal Adaptive Behavioral Outcomes in Ogden Syndrome by Seizure Status and Therapeutic Intervention
Authors: Makwana Rikhil , Christ Carolina , Marchi Elaine , Harpell Randie , Lyon Gholson J.
Published: March 2024

Ogden syndrome, also known as NAA10-related neurodevelopmental syndrome, is a rare genetic condition associated with pathogenic variants in the NAA10 N-terminal acetylation family of proteins. The condition was initially described in 2011, and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia and others. Previously published articles have described the etiology and phenotype of Ogden syndrome, mostly with retrospective analyses; herein, we report prospective data concerning its progress over time. Additionally, we describe the nature of seizures in this condition in greater detail, as well as investigate how already-available non-pharmaceutical therapies impact individuals with NAA10-related neurodevelopmental syndrome. Using Vineland-3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome. Sub-domain analysis found the decline to be present across all modalities. Additional investigation between seizure and non-seizure groups showed no significant difference in adaptive behavior outcomes. Therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome, followed by occupational and physical therapy. with more severely affected individuals receiving more types of therapy than their less-severe counterparts. Early intervention analysis was only significantly effective for speech therapy, with analyses of all other therapies being non-significant. Our study portrays the decline in cognitive function over time of individuals within our cohort, independent of seizure status and therapies being received, and highlights the urgent need for the development of effective treatments for Ogden syndrome.
Application of Artificial Intelligence of Machine learning in Assessing Stroke Among HIV Patients on Protease Inhibitors-ART: A Bayesian Network Approach
Authors: Chiluba Brian Chanda
Published: March 2024

Background

In our investigation, we aim to utilize Bayesian network models in the field of machine learning to assess the likelihood of CVD in adults who are HIV positive and receiving protease inhibitors-antiretroviral therapy (PIs-ART). It is imperative to comprehend the risk factors and prognosis of stroke in order to effectively manage individuals infected with HIV, particularly those who have not yet initiated HAART.

Methods

This retrospective cohort study investigates stroke prevalence among HIV patients on Protease Inhibitors-ART at Zambia’s Adult Infectious Disease Center from 2009 to 2019. Data from 2867 patients’ EHRs were analyzed for demographic, clinical, and mortality information. Demographic and clinical data were obtained from an anonymous electronic case system. We utilized descriptive analysis along with logistic regression and Bayesian Network Model models to elucidate the characteristics and predictors of stroke among HAART-naive PLWH.

Results

This study analyzed data from 2867 HIV patients on Protease Inhibitors-ART to assess stroke prevalence and associated risk factors. Of the cohort, 105 individuals had stroke (prevalence: 3.7%), primarily ischemic infarction (56.2%). Most patients were aged 30-55 years (64.4%) and male (90.2%). Common comorbidities included diabetes (3.8%), hypertension (12.2%), and opportunistic infections like CMV (27.9%) and PCP (36.1%). Mortality rate was 6.6%. Bayesian network modeling predicted post-stroke outcomes, identifying age, CD4 count, lipid profile, comorbidities, and previous cardiovascular events as significant predictors. These findings highlight the complex interplay of risk factors in stroke occurrence among HIV patients on ART.

Conclusions

Our findings highlight the significance of early screening for stroke, timely intervention for risk factors across various age groups, and management of CD4 count among HAART-naive PLWH in order to alleviate the burden of stroke. These insights are crucial for informing targeted interventions aimed at reducing the occurrence and mortality associated with stroke in this population.
Hypervariable DOM properties in coastal NW Mediterranean Sea -Evidences of strong human influences and potential consequences for the heterotrophic base of planktonic food webs
Authors: Dignan Clara , Lenoble Véronique , Garcia Nicole , Oursel Benjamin , Cindrić Ana-Marija , Misson Benjamin
Published: March 2024

Marine DOM plays a key role in the carbon cycle. Though there is growing interest for its chemical and ecological properties, its variability in the very heterogeneous coastal environment is poorly documented. In this study, we assessed the spatial and temporal variations in marine coastal DOM chemical properties and its potential to support the growth of the heterotrophic basis of the planktonic food-web. For that, we considered two NW Mediterranean coastal sampling stations under contrasted continental and human influences. From January to July 2022, DOC concentration demonstrated a progressive increasing trend in addition to marked spatial differences. DOM composition presented more variations in time than in space. These variations appeared related to a combination of direct freshwater inputs tracked by salinity variations, direct human contaminations tracked by concentrations in Cu and Pb, and phytoplanktonic production. An experimental approach was also used at each sampling date to evaluate DOM ability to support the growth of heterotrophic prokaryotes. Significantly higher growth was observed with DOM from a site under higher continental and human influences. Water temperature exerted a higher control on growth than DOM properties. Correlation analysis with DOM sources suggested the uncoupling of phytoplanktonic production and growth of heterotrophic prokaryotes, which appeared better supported by human contaminations and, to a lesser extent, freshwater inputs. Sediment resuspension in harbors and antifouling paints could represent two important sources of bioavailable resources, favoring fast heterotrophic growth and higher net production, respectively.
A torpor-like state (TLS) in mice slows blood epigenetic aging and prolongs healthspan
Authors: Jayne Lorna , Lavin-Peter Aurora , Roessler Julian , Tyshkovskiy Alexander , Antoszewski Mateusz , Ren Erika , Markovski Aleksandar , Sun Senmiao , Yao Hanqi , Sankaran Vijay G. , Gladyshev Vadim N. , Brooke Robert T. , Horvath Steve , Griffith Eric C. , Hrvatin Sinisa
Published: March 2024

Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase health span, remain unknown. We demonstrate that the activity of a spatially defined neuronal population in the avMLPA, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves health span. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the pro-longevity effect of torpor-like states is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the pro-longevity effects of torpor and hibernation and support the growing body of evidence that Tbis an important mediator of aging processes.
Design, synthesis and pharmacological characterization of the first photoswitchable small-molecule agonist for the Atypical Chemokine Receptor 3
Authors: Bérenger Sophie , Adamska Justyna M. , Deflorian Francesca , de Graaf Chris , Palmer Christie B. , Szpakowska Martyna , Chevigné Andy , de Esch Iwan J. P. , Zarzycka Barbara , Vischer Henry F. , Wijtmans Maikel , Leurs Rob
Published: March 2024

1.

Photopharmacology offers the promise of optical modulation of cellular signaling in a spatially and temporally controlled fashion with light-sensitive molecules. This study presents the first small-molecule photoswitchable agonist for an atypical G protein-coupled receptor (GPCR), the atypical chemokine receptor 3 (ACKR3). Inspired by a known benzylpiperidine-based ACKR3 agonist scaffold, 12 photoswitchable azobenzene-containing analogs were synthesized and characterized for their interaction with ACKR3. After analysis of Structure-Photochemistry and Structure-Affinity Relationships (SAR), compound3ewas selected as the best photoswitchable ACKR3 agonist in the series. Compound3ecan be effectively switched from its thermodynamically stabletransstate to the less activecis-isomer with a PhotoStationary State of 96 %. The thermodynamically less stablecis-3eonly slowly switches back to thetransstate (t1/2,37 °C= 15 days), andtrans-3ebinds and activates ACKR3 at 10-fold lower concentrations compared to itscis-isomer. Compound3edemonstrates selectivity for ACKR3 within in a panel of chemokine receptors. Using the recently published ACKR3 cryo-EM structures in computational studies, a binding mode fortrans-3eis proposed and is perfectly in line with the observed SAR and the loss of interaction with ACKR3 upon photoswitching. ACKR3 agonist3e(VUF25471) is the first photoswitchable ligand for an atypical GPCR and will be a useful tool to investigate the role of ACKR3 in biological settings.
PHARAOH: A collaborative crowdsourcing platform for PHenotyping And Regional Analysis Of Histology
Authors: Faust Kevin , Chen Min Li , Zadeh Parsa Babaei , Oreopoulos Dimitrios , Leon Alberto J. , Kamski-Hennekam Evelyn Rose , Mikhail Marly , Duan Xianpi , Duan Xianzhao , Liu Mugeng , Ahangari Narges , Cotau Raul , Castillo Vincent Francis , Nikzad Nikfar , Sugden Richard J. , Murphy Patrick , Done Susan , Aljohani Safiyh S. , Echelard Philippe , Jakate Kiran , Alwelaie Yazeed , Alyousef Mohammed J. , Alsafwani Noor Said , Alrumeh Assem Saleh , Saleeb Rola , Richer Maxime , Marins Lidiane Vieira , Yousef George M. , Diamandis Phedias
Published: March 2024

Deep learning has proven to be capable of automating key aspects of histopathologic analysis, but its continual reliance on large expert-annotated training datasets hinders widespread adoption. Here, we present an online collaborative portal that streamlines tissue image annotation to promote the development and sharing of custom computer vision models for PHenotyping And Regional Analysis Of Histology (PHARAOH;https://www.pathologyreports.ai/). PHARAOH uses a weakly supervised active learning framework whereby patch-level image features are leveraged to organize large swaths of tissue into morphologically-uniform clusters for batched human annotation. By providing cluster-level labels on only a handful of cases, we show how custom PHARAOH models can be developed and used to guide the quantification of cellular features that correlate with molecular, pathologic and patient outcome data. Both custom model design and feature extraction pipelines are amenable to crowdsourcing making PHARAOH a fully scalable systems-level solution for the systematic expansion and cataloging of computational pathology applications.
In Vitro Efficacy of Next Generation Dihydrotriazines and Biguanides Against Babesiosis and Malaria Parasites
Authors: Vydyam Pratap , Chand Meenal , Gihaz Shalev , Renard Isaline , Heffernan Gavin D. , Jacobus Laura R. , Jacobus David P. , Saionz Kurt W. , Shah Raju , Shieh Hong-Ming , Terpinski Jacek , Zhao Wenyi , Cornillot Emmanuel , Mamoun Choukri Ben
Published: March 2024

BabesiaandPlasmodiumpathogens, the causative agents of babesiosis and malaria, are vector-borne intraerythrocytic protozoan parasites, posing significant threats to both human and animal health. The widespread resistance exhibited by these pathogens to various classes of antiparasitic drugs underscores the need for the development of novel and more effective therapeutics strategies. Antifolates have long been recognized as attractive antiparasitic drugs as they target the folate pathway, which is essential for the biosynthesis of purines and pyrimidines, and thus are vital for the survival and proliferation of protozoan parasites. More efficacious and safer analogs within this class are needed to overcome challenges due to resistance to commonly used antifolates such as the aminopyrimidine, pyrimethamine, and to address liabilities associated with the dihydrotriazines, WR99210 and JPC-2067. Here we utilized an in vitro culture condition suitable for continuous propagation ofB. duncani, B. divergens, B. MO1andP. falciparumin human erythrocytes to screen a library of 51 dihydrotriazines and 28 biguanides for their efficacy in vitro and to compare their potency and therapeutic indices across different species and isolates. We identified nine analogs that inhibit the growth of all species, including theP. falciparumpyrimethamine-resistant strain HB3 with IC50values below 10 nM and demonstrated excellent therapeutic indices. These compounds hold substantial promise as lead antifolates for further development as broad-spectrum antiparasitic drugs.
Molecular stratification of human fetal vaginal epithelium by spatial transcriptome analysis
Authors: Ye Ziying , Jiang Peipei , Zhu Qi , Pei Zhongrui , Hu Yali , Zhao Guangfeng
Published: March 2024

The human vaginal epithelium is a crucial component in numerous reproductive processes and serves as a vital protective barrier against pathogenic invasion. Despite its significance, a comprehensive exploration of its molecular profiles, including molecule expression and distribution across its multiple layers, remains elusive. In our study, we undertook a spatial transcriptomic analysis within the vaginal wall of human fetuses to fill this knowledge gap. We successfully categorized vaginal epithelium into four distinct zones based on their transcriptomic profiles and anatomical features. This approach unveiled unique transcriptomic signatures within these regions, allowing us to identify differentially expressed genes and uncover novel markers for distinct regions of the vaginal epithelium. Additionally, our findings have highlighted the varied expression of KRT genes across different zone of the vaginal epithelium, with a gradual shift in expression patterns observed from the basal layer to the surface/superficial layer. This suggests a potential differentiation trajectory of human vaginal epithelium, shedding light on the dynamic nature of this tissue. Furthermore, abundant biological processes were found to be enriched in the basal zone by the KEGG pathway analysis, indicating an active state of the basal zone cells. Subsequently, the expression of latent stem cell markers in the basal zone were identified. In summary, our research provides crucial understanding of human vaginal epithelial cells and the complex mechanisms of the vaginal mucosa, with potential applications in vaginal reconstruction and drug delivery, making this atlas a valuable tool for future research in women’s health and reproductive medicine.
Sensory integration of food availability and population density during the diapause exit decision involves insulin-like signaling inCaenorhabditis elegans
Authors: Zhang Mark G , Seyedolmohadesin Maedeh , Hawk Soraya , Park Heenam , Finnen Nerissa , Schroeder Frank , Venkatachalam Vivek , Sternberg Paul W
Published: March 2024

Decisions made over long time scales, such as life cycle decisions, require coordinated interplay between sensory perception and sustained gene expression. TheCaenorhabditis elegansdauer (or diapause) exit developmental decision requires sensory integration of population density and food availability to induce an all-or-nothing organismal-wide response, but the mechanism by which this occurs remains unknown. Here, we demonstrate how the ASJ chemosensory neurons, known to be critical for dauer exit, perform sensory integration at both the levels of gene expression and calcium activity. In response to favorable conditions, dauers rapidly produce and secrete the dauer exit-promoting insulin-like peptide INS-6. Expression ofins-6in the ASJ neurons integrate population density and food level and can reflect decision commitment since dauers committed to exiting have higherins-6expression levels than those of non-committed dauers. Calcium imaging in dauers reveals that the ASJ neurons are activated by food, and this activity is suppressed by pheromone, indicating that sensory integration also occurs at the level of calcium transients. We find thatins-6expression in the ASJ neurons depends on neuronal activity in the ASJs, cGMP signaling, a CaM-kinase pathway, and the pheromone components ascr#8 and ascr#2. We propose a model in which decision commitment to exit the dauer state involves an autoregulatory feedback loop in the ASJ neurons that promotes high INS-6 production and secretion. These results collectively demonstrate how insulin-like peptide signaling helps animals compute long-term decisions by bridging sensory perception to decision execution.

Summary/Significance Statement

Animals must respond appropriately to multiple sensory stimuli to make informed decisions. It remains unclear how the nervous system is able to integrate different sensory cues and propagate that information towards making decisions over longer timescales. We use the nematodeCaenorhabditis elegansto investigate how sensory integration occurs during the decision to exit diapause, a stress-resistant developmentally arrested state triggered by multiple sensory inputs including food availability and population density. We show how expression of an insulin-like peptide critical to dauer exit reflects the sensory integration process and decision commitment, and we dissect the regulation of this insulin-like peptide’s expression. Our study explicitly analyzes the relationship between neuronal activity and neuropeptide expression during a complex decision with diverse sensory inputs.
Blood immune profiles reveal a CXCR3/CCR5 axis of dysregulation in early sepsis
Authors: Kealy David , Wilson Julie , Jaconelli Tom , Hogg Karen , Coop Rebecca , Forshaw Greg , Todd Neil , Yates David , Signoret Nathalie
Published: March 2024

Sepsis is defined as a systemic inflammatory host response syndrome after serious microbial infection, which requires prompt treatment to lower the risk of complications and death. However, early sepsis recognition can be a challenge at presentation when patients show symptoms difficult to distinguish from other acute conditions.

We designed a pilot study to explore whether blood immune signatures could reveal early specific indicator profiles for patients meeting sepsis criteria upon admission at the hospital Emergency Department. We analysed blood samples from study-recruited sepsis-suspected patients (N=20) and of age-spanning healthy volunteers (N=12), using flow cytometry-based assays. 25 circulating inflammatory cytokines and chemokines (CCs) were measured from blood plasma, while freshly isolated unfixed blood leukocytes were immunophenotyped to ascertain major cell subsets representation and expression of activation markers, including chemokine receptors. We found that beside IL-6 and sCD14, blood levels of CXCL9 and CXCL10 (two ligands of CXCR3) show good separation between healthy controls and sepsis-suspected patients. The abundance of CD4+T cells was significantly reduced while the expression of chemokine receptors was altered on monocytes, B and all T cells from patients. In particular, we report substantial losses of CCR5-expressing monocytes and CXCR3/CCR5 double positive T cells. Full dataset analysis and post-hoc subgrouping of patients according to their diagnosis on discharge (confirmed or unconfirmed sepsis), identified CXCR3/CCR5 double expression on T cells as a separating characteristic within the study. Overall, our observational study suggests a new CCR5 and CXCL9-10/CXCR3 axis of dysregulation in early sepsis.
MULTIPLE ENDEMIC EQUILIBRIA IN AN ENVIRONMENTALLY-TRANSMITTED DISEASE WITH THREE DISEASE STAGES
Authors: Islas José Manuel , Corona-Moreno Ruth , Velasco-Hernández Jorge X.
Published: March 2024

We construct, analyze and interpret a mathematical model for an environmental transmitted disease characterized for the existence of three disease stages, acute, severe and asymptomatic where severe and asymptomatic cases may present relapse between them. Transmission dynamics driven by the contact rates (as normally occur in directly-transmitted or vector-transmitted diseases) only occurs when a parameterR*>1. In this case, the forward transcritical bifurcation that exists forR*<1, becomes a backward bifurcation, producing multiple steady-states, a hysteresis effect and dependence on initial conditions. A threshold parameter for an epidemic outbreak, independent ofR*is only the ratio of the external contamination inflow shedding rate to the environmental clearance rate.R*describes the strength of the transmission to infectious classes other than theI-(acute) type infections. The epidemic outbreak conditions and the structure ofR*appearing in this model are both resposible for the existence of endemic states.
Risk factors for anaemia among pregnant women: A cross-sectional study in Upper East Region, Ghana
Authors: Asobuno Clotilda , Adjei-Gyamfi Silas , Aabebe Felix Gumaayiri , Hammond John , Taikeophithoun Chansathit , Amuna Norbert Ndaah , Aoki Tsunoneri , Aiga Hirotsugu
Published: March 2024

Background

Anaemia in pregnancy (AIP) is a public health concern due to its devastating effects on women and their unborn babies, resulting in increased maternal and neonatal deaths in developing countries. Despite several Ghanaian health policies to combat AIP, AIP is still on the rise. It becomes imperative to identify geographic-specific factors for developing appropriate interventions for the management of AIP. However, Kassena Nankana West District (KNWD) in the Upper East Region of Ghana lacks a study on anaemia risk factors, therefore, this study estimated the prevalence and risk factors for anaemia among pregnant women in the district.

Methods

A household-based cross-sectional study was conducted on 376 pregnant women in their third trimester from February to March 2023. Anthropometric, obstetric, sociodemographic, and health facility resource characteristics were collected using structured questionnaires and antenatal records. Mixed-effect logistic regression was used to identify independent factors of anaemia at 95% confidence interval.

Results

Prevalence of AIP was 53.9%. Mild, moderate, and severe anaemia prevalence was 16.9%, 35.3%, and 1.7% respectively. Malaria infection during pregnancy (aOR=1.563; 95%CI:1.087 – 2.475) and accessing health facilities without trained laboratory personnel (aOR=5.271; 95%CI:1.641 – 16.93) were associated with increased odds of AIP. Belonging to the major ethnic group (aOR=0.431; 95%CI:0.280 – 0.675), accessing health facilities without laboratory services (aOR=0.151; 95%CI:0.047 – 0.487), and accessing health facilities without sulphadoxine-pyrimethamine drugs (aOR=0.234; 95%CI:0.061 – 0.897) in KNWD were also associated with decreased odds of AIP.

Conclusion

AIP prevalence remains high in the KNWD. Maternal and health facility-related factors were responsible for anaemia in the district. These factors are preventable. Therefore, health facility strengthening and enhanced strategies for malaria prevention are recommended for anaemia control in the district.
Psychological distress after COVID-19 recovery and subsequent prolonged post-acute sequelae of COVID-19: A longitudinal study with 1-year follow-up in Japan
Authors: Hazumi Megumi , Kataoka Mayumi , Narita Zui , Usuda Kentaro , Okazaki Emi , Nishi Daisuke
Published: March 2024

Background

This study investigated the longitudinal association between psychological distress in the post-acute phase and the subsequent prolonged post-acute sequelae of COVID-19 (PASC) among individuals with PASC.

Methods

An online longitudinal survey with 1-year interval was conducted from July to September 2021 (T1) and July to September 2022 (T2). Individuals who were 20-years-old or older, had a positive Polymerase Chain Reaction test, were one month post-infection, and did not select “Nothing” to a question regarding PASC presence were included. The primary outcome was the presence of PASC at T2. The presence of general, respiratory, muscular, neurological, gastrointestinal, dermatological, and cardiac symptoms at T2 was also used as an outcome among patients with relevant symptoms at time 1 (T1). Exposure was measured using the Kessler distress scale (K6) at T1, and those whose K6 was 13 or higher were identified as having psychological distress. Marginal structure models with robust standard errors were used to examine the association between psychological distress at T1 and any PASC symptoms at T2, and the associations between psychological distress and each symptom at T2 among participants with relevant symptoms at T1.

Results

A total of 1674 patients were analyzed; 17%had psychological distress. ; In total, 818 (48.9%), 523 (31.2%), and 672 (40.1%) patients reported general, respiratory, and neurological symptoms at T1, respectively. Individuals with psychological distress had higher odds of any symptoms at T2 (Odds Ratio [OR] =1.81, 95% Confidence Interval [CI]= 1.08 – 3.03) and general and respiratory symptoms at T2 among participants with relevant symptoms at T1 (OR = 1.95, 95% CI = 1.02 – 3.76; OR = 2.44, 95% CI = 1.03 – 5.80).

Conclusion

Psychological distress in the post-acute phase may lead to prolonged PASC symptoms, mainly general and respiratory symptoms, at the 1-year follow-up in individuals with PASC.

Key Messages

Psychological distress before infection and during the acute phase predicts prolonged Post-Acute Sequelae of COVID-19 (PASC); however, in individuals with PASC, it is unclear whether psychological distress during the post-acute phase predicts prolonged PASC. This longitudinal survey indicated that psychological distress in the post-acute phase led to prolonged any levels of PASC, especially general and respiratory symptoms, at the 1-year follow-up. Therefore, mental health care for individuals with PASC may help to improve or mitigate prolonged PASC.
Engineering of highly active and diverse nuclease enzymes by combining machine learning and ultra-high-throughput screening
Authors: Thomas Neil , Belanger David , Xu Chenling , Lee Hanson , Hirano Kathleen , Iwai Kosuke , Polic Vanja , Nyberg Kendra D , Hoff Kevin G , Frenz Lucas , Emrich Charlie A , Kim Jun W , Chavarha Mariya , Ramanan Abi , Agresti Jeremy J , Colwell Lucy J
Published: March 2024

Optimizing enzymes to function in novel chemical environments is a central goal of synthetic biology, but optimization is often hindered by a rugged, expansive protein search space and costly experiments. In this work, we present TeleProt, an ML framework that blends evolutionary and experimental data to design diverse protein variant libraries, and employ it to improve the catalytic activity of a nuclease enzyme that degrades biofilms that accumulate on chronic wounds. After multiple rounds of high-throughput experiments using both TeleProt and standard directed evolution (DE) approaches in parallel, we find that our approach found a significantly better top-performing enzyme variant than DE, had a better hit rate at finding diverse, high-activity variants, and was even able to design a high-performance initial library using no prior experimental data. We have released a dataset of 55K nuclease variants, one of the most extensive genotype-phenotype enzyme activity landscapes to date, to drive further progress in ML-guided design.
Hepatitis B Virus genomes associate with cellular sites of DNA damage by inducing replication stress
Authors: Marcoe Gavin J. , Larsen Clairine I. S. , Majumder Kinjal
Published: March 2024

Hepatitis B Virus (HBV) is a leading cause of liver cancer, with almost 300 million infected individuals worldwide. Although HBV-infected patients benefit from drug regimens that help to control chronic infection, they are rarely clinically cured of HBV. The HBV genome persists in the nucleus of infected hepatocytes in the form of a covalently closed circular DNA (cccDNA) molecule, a reservoir of HBV DNA molecules that serve as the template for reactivation of long-term chronic HBV. However, despite playing a central role in the viral life cycle, little is understood about where cccDNA molecules localize, why they are so stable, and how they impact the host nuclear compartment. Perhaps because of this, there are few treatments that target cccDNA, which is critical for eradication of clinical HBV. Here, we show that HBV infection induces a cellular DNA Damage Response (DDR) that is comparable with cells undergoing replication stress, and this cellular replication stress is initiatedafterthe formation of cellular cccDNA molecules. Using a novel high-throughput chromosome conformation capture technology that monitors the localization of HBV cccDNA molecules, we show that cccDNA molecules persist in the vicinity of many cellular fragile sites. Induction of cellular DNA damage leads to relocalization of the viral HBx oncoprotein to DDR sites in an ATM, ATR and DNA-PK dependent manner. Our findings contribute to the understanding of how HBV cccDNA navigates the host nuclear environment, identifying functional targets for development of therapies against HBV infection and resulting liver cancer.

Importance

Hepatitis B Virus (HBV) is the leading infectious cause of liver cancer globally. The virus persists in the nucleus long term by forming reservoirs in human liver cells. We have discovered that the HBV DNA localizes to sites on the host genome associated with DNA damage, and in doing so, HBV interferes with the host’s ability to efficiently amplify itself. This results in the induction of cellular DNA breaks, which we propose contributes to eventual cancer progression. Our findings provide new insights into how HBV infection may lead to liver cancer.
A high-throughput zebrafish screen identifies novel candidate treatments for Kaposiform Lymphangiomatosis (KLA)
Authors: Bassi Ivan , Jabali Amani , Farag Naama , Egozi Shany , Moshe Noga , Leichner Gil S. , Geva Polina , Levin Lotan , Barzilai Aviv , Avivi Camila , Long Jonathan , Otterstrom Jason J. , Paran Yael , Barr Haim , Yaniv Karina , Greenberger Shoshana
Published: March 2024

Kaposiform Lymphangiomatosis (KLA) is a rare, aggressive, and incurable disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). The development of new therapeutic avenues is hampered by the lack of animal models faithfully replicating the clinical manifestations of KLA. Here, we established a novel zebrafish model of KLA by driving conditional expression of the human NRAS mutation in venous and lymphatic ECs. We find that mutant embryos recapitulated clinical features of KLA, including pericardial edema and a dilated thoracic duct, and that the phenotypes were reverted by Trametinib, a MEK inhibitor used for KLA treatment. We further leverage this model in combination with an AI-based high-throughput drug screening platform to search for small compounds selectively reverting the mutant phenotypes and identify Cabozantinib, an FDA-approved tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as leading hits. Finally, we test these drugs in cultured cells derived from KLA patient and demonstrate their ability to normalize LEC sprouting and block NRAS downstream pathways, underscoring the potential of GSK690693 and Cabozantinib as potential KLA treatments. Overall, our novel zebrafish model provides a valuable tool for research into the etiology of KLA and for identifying new therapeutic avenues.
Trends in Perioperative Catheter Utilization by Surgical Procedure Type in the United States, 2010 – 2017: Evidence from the Nationwide Inpatient Sample
Authors: Anderton Priscilla D. , Waddimba Anthony C. , Ogola Gerald O. , Ramsay Michael A. , Kim Bryan , Thoreson Gregory R.
Published: March 2024

Background

Indwelling urethral catheters are regularly used in the operative setting to monitor urinary output, decompress the bladder, or manage post-operative urinary retention. Indwelling urethral catheterization can be associated with significant complications, such as nosocomial infections and urethral trauma, hence the contemporary national and institutional efforts to reduce indwelling urethral catheter usage.

Objectives

The purpose of this study is to investigate national trends in perioperative catheter usage across surgical procedure categories.

Methods

This is a retrospective study of adults who received indwelling urethral catheters during elective surgical procedures performed in United States (U.S.) hospitals during 2010-2017. We utilized the National Inpatient Sample (NIS) procedure codes to identify surgical procedure types and insertions of indwelling urethral catheters. Yearly catheterization rates were utilized to assess significant differences in nationwide temporal trends.

Results

We sampled 81,128,725 perioperative catheterizations across twelve procedure categories. When specific categories were examined separately, the annual proportion of procedures utilizing catheterizationdecreasedfor eye (−0.05% [95% CI, -0.10%; -0.02%], p-value 0.013), musculoskeletal (−0.04% [95% CI, -0.09%; 0.003%] p-value 0.063), and urinary system surgeries (−0.54% [95% CI, -0.76%; -0.33%] p-value 0.001). The proportion that utilized urethral cathetersincreasedannually for female reproductive (+0.05% [95% CI, 0.04%; 0.07%] p-value <0.001), male reproductive (+0.31% [95% CI, 0.18%; 0.44%] p-value 0.001), and respiratory system surgeries (0.08% [95% CI, 0.02%; 0.13%] p-value 0.015). When all operative procedures were examined together, the overall annual proportion involving urethral catheterization did not significantly vary during 2010-2017.

Conclusion

Despite wide dissemination of clinical guidelines and institutional efforts to reduce catheterizations, we observed no significant changes in the overall proportion of all surgical procedures (irrespective of procedure category) that utilized urethral catheters during our study period.
Do the Health Benefits of Boiling Drinking Water Outweigh the Negative Impacts of Increased Indoor Air Pollution Exposure?
Authors: Floess Emily , Ercumen Ayse , Harris Angela , Grieshop Andrew P.
Published: March 2024

Background

Billions of the world’s poorest households are faced with the lack of access to both safe drinking water and clean cooking. One solution to microbiologically contaminated water is boiling, often promoted without acknowledging the additional risks incurred from indoor air degradation from using solid fuels.

Objectives

This modeling study explores the tradeoff of increased air pollution from boiling drinking water under multiple contamination and fuel use scenarios typical of low-income settings.

Methods

We calculated the total change in disability-adjusted life years (DALYs) from indoor air pollution (IAP) and diarrhea from fecal contamination of drinking water for scenarios of different source water quality, boiling effectiveness, and stove type. We used Uganda and Vietnam, two countries with a high prevalence of water boiling and solid fuel use, as case studies.

Results

Boiling drinking water reduced the diarrhea disease burden by a mean of 1110 DALYs and 368 DALYs per 10,000 people for those under and over <5 years of age in Uganda, respectively, for high-risk water quality and the most efficient (lab-level) boiling scenario, with smaller reductions for less contaminated water and ineffective boiling. Similar results were found in Vietnam, though with fewer avoided DALYs in children under 5 due to different demographics. In both countries, for households with high baseline IAP from existing solid fuel use, adding water boiling to cooking on a given stove was associated with a limited increase in IAP DALYs due to the log-linear dose-response curves. Boiling, even at low effectiveness, was associated withnetDALY reductions for medium- and high-risk water, even with unclean stoves/fuels. Use of clean stoves coupled with effective boiling significantly reduced total DALYs.

Discussion

Boiling water generally resulted in net decreases in DALYs. Future efforts should empirically measure health outcomes from IAP vs. diarrhea associated with boiling drinking water using field studies with different boiling methods and stove types.
Measuring Planetary Eco-Emotions: A Systematic Review of Currently Available Instruments and Their Psychometric Properties
Authors: Kırımer-Aydınlı Fulya , Juaréz Castelán Mariel , Hakim Nilab , Gul Pelin , Unal A. Berfu , Aguayo-Estremera Raimundo , Perez Fortis Adriana , Rojas-Russell Mario E. , Gallo Valentina
Published: March 2024

Background

The climate crisis has a wide range of direct and indirect mental health impacts on populations. However, their quantification is limited by the lack of unified definitions and assessment tools. The aim of this systematic review is to map all psychometric instruments used to measure emotions associated with the climate crisis, evaluate their psychometric characteristics, and identify any existing gaps.

Methods

The protocol was registered on PROSPERO. Data were reported following the COSMIN Risk of Bias of PROM and PRISMA checklists. Original articles describing the psychometric properties and/or validation of self-report measures designed to assess eco-anxiety and other climate change-related emotions in the general population were within the scope of this review. PubMed, PsycINFO, and Web of Science were the search engines used.

Findings

A total of 10 different psychometric scales measuring various eco-emotions were identified. Four focused on anxiety, while the remaining six focused on combinations of other negative emotions. The definitions of eco-emotions were not consistent across papers. Most of the instruments were developed in the Global North. Six of the instruments were multidimensional. All but one scale included at least one item indicating behavioural, cognitive, or physical aspects of emotions toward climate crises. The most recurrent emotion was worry, followed by anxiety, fear, and sadness. Including ten scale development studies, a total of 22 studies reporting instrument validation were reviewed. Two of the instruments have been validated in other populations.

Interpretation

To what extent the emotions covered by the instruments may overlap in relation to climate change is, to date, not clear. This is due to the lack of consistent definitions of climate-related emotions. Moreover, the mention of emotions was derived by a top-down approach, in all included studies. No positive emotions, such as hopefulness, humor, anticipated pride, gratitude, optimism, or feeling strong to do something though own contributions, have been detected.
in-Silico TRials guide optimal stratification of ATrIal FIbrillation patients to Catheter Ablation and pharmacological medicatION: The i-STRATIFICATION study
Authors: Dasí Albert , Nagel Claudia , Pope Michael T.B. , Wijesurendra Rohan S. , Betts Timothy R. , Sachetto Rafael , Loewe Axel , Bueno-Orovio Alfonso , Rodriguez Blanca
Published: March 2024

Background and Aims

Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for second treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation therapies, through in-silico trials.

Methods

A cohort of 800 virtual patients, with variability in atrial anatomy, electrophysiology, and tissue structure (low voltage areas, LVA), was developed and validated against clinical data from ionic currents to ECG. Virtual patients presenting AF post-PVI underwent 13 secondary treatments.

Results

Sustained AF developed in 522 virtual patients after PVI. Second ablation procedures involving left atrial ablation alone showed 55% efficacy, only succeeding in small right atria (<60mL). When additional cavo-tricuspid isthmus ablation was considered, Marshall-Plan sufficed (66% efficacy) for small left atria (<90mL). For bigger left atria, a more aggressive ablation approach was required, such as anterior mitral line (75% efficacy) or posterior wall isolation plus mitral isthmus ablation (77% efficacy). Virtual patients with LVA greatly benefited from LVA ablation in the left and right atria (100% efficacy). Conversely, in the absence of LVA, synergistic ablation and pharmacotherapy could terminate AF. In the absence of ablation, the patient’s ionic current substrate modulated the response to antiarrhythmic drugs, being the inward currents critical for optimal stratification to amiodarone or vernakalant.

Conclusion

In-silico trials identify optimal strategies for AF treatment based on virtual patient characteristics, evidencing the power of human modelling and simulation as a clinical assisting tool.
Large-scale Mendelian randomization identifies novel pathways as therapeutic targets for heart failure with reduced ejection fraction and with preserved ejection fraction
Authors: Rasooly Danielle , Giambartolomei Claudia , Peloso Gina M. , Dashti Hesam , Ferolito Brian R. , Golden Daniel , Horimoto Andrea R. V. R. , Pietzner Maik , Farber-Eger Eric H , Wells Quinn Stanton , Bini Giorgio , Proietti Gabriele , Tartaglia Gian Gaetano , Kosik Nicole M. , Wilson Peter W. F. , Phillips Lawrence S. , Munroe Patricia B. , Petersen Steffen E. , Cho Kelly , Gaziano John Michael , Leach Andrew R. ,   VA Million Veteran Program, Whittaker John , Langenberg Claudia , Aung Nay , Sun Yan V. , Pereira Alexandre C. , Joseph Jacob , Casas Juan P.
Published: March 2024

We used expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) to conduct genome-wide Mendelian randomization (MR) using 27,799 cases of heart failure (HF) with reduced ejection fraction (HFrEF), 27,579 cases of HF with preserved ejection fraction (HFpEF), and 367,267 control individuals from the Million Veteran Program (MVP). We identified 70 HFrEF and 10 HFpEF gene-hits, of which 58 are novel. In 14 known loci for unclassified HF, we identified HFrEF as the subtype responsible for the signal. HFrEF hitsZBTB17,MTSS1,PDLIM5, andMLIPand novel HFpEF hitsNFATC2IP,andPABPC4showed robustness to MR assumptions, support from orthogonal sources, compelling evidence on mechanism of action needed for therapeutic efficacy, and no evidence of an unacceptable safety profile. We strengthen the value of pathways such as ubiquitin-proteasome system, small ubiquitin-related modifier pathway, inflammation, and mitochondrial metabolism as potential therapeutic targets for HF management. We identifiedIL6R,ADM,andEDNRAas suggestive hits for HFrEF andLPAfor HFrEF and HFpEF, which enhances the odds of success for existing cardiovascular investigational drugs targeting. These findings confirm the unique value of human genetic studies in HFrEF and HFpEF for discovery of novel targets and generation of therapeutic target profiles needed to initiate new validation programs in HFrEF and HFpEF preclinical models.