bluuebunny/crossref_metadata_2025 huggingface dataset:
The Efficacy of Tranexamic Acid for the Treatment of Traumatic Hip Fractures: A Network Meta-Analysis
Authors: Bloom David A. , Lin Charles C. , Manzi Joseph E. , Mojica Edward S. , Telgheder Zachary L. , Chapman Cary B. , Konda Sanjit R.
Published: February 2023

Objectives:

To compare the efficacy of different dosages of intravenous (IV) tranexamic acid (TXA) in the treatment of traumatic hip fractures against that of the control group of no TXA.

Data Sources:

This study used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to perform a network meta-analysis on the use of TXA for the treatment of hip fractures. The study team used Ovid MEDLINE, Cochrane Reviews, Scopus, Embase, and Web of Science databases to perform the search. Studies that were published in English between the years 2010 and 2020 were selected.

Study Selection/Data Extraction:

For inclusion in this study, selected articles were required to be randomized controlled trials with at least 1 control group that had no antifibrinolytic intervention to serve as a control, and IV formulations of TXA were used as part of the treatment group. Furthermore, all study participants must have undergone surgical intervention for traumatic hip fractures. Studies that did not immediately meet criteria for inclusion were saved for a review by the full investigating team and were included based on consensus.

Data Synthesis:

All statistical analyses conducted for this study were performed using R software (R Foundation for Statistical Computing, Vienna, Austria). Network meta-analyses were conducted with a frequentist approach with a random-effects model using the netmeta package version 0.9–6 in R. The frequentist equivalent to surface under the cumulative ranking probabilities, termed “P score,” was used to rank different treatments.

Conclusion:

The use of TXA in the surgical management of traumatic hip fractures reduces the number of transfusions and perioperative blood loss, with minimal to no increased incidence of thrombotic events when compared with those in controls. When comparing formulations, no route of administration is clearly superior in reducing perioperative blood loss.

Level of Evidence:

Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Human liver organoids: From generation to applications
Authors: Afonso Marta B. , Marques Vanda , van Mil Saskia W.C. , Rodrigues Cecilia M.P.
Published: February 2023

In the last decade, research into human hepatology has been revolutionized by the development of mini human livers in a dish. These liver organoids are formed by self-organizing stem cells and resemble their native counterparts in cellular content, multicellular architecture, and functional features. Liver organoids can be derived from the liver tissue or pluripotent stem cells generated from a skin biopsy, blood cells, or renal epithelial cells present in urine. With the development of liver organoids, a large part of previous hurdles in modeling the human liver is likely to be solved, enabling possibilities to better model liver disease, improve (personalized) drug testing, and advance bioengineering options. In this review, we address strategies to generate and use organoids in human liver disease modeling, followed by a discussion of their potential application in drug development and therapeutics, as well as their strengths and limitations.
Comparison of mycology between different types of chronic rhinosinusitis
Authors: Jiang Rong-San , Su Mao-Chang
Published: February 2023

Background:

The aim of this study was to culture fungi from the nasal discharge of patients with chronic rhinosinusitis (CRS) using both a traditional and Ponikau et al’s method, and subsequently compare the culture results between CRS with nasal polyps (CRSwNPs) and without nasal polyps (CRSsNPs), and between eosinophilic and noneosinophilic CRS.

Methods:

Eighty-one CRS patients with CRS who underwent functional endoscopic sinus surgery were enrolled. Before surgery, the severity of each patient’s CRS was evaluated through an endoscopic examination and CT scan. Swab samples were collected from the middle meatus for traditional fungal cultures using cotton-tipped sticks. Afterward, the ipsilateral nasal cavity was irrigated, with the irrigated fluid processed using Ponikau et al’s method for fungal culture.

Results:

The endoscopic and CT scores were significantly higher in CRSwNPs than CRSsNPs, but were not different between eosinophilic CRS and noneosinophilic CRS. Using Ponikau et al’s method, 61/81 (75.3%) of the specimens grew fungi. Among them, 20 of 32 (62.5%) CRSwNPs specimens and 41 of 49 (83.7%) CRSsNPs specimens grew fungi. For eosinophilic CRS specimens, 35 of 46 (76.1%) grew fungi, and 26 of 35 (74.3%) noneosinophilic CRS specimens grew fungi. The fungal culture rate was borderline significantly higher in CRSsNPs than CRSwNPs (p = 0.058) but was not significantly different between eosinophilic CRS and noneosinophilic CRS (p = 1). However, Cladosporium was significantly more common in CRSsNPs than CRSwNPs (p = 0.048).

Conclusion:

Our results showed that the mycology of CRS was different between CRSwNPs and CRSsNPs.
Quality of Anticoagulation With Phenprocoumon and Warfarin in Left Ventricular Assist Device Patients: A Multicenter Study
Authors: Schlöglhofer Thomas , Marschütz Angelika , Combs Pamela , Stonebraker Corinne , Lupo Sydney , Jeevanandam Valluvan , Riebandt Julia , Schima Heinrich , Zimpfer Daniel , Meehan Karen
Published: February 2023

Anticoagulation in left ventricular assist device (LVAD) patients is essential to prevent hemocompatibility-related adverse events (HRAEs) but is challenging due to individual variability in dose-response and the small therapeutic window. Primary outcomes were international normalized ratio (INR) time in therapeutic range (TTR) and percentage of tests in range over 1 year after the first follow-up visit (FFUV), and secondary outcomes included all-cause mortality and HRAEs risk factors among phenprocoumon and warfarin users. This retrospective, multicenter study included 179 patients (age: 57.4 ± 11.8 years; female: 23.5%; HeartMate 3/HVAD: 50.8%/49.2%) implanted at the Medical University of Vienna (n = 102 phenprocoumon) and University of Chicago (n = 77 warfarin). Phenprocoumon users had a significantly higher TTR (64.9 ± 16.1% vs. 37.7 ± 21.8%, p < 0.001). One year survival (p = 0.65) and freedom from HRAE (p = 0.54) were comparable for both drugs. A multivariate analysis associated female gender (hazard ratio [HR], 2.15; 95% confidence interval [CI], 1.12–4.11; p = 0.021), no beta blockers at FFUV (HR, 2.16; 95% CI, 1.03–4.52; p = 0.042), gastrointestinal bleeding (GIB) preimplant (HR, 3.41; 95% CI, 1.32–9.45; p = 0.018), and time between INR tests (HR, 0.85; 95% CI, 0.74–0.99; p = 0.03) with a higher risk of HRAEs. To conclude, phenprocoumon versus warfarin users had better anticoagulation quality. Female gender, longer time between INR tests, no beta blockers at FFUV, and GIB preimplant were independent risk factors for HRAEs during LVAD support.

Visual Abstract:

Summary of key results. INR, international normalized ratio; TTR, time in therapeutic range; PTR, percentage of tests in range; HRAE, hemocompatibility-related adverse event; FFUV, first follow-up visit; GIB, gastrointestinal bleeding; HR, hazard ratio.

http://links.lww.com/ASAIO/A961
Imaging of the biliary tract
Authors: Iorio Pauline , Vanderbecq Quentin , Mouhadi Sanaâ El , Arrivé Lionel
Published: February 2023

Purpose of review

Magnetic resonance cholangiopancreatography (MRCP) has become the reference examination for the exploration of the biliary tract and has replaced endoscopic cholangiography for the analysis of the biliary tract because of its equivalent performance and its noninvasive character.

Recent findings

Based on the International Primary Sclerosing Cholangitis (PSC) Study Group recommendations for MR imaging in PSC, two protocols can be distinguished for the imaging of biliary tract: a basic protocol and a more complete protocol. It is essential to know the main pitfalls in order not to wrongly describe biliary anomalies. In addition to the excellent performance of MR imaging with MRCP in analyzing the anatomy and the anomalies of the biliary tree, complementary techniques have recently been developed. Several MR prognostic factors have been described. New hepato-specific contrast agents are now available for assessment of the general and segmental liver function. MR Elastography and Diffusion-weighted MR sequences are accurate to evaluate the degree of hepatic fibrosis. Finally, images obtained in MRCP can be postprocessed by a software that will analyze and model the biliary tree in order to quantitatively evaluate the biliary system.

Magnetic resonance imaging with its recent developments becomes by now an essential tool for the evaluation of biliary diseases
A MODIFIED SURGICAL SEPSIS MODEL SATISFYING SEPSIS-3 AND HAVING HIGH CONSISTENCY OF MORTALITY
Authors: Wang Jiebo , Liao Lianming , Chen Ying , Chen Liji , Lai Zhongmeng , Zhang Liangcheng
Published: February 2023

Background: Cecal ligation and perforation (CLP) is currently considered the criterion standard model of sepsis; however, there are some deficiencies, such as low clinical relevance, inconsistency in severity grading, and an unknown proportion of CLP animals meeting the requirements of sepsis-3. Methods: Adult rats were randomly divided into the following three groups: modified CLP (M-CLP) group, CLP group, and sham group. The vital organ function of rats was evaluated 24 hours postoperatively by blood pressure, behavioral testing, histopathology, and blood test. Cytokine levels were determined by enzyme-linked immunosorbent assay, and T-cell suppression was assessed by flow cytometry. The stability of the model was evaluated by comparing the survival rates of repeated experiments in all groups from day 1 to day 14. Results: More rats in the M-CLP group met Sepsis-3 criteria than those in the CLP group 24 hours postoperatively (53.1% vs. 21.9%, P = 0.01). Rats in the M-CLP group developed more serious hepatic, pulmonary, and renal dysfunction. Similar to human sepsis, rats in the M-CLP group demonstrated more serious immunosuppression and systemic inflammation compared with the CLP group. In addition, disease development and severity, which was indicated by the stable survival rates of model animals, were more stable in the M-CLP group. Conclusions: More rats could meet Sepsis-3 criteria with this novel surgical procedure, which may reduce the number of animals needed in preclinical sepsis experiments. This stable M-CLP model may contribute to the development of new therapies.
Long-term Outcome of Pediatric Liver Transplant Recipients Who Have Reached Adulthood: A Single-center Experience
Authors: Lund Louisa Katharina , Grabhorn Enke Freya , Rüther Darius , Buchholz Angela , Lang Melanie , Herden Uta , Fischer Lutz , Sterneck Martina
Published: February 2023

Background.

As long-term survival of pediatric liver transplant recipients increases, the assessment of physical, psychological, and social well-being becomes more important.

Methods.

In this retrospective analysis, 120 young adult patients (age ≥18 y) who underwent liver transplantation in childhood were studied. Patients with ideal outcome were defined as patients with perfect graft function, with no complications from the immunosuppressive medication, no late retransplantation, and no steroid treatment. Also, the patients’ drug adherence and their psychosocial situation were assessed.

Results.

After a median follow-up of 19 y, only 16.7% of the patients (mean age: 26.5 y) were considered patients with ideal outcome. The main reasons precluding ideal outcome were chronic kidney disease (38.3%), elevated liver enzymes (33.3%), and arterial hypertension (31.7%). Ideal outcome decreased over time from 54% to 42%, 26%, and 8% at 10-, 15-, 20-, and 25-y follow-up, respectively. Reduced drug adherence was noted in 24.8% of patients and associated with a significantly higher prevalence of donor-specific antibodies class II (P = 0.015), elevated transaminases (P = 0.010), and chronic rejection (P < 0.001). Also, 15% of patients had a psychiatric disease, mainly depression.

Conclusions.

The morbidity of young adults who underwent liver transplantation as children was high and increased over time. The majority developed complications from immunosuppression or chronic graft dysfunction. More than 1 in 7 patients had a psychiatric disease and 1 in 4 was not perfectly drug adherent. Therefore, immunosuppressive treatment and psychological care should be optimized for these particularly vulnerable patients.
Gray Matter Volume as Evidence for Cognitive Reserve in Bilinguals With Mild Cognitive Impairment
Authors: Calvo Noelia , Anderson John A.E. , Berkes Matthias , Freedman Morris , Craik Fergus I.M. , Bialystok Ellen
Published: February 2023

Background:

Compared with monolinguals, bilinguals have a later onset of mild cognitive impairment (MCI) and Alzheimer disease symptoms and greater neuropathology at similar cognitive and clinical levels. The present study follows a previous report showing the faster conversion from MCI to Alzheimer disease for bilingual patients than comparable monolinguals, as predicted by a cognitive reserve (CR).

Purpose:

Identify whether the increased CR found for bilinguals in the previous study was accompanied by greater gray matter (GM) atrophy than was present for the monolinguals.

Methods:

A novel deep-learning technique based on convolutional neural networks was used to enhance clinical scans into 1 mm MPRAGEs and analyze the GM volume at the time of MCI diagnosis in the earlier study.

Patients:

Twenty-four bilingual and 24 monolingual patients were diagnosed with MCI at a hospital memory clinic.

Results:

Bilingual patients had more GM loss than monolingual patients in areas related to language processing, attention, decision-making, motor function, and episodic memory retrieval. Bilingualism and age were the strongest predictors of atrophy after other variables such as immigration and education were included in a multivariate model.

Discussion:

CR from bilingualism is evident in the initial stages of neurodegeneration after MCI has been diagnosed.
Alteration of a Shiga toxin-encoding phage associated with a change in toxin production level and disease severity in Escherichia coli
Authors: Miyata Tatsuya , Taniguchi Itsuki , Nakamura Keiji , Gotoh Yasuhiro , Yoshimura Dai , Itoh Takehiko , Hirai Shinichiro , Yokoyama Eiji , Ohnishi Makoto , Iyoda Sunao , Ogura Yoshitoshi , Hayashi Tetsuya
Published: February 2023

Among the nine clades of Shiga toxin (Stx)-producing

Escherichia coli

O157:H7, clade 8 is thought to be highly pathogenic, as it causes severe disease more often than other clades. Two subclades have been proposed, but there are conflicting reports on intersubclade differences in Stx2 levels, although Stx2 production is a risk factor for severe disease development. The global population structure of clade 8 has also yet to be fully elucidated. Here, we present genome analyses of a global clade 8 strain set (n=510), including 147 Japanese strains sequenced in this study. The complete genome sequences of 18 of the 147 strains were determined to perform detailed clade-wide genome analyses together with 17 publicly available closed genomes. Intraclade variations in Stx2 production level and disease severity were also re-evaluated within the phylogenetic context. Based on phylogenomic analysis, clade 8 was divided into four lineages corresponding to the previously proposed SNP genotypes (SGs): SG8_30, SG8_31A, SG8_31B and SG8_32. SG8_30 and the common ancestor of the other SGs were first separated, with SG8_31A and SG8_31B emerging from the latter and SG8_32 emerging from SG8_31B. Comparison of 35 closed genomes revealed the overall structure of chromosomes and pO157 virulence plasmids and the prophage contents to be well conserved. However, Stx2a phages exhibit notable genomic diversity, even though all are integrated into the argW locus, indicating that subtype changes in Stx2a phage occurred from the γ subtype to its variant (γ_v1) in SG8_31A and from γ to δ in SG8_31B and SG8_32 via replacement of parts or almost entire phage genomes, respectively. We further show that SG8_30 strains (all carrying γ Stx2a phages) produce significantly higher levels of Stx2 and cause severe disease more frequently than SG8_32 strains (all carrying δ Stx2a phages). Clear conclusions on SG8_31A and SG8_31B cannot be made due to the small number of strains available, but as SG8_31A (carrying γ_v1 Stx2a phages) contains strains that produce much more Stx2 than SG8_30 strains, attention should also be paid to this SG.
Determinants associated with infant mortality in Ethiopia: Using the recent 2019 Ethiopia mini demographic and health survey
Authors: Yihuna Yeshambel Kindu , Lakew Abay Kassie , Takele Nigist Mulu , Agelu Seyoum Woldebrehan , Enigda Adane Agegn
Published: February 2023

Background

Infant mortality is the number of deaths under the age of one year and it is one of the most essential and sensitive indicators of the health status of the country. This study aims to identify the determinants that affect infant deaths in Ethiopia using the 2019 EMDHS.

Methods

This study used the 2019 Ethiopia mini demographic and health survey and 1,397 infants born from mothers who had been interviewed about births in the five years before the survey. The data were first analyzed with a chi-square test of association, and then potential factors were evaluated with binary logistic regression models. An adjusted odds ratio (AOR) along with a 95 % confidence interval (CI) of parameters was used to interpret the result

Results

The prevalence of infant death was 21%. The study also showed that age at first birth (16-32) infant (AOR = 0.541, 95%CI: 0.353, 0.827), mothers who had breastfed (AOR = 0.022, 95% CI: 0.014,), preceding birth interval less than 24 months (AOR = 0.183, 95% CI 0.117, 0.287), mothers who born their child in the health sector (AOR = AOR = 0.442, 95% CI: 0.304, 0.802) statistically related with a lower risk of infant mortality. Although mothers age group 35-49 (AOR = 2.682 1.446 4.974), mothers who had no ANC visits (AOR = 5.029, 95% CI: 2.923, 8.64), multiple births (AOR = 6.094, 95% CI: 2.684, 13.837, P=0.000) were statistically associated with a higher risk of infant mortality.

Conclusions

It is greatly suggested that maternal and child health care services (ANC visits) are strengthened. Preceding birth interval of fewer than 24 months, multiple births, and please of delivery at home needs special attention. We recommend also health institutions play a great roll to give awareness to mothers about family planning to reduce infant mortality.
Clinical outcome and outcome prediction of octogenarians with acute basilar artery occlusion and endovascular stroke treatment compared to younger patients
Authors: Mutke Matthias Anthony , Zimmermann Amanda , Schmitt Niclas , Seker Fatih , Chen Min , Schönenberger Silvia , Möhlenbruch Markus A. , Bendszus Martin , Weyland Charlotte S. , Jesser Jessica
Published: February 2023

Background and Aims

Elderly patients, especially octogenarians, are underrepresented in recently published studies, that showed a benefit of endovascular stroke treatment (EST) for patients with acute basilar artery occlusion (BAO). We aimed to compare the clinical outcome of octogenarians with BAO and EST compared to younger patients and to identify independent outcome predictors.

Methods

This is a retrospective, single-center analysis of patients treated for BAO with EST from 01/2013 until 06/2021 in a tertiary stroke center. Octogenarians (≥ 80 years) were compared to younger patients. Study endpoint was the clinical outcome as per modified Rankin Scale (mRS) 90d after stroke onset. The study groups were compared in univariate analysis and a multivariable logistic regression analysis was performed to define independent predictors for clinical outcome.

Results

In this study cohort, 74/191 (38.7 %) octogenarians had a higher pre-stroke mRS (Median, IQR: 2, 1 – 3 octogenarians vs. 0, 0 – 1 younger patients, p < 0.001) and a comparable NIHSS before EST (Median, IQR: 21, 8 – 34 vs. 22, 10 – 38 younger, p = 0.712). They showed a comparable mRS 90d after stroke onset (Median, IQR: 5, 2 – 6 younger vs. 5, 3 – 6 octogenarians, p = 0.194), but less often a good clinical outcome (mRS 0-2: n = 27, 23% younger vs. n = 9, 11.7% octogenarians, p = 0.004). The rate of bad clinical outcome was comparable (mRS 5-6, n = 63, 46.7% younger vs. 39, 50.6 % octogenarians, p = 0.194). Baseline NIHSS was a stable independent predictor for clinical outcome in both study groups (e.g. for bad clinical outcome: in octogenarians OR 1.04, CI 100 – 10.85, p = 0.0019, in younger OR 1.061, CI 1.027-1.098, p = 0.005)

Conclusion

Octogenarians with acute BAO eligible for EST are less likely to be functionally independent at 90 days after stroke onset, but the rate of death or severe handicap is comparable to younger patients. The admission NIHSS predicts clinical outcome in both age groups.
First report of genetic variants detected in Argentinian patients with clinical Long QT Syndrome diagnosis
Authors: Leonardo Dionisio , Sofía Stupniki , Eugenio Aztiria , Ezequiel Rías , Leandro Dye , Leonardo Onetto , Franco Gregorietti , Roberto Keegan , Guillermo Spitzmaul
Published: February 2023

Background

Long QT Syndrome (LQTS) is a genetic cardiac condition in which disease severity and response to pharmacological treatments vary according to genetic variations. In Argentina, most of the LQTS diagnoses are made by clinical exploration and ECG analysis. In this work, we evaluated a group of subjects from our community to correlate their clinical LQTS diagnosis with genetic modifications.Material and methods: Using gDNA isolation, PCR, and exome sequencing, we screened the coding sequences of theKCNQ1, KCNH2, andSCN5Agenes in the studied cohort.

Results

We identified several DNA changes, among synonymous and non-synonymous, most of them previously described in the literature. In addition, we found a non reported alteration in the sequence ofKCNQ1sequence that suggests the lack (deletion) of an exon or a large part of it indicating exon deletion. 16 which did not allow us to amplify it.

Conclusions

This is the first report of genetic variations in LQTS-associated genes in Argentina. The variations detected could explain the prolongation of the QT interval observed in the ECG of some of the individuals or those with a suspicious family history and could improve treatment, making it more rational as well as providing genetic counselling to first-degree relatives.

Highlights

Genetic screening correlates with clinical diagnosis in LQT patients

Studied cases carry more than one variation in at least 2 genes simultaneously

A Non-reported variation in KCNQ1 exon 16 was founded in one case
GABAergic regulation of auditory repetition suppression in adults with and without Autism Spectrum Disorder
Authors: Huang Qiyun , Velthuis Hester , Pereira Andreia C. , Ahmad Jumana , Cooke Samuel F. , Ellis Claire L. , Ponteduro Francesca M. , Puts Nicolaas A. J. , Dimitrov Mihail , Batalle Dafnis , Wong Nichol M. L. , Kowalewski Lukasz , Ivin Glynis , Daly Eileen , Murphy Declan G. M. , McAlonan Gráinne M.
Published: February 2023

Suppressing responses to repetitive sounds, while staying vigilant to rare sounds, is a cross-species trait vital for survival, which is altered in autism spectrum disorder (ASD). Preclinical models implicate ϒ-aminobutyric acid (GABA) in this process. Although differences in GABA genes, post-mortem markers and bulk tissue GABA levels have been observed in ASD, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. Here, we directly evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD). Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. We first established that temporal mismatch negativity was comparable between control participants and those with ASD. Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in controls. An individual ‘sensitivity index’ of arbaclofen-elicited shift in suppression strongly correlated with autistic symptomatology measured using the Autism Quotient. Thus, our results confirm: GABAergic dysfunction is fundamental to the neurophysiology of auditory sensory processing alterations in ASD, which can be modulated by targeting GABABactivity; and these GABA-dependent sensory differences may be upstream of more complex autistic phenotypes.

One Sentence Summary

Differences in GABAergic function are fundamental to autistic (auditory) sensory neurobiology; but are modulated by targeting GABAB.
Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response
Authors: Campos-Martin Rafael , Bey Katharina , Elsner Björn , Reuter Benedikt , Klawohn Julia , Philipsen Alexandra , Kathmann Norbert , Wagner Michael , Ramirez Alfredo
Published: February 2023

Obsessive-compulsive disorder (OCD) is a mental disorder affecting 2-3% of the general population. The dynamic nature of epigenetics provides a unique opportunity to find biomarkers of OCD symptoms, clinical progression, and treatment response. Consequently, we analyzed a case-control study on Illumina Methylation EPIC BeadChip from 185 OCD patients and 199 controls. Patients and controls were assessed by trained therapists using the Structured Clinical Interview for DSM-IV. We identified 12 CpGs capable of classifying OCD patients and predicting symptom severity. These CpGs are enriched withthe sweet-compulsive brain hypothesis, which proposes that OCD patients may have impaired insulin signaling sensitivity due to abnormal dopaminergic transmission in the striatum. Three of the twelve CpG signals were replicated in an independent study reported in the Han Chinese population. Our findings support the role of epigenetic mechanisms in OCD and may help pave the way for biologically-informed and individualized treatment options.
Risk factors for eight common cancers revealed from a phenome-wide Mendelian randomisation analysis of 378,142 cases and 485,715 controls
Authors: Went Molly , Sud Amit , Mills Charlie , Hyde Abi , Culliford Richard , Law Philip , Vijayakrishnan Jayaram , Gockel Ines , Maj Carlo , Schumacher Johannes , Palles Claire , Kaiser Martin , Houlston Richard
Published: February 2023

For many cancers there are few well-established risk factors. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify causal relationships. We performed a MR-PheWAS of breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, comprising 378,142 cases and 485,715 controls. To derive a more comprehensive insight into disease aetiology we systematically mined the literature space for supporting evidence. We evaluated causal relationships for over 3,000 potential risk factors. In addition to identifying well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we provide evidence for specific factors, including dietary intake, sex steroid hormones, plasma lipids and telomere length as determinants of cancer risk. We also implicate molecular factors including plasma levels of IL-18, LAG-3, IGF-1, CT-1, and PRDX1 as risk factors. Our analyses highlight the importance of risk factors that are common to many cancer types but also reveal aetiological differences. A number of the molecular factors we identify have the potential to be biomarkers. Our findings should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app (https://mrcancer.shinyapps.io/mrcan/) to visualise findings.
Moderators of Treatment Outcomes for LGBTQ+ Military Veterans in the PRIDE in All Who Served Health Promotion Group
Authors: Hilgeman Michelle M. , Cramer Robert J. , Kaniuka Andréa R. , Robertson Ryan , Bishop Teddy , Wilson Sarah M. , Sperry Heather A. , Lange Tiffany M.
Published: February 2023

Background

Veterans who identify as lesbian, gay, bisexual, transgender, queer, questioning, and related identities (LGBTQ+) have faced discrimination that puts them at increased risk for depression, anxiety, and suicide. Upstream interventions like the PRIDE in All Who Served program can improve internalized prejudice, suicide attempt likelihood, symptoms of depression, and symptoms of anxiety by addressing minority stress, facilitating social connection, and promoting engagement with the healthcare system. Yet, little is known about who benefits most from these types of services.

Methods

Sixty-six US military veterans (Mean age = 47.06, SD = 13.74) provided outcome surveys before and after a 10-week health promotion group for LGBTQ+ individuals at one of 10 Veterans Health Administration (VA) Medical Centers. Coping self-efficacy and key demographic factors were examined as moderators of treatment outcomes.

Results

Coping self-efficacy moderated effects across treatment outcomes with those lower in coping self-efficacy beliefs reporting the greatest benefit of the intervention. Reduction in anxiety symptoms was moderated only by problem-solving coping self-efficacy, while suicide attempt likelihood was moderated only by social support. Reduction of internalized prejudice and depression symptoms were moderated by both problem-solving and social support coping self-efficacy, while thought-stopping (a frequent target of traditional cognitive therapies) only moderated internalized prejudice, but not clinical symptom indicators. Most demographic factors (e.g., age, race, gender) did not impact treatment outcomes; however, sexual orientation was significant such that those who identified as bisexual, queer, or something else (e.g., pansexual) had greater reductions in internalized prejudice than their single gender-attracted peers.

Conclusion

Individual differences like coping self-efficacy and sexual orientation are rarely considered in clinical care settings when shaping policy or implementing tailored programs. Understanding implications for who is most likely to improve could inform program refinement and implementation of affirming interventions for minoritized people.
Strong isolation by distance and evidence of population microstructure reflect ongoingPlasmodium falciparumtransmission in Zanzibar
Authors: Connelly Sean V. , Brazeau Nicholas F. , Msellem Mwinyi , Ngasala Billy E. , Aydemir Özkan , Goel Varun , Niaré Karamoko , Giesbrecht David J. , Popkin-Hall Zachary R. , Hennelly Christopher M. , Park Zackary , Moormann Ann M. , Ong’echa John Michael , Verity Robert , Mohammed Safia , Shija Shija J. , Mhamilawa Lwidiko E. , Morris Ulrika , Mårtensson Andreas , Lin Jessica T. , Björkman Anders , Juliano Jonathan J. , Bailey Jeffrey A.
Published: February 2023

The Zanzibar archipelago of Tanzania has become a low-transmission area forPlasmodium falciparum.Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania, and continued local transmission. To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282P. falciparumisolates collected across Zanzibar and in Bagamoyo District on the coastal mainland from 2016-2018. Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to rapid decay of parasite relatedness over very short distances. This, along with highly related pairs withinshehias, suggests ongoing low level local transmission. We also identified highly related parasites acrossshehiasthat reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes. Our data support importation as a main source of genetic diversity and contribution to the parasite population on Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive for malaria reemergence due to susceptible hosts and competent vectors.
DETERMINANTS OF SECOND CHILD BIRTH INTERVAL AMONG WOMEN OF LUSAKA PROVINCE: A COX REGRESSION MODEL
Authors: Zambwe M , Zambwe M , Mutemwa R
Published: February 2023

Background

Child birth intervalis the length of time between two successful live births.Shorter child birth interval among women of reproductive age is a serious global public health challenge. It is associated with low birth weight, child malnutrition, and child mortality.There is a general dearth of literature on this subject in Zambia. Therefore, the aim of this study was to establish the determinants of second child birth interval among women.

Methods

A cross-sectional study involving 100 women of reproductiveage group in Lusaka province. The participants were purposively and convenientlyselected. A pre tested structured questionnaire was used to collect the data. The key variables in the data were age, marital status, educational level, tribe, income. The data from the questionnaires were summarized into a Microsoft excel sheet, and cleaned for errors and duplications.Thereafter the excel sheet was exported to Stata version 14.2 for analysis.Kaplan-Meier and Cox regression analysis wereapplied.

Results

The p-value for age was 0.00 which was statistically significant. Within the age group 18-25 years the average second birth interval was 23 months. In the age group 26-44 years, the average second birth interval was 42 months. The reported p-value for income was 0.049 which was significant. The results also showed that those with income between K0-K350 had an average second birth interval of child of 27 months. Those with income of K3500-K16000, had an average second birth interval 69 months. Women in urban areas had a longer second birth interval than those in rural areas.

Conclusion

Age, income and location were found to be significantly associated with the incidence of a second birth. A lot of awareness activities on birth control are therefore recommended among young, low income and rural women.
Physical and brain frailty in stroke: shared occurrence and outcomes. A cohort study
Authors: Taylor-Rowan M , Hafdi M , Drozdowska B , Elliott E , Wardlaw J , Quinn T
Published: February 2023

Background

There is increasing interest in the concept of frailty in stroke, including both physical frailty and imaging-evidence of brain frailty. We aimed to 1)establish concurrent validity of a brain frailty measurement against traditional measures of physical and global frailty 2)establish prevalence of brain frailty in stroke survivors with and without pre-existing frailty 3)establish the predictive validity of measures of physical, global, and brain frailty against long-term cognitive outcomes.

Methods

We included consecutively admitted stroke or transient ischaemic attack (TIA) survivors from participating stroke centres. Baseline CT scans were used to identify leukoaraiosis, atrophy, or old infarcts; these were then combined to generate an overall brain frailty score for each participant on a scale ranging from 0-3 (3=higher brain frailty). Global frailty was measured using Rockwood frailty index, and physical frailty using a Fried frailty screening tool. Presence of major or minor neurocognitive disorder at 18-months following stroke was established via a multicomponent assessment. We assessed the concurrent validity of brain frailty and frailty scales via Spearman’s rank correlation. Prevalence of brain frailty was established based upon observed percentages within groups defined by frailty status (robust, pre-frail, frail). We conducted multivariable logistic regression analyses to evaluate association between brain, global, and physical frailty with 18-month cognitive impairment.

Results

Three-hundred-forty-one stroke survivors participated. Brain frailty was weakly correlated with Rockwood frailty (Rho:0.336;p<0.001) and with Fried frailty (Rho:0.230;p<0.001). Three-quarters of people who were frail had moderate-severe brain frailty and prevalence increased according to frailty status. Brain frailty (OR:1.64,95%CI=1.17-2.32), Rockwood frailty (OR:1.05,95%CI=1.02-1.08) and Fried frailty (OR:1.93,95%CI=1.39-2.67) were each independently predictive of cognitive impairment at 18 months following stroke. Fried frailty was predictive independent of age, sex, stroke severity, education, baseline cognitive test performance, and brain frailty status (OR:1.49,95%CI=1.03-2.18)

Conclusions

Physical and brain frailty are separate concepts, although they frequently co-exist. Both are associated with adverse cognitive outcomes and physical frailty remains important when assessing cognitive outcomes.
Lysosomal Storage Dysfunction, a Germline Variants Affecting Pancreatic Ductal Adenocarcinoma Development and Progression
Authors: Koh Youngil , Kim Hyemin , Song Seulki , Choi Young Hoon , Joo So Young , Kim Hyung Rae , Moon Byul , Byun Jamin , Hong Junshik , Shin Dong-Yeop , Park Solip , Lee Kwang Hyuck , Lee Kyu Taek , Lee Jong Kyun , Park Daechan , Jang Jin-Young , Lee Hyunsook , Kim Jung-Ae , Yoon Sung-Soo , Park Joo Kyung
Published: February 2023

Lysosome is closely linked to autophagy, which plays a vital role in pancreatic adenocarcinoma (PDAC) tumor biology. This study investigated whether lysosome storage dysfunction (LSD) contributes to PDAC development. Germline putative pathogenic variants (PPVs) in genes involved in lysosome functions were compared between PDAC patients (N=418) and healthy controls (N=845). Furthermore,Galc-knockout mouse pancreas organoids and human PDAC organoids were used to evaluate the consequences of PPV status in PDAC development and establishment. LSD PPVs were enriched in PDAC patients (Log2OR=1.65, P=3.08×10−3). PPV carriers diagnosed with PDAC were younger than non-carriers (61.5 vs. 65.3 years, P=0.031). Hampered autophagolysosome activity with increased autophagy flux and elevated Ki-67 index were observed following GALC downregulation. RNA sequencing of human PDAC organoids revealed upregulation of metabolism related to LSD. Genetically defined lysosome dysfunction is frequently observed in young-age onset PDACs. Lysosome dysfunction might contribute to PDAC development via altered metabolism and impaired autophagolysosome activity.
Early postpartum HbA1c after hyperglycemia first detected in pregnancy - imperfect but not without value
Authors: Coetzee Ankia , Hall David R , van de Vyver Mari , Conradie Magda
Published: February 2023

Background

South Africanwomen of childbearing age are disproportionally affected by obesity and at significant risk of Type 2 Diabetes Mellitus (T2DM). Unless pregnant, they do not readily undergo screening for T2DM. With a local focus on improved antenatal care, hyperglycemia is often first detected in pregnancy (HFDP). This may erroneously be attributed to Gestational Diabetes Mellitus (GDM) in all without considering T2DM. Glucose evaluation following pregnancy is essential for early detection and management of women with T2DM in whom persistent hyperglycemia is to be expected. Conventional testing with an oral glucose tolerance test (OGTT) is cumbersome, prompting investigation for alternate solutions.

Aim

To compare the diagnostic performance of HbA1c to the current gold standard OGTT in women with HFDP 4-12 weeks post-delivery.

Methods

Glucose homeostasis was assessed with OGTT and HbA1c in 167 women with HFDP, 4-12 weeks after delivery. Glucose status was based on American Diabetes Association criteria.

Results

Glucose homeostasis was assessed at 10 weeks (IQR 7-12) after delivery. A total of 52/167 (31%) participants had hyperglycemia, 34 (20%) had prediabetes, and 18 (11%) had T2DM. For patients with prediabetes, fasting plasma glucose (FPG) and 2 hour plasma glucose (2hPG) were diagnostic in 12 patients, whereas in two-thirds (22/34) only one time point was diagnostic. FPG and 2hPG values were both in the prediabetes diagnostic range in six women with T2DM. Based on FPG, 15 women with persistent hyperglycemia (11 with prediabetes and four with T2DM) would have been missed (15/52; 29%). The HbA1c accurately classified 85% of the 52 participants with gold standard OGTT defined hyperglycemia and 15 of 18 women with postpartum persistent T2DM. When compared to an OGTT, a single HbA1c of 6.5% (48mmol/mol) postpartum demonstrated a sensitivity of 83% and specificity of 97% for the identification of T2DM.

Conclusion

HbA1c may improve access to postpartum testing in overburdened clinical settings where the required standards of OGTT cannot be guaranteed. HbA1c is a valuable test to detect women who will benefit most from early intervention but cannot unequivocally replace OGTT.
Patients with fibrosis from non-alcoholic steatohepatitis have heterogeneous intrahepatic macrophages and therapeutic targets
Authors: Saldarriaga Omar A. , Krishnan Santhoshi , Wanninger Timothy G. , Oneka Morgan , Rao Arvind , Bao Daniel , Arroyave Esteban , Gosnell Joseph , Kueht Michael , Moghe Akshata , Millian Daniel , Jiao Jingjing , Sanchez Jessica I. , Spratt Heidi , Beretta Laura , Stevenson Heather L.
Published: February 2023

Background and Aims

In clinical trials for reducing fibrosis in NASH patients, therapeutics that target macrophages have had variable results. We evaluated intrahepatic macrophages in patients with non-alcoholic steatohepatitis to determine if fibrosis influenced phenotypes and expression of CCR2 and Galectin-3.

Approach & Results

We used nCounter to analyze liver biopsies from well-matched patients with minimal (n=12) or advanced (n=12) fibrosis to determine which macrophage-related genes would be significantly different. Known therapy targets (e.g., CCR2 and Galectin-3) were significantly increased in patients with cirrhosis.

However, several genes (e.g., CD68, CD16, and CD14) did not show significant differences, and CD163, a marker of pro-fibrotic macrophages was significantly decreased with cirrhosis. Next, we analyzed patients with minimal (n=6) or advanced fibrosis (n=5) using approaches that preserved hepatic architecture by multiplex-staining with anti-CD68, Mac387, CD163, CD14, and CD16. Spectral data were analyzed using deep learning/artificial intelligence to determine percentages and spatial relationships. This approach showed patients with advanced fibrosis had increased CD68+, CD16+, Mac387+, CD163+, and CD16+CD163+ populations. Interaction of CD68+ and Mac387+ populations was significantly increased in patients with cirrhosis and enrichment of these same phenotypes in individuals with minimal fibrosis correlated with poor outcomes. Evaluation of a final set of patients (n=4) also showed heterogenous expression of CD163, CCR2, Galectin-3, and Mac387, and significant differences were not dependent on fibrosis stage or NAFLD activity.

Conclusions

Approaches that leave hepatic architecture intact, like multispectral imaging, may be paramount to developing effective treatments for NASH. In addition, understanding individual differences in patients may be required for optimal responses to macrophage-targeting therapies.
Characteristics and Outcomes of Multisystem Inflammatory Syndrome in Children: A Multicenter, Retrospective, Observational Cohort Study in Mexico
Authors: González-García Nadia , Yamazaki-Nakashimada Marco Antonio , Márquez-González Horacio , Miranda-Novales Guadalupe , Neme Díaz Gonzalo Antonio , Prado Duran Sandhi Anel , Velázquez Antonio Luévanos , Castilla-Peon Maria F. , Sánchez Duran Miguel Alejandro , Márquez Aguirre Martha Patricia , Villasis-Keever Miguel Angel , Aragón Nogales Ranferi , Enríquez Carlos Núñez , Martinez Bustamante Maria Elena , Argüello Carlos Aguilar , de los Santos Jesús Ramírez , Pérez Barrera Alejandra , Palacios Cantú Lourdes Anais , Mondragón Jesús Membrila , Alvarado Paloma Vizcarra , Jiménez Juárez Rodolfo Norberto , López Víctor Olivar , Chávez Adrián López
Published: February 2023

Multisystem inflammatory syndrome in children temporally associated with coronavirus disease 2019 (MIS-C), a novel hyperinflammatory condition secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with severe outcomes such as coronary artery aneurysm and death. This multicenter, retrospective, observational cohort study including eight centers in Mexico, aimed to describe the clinical characteristics and outcomes of patients with MIS-C. Patient data were evaluated using latent class analysis to categorize patients into three phenotypes: toxic shock syndrome-like (TSSL)-MIS-C, Kawasaki disease-like (KDL)-MIS-C, and nonspecific MIS-C (NS-MIS-C). Risk factors for adverse outcomes were estimated using multilevel mixed-effects logistic regression. The study included 239 patients with MIS-C, including 61 (26%), 70 (29%), and 108 (45%) patients in the TSSL-MIS-C, KDL-MIS-C, and NS-MIS-C groups, respectively. Fifty-four percent of the patients were admitted to the intensive care unit, and 42%, 78%, and 41% received intravenous immunoglobulin, systemic glucocorticoids, and anticoagulants, respectively. Coronary artery dilatation and aneurysm were found in 5.7% and 13.2% of the patients, respectively. The rate of mortality due to SARS-CoV-2-related factors was 4.6%. Delay of ≥10 days in hospital admission was associated with coronary artery aneurysm or dilatation (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.2–2.0). Age ≥ 10 years (OR 5.6, 95% CI 1.4–2.04), severe underlying condition (OR 9.3, 95% CI 2.8–31.0), platelet count < 150,000/mm3(OR 4.2, 95% CI 1.2–14.7), international normalized ratio > 1.2 at admission (OR 3.8, 95% CI 1.05–13.9), and serum ferritin concentration > 1500 mg/dL (OR 52, 95% CI 5.9–463) were risk factors for death.