bluuebunny/crossref_metadata_2025 huggingface dataset:
Weanling pigs consume more feed if hybrid rye replaces corn in diets, but average daily gain and fecal scores are not impacted by hybrid rye
Authors: McGhee Molly L , Acosta Jessica P , Stein Hans H
Published: February 2023

An experiment was conducted to test the hypothesis that growth performance and health status of pigs will not be reduced if hybrid rye is included in diets at the expense of corn during the initial 5 wk post-weaning. A total of 128 weanling pigs (5.6 ± 0.5 kg) were randomly allotted to 32 pens and 4 dietary treatments. Pigs were fed experimental diets for 35 d in three phases with days 1 to 7 being phase 1, days 8 to 21 being phase 2, and days 22 to 35 being phase 3. Within each phase, a control diet primarily based on corn and soybean meal was formulated, and three additional diets were formulated by including 8.0, 16.0, or 24.0% (phase 1), 16.0, 32.0, or 48.0% (phase 2), and 20.0, 40.0, or 60.3% (phase 3) hybrid rye in the diet at the expense of corn. Pig weights were recorded at the start and conclusion of each phase, fecal scores were visually assessed every other day on a pen basis, and blood samples were obtained from 1 pig per pen on days 21 and 35. Results indicated that average daily gain (ADG) in phase 1 increased (linear, P < 0.05) as the inclusion of hybrid rye increased, but no other differences in ADG were observed. Average daily feed intake linearly increased in phase 1, phase 3, and overall (P < 0.05) as hybrid rye inclusion increased in the diets, and gain:feed was negatively impacted by the inclusion of hybrid rye in the diet (phase 1, linear, P < 0.05; phases 2, 3, and overall, quadratic, P < 0.05). No differences in average fecal scores or diarrhea incidence were observed. On days 21 and 35, blood urea N increased (linear, P < 0.05) as hybrid rye increased in the diets; and on day 21, serum total protein also increased (linear, P < 0.05) with increasing hybrid rye inclusion in the diet. Mean blood hemoglobin concentration on day 35 increased and then decreased as hybrid rye inclusion increased (quadratic, P < 0.05). On day 21, interleukin (IL) 2 and IL 10 decreased and then increased (quadratic, P < 0.05) as hybrid rye inclusion increased. On day 35, IL 8 and IL 12 increased and then decreased (quadratic, P < 0.05) and interferon-gamma decreased and then increased (quadratic, P < 0.01) as hybrid rye inclusion increased. In conclusion, the ADG of pigs was not different among treatments, but at the highest hybrid rye inclusion level, pigs consumed more feed than if corn was fed and gain:feed was reduced with increasing hybrid rye in diets. Differences in blood serum cytokines indicate the immune system was affected differently when hybrid rye instead of corn was fed.
A Physician’s Sense of Responsibility to Address Disparities: Does It Relate to Reported Behaviors About Screening for and Addressing Social Needs?
Authors: Peek Monica E. , Wan Wen , Noriea Ashley
Published: February 2023

Purpose

It is widely accepted that negative social determinants of health (e.g., poverty) are underlying drivers of poor health and health disparities. There is overwhelming support among physicians to screen for patient-level social needs, but only a minority of clinicians actually do so. The authors explored potential associations between physician beliefs about health disparities and behaviors to screen and address social needs among patients.

Method

The authors used 2016 data from the American Medical Association Physician Masterfile database to identify a purposeful sample of U.S. physicians (n = 1,002); data obtained in 2017 were analyzed. Chi-squared tests of proportions and binomial regression analyses were employed to investigate associations between the belief that it is a physician’s responsibility to address health disparities and perceptions of physician behaviors to screen for and address social needs, accounting for physician, clinical practice, and patient characteristics.

Results

Of 188 respondents, respondents who felt that physicians have a responsibility to address health disparities were more likely than their peers (who did not feel that physicians have such a responsibility) to report that a physician on their health care team would screen for social needs that were psychosocial (e.g., safety, social support) (45.5% vs 29.6%, P = .03) and material (e.g., food, housing) (33.0% vs 13.6%, P < .0001). They were also more likely to report that a physician on their health care team would address both psychosocial needs (48.1% vs 30.9%, P = .02) and material needs (21.4% vs 9.9%, P = .04). With the exception of screening for psychosocial needs, these associations persisted in adjusted models.

Conclusions

Engaging physicians to screen for and address social needs should couple efforts to expand infrastructure with educational efforts about professionalism and health disparities, especially underlying drivers such as structural racism and the social determinants of health.
Prophylactic Antibiotics for Deep Inferior Epigastric Perforator Flap Breast Reconstruction: A Comparison between Three Different Duration Approaches
Authors: Changchien Chih-Hsuan , Fang Chien-Liang , Tsai Chong-Bin , Hsu Chin-Hao , Yang Hsin-Yi , Chen Ming-Shan , Lin Yi-Ling
Published: February 2023

Background:

There is no consensus on the duration of prophylactic antibiotic use for autologous breast reconstruction after mastectomy. We attempted to standardize the use of prophylactic antibiotics after mastectomy using a deep inferior epigastric perforator flap for the breast reconstruction procedure.

Methods:

This retrospective case series included 108 patients who underwent immediate breast reconstruction with a deep inferior epigastric perforator flap at the Ditmanson Medical Foundation Chia-Yi Christian Hospital between 2012 and 2019. Patients were divided into three groups based on the duration of prophylactic antibiotic administration (1, 3, and >7 days) for patients with drains. Data were analyzed between January and April 2021.

Results:

The prevalence of surgical site infection in the breast was 0.93% (1/108), and in the abdomen it was 0%. The patient groups did not differ by age, body mass index, smoking status, or neoadjuvant chemotherapy. Only one patient experienced surgical site infection in the breast after half-deep necrosis of the inferior epigastric perforator flap. There were no significant differences in surgical site infection based on the duration of prophylactic antibiotic use. The operation time, methods of breast surgery, volume of fluid drainage in the first 3 days of the abdominal and breast drains, and day of removal of the abdominal and breast drains did not affect surgical site infection.

Conclusion:

Based on these data, we do not recommend extending prophylactic antibiotics beyond 24 hours in deep inferior epigastric perforator reconstruction.
Promoting Patient-Centered Fasting Through E-Mail Reminders
Authors: Robbins Karen M.
Published: February 2023

Historical fasting practices before 1999 advised that surgical patients should have nothing to eat or drink after midnight to minimize the risk of aspiration. This practice can lead to prolonged fasting from food and liquids, which causes irritability, hunger, excessive thirst, and stress for the child and their caregiver. In addition, an increased inflammatory response and insulin resistance can occur during surgery. Research has demonstrated that fasting from clear liquids for 1–2 hours before surgery does not increase the risk of aspiration in children. A pre- and post-intervention quality improvement project was conducted in a pediatric surgical department in central Florida. From March to August 2022, 346 parents of children scheduled for general surgery were included in the project. Both groups received a reminder phone call the day before surgery with their preoperative instructions. In addition to a phone call, the post-intervention group also received an e-mail summarizing fasting instructions and times. This quality improvement project compared fasting times from food, nonclear liquids, and clear liquids before and after implementing an e-mail message reminder. The mean fasting times for clear and nonclear liquids did not change significantly from the baseline group to the post-intervention group. However, the mean solid fasting times did decrease significantly from 13.8 to 12.9 hours (p < .05) in the post-intervention group. Sending an e-mail reminder the day before surgery significantly reduced the mean fasting times for food. However, additional interventions and parental education may be needed to promote a reduction in fasting from clear and nonclear liquids.
Use of machine learning in the field of prosthetics and orthotics: A systematic narrative review
Authors: Choo Yoo Jin , Chang Min Cheol
Published: February 2023

Although machine learning is not yet being used in clinical practice within the fields of prosthetics and orthotics, several studies on the use of prosthetics and orthotics have been conducted. We intend to provide relevant knowledge by conducting a systematic review of prior studies on using machine learning in the fields of prosthetics and orthotics. We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane, Embase, and Scopus databases and retrieved studies published until July 18, 2021. The study included the application of machine learning algorithms to upper-limb and lower-limb prostheses and orthoses. The criteria of the Quality in Prognosis Studies tool were used to assess the methodological quality of the studies. A total of 13 studies were included in this systematic review. In the realm of prostheses, machine learning has been used to identify prosthesis, select an appropriate prosthesis, train after wearing the prosthesis, detect falls, and manage the temperature in the socket. In the field of orthotics, machine learning was used to control real-time movement while wearing an orthosis and predict the need for an orthosis. The studies included in this systematic review are limited to the algorithm development stage. However, if the developed algorithms are actually applied to clinical practice, it is expected that it will be useful for medical staff and users to handle prosthesis and orthosis.
Chronic Intratendinous Tophaceous Gout in Repaired Second Extensor Digitorum Communis and Extensor Indicis Proprius Tendons
Authors: Heo Jae-Woo , Whang Jong Ick , Park Hyun Sik
Published: February 2023

A 26-year-old male patient visited outpatient clinic for pain and palpable mass at 2nd extensor digitorum communis zone V region since last year. He underwent a posttraumatic extensor tenorrhaphy on the same location 11 years ago. Otherwise previously healthy, his blood test revealed an elevated uric acid level. Preoperative magnetic resonance imaging scan suggested a lesion, such as tenosynovial hemangioma and neurogenic tumor. Excisional biopsy was performed, and total excision of the compromised second extensor digitorum communis and extensor indicis proprius tendons was also necessary. Palmaris longus tendon was grafted to the defect. Postoperative biopsy report confirmed a crystalloid material with giant cell associated granulomas, suggestive of gouty tophi.
Mortality by cause of death in Brazil: effects of the COVID-19 pandemic and contribution to changes in life expectancy at birth
Authors: Fernandes Fernando , Turra Cássio M. , França Giovanny V. A. , Castro Marcia C.
Published: February 2023

We investigate the consequences of the COVID-19 pandemic on other underlying causes of death in Brazil in 2020 and 2021. We estimate monthly age-standardized mortality rates for 2010-2021 and decompose those time series into three additive components: trend, seasonality, and remainder. Given the long-term trend and historical seasonal fluctuations, we assume that any impact from the pandemic will be left on the remainder. We also decompose the contributions of COVID-19 deaths (direct effect) and those from other causes (indirect effects) to the annual change in life expectancy at birth (𝑒0) from 2017 to 2021. Broadly, the remainder mirrors the trajectory of pandemic waves. The impact of the COVID-19 pandemic on other causes of death was not limited to increases but also decreases. The direct effects of the pandemic reduced 𝑒0by 1.89 years between 2019 and 2020 and 1.77 between 2020 and 2021. Indirect effects increased 𝑒0by 0.44 between 2019 and 2020 and had virtually no impact on 𝑒0between 2020 and 2021. Whether trajectories in mortality rates and annual gains in 𝑒0will quickly return to pre-pandemic levels depends on governmental actions to mitigate the consequences of the COVID-19 pandemic.
The prevalence of low dose aspirin use for prevention of adverse cardiovascular events and its associated factors among patients with diabetes mellitus: A hospital based cross-sectional study
Authors: Tukeni Kedir Negesso , Mohammed Ebrahim Umer , Regassa Nigatu Asfaw , Abera Eyob Girma
Published: February 2023

Background

Cardiovascular diseases (CVD) are the most common causes of mortality and morbidity among diabetic patients. Aspirin is recommended for primary and secondary prevention of cardiovascular events in patients with diabetics who are eligible for therapy based on active international guidelines. However, these active guidelines are underutilized. Hence, this article helps to assess low dose aspirin use and its associated factors in patients with diabetes mellitus on follow-up at the diabetes clinic of Jimma Medical Center (JMC).

Method

A cross-sectional study was conducted among 388 diabetic patients on follow-up at the diabetic clinic of JMC during October 1, 2020 to November 15, 2020. The collected data were cleaned and entered into EpiData version 4.6 then exported to STATA version 16.0 for analysis. Descriptive statistics and multivariable logistic regression was employed to identify the relationship between dependent and independent variables with declaring statistical significance if P value is less than 0.05.

Result

Out of the total 388 diabetic patients interviewed, Most of the patients were in the age group of 50-54 (35.8%) with the mean age of 48.8 [48.2, 51.4] years old. About half (48.7%) of them had a history of hypertension. Nearly double of the study participants (47.2%) were utilizing a low dose aspirin. Aspirin was indicated for 80 (20.6%) of the patients despite 21 (26.2%) of them were not using it. It was both indicated and prescribed in 59 (15.2%) of the cases. Older age, longer duration of DM, dyslipidemia, and hypertension were associated with more likely utilization of low dose aspirin.

Conclusion

About half of the DM patients were utilizing low dose aspirin, while only one fifth of them were having indications to do so. Furthermore, one fourth of the patients were not taking low dose aspirin for the prevention of cardiovascular events despite they were supposed to use it. Therefore, these findings suggest a greater need for physicians to carefully assess the indications to prescribe aspirin with a clear explanation of the it’s advantages in these specific patient population. Ultimately, future studies should examine the influence of updating guidelines on clinician behaviors to avoid irrational use of aspirin and the association of changing trends in preventive aspirin use with the development of CVD in patients with DM.
Protective effect of plasma neutralization from prior SARS-CoV-2 Omicron infection against BA.5 subvariant symptomatic reinfection
Authors: Chen Xiaosu , Xu Yanli , Xie Yan , Song Weiliang , Hu Ye , Yisimayi Ayijiang , Shao Fei , Geng Li , Wang Ying , Gao Hongmei , Shi Yansong , Gao Fei , Jin Ronghua , Shen Zhongyang , Cao Yunlong
Published: February 2023

From December 2022 to January 2023, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections caused by BA.5 and BF.7 subvariants of B.1.1.529 (Omicron) swept across mainland China. It is crucial to estimate the protective effect of the neutralizing antibodies generated by such mass infections against the next potential SARS-CoV-2 reinfection wave, especially if driven by CH.1.1 or XBB.1.5. Previously, we recruited and continuously followed a cohort of individuals that experienced Omicron BA.1, BA.2, and BA.5 breakthrough infections, as well as a control cohort with no history of SARS-CoV-2 infection. In the previously uninfected cohort, the total symptomatic infection rate surveyed during the outbreak was 91.6%, while the symptomatic reinfection rate was 32.9%, 10.5%, and 2.8% among individuals with prior Omicron BA.1, BA.2 and BA.5 infection, respectively, with median intervals between infections of 335, 225 and 94 days. Pseudovirus neutralization assays were performed in plasma samples collected from previously Omicron BA.1-infected individuals approximately 3 months before the outbreak. Results indicate a robust correlation between the plasma neutralizing antibody titers and the protective effect against symptomatic reinfection. The geometric mean of the 50% neutralizing titers (NT50) against D614G, BA.5, and BF.7 were 2.0, 2.5, and 2.3-fold higher in individuals without symptomatic reinfection than in those with symptomatic reinfection (p< 0.01). Low plasma neutralizing antibody titer (below the geometric mean of NT50) was associated with an enhanced cumulative risk of symptomatic reinfection, with a hazard ratio (HR) of 23.55 (95% CI: 9.23-60.06) against BF.7 subvariant. Importantly, neutralizing antibodies titers post one month after BF.7/BA.5 breakthrough infections against CH.1.1 and XBB.1.5 are similar to that against BF.7 from individuals with prior BA.1 infection while not experiencing a symptomatic BF.7/BA.5 reinfection (plasma collected 3 months before the outbreak), suggesting that the humoral immunity generated by the current BF.7/BA.5 breakthrough infection may provide protection against CH.1.1 and XBB.1.5 symptomatic reinfection wave for 4 months. Of note, the higher hACE2 binding of XBB.1.5 may reduce the protection period since the potential increase of infectivity.
Dying to make a care policy: Community perception of causes of deaths using standardized verbal autopsy method: Saudi type 2 diabetes mellitus register data
Authors: Alyazidi Faleh , Shakely Deler , Petzold Max , Alyazidi Fawaz , Hussain-Alkhateeb Laith
Published: February 2023

Diabetes mellitus (DM) is a serious global health issue which significantly impacts public health and socioeconomic development. Exploring how the community perceives the causes of deaths and their associated risk factors is crucial for public health. This study combines verbal autopsy (VA) with the Type 2 Diabetes Mellitus (T2DM) register to explore community perceptions of causes of death and associated influential factors in the western region of Saudi Arabia. 302 VA interviews were conducted with relatives or caregivers of deceased who died between 2017 and 2021 based on T2DM medical register from Alnoor Specialist Hospital in Makkah city, Saudi Arabia. Cause-specific mortality fractions (CSMFs) obtained from the VA using the InterVA-5 model were utilized to assess community perception. We used a multivariable logistic regression model to determine factors influencing community perceptions of causes of death. Lin’s CCC with 95% CI was used to analyze the concordance for the CSMFs from verbal autopsy causes of death (VACoD) as a presumed reference standard and family-reported causes of death (FRCoD). The outcomes of this study demonstrate a generally broad spectrum of community perceived mortalities, with some critical misconceptions based on the type of death and the deceased’s background and characteristics, with an overall CCC of 0.60 (95% CI: 0.20-1.00; p=003). The study findings demonstrate that community perception is weak if the deceased was male compared to female (aOR: 0.52; 95% CI: 0.26 –1.03) and if the deceased was >=80 years compared to 34–59 years (aOR: 0.48; 95% CI: 0.16-1.38), but it significantly improves among married compared to single (aOR: 2.13; 95% CI: 1.02 –4.42). The Saudi community perception of causes of death with reported type 2 diabetes was relatively plausible but varied substantially based on the type of death, sex, age >=80 years, and other vital events like marital status. Higher or lower community perception is attributed to how people may perceive risk factors associated with the causes of death, which can guide public health planning and interventional programs. The study findings further emphasize the need to employ robust and standardized VA methods within the routine medical services for a systemized assessment of families’ reported causes of death.
Long-term near-continuous recording with neuropixels probes in healthy and epileptic rats
Authors: Ghestem Antoine , Pompili Marco N , Dipper-Wawra Matthias , Quilichini Pascale P , Bernard Christophe , Ferraris Maëva
Published: February 2023

Neuropixels probes have become a crucial tool for high-density electrophysiological recordings. Although most research involving these electrodes is in acute preparations, some scientific inquiries require long-term recordings in freely moving animals. Recent reports have presented prosthesis designs for chronic recordings, but some of them do not allow for probe recovery, which is desirable given their cost. Others appear to be fragile, as these articles describe numerous broken implants. This fragility presents a challenge for recordings in rats, particularly in epilepsy models where strong mechanical stress impinges upon the prosthesis. To overcome these limitations, we present a new prosthesis specifically designed to protect the probes from strong shocks and enable the safe retrieval of electrodes after experiments. This implant was successfully used to record from healthy and epileptic rats for up to three weeks almost continuously, with a probe retrieval and reuse success rate of 91%, improving previously described recycling performances.
Designing a protein with emergent function by combinedin silico, in vitroandin vivoscreening
Authors: Kohyama Shunshi , Frohn Béla P. , Babl Leon , Schwille Petra
Published: February 2023

Recently, utilization of machine learning (ML) based methods has led to astonishing progress in protein design and, thus, the design of new biological functionality. However, emergent functions that require higher-order molecular interactions, such as the ability to self-organize, are still extremely challenging to implement. Here, we describe a comprehensivein silico, in vitro, andin vitroscreening pipeline (i3-screening) to develop and validate ML-designed artificial homologs of a bacterial protein that confers its role in cell division through the emergent function of spatiotemporal pattern formation. Moreover, we present complete substitution of a wildtype gene by an ML-designed artificial homolog inEscherichia coli. These results raise great hopes for the next level of synthetic biology, where ML-designed synthetic proteins will be used to engineer cellular functions.
Population genomics-guided engineering of phenazine biosynthesis inPseudomonas chlororaphis
Authors: Thorwall Sarah , Trivedi Varun , Wheeldon Ian
Published: February 2023

The emergence of next-generation sequencing (NGS) technologies has made it possible to not only sequence entire genomes, but also identify metabolic engineering targets across the pangenome of a microbial population. This study leverages NGS data as well as existing molecular biology and bioinformatics tools to identify and validate genomic signatures for improving phenazine biosynthesis inPseudomonas chlororaphis. We sequenced a diverse collection of 34Pseudomonasisolates using short- and long-read sequencing techniques and assembled whole genomes using the NGS reads. In addition, we assayed three industrially relevant phenotypes (phenazine production, biofilm formation, and growth temperature) for these isolates in two different media conditions. We then provided the whole genomes and phenazine production data to a unitig-based microbial genome-wide association study (mGWAS) tool to identify novel genomic signatures responsible for phenazine production inP. chlororaphis. Post-processing of the mGWAS analysis results yielded 330 significant hits influencing the biosynthesis of one or more phenazine compounds. Based on a quantitative metric (called the phenotype score), we elucidated the most influential hits for phenazine production and experimentally validated themin vivoin the most optimal phenazine producing strain. Two genes significantly increased phenazine-1-carboxamide (PCN) production: a histidine transporter (ProY_1), and a putative carboxypeptidase (PS__04251). A putative MarR-family transcriptional regulator decreased PCN titer when overexpressed in a high PCN producing isolate. Overall, this work seeks to demonstrate the utility of a population genomics approach as an effective strategy in enabling identification of targets for metabolic engineering of bioproduction hosts.
Remote Research Practices Enhance Acute Stroke Clinical Trial Enrollment
Authors: Streib Christopher D , Staugaitis Abbey , Tessmer Megan , Gaffney Denise , Khan Shayan , Broderick Joseph P. , Khatri Pooja , Sangha Navdeep S
Published: February 2023

Background

Many acute stroke clinical trials (ASCTs) are underpowered or terminated early due to poor recruitment. A pervasive challenge to ASCT recruitment is the physical separation of patients, their legally authorized representatives, research coordinators, and clinician investigators when trial-eligible patients are identified. Remote research practices (RRPs) can facilitate time-critical ASCT enrollment and follow-up assessments, however, the feasibility and effectiveness are unknown.

Methods

This case-control study retrospectively reviewed ASCT enrollment at two institutions. When conventional in-person clinical research was not possible, completion of study specific essential clinical trial events (ECTEs) were attempted via RRPs utilizing telemedicine evaluation or telephone communication. The primary outcome was successful execution of ECTEs by modality: in-person, telemedicine evaluation, or telephone communication. The secondary outcome was protocol violation rate by modality. We utilized Fisher’s Exact Test for primary and secondary outcomes and descriptive statistics to report RRP utilization.

Results

A total of 1603 individual ECTEs were attempted for 171 subjects. RRPs were utilized for 53.9% of ECTEs (19.3% telemedicine, 34.6% telephone communication). ECTEs were more likely to be completed successfully via telemedicine (100%) than in-person (98.2%) or telephone (92.3%), (p<0.01). Additionally, protocol deviations were less common with telemedicine (0.0%) than in-person (2.6%), or telephone (2.8%) (p=0.04). More than half (53.4%) of randomized ASCT enrollments were dependent upon RRPs. Randomization (94.7%) and outpatient assessments (84.6%) were more frequently completed via RRPs compared to eligibility screening (40.7%), informed consent (40.4%), supervision of study intervention (44.6%), and inpatient assessments (18.8%).

Conclusion

Remote research practices were effective and doubled randomized ASCT enrollments in comparison to conventional research models that are restricted to in-person interaction alone. Telemedicine was associated with the highest rate of successful ECTE execution and the lowest rate of protocol deviations. These findings may be confounded by indication and further definitive study is indicated.
Protocol for a cluster randomised controlled trial to evaluate the effectiveness of digital health interventions in improving non-communicable disease management during the pandemic in rural Pakistan
Authors: Wei Xiaolin , Khan Nida , Durrani Hammad , Muzaffar Naila , Haldane Victoria , Walley John D , Thorpe Kevin , Ge Erjia , Ge Shiliang , Dodd Warren , Wallace James , Aslanyan Garry , Laporte Audrey , Khan Muhammad Amir
Published: February 2023

Background: The COVID-19 pandemic has revealed gaps in global health systems, especially in the low- and middle-income countries (LMICs). Evidence shows that patients with non-communicable diseases (NCDs) are at higher risk of contracting COVID-19 and suffering direct and indirect health consequences. Considering the future challenges such as environmental disasters and pandemics to the LMICs health systems, digital health interventions (DHI) are well poised to strengthen health care resilience. This study aims to implement and evaluate a comprehensive package of DHIs of integrated COVID-NCD care to manage NCDs in primary care facilities in rural Pakistan. Methods The study is designed as a pragmatic, parallel two-arm, multi-centre, cluster randomised controlled trial. We will randomise 30 primary care facilities in three districts of Punjab, where basic hypertension and diabetes diagnosis and treatment is provided, with a ratio of 1:1 between intervention and control. In each facility, we will recruit 50 patients who have uncontrolled hypertension. The intervention arm will receive training on an integrated COVID-NCD guideline, and will use a smartphone app-based telemedicine platform where patients can communicate with health providers and peer-supporters, along with a remote training and supervision system. Usual care will be provided in the control arm. Patients will be followed up for 10 months. Our primary indicator is systolic blood pressure measured at 10 months. A process evaluation guided by implementation science frameworks will be conducted to explore implementation questions. A cost-effectiveness evaluation will be conducted to inform future scale up in Pakistan and other LMICs. Discussion: Our study is one of the first randomised controlled trials to evaluate the effectiveness of DHIs to manage NCDs to strengthen health system resilience in LMICs. We will also evaluate the implementation process and cost-effectiveness to inform future scale-up in similar resource constrained settings.
Metabolic model predictions enable targeted microbiome manipulation through precision prebiotics
Authors: Marinos Georgios , Hamerich Inga K. , Debray Reena , Obeng Nancy , Petersen Carola , Taubenheim Jan , Zimmermann Johannes , Blackburn Dana , Samuel Buck S. , Dierking Katja , Franke Andre , Laudes Matthias , Waschina Silvio , Schulenburg Hinrich , Kaleta Christoph
Published: February 2023

The microbiome is increasingly receiving attention as an important modulator of host health and disease. However, while numerous mechanisms through which the microbiome influences its host have been identified, there is still a lack of approaches that allow to specifically modulate the abundance of individual microbes or microbial functions of interest. Moreover, current approaches for microbiome manipulation such as fecal transfers often entail a non-specific transfer of entire microbial communities with potentially unwanted side effects. To overcome this limitation, we here propose the concept of precision prebiotics that specifically modulate the abundance of a microbiome member species of interest. In a first step, we show that defining precision prebiotics by compounds that are only taken up by the target species but no other species in a community is usually not possible due to overlapping metabolic niches. Subsequently, we present a metabolic modeling network framework that allows us to define precision prebiotics for a two-member C. elegans microbiome model community comprising the immune-protective Pseudomonas lurida MYb11 and the persistent colonizer Ochrobactrum vermis MYb71. Thus, we predicted compounds that specifically boost the abundance of the host-beneficial MYb11, four of which were experimentally validated in vitro (L-serine, L-threonine, D-mannitol, and γ-aminobutyric acid). L-serine was further assessed in vivo, leading to an increase in MYb11 abundance also in the worm host. Overall, our findings demonstrate that constraint-based metabolic modeling is an effective tool for the design of precision prebiotics as an important cornerstone for future microbiome-targeted therapies.
Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing
Authors: Butterfield Russell J , Dunn Diane M , Duval Brett , Moldt Sarah , Weiss Robert B
Published: February 2023

Fascioscapulohumeral muscular dystrophy (FSHD) is caused by a unique genetic mechanism that relies on contraction and hypomethylation of the D4Z4 macrosatellite array on the chromosome 4q telomere allowing ectopic expression of theDUX4gene in skeletal muscle. Genetic analysis is difficult due to the large size and repetitive nature of the array, a nearly identical array on the 10q telomere, and the presence of divergent D4Z4 arrays scattered throughout the genome. Here, we combine nanopore long-read sequencing with Cas9-targeted enrichment of 4q and 10q D4Z4 arrays for comprehensive genetic analysis including determination of the length of the 4q and 10q D4Z4 arrays with base-pair resolution. In the same assay, we differentiate 4q from 10q telomeric sequences, determine A/B haplotype, identify paralogous D4Z4 sequences elsewhere in the genome, and estimate methylation for all CpGs in the array. Asymmetric, length-dependent methylation gradients were observed in the 4q and 10q D4Z4 arrays that reach a hypermethylation point at approximately 10 D4Z4 repeat units, consistent with the known threshold of pathogenic D4Z4 contractions. High resolution analysis of individual D4Z4 repeat methylation revealed areas of low methylation near the CTCF/insulator region and areas of high methylation immediately preceding theDUX4transcriptional start site. Within theDUX4exons, we observed a waxing/waning methylation pattern with a 180-nucleotide periodicity, consistent with phased nucleosomes. Targeted nanopore sequencing complements recently developed molecular combing and optical mapping approaches to genetic analysis for FSHD by adding precision of the length measurement, base-pair resolution sequencing, and quantitative methylation analysis.
Discovery of multi-state gene cluster switches determining the adaptive mitochondrial and metabolic landscape of breast cancer
Authors: Menegollo Michela , Bentham Robert B. , Henriques Tiago , Qi Ng Seow , Ren Ziyu , Esculier Clarinde , Agarwal Sia , Tong Emily , Lo Clement , Ilangovan Sanjana , Szabadkai Zorka , Suman Matteo , Patani Neill , Ghanate Avinash , Bryson Kevin , Stein Robert C. , Yuneva Mariia , Szabadkai Gyorgy
Published: February 2023

Adaptive metabolic switches are proposed to underlie conversions between cellular states during normal development as well as in cancer evolution, where they represent important therapeutic targets. However, the full spectrum, characteristics and regulation of existing metabolic switches are unknown. We propose that metabolic switches can be recognised by locating large alternating gene expression patterns and associate them with specific metabolic states. We developed a method to identify interspersed genesets by massive correlated biclustering (MCbiclust) and to predict their metabolic wiring. Testing the method on major breast cancer transcriptome datasets we discovered a series of gene sets with switch-like behaviour, predicting mitochondrial content, activity and central carbon fluxes in tumours associated with different switch positions. The predictions were experimentally validated by bioenergetic profiling and metabolic flux analysis of13C-labelled substrates and were ultimately extended by geneset analysis to link metabolic alterations to cellular states, thus predicting tumour pathology, prognosis and chemosensitivity. The method is applicable to any large and heterogeneous transcriptome dataset to discover metabolic and associated pathophysiological states.

Statement of significance

We present a novel method to identify the transcriptomic signatures of metabolic switches underlying divergent routes of cellular transformation. We illustrate the power of the method by stratifying breast cancer into metabolic subtypes, predicting their biology, architecture and clinical outcome.
Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia
Authors: Ferrer Miriam , Mourikis Nicholas , Davidson Emma E. , Kleeman Sam O. , Zaccaria Marta , Habel Jill , Rubino Rachel , Flint Thomas R. , Connell Claire M. , Lukey Michael , White Eileen P. , Coll Anthony P. , Venkitaraman Ashok R. , Janowitz Tobias
Published: February 2023

The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.
Spenito-dependent metabolic sexual dimorphism intrinsic to fat storage cells
Authors: Diaz Arely V. , Matheny Tyler , Stephenson Daniel , Nemkov Travis , D’Alessandro Angelo , Reis Tânia
Published: February 2023

Metabolism in males and females is distinct. Differences are usually linked to sexual reproduction, with circulating signals (e.g. hormones) playing major roles. By contrast, sex differences prior to sexual maturity and intrinsic to individual metabolic tissues are less understood. We analyzedDrosophila melanogasterlarvae and find that males store more fat than females, the opposite of the sexual dimorphism in adults. We show that metabolic differences are intrinsic to the major fat storage tissue, including many differences in the expression of metabolic genes. Our previous work identified fat storage roles for Spenito (Nito), a conserved RNA-binding protein and regulator of sex determination. Nito knockdown specifically in the fat storage tissue abolished fat differences between males and females. We further show that Nito is required for sex-specific expression of the master regulator of sex determination, Sex-lethal (Sxl). “Feminization” of fat storage cells via tissue-specific overexpression of a Sxl target gene made larvae lean, reduced the fat differences between males and females, and induced female-like metabolic gene expression. Altogether, this study supports a model in which Nito autonomously controls sexual dimorphisms and differential expression of metabolic genes in fat cells in part through its regulation of the sex determination pathway.
Speedy-PASEF: Analytical flow rate chromatography and trapped ion mobility for deep high-throughput proteomics
Authors: Szyrwiel Lukasz , Gille Christoph , Mülleder Michael , Demichev Vadim , Ralser Markus
Published: February 2023

Increased throughput in proteomic experiments can improve accessibility of proteomic platforms, reduce costs and facilitate new approaches in systems biology and biomedical research. Here we propose Speedy-PASEF, a combination of analytical flow rate chromatography with ion mobility separation of peptide ions, data-independent acquisition and data analysis with the DIA-NN software suite, for conducting fast, high-quality proteomic experiments that require only moderate sample amounts. For instance, using a 500-μl/min flow rate and a 3-minute chromatographic gradient, Speedy-PASEF quantified 5,211 proteins from 2 μg of a mammalian cell-line standard at high quantitative accuracy and precision. We further used Speedy-PASEF to analyze blood plasma samples from a cohort of COVID-19 inpatients, using a 3-minute chromatographic gradient and alternating column regeneration on a dual pump system, for processing 398 samples per day. Speedy-PASEF delivered a comprehensive view of the COVID-19 plasma proteome, allowing classification of the patients according to disease severity and revealing plasma biomarker candidates. Speedy-PASEF thus facilitates acquisition of high-quality proteomes in large numbers.
AC. elegansmale pheromone feminizes germline gene expression in hermaphrodites and imposes life-history costs
Authors: Angeles-Albores David , Aprison Erin Z. , Dzitoyeva Svetlana , Ruvinsky Ilya
Published: February 2023

Abstract

Sex pheromones improve reproductive success, but also impose costs. Here we show that even brief exposure to physiological amounts of the dominantC. elegansmale pheromone, ascr#10, alters the expression of thousands of genes in hermaphrodites. The most dramatic effect on the transcriptome was the upregulation of genes expressed during oogenesis and downregulation of genes associated with male gametogenesis. Among the detrimental effects of ascr#10 on hermaphrodites is the increased risk of persistent infections caused by pathological pharyngeal hypertrophy. Our results reveal a way in which social signals help to resolve the inherent conflict between spermatogenesis and oogenesis in a simultaneous hermaphrodite, presumably to optimally align reproductive function to the presence of potential mating partners. They also show that the beneficial effects of the pheromone are accompanied by harmful consequences that reduce lifespan.
Integrated Cell Landscape and Dynamics in the Progression of Bone Repair
Authors: Shi Junfeng , Wang Jie , Yin Shi , Lin Sihan , Jiang Fei , Zhang Maolin , Wu Xiaolin , Shen Lijuan , Gu Xuefeng , Yang Ruomeng , Yang Jiawei , Wen Jin , Zhang Wenjie , Chang Qing , Jiang Xinquan
Published: February 2023

Bone homeostasis and repair is a systematic progress with spatiotemporal interaction of multiple cell types involved in skeletal and immune system. Precise spatiotemporal regulation of cell type-specific functions in bone repair contributes to further development of tissue engineering and regenerative medicine. Here, we utilized single-cell RNA sequencing to illustrate a map of cell landscape and dynamics in the progression of rodent bone self-healing and a perturbation by lymphoid cell-deficiency. We identified different functions of myeloid cell and lymphoid cell to osteogenesis and angiogenesis during bone repair and their mutual complementation under lymphoid cell-deficient condition. Additionally, we used CD34+humanized reconstituted mice to reveal further insights into the mechanism of human bone homeostasis and repair. Our integrated cellular analysis of bone repair explores the functional diversity and complementation between myeloid cells and lymphoid cells during bone healing process and provides further therapeutic implications for the treatment of bone disease and degeneration following ageing.
Repeatability of adaptation in sunflowers: genomic regions harbouring inversions also drive adaptation in species lacking an inversion
Authors: Soudi Shaghayegh , Jahani Mojtaba , Todesco Marco , Owens Gregory L. , Bercovich Natalia , Rieseberg Loren H. , Yeaman Sam
Published: February 2023

Local adaptation commonly involves alleles of large effect, which experience fitness advantages when in positive linkage disequilibrium (LD). Because segregating inversions suppress recombination and facilitate the maintenance of LD between locally adapted loci, they are also commonly found to be associated with adaptive divergence. However, it is unclear what fraction of an adaptive response can be attributed to inversions and alleles of large effect, and whether the loci within an inversion could still drive adaptation in the absence of its recombination-suppressing effect. Here, we use genome-wide association studies to explore patterns of local adaptation in three species of sunflower:Helianthus annuus,H. argophyllus, andH. petiolaris, which each harbour a large number of species-specific inversions. We find evidence of significant genome-wide repeatability in signatures of association to phenotypes and environments, which are particularly enriched within regions of the genome harbouring an inversion in one species. This shows that while inversions may facilitate local adaptation, at least some of the loci can still harbour mutations that make substantial contributions without the benefit of recombination suppression in species lacking a segregating inversion. While a large number of genomic regions show evidence of repeated adaptation, most of the strongest signatures of association still tend to be species-specific, indicating substantial genotypic redundancy for local adaptation in these species.
Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis
Authors: Hasegawa Yoshihiro , Franks Jennifer M. , Tanaka Yusuke , Uehara Yasuaki , Read David F. , Williams Claire , Srivatsan Sanjay , Pitstick Lori B. , Nikolaidis Nikolaos M. , Shaver Ciara M. , Wu Huixing , Gardner Jason C. , Osterburg Andrew R. , Yu Jane J. , Kopras Elizabeth J. , Teitelbaum Steven L. , Wikenheiser-Brokamp Kathryn A. , Trapnell Cole , McCormack Francis X.
Published: February 2023

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored the mechanisms of silica-induced pulmonary fibrosis in a mouse model using multiple modalities including wholelung single-nucleus RNA sequencing. These analyses revealed that in addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor-κB ligand (RANKL) in pulmonary lymphocytes and alveolar type II cells. Furthermore, anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated silica-induced pulmonary fibrosis. We conclude that silica induces osteoclast-like differentiation of distinct recruited and tissue resident monocyte populations, leading to progressive lung injury, likely due to sustained elaboration of bone resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.

One Sentence Summary

Silica induces the alveolar epithelium to reprogram recruited and resident pulmonary myeloid cells to become osteoclasts that contribute to pulmonary fibrosis.