bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioinformatics analysis of the clinical significance of HLA class II in breast cancer
Authors: Wu Guihua , Xiao Gaofang , Yan Yuhang , Guo Chengwei , Hu Ningdong , Shen Sandi
Published: October 2022

Human leukocyte antigen (HLA) class II plays critical roles in antigen presentation and the initiation of immune responses. However, the correlation between the HLA class II gene expression level and the survival of patients with breast cancer is still under investigation. We analyzed microarray and RNA-Seq data of breast cancer from the cancer genome atlas (TCGA), genotype-tissue expression (GTEx) and Oncomine databases by using bioinformatics tools. The expression of the HLA-DQA1, HLA-DQA2, and HLA-DQB2 genes was significantly upregulated in breast cancer. Higher expression levels of HLA class II genes in breast cancer, especially HLA-DOB and HLA-DQB2, were significantly associated with better overall survival. Furthermore, the expression of HLA class II genes was more closely associated with survival in breast cancer than in other cancer types. CD48 coexpressed with both HLA-DOB and HLA-DQB2 was also positively associated with the overall survival of breast cancer patients. The results indicated that HLA class II and CD48 may enhance antitumor immunity, and their expression patterns may serve as potential prognostic biomarkers and therapeutic targets in breast cancer.
Growth modulation for angular knee deformities: a practical guideline
Authors: Braga Susana Reis , Santili Claudio , Rodrigues Natasha Vogel Majewski , Soni Jamil F. , Green Daniel W.
Published: October 2022

Purpose of review

This study aimed to review the established concepts and advances related to growth modulation for treating knee angular deformities. Although they are considered well tolerated procedures, careful indications and accurate techniques are necessary to ensure good results.

Recent findings

In addition to general clinical and radiographic evaluations, new tools such as two-dimensional low-dose radiography and gait analysis have been used to clarify angular and torsional combinations and the impact of mild angulations on the knee joint. Temporary epiphysiodesis is commonly the choice, and it can be performed with different implants such as staples, tension band plates (TBP), percutaneous transphyseal screws (PETS), sutures, and screws.

Considering its principles, TBP has been preferred for younger children. Cost can be a limitation, and research for alternative implants such as screws and nonabsorbable sutures indicate they might be an alternative in the future. In adolescents, PETS becomes an attractive alternative; however, its reversible character has been controversial, and further studies are needed to establish limits in younger patients.
The effect of autologous fat grafting and platelet-rich plasma injections in osteoarthritis of the CMC joint of the thumb: a systematic review and meta-analysis
Authors: Winter Raimund , Hasiba-Pappas Sophie K. , Tuca Alexandru-Cristian , Zrim Robert , Nischwitz Sebastian , Popp Daniel , Lumenta David Benjamin , Girsch Werner , Kamolz Lars-P.
Published: October 2022

Background:

For the treatment of CMC arthritis of the thumb various therapies are used. Infiltration therapy with autologous substances such as platelet-rich plasma and autologous fat have recently gained increasing attention due to beneficial pain-reducing effects in arthritis and the associated regenerative potential.

The extent of clinical evidence in this area, however, and how well autologous substances work in terms of pain reduction and improvements in hand function remains unclear.

Methods:

A systematic review and meta-analysis were conducted to evaluate the current evidence and to provide more insight into pain reduction and improvement in hand function after infiltration of autologous substances. We identified 11 clinical trials of which we included 8 in the meta-analysis.

Results:

Autologous substances achieved a good and long-lasting pain reduction, which may also be accompanied by corresponding improvement in hand function. Autologous substances appear to be more effective than corticoid infiltrations. The infiltration of autologous fat seems to be particularly promising in more advanced stages of CMC arthritis of the thumb also.

Our meta-analysis showed a mean pain reduction of 2.4-3 in VAS score and a reduction of 18-19 points in the DASH questionnaire after infiltration with autologous substances.

Conclusions:

In conclusion, both PRP and autologous fat infiltration offer an efficient and long lasting minimally invasive therapy option in the treatment of CMC arthritis of the thumb.
“Deconstructing Allograft Adipose and Fascia Matrix to Treat Soft Tissue Defects: The Addition of Fascia Matrix to Adipose Matrix Improves Angiogenesis, Volume Retention and Adipogenesis in a Rodent Model”
Authors: Ziegler Mary E. , Sorensen Alexandria M. , Banyard Derek A. , Sayadi Lohrasb R. , Chnari Evangelia , Hatch Michaela M. , Tassey Jade , Mirzakhanyan Yeva , Gershon Paul D. , Hughes Christopher C.W. , Evans Gregory R.D. , Widgerow Alan D.
Published: October 2022

Background:

Autologous fat grafting is commonly used for soft tissue repair (~90,000 cases/year in the US), but outcomes are limited by volume loss (20-80%) over time. Human allograft adipose matrix (AAM) stimulates de novo adipogenesis in vivo, but retention requires optimization. The extracellular matrix derived from superficial fascia, interstitial within the adipose layer, is typically removed during AAM processing. Thus, fascia, which contains numerous important proteins, might cooperate with AAM to stimulate de novo adipogenesis, improving long-term retention compared to AAM alone.

Methods:

Human AAM and fascia matrix proteins (back and upper leg regions) were identified by mass spectrometry and annotated by gene ontology (GO). A 3D in vitro angiogenesis assay was performed. Finally, AAM and/or fascia (1mL) was implanted into 6-8-week-old male Fischer rats. After 8 weeks, we assessed graft retention by gas pycnometry and angiogenesis (CD31) and adipocyte counts (H&E) histologically.

Results:

GO annotation revealed an angiogenic enrichment pattern unique to the fascia, including lactadherin, collagen alpha-3(V) chain and tenascin-C. In vitro, AAM stimulated 1.0±0.17 angiogenic sprouts/bead. The addition of fascia matrix increased sprouting by 88% (2.0±0.12; p<0.001). A similar angiogenic response (CD31) was observed in vivo. Graft retention volume was 25% (0.25±0.13) for AAM, significantly increasing to 60% (0.60±0.14) for AAM/fascia (p<0.05). De novo adipogenesis was 12% (12.4±7.4) for AAM, significantly increasing to 51% (51.2±8.0) for AAM/fascia (p<0.001) via adipocyte quantification.

Conclusion:

Combining fascia matrix with AAM improves angiogenesis and adipogenesis compared to AAM alone in rats. These preliminary in vitro and pilot animal studies should be further validated before definitive clinical adoption.
Programmatic Retention in Prevention of Mother-to-Child Transmission (PMTCT) Programs: Estimated Rates and Cofactors Using Different Nonretention Measures
Authors: Jiang Wenwen , Ronen Keshet , Osborn Lusi , Drake Alison L. , Unger Jennifer A. , Matemo Daniel , Richardson Barbra A. , Kinuthia John , John-Stewart Grace
Published: October 2022

Background:

Prevention of mother‐to‐child transmission programs serve women continuing and initiating antiretroviral therapy (ART) in pregnancy, and follow-up schedules align to delivery rather than ART initiation, making conventional HIV retention measures (assessed from ART initiation) challenging to apply. We evaluated 3 measures of peripartum nonretention in Kenyan women living with HIV from pregnancy to 2 years postpartum.

Methods:

This longitudinal analysis used programmatic data from the Mobile WAChX trial (NCT02400671). Outcomes included loss to follow-up (LTFU) (no visit for ≥6 months), incomplete visit coverage (<80% of 3-month intervals with a visit), and late visits (>2 weeks after scheduled date). Predictors of nonretention were determined using Cox proportional hazards, log-binomial, and generalized estimating equation models.

Results:

Among 813 women enrolled at a median of 24 weeks gestation, incidence of LTFU was 13.6/100 person-years; cumulative incidence of LTFU by 6, 12, and 24 months postpartum was 16.7%, 20.9%, and 22.5%, respectively. Overall, 35.5% of women had incomplete visit coverage. Among 794 women with 12,437 scheduled visits, a median of 11.1% of visits per woman were late (interquartile range 4.3%–23.5%). Younger age, unsuppressed viral load, unemployment, ART initiation in pregnancy, and nondisclosure were associated with nonretention by all measures. Partner involvement was associated with better visit coverage and timely attendance. Women who became LTFU had higher frequency of previous late visits (16.7% vs. 7.7%, P < 0.0001).

Conclusions:

Late visit attendance may be a sentinel indicator of LTFU. Identified cofactors of prevention of mother‐to‐child transmission programmatic retention may differ depending on retention measure assessed, highlighting the need for standardized measures.
Impact of FDG PET/CT Scan in Changing Management of Well-Differentiated Neuroendocrine Tumors With Ki67 Index Less Than or Equal to 5%
Authors: Choudhury Sayak , Agrawal Archi , Rangarajan Venkatesh , Puranik Ameya , Bal Munita , Chaudhari Vikram , Bhandare Manish , Purandare Nilendu , Shah Sneha , Ramaswamy Anant , Ostwal Vikas , Shrikhande Shailesh V.
Published: October 2022

Objectives

This study aimed to see the impact of FDG PET/CT with somatostatin receptor PET (SSTR PET) in directing the treatment plan in lower-grade well-differentiated neuroendocrine tumors (NETs) with Ki67 index ≤5%.

Methods

Sixty-three NET cases with Ki67 index ≤5% with both FDG PET and SSTR PET (68Ga-DOTANOC PET) were included for this retrospective observational study. FDG PET findings were classified into positive, weakly positive, and negative based on a visual scale. Clinical factors considered while referring for FDG PET scan were audited from electronic medical records. The addition of chemotherapy was considered as FDG-directed change in treatment.

Results

Sixty patients showed intense SSTR expression in the primary and metastatic sites (if present). Three patients showed no evidence of SSTR expression, in whom the scans were done after resection of the primary tumor. The FDG PET was positive in 25 (39.6%), weakly positive in 11 (17.4%), and negative in 27 (42.8%). Specific clinical reason for doing FDG PET was found in 34 patients, and in the remaining 29, there was no justification or specific indication for doing the FDG study; 73.5% of patients from the former group was either FDG positive or weakly positive, and 26.5% were negative; in the other group, 62.1% were FDG-negative, and 37.9% were positive (P = 0.004). Treatment-naive patients with symptom duration of ≤5 months were associated with more FDG positivity than patients with >5 months' symptom duration (P = 0.006). FDG PET/CT led to change in management in 17.4% of all the patients, 9.6% of grade 1, and 25% of grade 2 patients.

Conclusions

In lower-grade NET, FDG positivity was seen in a sizable number of the cases, and this led to change in management in 17.4% of the cases. Specific clinical features could be utilized to successfully discriminate between FDG-avid and non–FDG-avid disease in lower-grade NETs, and this had impact in management change as well.
Orbital Extenteration Defects: Ablative and Reconstructive Flowchart Proposal
Authors: Mannelli Giuditta , Comini Lara V. , Marzola Antonio , Volpe Yari , Mazzini Cinzia , Santoro Nicola , Delcroix Luca , Molteni Gabriele , Spinelli Giuseppe
Published: October 2022

Orbital exenteration is a radical and disfiguring operation. It is still under debate the absence of correlation between the term describing the resulting orbital defect and the type of reconstruction. Authors’ goal was to propose a consistent and uniform terminology for Orbital Exenteration surgery in anticipation of patients’ tailored management. Twenty-five patients who underwent orbital exenteration between 2014 and 2020 were reviewed. A parallel comprehensive literature review was carried on. Five different types of orbital exenteration where outlined. Multiple reconstructive procedures were enclosed. An algorithm for orbital reconstruction was proposed based on anatomic boundaries restoration. Eyelid removal was first considered as an independent reconstructive factor, and both orbital roof and floor were indicated as independent reconstructive goals, which deserve different defect classification. In our opinion, this algorithm could be a useful tool for patient counseling and treatment selection, which might allow a more tailored patient care protocol.

Level of Evidence

Level III.
Transantral Approach With an Optical Navigation System for Cystic Lesions at the Pterygoid Process
Authors: Cho Seongji , Han Jisuk , Kwon Ik-Jae , Myoung Hoon
Published: October 2022

A 48-year-old woman with hypernasality symptoms and discomfort in the right maxillary area was diagnosed with cystic lesions at the pterygoid process and linguoposterior mandible area. Cyst enucleation was performed through a transantral approach with an optical navigation system. A bony window on the anterior sinus wall was created, and an optical navigation system was used to locate the cystic lesions. After the cystic mass was removed, the bony window was repositioned with prebent plates. Both cystic lesions were diagnosed as postoperative maxillary cysts, and no other complications were observed.
Postgraduate Surgical Education in East, Central, and Southern Africa: A Needs Assessment Survey
Authors: Elmaraghi Shady , Park Keon Min , Rashidian Nikdokht , Yap Ava , Faktor Kara , Ozgediz Doruk , Borgstein Eric , Bekele Abebe , Alseidi Adnan , Tefera Girma
Published: October 2022

Background:

The Lancet Commission on Global Surgery has identified workforce development as an important component of National Surgical Plans to advance the treatment of surgical disease in low- and middle- income countries. The goal of our study is to identify priorities of surgeon educators in the region so that collaboration and intervention may be appropriately targeted.

Study Design:

The American College of Surgeons (ACS) Operation Giving Back (OGB), in collaboration with leaders of the College of Surgeons of Eastern, Central and Southern Africa (COSECSA), developed a survey to assess the needs and limitations of surgical educators working under their organizational purview. COSECSA members were invited to complete an online survey to identify and prioritize factors within five domains: (1) Curriculum Development, (2) Faculty Development, (3) Structured Educational Content, (4) Skills and Simulation Training, and (5) Trainee Assessment and Feedback.

Results:

One-hundred sixty-six responses were received after three calls for participation, representing all countries in which COSECSA operates. The majority of respondents (78%) work in tertiary referral centers. Areas of greatest perceived need were identified in the Faculty Development and Skills and Simulation domains. Although responses differed between domains, clinical responsibilities, cost, and technical support were commonly cited as barriers to development.

Conclusion:

This needs assessment identified educational needs and priorities of COSECSA surgeons. Our study will serve as a foundation for interventions aimed at further improving graduate surgical education and ultimately patient care in the region.
Alfentanil Pretreatment for Electroconvulsive Therapy–Associated Hemodynamic Lability
Authors: McCutchen Thomas M. , Gligorovic Predrag V. , Tighe Nathaniel T.G. , Templeton T. Wesley , Saha Amit K.
Published: October 2022

Objectives

Electroconvulsive therapy (ECT) is frequently associated with significant hemodynamic changes that increase myocardial oxygen demand including significant hypertension poststimulus. This raises concern about the cumulative effect of repetitive stress from ECT. Historically, various agents have been used to blunt this response and reduce hemodynamic fluctuations in these patients with varying degrees of efficacy. We hypothesized that bolus alfentanil administration timed with the ECT stimulus may reduce near-term hypertension and heart rate (HR) increases in patients undergoing ECT.

Methods

A randomized, double-blind, placebo-controlled AB/BA crossover trial of 87 patients 18 years or older with mood disorders was carried out. Patients received a standardized anesthetic regimen including induction with methohexital and succinylcholine and were randomized to receive either 20 μg/kg ideal bodyweight of alfentanil or placebo 60 seconds before the ECT stimulus for the first treatment and then crossed over to the other group for the second treatment. The primary outcome was the within-individual difference in preinduction systolic blood pressure and the first systolic blood pressure after the ECT stimulus.

Results

Eighty-seven patients completed the protocol. The primary outcome of increase in systolic blood pressure pre-ECT to post-ECT was 16.9 mm Hg less in the alfentanil group than the placebo group (95% confidence interval, −26.0 to −7.8; P < 0.001). The maximum HR was 6.5 beats per minute lower (95% confidence interval, −12.1 to −0.9; P = 0.024) when patients received alfentanil compared with placebo.

Conclusions

Premedication with alfentanil reduces poststimulus hypertension and increased HR in patients receiving ECT and therefore, may reduce morbidity related to this in susceptible patients.
Acute and Prophylactic Management of Postictal Agitation in Electroconvulsive Therapy
Authors: Sterina Evelina , Gregory Neha , Hermida Adriana P.
Published: October 2022

Postictal agitation (PIA) is a common adverse effect of electroconvulsive therapy (ECT), a treatment used for a variety of psychiatric disorders. Because of risk of harm to patients and health providers when patients develop PIA, its acute management and prophylaxis are of vital importance for ECT practitioners. This article describes PIA risk factors, as well as practical steps to manage this ECT complication. Nonpharmacologic patient safety interventions are critical components of PIA management. Benzodiazepines, antipsychotics, and additional anesthetic doses are discussed as acute treatment interventions. Prophylactic pharmacologic choices described include antipsychotics, postseizure anesthetics, and dexmedetomidine. Exploratory choices such as melatonin and intranasal formulations of sedatives are also discussed. This review suggests that common medication like olanzapine and propofol are cost-effective considerations to decrease PIA incidence and/or severity after ECT. In addition, dexmedetomidine presents a management alternative for treatment-resistant PIA. This literature review outlines treatment choices while suggesting future directions for considering effective treatments of postictal agitation in clinical settings.
Preparing future STEM faculty nationwide through flexible teaching professional development
Authors: Goldberg B. B. , Bruff D. , Greenler R. , Barnicle K. , Green N. , Campbell L. E. P. , Laursen S. L. , Ford M. , Serafini A. , Mack C. , Carley T. , Maimone C. , Campa H.
Published: October 2022

We report on a five-year initiative that has prepared thousands of future STEM faculty around the world to adopt evidence-based instructional practices by participating in two massive open online courses (MOOCs) and facilitated in-person learning communities. This novel combination of asynchronous online and coordinated, structured face-to-face learning community experiences provides flexible options for STEM graduate students and postdoctoral fellows to pursue teaching professional development, while leveraging the affordances of educational technologies and the geographically clustered nature of this target learner demographic. A total of 14,977 participants enrolled in seven offerings of the introductory course held 2014-2018, with 1,725 participants from approximately 60 countries completing at an average course completion rate of 13%. The preparation of future STEM faculty makes an important difference in establishing high-quality instruction that meets the diverse needs of all undergraduate students, and the initiative described here can serve as a model for increasing access to such preparation.
Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin – but not through altered drug metabolism in patients with type 2 diabetes
Authors: Dunvald Ann-Cathrine Dalgård , Nielsen Flemming , Olsen Dorte Aalund , Ernst Martin Thomsen , Donnelly Louise , Soto-Pedre Enrique , Kristiansen Maja Refshauge , Nielsen Jens Steen , Persson Frederik , Højlund Kurt , Madsen Jonna Skov , Søndergaard Jens , Pearson Ewan , Pottegård Anton , Stage Tore Bjerregaard
Published: October 2022

Drug metabolism might be altered in patients with type 2 diabetes. We aimed to evaluate if initiation of glucose-lowering drugs impacts warfarin efficacy and drug metabolism.

First, we conducted a register-based self-controlled cohort study on Danish and Scottish warfarin users. Warfarin efficacy (International Normalized Ratio (INR)) was compared before and after initiation of glucose-lowering drugs. Second, we conducted a clinical pharmacokinetic trial comprising treatment-naïve type 2 diabetes patients. Patients ingested probe drugs for drug-metabolizing enzymes (the Basel Cocktail) before initiating glucose-lowering treatment, and after three and 12 weeks of treatment. Drug metabolism, glycemic control, and inflammation were assessed on each visit.

In the Danish and Scottish cohorts, initiating glucose-lowering drugs reduced warfarin efficacy (n=982 and n=44, respectively). INR decreased from 2.47 to 2.21 in the Danish cohort (mean difference -0.26; 95% CI -0.35;-0.17) and from 2.33 to 2.13 in the Scottish cohort (−0.21; 95% CI - 0.52;0.11) after initiation of glucose-lowering treatment. This impact on INR was more pronounced among individuals with stronger effects of glucose-lowering treatment. In the clinical pharmacokinetic trial (n=10), initiating metformin did not affect drug metabolism after three weeks (geometric mean ratio of CYP3A4 metabolic ratio: 1.12 (95% CI: 0.95;1.32)) or 12 weeks of metformin treatment. Glycemic control improved during treatment, while inflammation remained low and unchanged during treatment.

In conclusion, initiation of glucose-lowering drugs among chronic warfarin users is associated with a reduction in INR, particularly among individuals with a large decrease in HbA1c. This effect seems unrelated to CYP enzyme activity and warfarin drug metabolism.

Registry number

ClinicalTrials.govidentifierNCT04504045.
Detection of maternal transmission of resistant Gram-negative bacteria in a Cambodian hospital setting
Authors: Chomkatekaew Chalita , Thaipadungpanit Janjira , Hearn Pasco , Soeng Sona , Pol Sreymom , Neou Leakhena , Hopkins Jill , Turner Paul , Batty Elizabeth M.
Published: October 2022

Infection with Extended-spectrum beta-lactamase -producingEnterobacterales(ESBL-E) is common in infants leading to increased intensive care unit admission and mortality, but the role of maternal transmission in colonisation of infants is unclear. Using paired isolates from 50 pairs of mothers and neonates admitted to a Cambodian hospital, we investigated antimicrobial resistance inEscherichia coliandKlebsiella pneumoniaeusing whole genome sequencing. We detected a wide variety of ESBL-E genes present in this population along with high levels of multidrug resistance. From 21 pairs where the same organism was present in both mother and neonate, we identified eight pairs with identical or near-identical isolates from both individuals suggestive of transmission at or around birth, including a pair with transmission of multiple strains. We found no evidence for transmission of plasmids only from mother to infant. This suggests vertical transmission outside hospitals as a common cause of ESBL-E colonisation in neonates.
Altered brain dynamics across bipolar disorder and schizophrenia revealed by overlapping brain states
Authors: Ye Jean , Sun Huili , Gao Siyuan , Dadashkarimi Javid , Rosenblatt Matthew , Rodriguez Raimundo X. , Mehta Saloni , Jiang Rongtao , Noble Stephanie , Westwater Margaret L. , Scheinost Dustin
Published: October 2022

Aberrant brain dynamics putatively characterize bipolar disorder (BD) and schizophrenia (SCZ). Previous studies often adopted a state discretization approach when investigating how individuals recruited recurring brain states. Since multiple brain states are likely engaged simultaneously at any given moment, focusing on the dominant state can obscure changes in less prominent but critical brain states in clinical populations. To address this limitation, we introduced a novel framework to simultaneously assess brain state engagement for multiple brain states, and we examined how brain state engagement differs in patients with BD or SCZ compared to healthy controls (HC). Using task-based data from the Human Connectome Project, we applied nonlinear manifold learning and K-means clustering to identify four recurring brain states. We then examined how the engagement and transition variability of these four states differed between patients with BD, SCZ, and HC across two other international, open-source datasets. Comparing these measures across groups revealed significantly altered state transition variability, but not engagement, across all four states in individuals with BD and SCZ during both resting-state and task-based fMRI. In our post hoc and exploratory analysis, we also observed associations between state transition variability and age as well as avolition. Our results suggest that disrupted state transition variability affects multiple brain states in BD and SCZ. By studying several brain states simultaneously, our framework more comprehensively reveals how brain dynamics differ across individuals and in psychiatric disorders.
Sex-Specific Association Between Genetic Risk of Psychiatric Disorders and Cardiovascular Diseases
Authors: Jiang Jiayue-Clara , Singh Kritika , Davis Lea K. , Wray Naomi R. , Shah Sonia
Published: October 2022

Background

The lack of research on female-specific risk factors for cardiovascular diseases (CVD) has led to sex-based disparities in cardiovascular health. Though epidemiological studies show increased CVD risks amongst individuals with psychiatric disorders, findings on sex differences in comorbidity have been inconsistent.

Methods

This genetic epidemiology study examined the sex-specific association between the genetic risk of three psychiatric disorders [major depression (MD), schizophrenia and bipolar disorder], estimated using polygenic scores (PGS), and risks of three CVDs [atrial fibrillation (AF), coronary artery disease (CAD) and heart failure (HF)] in 345,169 European-ancestry individuals (UK Biobank), with analyses replicated in an independent BioVU cohort (N=49,057). Mediation analysis was conducted to determine whether traditional CVD risk factors could explain any observed sex difference.

Results

In UK Biobank, PGSMDwas significantly associated with the incident risks of all three CVDs in females after multiple testing correction [hazard ratio (HR)AF-female=1.04 (95% CI: 1.02-1.06; p=0.00015); HRCAD-female=1.07 (1.04-1.11; p=2.6E-06); HRHF-female=1.09 (1.06-1.13; p=9.7E-10)], but not in males. These female-specific associations remained even in the absence of any psychiatric disorder diagnosis or psychiatric medication use. Although mediation analysis demonstrated that the association between PGSMDand CVDs in females was partly mediated by baseline BMI, hypercholesterolemia, hypertension and smoking, these risk factors did not explain the higher risk compared to males. The association between PGSMDand CAD was consistent between females who were pre-menopausal and post-menopausal at baseline (mean baseline age of 44.9 and 60.8 years, respectively), while the association with AF and HF was only observed in the baseline post-menopausal cohort. No significant association with CVD risks was observed for the PGS of schizophrenia or bipolar disorder. The positive association of PGSMDwith CAD and HF risk in females was replicated in BioVU, where the corresponding associations in males also reached nominal significance.

Conclusions

Genetic predisposition to MD confers a greater risk of CVDs in females versus males, even in the absence of any depression diagnosis. This study warrants further investigation into whether genetic predisposition to depression could be useful for improving cardiovascular risk prediction even in the absence of a depression diagnosis, especially in women.
Associations Between Reported Post-COVID-19 Symptoms and Subjective Well-Being, Israel, July 2021 -April 2022
Authors: Gorelik Yanay , Dror Amiel , Zayyad Hiba , Wertheim Ofir , Jabal Kamal Abu , Nazzal Saleh , Otiku Paul , Elsinga Jelte , Glikman Daniel , Edelstein Michael
Published: October 2022

The impact of individual symptoms reported post-COVID-19 on subjective well-being (SWB) is unknown. We described associations between SWB and selected reported symptoms following SARS-CoV-2 infection. We analysed reported symptoms and subjective well being from 2295 participants (of which 576 reporting previous infection) in an ongoing longitudinal cohort study taking place in Israel. We estimated changes in SWB associated with reported selected symptoms at three follow-up time points (3-6, 6-12, and 12-18 months post infection) among participants reporting previous SARS-CoV-2 infection, adjusted for key demographic variables, using linear regression. Our results suggest that the biggest and most sustained changes in SWB stems from non-specific symptoms (fatigue −7.7 percentage points (pp), confusion/ lack of concentration −10.7 pp, and sleep disorders −11.5pp, p<0.005), whereas the effect of system-specific symptoms, such as musculoskeletal symptoms (weakness in muscles and muscle pain) on SWB, are less profound and more transient. Taking a similar approach for other symptoms and following individuals over time to describe trends in SWB changes attributable to specific symptoms will help understand the post-acute phase of COVID-19 and how it should be defined and better managed.
Chromosome territory reorganization through artificial chromosome fusion is negligible to cell fate determination and mouse development
Authors: Wang Yuang , Qu Zhen , Fang Yi , Chen Yulong , Peng Jiayin , Song Jiawen , Li Jinsong , Shi Jiantao , Zhou Jin-Qiu , Zhao Yun
Published: October 2022

Chromosomes occupy discrete spaces in the interphase cell nucleus, called chromosome territory. The structural and functional relevance of chromosome territory remains elusive. We fused chromosome 15 and 17 in mouse haploid embryonic stem cells (haESCs), resulting in distinct changes of territories in the corresponding native chromosomes, but affecting little on gene expression, pluripotency and gamete functions of haESCs. The karyotype engineered haESCs were successfully implemented in cultivating heterozygous (2n=39) and homozygous (2n=38) mouse models. The mice containing fusion-chromosome are fertile, and their representative tissues and organs display no phenotypic abnormalities, suggesting mouse development unscathed. These results indicate that the mammalian chromosome architectures are highly resilient, and reorganization of chromosome territories can be readily tolerated during cell differentiation and mouse development.
Metagenomic analysis unravels novel taxonomic differences in the uterine microbiome between healthy mares and mares with endometritis
Authors: Virendra Aeknath , Gulavane Sarita U. , Ahmed Zulfikar A. , Reddy Ravi , Chaudhari Ravindra J. , Gaikwad Sandeep M. , Shelar Raju R. , Ingole Shailesh D. , Thorat Varsha D. , Khanam Afroza , Khan Firdous Ahmad
Published: October 2022

The application of high throughput technologies has enabled unravelling of unique differences between healthy mares and mares with endometritis at transcriptomic and proteomic levels. However, differences in the uterine microbiome are yet to be investigated. The present study was aimed at evaluating the differences in uterine microbiome between healthy mares and mares with endometritis. Low-volume lavage (LVL) samples were collected from the uterus of 30 mares classified into healthy (n=15) and endometritis (n=15) based on their reproductive history, intrauterine fluid accumulation, gross appearance of LVL samples, endometrial cytology, and bacterial culture. The samples were subjected to metagenomic analysis using 16S rRNA sequencing. Notable differences in the uterine microbiome were observed between healthy mares and mares with endometritis at various taxonomic levels. In healthy mares, the most abundant phylum, class, order, and family were Firmicutes, Bacilli, Bacillales, and Paenibacillaceae, respectively. In contrast, the most abundant corresponding taxonomic levels in mares with endometritis were Proteobacteria, Gammaproteobacteria, Enterobacterales, and Enterobacteriaceae, respectively. At the genus level,BrevibacillusandPaenibacilluswere more abundant in healthy mares, whereasEscherichia, Salmonella, andKlebsiellawere more abundant in mares with endometritis. In healthy mares,Brevibacillus breviswas the most abundant species, followed byBrevibacillus choshinensisandPaenibacillus sp JDR-2. However, in mares with endometritis,Escherichia coliwas the most abundant species, followed bySalmonella entericaandKlebsiella pneumoniae. These results indicate novel differences in the uterine microbiome between healthy mares and mares with endometritis. The findings can potentially help formulate new approaches to prevent or treat equine endometritis.
Gut commensalEnteroclosterspecies host inoviruses that are secretedin vitroandin vivo
Authors: Burckhardt Juan C. , Chong Derrick H.Y. , Pett Nicola , Tropini Carolina
Published: October 2022

Background

Bacteriophages in the familyInoviridae, or inoviruses, are under-characterized phages previously implicated in bacterial pathogenesis by contributing to biofilm formation, immune evasion, and toxin secretion. Unlike most bacteriophages, inoviruses do not lyse their host cells to release new progeny virions; rather, they encode a secretion system that actively pumps them out of the bacterial cell. To date, no inovirus associated with the human gut microbiome has been isolated or characterized.

Results

In this study, we utilizedin silico, in vitroandin vivomethods to detect inoviruses in bacterial members of the gut microbiota. By screening a representative genome library of gut commensals, we detected inovirus prophages inEnterocloster spp. and we confirmed the secretion of inovirus particles inin vitrocultures of these organisms using imaging and qPCR. To assess how the gut abiotic environment, bacterial physiology, and inovirus secretion may be linked, we deployed a tripartitein vitroassay that progressively evaluated growth dynamics of the bacteria, biofilm formation, and inovirus secretion in the presence of changing osmotic environments. Counter to other inovirus-producing bacteria, inovirus production was not correlated with biofilm formation inEnterocloster spp. Instead, theEnteroclosterstrains’ inoviruses had heterogeneous responses to changing osmolality levels relevant to gut physiology. Notably, increasing osmolality induced inovirus secretion in a strain-dependent manner. We confirmed inovirus secretion in a gnotobiotic mouse model inoculated with individualEnteroclosterstrainsin vivoin unperturbed conditions. Furthermore, consistent with ourin vitroobservations, inovirus secretion was regulated by a changed osmotic environment in the gut due to osmotic laxatives.

Conclusion

In this study, we report on the detection and characterization of novel inoviruses from gut commensals in theEnteroclostergenus. Together, our results demonstrate that human gut-associated bacteria can secrete inoviruses and begin to elucidate the environmental niche filled by inoviruses in commensal bacteria.
Development of serological assays to identifyHelicobacter suisandHelicobacter pyloriinfections
Authors: Matsui Hidenori , Rimbara Emiko , Suzuki Masato , Tokunaga Kengo , Suzuki Hidekazu , Sano Masaya , Ueda Takashi , Tsugawa Hitoshi , Nanjo Sohachi , Takeda Akira , Sasaki Makoto , Terao Shuichi , Suda Tsuyoshi , Aoki Sae , Shibayama Keigo , Ota Hiroyoshi , Mabe Katsuhiro
Published: October 2022

Helicobacter suishosted by hogs is the most prevalent gastric non-Helicobacter pylori Helicobacterspecies found in humans. Recent studies suggest that theH. suisinfection has already induced many cases of gastric disease. However, the infection period and route ofH. suisfrom hogs remain unclear. Because diagnostic methods based on the urease activity ofH. suisoften yield negative judgments, there is no reliable method for diagnosingH. suisinfection in clinical practice without gastric biopsy specimens. We developed the world’s first ELISA to simultaneously diagnoseH. suisandH. pyloriinfection in a single test. The area under the ROC curve was 0.9648 or 0.9200 for identifyingH. suisorH. pyloriinfection, respectively. The sensitivity, specificity, and positive and negative predictive values for identifyingH. suisinfection were 100%, 92.6%, 76.9%, and 100%, and those for identifyingH. pyloriinfection were 88.2%, 87.5%, 65.2%, and 96.6%, respectively. (150 words)
Building Population Phenotypic Journeys from Laboratory Tests in Electronic Health Records for Translational Research
Authors: Zhang Xingmin A , Lee Kyeryoung , Jin Lan , Liu Zongzhi , Ai Lei , Jun Tomi , Higashi Mitch K. , Pan Qi , Oh William , Stolovitzky Gustavo , Schadt Eric , Robinson Peter N. , Wang Xiaoyan
Published: October 2022

Abundant volumes of clinical laboratory test results available within Electronic health records (EHRs) are essential for differential diagnosis, treatment monitoring, and outcome evaluation. LOINC2HPO is a recently developed deep phenotyping approach to transform laboratory test results into the Human Phenotype Ontology (HPO) terms. Here, we deployed the approach on a large EHR dataset from the Sema4 Data Warehouse to build patient phenotypic journeys at scale. Among 1.07 billion laboratory test results, we successfully transformed 774 million (72.5%) into HPO-coded phenotypes and built a patient phenotypic journey for over 2.2 million patients. First, a global analysis of patient phenotypic journeys revealed a longitudinal increase in patients with genitourinary system abnormality. The analysis also revealed abnormal phenotypes with strong racial patterns. Second, using severe asthma as an example case, we identified abnormal phenotypes in the past three years that were correlated with asthma progression to severe state. Lastly, we demonstrated that converting laboratory test results into HPO terms resulted in limited information loss. Our study demonstrated that the phenotypic journey framework opens the way to characterize phenotypic trajectories in population level and screen biomarkers for translational research.
Rehabilitation in Survivors of COVID-19 (RE2SCUE): a non-randomized, controlled and open study
Authors: Campos Maria Cristine , Nery Tatyana , Speck Ana Elisa , Arpini Maiqueli , Antunes Moisés Moraes , de Bem Alves Ana Cristina , de Souza Santos Naiara , Matos Maria Paula Pereira , Junior Nelson Schmidt , Bicca Letícia Roehe , Panisson Camila Mascarelo , Freitas Mariana Alves , Diefenthaeler Fernando , Kuriki Heloyse Uliam , Damin Vanessa , Da Rosa Rodrigo Oliveira , Gress Josiane Bueno , Schneider Ione Jayce Ceola , Vieira Danielle Soares Rocha , Arcêncio Livia , Aguiar Aderbal Silva
Published: October 2022

The sequelae of coronavirus disease-2019 (COVID-19) are another socio-economic problem of the pandemic. Fatigue and dyspnea are the most prevalent symptoms. It is not known whether exercise can be used to treat long COVID-19. This study aimed to investigate the effects of an 8-week face-to-face rehabilitation program on COVID-19 compared to a remote monitoring group. A total of 37 participants (24.3% hospitalized) were assessed before and after rehabilitation (n=22; 40.8±10.0 years) or remote monitoring (n=15; 45.4±10.5 years). The participants were allocated according to their preferences. Both groups showed improved fatigue and exercise capacity (Incremental Shuttle Walk Test). Participants in the face-to-face rehabilitation group showed improved dyspnea (Pulmonary Functional Status and Dyspnea Questionnaire), anxiety (Hospital Anxiety and Depression Scale), attention, and short-term memory (d2-R and Rey’s Auditory-Verbal Learning Test). Of the main sequelae, fatigue improves naturally, whereas dyspnea requires rehabilitation. Our results demonstrated the benefits of exercise for COVID-19 sequelae.
SPOP targets the immune transcription factor IRF1 for proteasomal degradation
Authors: Vunjak Milica , Schwartz Irene , Cantoran García Adriana , Mastrovito Marialaura , Hinterndorfer Matthias , de Almeida Melanie , Budroni Valentina , Wang Jingkui , Froussios Kimon , Jude Julian , Decker Thomas , Zuber Johannes , Versteeg Gijs A.
Published: October 2022

Adaptation of the functional proteome is essential to counter pathogens during infection, yet precisely timed degradation of these response proteins after pathogen clearance is likewise key to preventing autoimmunity. Interferon Regulatory Factor 1 (IRF1) plays an essential role as a transcription factor in driving the expression of immune response genes during infection. The striking difference in functional output with other IRFs, is that IRF1 also drives the expression of various cell cycle inhibiting factors, making it an important tumor suppressor. Thus, it is critical to regulate the abundance of IRF1 to achieve a “Goldilocks” zone in which there is sufficient IRF1 to prevent tumorigenesis, yet not too much which could drive excessive immune activation. Using genetic screening, we identified the E3 ligase receptor Speckle Type BTB/POZ Protein (SPOP) to mediate IRF1 proteasomal turnover. We identified four S/T-rich degrons in IRF1 required for its SPOP MATH domain-dependent turnover. In the absence of SPOP, increased IRF1 protein levels functionally drive increased transcription of IRF1-response-genes, underpinning the biological significance of SPOP in curtailing IRF1 protein abundance.
WITHDRAWN: In-silico analysis of regulatory proteins involved in tricarboxylic acid cycle of Arabidopsis thaliana and structural analysis by Alphafold and other software
Authors: Nayab Hina , Asim Noreen , Shafique Farheen , ul Hassan Mahreen , Butt Sadia , Akbar Nazia
Published: October 2022

Withdrawal Statement

The authors have withdrawn this manuscript because experiments are being repeated to validate the data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Investigating the roles for essential genes in the regulation of the circadian clock inSynechococcus elongatususing CRISPR interference
Authors: Boodaghian Nouneh , Park Hyunsook , Cohen Susan E.
Published: October 2022

Circadian rhythms are approximately 24-hour cycles that allow organisms to anticipate predictable environmental changes such as light intensity, temperature, and humidity. Circadian rhythms are found widely throughout nature where cyanobacteria are the simplest organisms known to carry out circadian rhythmicity. Circadian rhythmicity in cyanobacteria is carried out via the KaiA, KaiB and KaiC core oscillator proteins that keep ~24h time. A series of input and output proteins; CikA, SasA and RpaA, regulate the clock by sensing environmental changes, and time rhythmic activities, including global rhythms of gene expression. Our previous work identified a novel set of KaiC-interacting proteins, some of which are encoded by genes that are essential for viability. To understand the relationship of these essential genes to the clock we applied CRISPR interference (CRISPRi) which utilizes a deactivated Cas9 protein and single guide RNA (sgRNA) to reduce the expression of target genes but not fully abolish their expression to allow for survival. Eight candidate genes were targeted, and strains were analyzed by quantitative Reverse Transcriptase (RT)-PCR for reduction of gene expression and rhythms of gene expression were monitored to analyze circadian phenotypes. We present data that reduced expression of SynPCC942_0001, which encodes for the β-clamp of the replicative DNA polymerase, or SynPCC7942_1081, which likely encodes for KtrA involved in K+transport, displayed a long circadian period compared to the wild type. As neither of these proteins have been previously implicated in the circadian clock, these data suggest that diverse cellular processes, DNA replication and K+transport, can influence the circadian clock and represent new avenues to understand clock function.
Genomic tracking of SARS-COV-2 variants in Myanmar
Authors: Oo Khine Zaw , Htun Zaw Win , Aung Nay Myo , Win Ko Ko , Htoo Sett Paing , Oo Thet Wai , Linn Kyaw Zawl , Aung Phyo Kyaw , Zaw Myo Thiha , Tun Kyaw Myo , Myint Kyee , Lwin Ko Ko
Published: October 2022

Background

In December 2019, the COVID-19 disease started in Wuhan, China. WHO declared a pandemic on March 12, 2020, and the disease started in Myanmar on March 23, 2020. December brought variants around the world, threatening the healthcare systems. To counter those threats, Myanmar started the COVID-19 variant surveillance program in late 2020.

Methods

Whole genome sequencing was done six times between January 2021 and March 2022. We chose 83 samples with a PCR threshold cycle of less than 25. Then, we used MiSeq FGx for sequencing and Illumina DRAGEN COVIDSeq pipeline, command line interface, GISAID, and MEGA version 7 for data analysis.

Result and Discussion

January 2021 results showed no variant. The second run during the rise of cases in June 2021 showed multiple variants like Alpha, Delta, and Kappa. There is only Delta in the third run at the height of mortality in August, and Delta alone continued until the fourth run in December. After the world reported the Omicron variant in November, Myanmar started a surveillance program. The fifth run in January 2022 showed both Omicron and Delta variants. The sixth run in March 2022 showed only Omicron BA.2. Amino acid mutation at receptor binding domain (RBD) of Spike glycoprotein started since the second run coupling with high transmission, recurrence, and vaccine escape. We also found the mutation at the primer targets used in current RT-PCR platforms.

Conclusion

The occurrence of multiple variants and mutations claimed vigilance at ports of entry and preparedness for effective control measures. Genomic surveillance with the observation of evolutionary data is required to predict imminent threats of the current disease and diagnose emerging infectious diseases.
A role for caveolar proteins in regulation of the circadian clock
Authors: Fonseka Sachini , Weger Benjamin D. , Weger Meltem , Martel Nick , Hall Thomas E. , Moradi Shayli Varasteh , Gabriel Christian H. , Kramer Achim , Ferguson Charles , Fernández-Rojo Manuel A. , Alexandrov Kirill , Rawashdeh Oliver , McMahon Kerrie-Ann , Gachon Frederic , Parton Robert G
Published: October 2022

Caveolae are specialized invaginations of the plasma membrane that are formed by the co-assembly of caveolin integral membrane proteins and a cytoplasmic cavin coat complex. Previous work has proposed an interaction of the cavin coat protein, CAVIN3, with the key circadian clock protein, PER2. Here we show that cavin proteins can play a role in the regulation of the circadian clock by external stimuli. Loss ofCavin1in mice caused a shortening of the free-running period of locomotor activity. CAVIN1 and CAVIN3 were found to play a central role in core clock dynamics with either cavin protein directly interacting with PER2 and their perturbation leading to significant disruption in core clock mRNA expression and CRY1 protein oscillation. In cells, association of cavins and PER2 was increased upon caveola disassembly caused by oxidative stress or by calcium influx, stimuli linked to circadian clock regulation. We thus propose that the caveola system can play a modulatory role in circadian regulation through the cavin proteins.