bluuebunny/crossref_metadata_2025 huggingface dataset:
Viral Suppression Rates at 48 Weeks in People With Human Immunodeficiency Virus Starting Long-Acting Cabotegravir/Rilpivirine With Initial Viremia
Authors: Hickey Matthew D , Gistand Nathanael , Grochowski Janet , Mayorga-Munoz Francis , Imbert Elizabeth , Szumowski John D , Oskarsson Jon , Shiels Mary , Dilworth Samantha , Appa Ayesha , Havlir Diane V , Gandhi Monica , Christopoulos Katerina
Published: October 2024

Background

We previously demonstrated at the Ward 86 human immunodeficiency virus (HIV) clinic in San Francisco that long-acting (LA) cabotegravir (CAB)/rilpivirine (RPV) (LA-CAB/RPV) can rapidly lead to viral suppression in people with HIV (PWH) with viremia due to adherence challenges. We now evaluate the durability of viral suppression in this population.

Methods

We conducted a retrospective cohort study of PWH who started LA-CAB/RPV with viremia (HIV RNA viral load ≥50 copies/mL) before December 2022. Our primary outcome was viral suppression (viral load <50 copies/mL) with LA-CAB/RPV persistence (not discontinued or late by >14 days) at 48 weeks, using the viral load closest to 48 ± 8 weeks. We also describe viral failure, defined as a <2-log decline in viral load at 4 weeks or a viral load ≥200 copies/mL after initial viral suppression with emergent CAB- or RPV-associated resistance mutations; overall 48-week viral suppression including those switched to alternative antiretroviral therapy (ART).

Results

Fifty-nine PWH initiated LA-CAB/RPV with viremia and were included in the analysis; 49% had a CD4 cell count <200/µL, and the median baseline viral load was 42 900 copies/mL (quarter 1–quarter 3, 5272–139 038). At 48 weeks, 47 PWH met the primary outcome of viral suppression with LA-CAB/RPV persistence (80% [95% confidence interval, 67%–89%]). Five had viral failure with resistance (3 with RPV-associated and 2 with CAB- and RPV-associated mutations), and 1 was lost to follow-up. At week 48, 2 of those with viral failure were suppressed on alternative regimens (lenacapavir + bictegravir/tenofovir alafenamide/emtricitabine and CAB + lenacapavir). The overall viral suppression at week 48 with either LA-CAB/RPV or alternative ART was 92% (54 of 59).

Conclusions

In PWH initiating LA-CAB/RPV with initial viremia, 48-week viral suppression (<50 copies/mL) was seen in 92%. LA ART can be an important tool for improving viral suppression among patients who face adherence challenges to oral ART.
Association of hyperandrogenaemia with hypertension and cardiovascular events in pre-menopausal women: a prospective population-based cohort study
Authors: Tuorila Katri , Ollila Meri-Maija , Hurskainen Elisa , Tapanainen Juha , Franks Stephen , Piltonen Terhi , Kaikkonen Kari , Morin-Papunen Laure
Published: October 2024

Objective

The present study aimed to clarify the conflicting association of premenopausal hyperandrogenaemia (HA) with the development of hypertension and cardiovascular disease (CVDs) in women.

Design

A population-based cohort study including 5889 women.

Methods

The association of serum testosterone (T), sex hormone-binding globulin (SHBG), and free androgen index (FAI) at age 31 with blood pressure (BP) and hypertension (BP ≥ 140/90 mmHg and/or use of antihypertensive medication) at ages 31 and 46 and with CVDs (angina pectoris [AP] and/or acute myocardial infarction [AMI] n = 74, transitory cerebral ischaemia and/or stroke n = 150) and combined CVD events (AP, AMI, stroke, heart failure, or CVD mortality n = 160) by age 53 was investigated.

Results

T and FAI were positively associated with systolic and diastolic BP at ages 31 and 46 in the multivariable model. Compared to their lowest quartile, the highest quartiles of T and FAI were positively associated with hypertension at age 31 in the multivariable model. During the 22-year follow-up, FAI was positively associated with increased risk of AP/AMI (hazard ratio [HR]: 2.02, 95% CI: 1.06-3.85) and overall CVD events or mortality (HR: 1.54, 95% CI: 1.02-2.33) in the unadjusted models. However, the significance disappeared after adjusting for body mass index (BMI).

Conclusions

Women with HA at premenopausal age had an elevated risk of hypertension, and together with BMI, increased risk of CVD events and CVD mortality during the 22-year follow-up. However, because of several study limitations regarding ethnicity and BMI characteristics, a longer follow-up of this cohort and future studies in ethnically diverse populations are needed to verify the results.
Antihypertensive, anti-inflammatory, glycaemic, and satiety effects of cocoa-flavoured soy-based powder drink mix enriched with bioactive hydrolysates from nests of Aerodramus fuciphagus
Authors: Aris Hazimah Mohd , Kasim Zalifah Mohd , Zubairi Saiful Irwan
Published: October 2024

Objectives

Edible bird nest hydrolysates (EBNHs) are renowned for their health benefits. The study aimed to determine their functional effects as an ingredient in cocoa-flavoured soy-based powder drink mix (PDM). The glycaemic and satiety effects of the product were also studied.

Materials and Methods

The product was enriched with a reasonably low amount of spray-dried EBNH. The product’s functional effects with respect to in vitro angiotensin-converting enzyme (ACE) inhibitory activity and human red blood cell membrane stabilization (RBCMS) activity were evaluated using its water extract (90–95 °C). The glycaemic and satiety impacts were evaluated in twelve and thirty subjects, respectively, who consumed 250 mL of the product, which contained 25 g of available carbohydrates.

Results

The enriched PDM ACE inhibitory activity and RBCMS activity were significantly higher (P<0.05) than those that were devoid of EBNH. Two hundred and forty milliliters (12.5% (125 mg/mL)) of PDM (containing 3.0% EBNH, 75.44% soybean powder, 20% cocoa powder, 0.5% xanthan gum, 1.0% silicon dioxide, and 0.06% sucralose (mass fraction)) provides approximately 3.7 kcal/g energy. The 250 mL meal (consistency index of 14.17 Pa·sn) is high in protein and dietary fibre. The product’s glycaemic index (GI) and glycaemic load (GL) are low, 24 and 6.0, respectively, raising a normal level of 2-h postprandial blood glucose (<6 mmol/L) and satisfying hunger for approximately 2.5 h.

Conclusions

EBNH, as an ingredient, enhances the antihypertensive and anti-inflammatory properties of PDM. The overall findings suggest that the formulated PDM is a wellness food product capable of promoting good human health, including for dieters and individuals with diabetes.
Automated multimodal imaging of Caenorhabditis elegans behavior in multi-well plates
Authors: Ji Hongfei , Chen Dian , Fang-Yen Christopher
Published: October 2024

Assays of behavior in model organisms play an important role in genetic screens, drug testing, and the elucidation of gene-behavior relationships. We have developed an automated, high-throughput imaging and analysis method for assaying behaviors of the nematode Caenorhabditis elegans. We use high-resolution optical imaging to longitudinally record the behaviors of 96 animals at a time in multi-well plates, and computer vision software to quantify the animals’ locomotor activity, behavioral states, and egg-laying events. To demonstrate the capabilities of our system, we used it to examine the role of serotonin in C. elegans behavior. We found that egg-laying events are preceded by a period of reduced locomotion, and that this decline in movement requires serotonin signaling. In addition, we identified novel roles of serotonin receptors SER-1 and SER-7 in regulating the effects of serotonin on egg laying across roaming, dwelling, and quiescent locomotor states. Our system will be useful for performing genetic or chemical screens for modulators of behavior.
The Neighborhood Environment and Handgrip Strength: Longitudinal Findings From the Health and Retirement Study
Authors: Duchowny Kate A , Diaz-Ramirez L Grisell , Boscardin W John , Perera Rohini , Lin-Gomez Scarlett , Cawthon Peggy M , Noppert Grace A , Clarke Philippa J
Published: October 2024

Background

Muscle strength, as measured by handgrip strength (HGS), is associated with physical function and mortality. Yet the environmental context that influences muscle strength is poorly understood. We evaluated built and social neighborhood characteristics and their association with muscle strength over time.

Methods

Using data from the Health and Retirement Study (2006–2018), linear mixed models assessed how 11 built and social neighborhood variables were associated with baseline levels and changes in HGS over time.

Results

Among the 20 045 respondents (mean age = 63 years, standard deviation = 9.7) with up to 4 HGS measures, 8 455 were men and 11 590 were women. Among men, residing in a neighborhood with a 10% increment higher score on neighborhood disadvantage was associated with a ~1 kg lower HGS at baseline (B = −0.96 kg, 95% confidence interval [CI] = −1.39 to −0.53). Similarly, each 1-point increment on the physical disorder scale was associated with a −0.39 kg lower (95% CI = −0.65 to −0.12) baseline HGS value. Among women, each 10% increment in neighborhood disadvantage was associated with a 0.29 kg lower HGS at baseline (B = −0.29 kg for each 10% increment, 95% CI = −0.46, −0.13). Each 1-unit increment in the number of neighborhood gyms at baseline was associated with a 0.50 kg lower HGS (B = −0.50, 95% CI = −0.76 to −0.23). Each 1-point increment in physical disorder was associated with a −0.12 kg lower (95% CI = −0.24 to −0.00) baseline HGS value. None of the neighborhood features were associated with the HGS rate of change.

Conclusions

Findings suggest that residing in neighborhoods with greater disadvantages and physical disorders may pose challenges for HGS among middle-aged adults as they enter into older adulthood.
Diversity of human salivary heparan sulfate
Authors: Spliid Charlotte B , Mehta Sanjay , Fuster Mark M , Martino Cameron , Morris Claire L , Lee Nharae , Florentino Ivan , Tong Khang , Liu Lin , Ackermann Gail , Knight Rob , Esko Jeffrey D , Hurtado de Mendoza Tatiana
Published: October 2024

The human oral cavity and upper airway serves as an early barrier and reservoir in the transmission of SARS-CoV-2. Saliva in this microenvironment may serve as a key host factor that can modulate susceptibility to infection and eventual infection of the lower respiratory tract. We sought to analyze the content and composition of heparan sulfate, a glycosaminoglycan identified as an important co-receptor for viral entry, and whether there is any correlation with SARS-CoV-2 infection. We enlisted 98 participants stratified by age, gender, race, and COVID-19 history. Notably, the concentration of heparan sulfate in saliva increased with age, and its composition showed a wide range of variability within each age group independently of age. Heparan sulfate concentration and composition did not differ significantly with gender, ethnicity or race. Compared to patients with no COVID-19 history, patients with previous infection had a similar salivary heparan sulfate concentration, but significant increases in overall sulfation were noted. Moreover, in a subset of participants, for which data was available pre- and post- infection, significant elevation in N-sulfoglucosamine in heparan sulfate was observed post- COVID-19. Examination of salivary bacterial 16S rRNA, showed a significant reduction in species predicted to possess heparan sulfate-modifying capacity among participants >60 years old, which correlates with the increase in heparan sulfate content in older individuals. These findings demonstrate a surprisingly wide variation in heparan sulfate content and composition in saliva across the sampled population and confirm other findings showing variation in content and composition of glycosaminoglycans in blood and urine.
Paternal age, de novo mutations, and offspring health? New directions for an ageing problem
Authors: Aitken Robert John
Published: October 2024

This Directions article examines the mechanisms by which a father’s age impacts the health and wellbeing of his children. Such impacts are significant and include adverse birth outcomes, dominant genetic conditions, neuropsychiatric disorders, and a variety of congenital developmental defects. As well as age, a wide variety of environmental and lifestyle factors are also known to impact offspring health via changes mediated by the male germ line. This picture of a dynamic germ line responsive to a wide range of intrinsic and extrinsic factors contrasts with the results of trio studies indicating that the incidence of mutations in the male germ line is low and exhibits a linear, monotonic increase with paternal age (∼two new mutations per year). While the traditional explanation for this pattern of mutation has been the metronomic plod of replication errors, an alternative model pivots around the ‘faulty male’ hypothesis. According to this concept, the genetic integrity of the male germ line can be dynamically impacted by age and a variety of other factors, and it is the aberrant repair of such damage that drives mutagenesis. Fortunately, DNA proofreading during spermatogenesis is extremely effective and these mutant cells are either repaired or deleted by apoptosis/ferroptosis. There appear to be only two mechanisms by which mutant germ cells can escape this apoptotic fate: (i) if the germ cells acquire a mutation that by enhancing proliferation or suppressing apoptosis, permits their clonal expansion (selfish selection hypothesis) or (ii) if a genetically damaged spermatozoon manages to fertilize an oocyte, which then fixes the damage as a mutation (or epimutation) as a result of defective DNA repair (oocyte collusion hypothesis). Exploration of these proposed mechanisms should not only help us better understand the aetiology of paternal age effects but also inform potential avenues of remediation.
Vasa vasorum of the no-touch saphenous vein graft observed using frequency-domain optical coherence tomography
Authors: Sugaya Akira , Uesugi Satoshi , Doi Masayuki , Horikoshi Ryohei , Oka Norihiko , Imada Shuta , Komiya Kenji , Nakamura Masanori , Kawahito Koji
Published: October 2024

OBJECTIVES

One possible reason for the long-term patency of no-touch (NT) saphenous vein grafts (SVG) is the preservation of the vasa vasorum in the adventitia/perivascular adipose tissue (PAT). We investigated the vasa vasorum of the NT SVG in vivo using frequency-domain optical coherence tomography (FD-OCT), performed qualitative and quantitative analyses and compared them with the conventional SVG.

METHODS

An FD-OCT study was performed on 14 SVG at the postoperative coronary angiography 1–2 weeks postoperatively (NT group, n = 9; conventional group, n = 5).

RESULTS

Many signal-poor tubular lumen structures that can be recognized in the cross-sectional and longitudinal profiles, which indicates the vasa vasorum, were observed in the adventitial/PAT layer in the NT SVG. In contrast, the vasa vasorum were less abundant in the conventional SVG. The volume of vasa vasorum per millimetre of graft in the no-touch group was significantly higher than in the conventional group [0.0020 (0.0017, 0.0043) mm3 and 0.0003 (0.0000, 0.0006) mm3, P = 0.023].

CONCLUSIONS

FD-OCT showed abundant vasa vasorum in the thick adventitia/PAT layer of NT saphenous veins in vivo. In contrast, few vasa vasorum were observed in the conventional SVG.
Admission and outcomes of COVID-19 among chronic obstructive pulmonary diseases patients in Africa: protocol for a systematic review and meta-analysis
Authors: Mebrahtom Guesh , Hailay Abrha , Aberhe Woldu , Zereabruk Kidane , Haile Teklehaimanot Gereziher , Tadesse Degena Bahrey
Published: October 2024

When the coronavirus case was originally reported in Wuhan, China, in December 2019, it quickly spread throughout the world and became a global public health problem. Evidence of the admission and outcomes of coronavirus disease among patients with chronic obstructive pulmonary disease (COPD) has not been reported in Africa. Consequently, this research protocol uses a systematic review and meta-analysis of the admission and outcomes of COVID-19 in patients with COPD in Africa. All observational studies published in the English language and reporting on the prevalence, admission and outcomes of COVID-19 among patients with COPD in Africa will be included. A search strategy will be implemented using electronic databases and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol recommendations. The findings of this review will be reported to health program designers, decision-makers and healthcare providers.
Identification of morphologically similar genera based on reproductive systems and immature stages: a case study of Anastatus and Mesocomys (Hymenoptera: Eupelmidae)
Authors: Chen Yong-Ming , Qu Xing-Ran , Shang Cheng-Jie , Peng Ling-Fei , Zang Lian-Sheng
Published: October 2024

Parallel or convergent evolution may result in phenotypically closely similar species. Many studies have reported that using solely traditional external morphological features can result in misidentification. Here, we discuss using the reproductive systems and immature developmental stages for scientific classification in Eupelmidae (Hymenoptera: Chalcidoidea), exemplifying with Anastatus Motschulsky and Mesocomys Cameron (Eupelmidae, Eupelminae). Results show that there are at least 6 distinct differences in the immature stages and the reproductive systems of the adults between species of the 2 genera: (1) the terminal ends of the left and right ovarioles are connected together in the studied species of Anastatus but not in Mesocomys, (2) the base of the lateral oviduct of Anastatus has a diverticulum that is lobate-shaped, whereas this diverticulum is spherical in Mesocomys, (3) the peduncle of the egg of Anastatus is significantly longer than that of Mesocomys, (4) the head capsule of the terminal instar larvae of Anastatus is uniformly translucent, whereas in Mesocomys it has a brown pattern, (5) the ocelli of the Anastatus pupa are smooth and slightly raised whereas the ocelli of Mesocomys each have a long filament each, and (6) the phallobase of adult male Anastatus is sharp basally but rounded in Mesocomys. Our findings not only provide novel insights for the differentiation of similar genera that can be difficult to distinguish in the immature stages but also provide a more comprehensive theoretical basis for clarifying the evolutionary and phylogenic status of Anastatus and Mesocomys.
Revisiting the Environmental Impact of Inappropriate Clinical Laboratory Testing: A Comprehensive Overview of Sustainability, Economic, and Quality of Care Outcomes
Authors: Devis Luigi , Closset Mélanie , Degosserie Jonathan , Lessire Sarah , Modrie Pauline , Gruson Damien , Favaloro Emmanuel J , Lippi Giuseppe , Mullier François , Catry Emilie
Published: October 2024

Background

The use of laboratory resources has seen a substantial increase in recent years, driven by automation and emerging technologies. However, inappropriate use of laboratory testing, encompassing both overuse and underuse, poses significant challenges.

Content

This review explores the complex interplay between patient safety, economic, and environmental factors―known as the “triple bottom line” or “3Ps” for people, profit, and planet―associated with inappropriate use of laboratory resources. The first part of the review outlines the impact of inappropriate laboratory testing on patient safety and economic outcomes. Then the review examines the available literature on the environmental impact of laboratory activities. Several practical solutions for mitigating the environmental impact of laboratories are discussed. Finally, this review emphasizes how decreasing unnecessary laboratory testing results in cost savings and environmental benefits, as evidenced by interventional studies, without compromising patient safety.

The implementation of sustainable practices in laboratories can create a virtuous circle in which reduced testing enhances cost-efficiency, reduces the environmental footprint, and ensures patient safety, thereby benefiting the 3Ps. This review highlights the critical need for appropriate laboratory resource utilization in achieving sustainability in healthcare.
Failed labral reconstruction of the hip can be successfully revised to another labral reconstruction: improved patient-reported outcomes at a minimum of 2-year follow-up
Authors: White Brian J , Swann R. Presley , Spears Hannah , Shafer Anna , Constantinides Shannon M
Published: October 2024

The purpose of this study was to validate the success of revision arthroscopic circumferential allograft labral reconstruction (CLR) in nonarthritic hips, which, in the rare case of failure, had previously undergone labral reconstruction by the same surgeon. Using a minimum of 24-month follow-up, data from 24 hips having undergone revision CLR were analyzed to determine improvements in patient-reported outcomes (PROs). All included cases completed a minimum of 24 months follow-up, with a success rate of 96%. All PROs improved significantly, with exceptionally strong measures of effect. Modified Harris Hip Scores improved by a mean of 26.68 points, with 88% of patients meeting the minimal clinically important difference (MCID) (+6.49, P ≤ .001, d = 1.32). Lower Extremity Functional Scale scores improved by a mean of 21.88 points, with 78% of patients meeting the MCID (+7.79, P ≤ .001, d = 1.32). Pain as rated by the Visual Analog Scale, including at rest, during activities of daily living, and with sports, was significantly improved with strong measures of effect, with >75% of patients having met the MCID. This study validated that a failed labral reconstruction of the hip can be revised safely and effectively to another labral reconstruction of the hip. While labral reconstruction has broadly been shown to result in highly favorable outcomes, this study demonstrated that in the rare case of failure, revision CLR is not only feasible but results in improved pain and functionality.
Molecular systematics of chinchilla rats and taxonomic assessment of the Abrocoma cinerea species complex
Authors: González-Pinilla Francisco J , Latorre Claudio , Palma R Eduardo
Published: October 2024

Chinchilla rats (family Abrocomidae) are hystricomorph rodents primarily inhabiting the central Andes in South America with 8 species in the genus Abrocoma and 2 in Cuscomys. The systematics of this family—relying only on morphological differences—has faced several controversies, particularly in arid-adapted species of Abrocoma (the A. cinerea species complex, or ACC). By using partial DNA sequences of 1 mitochondrial (Cytochrome b) and 2 nuclear genes (GHR and RAG1), we: (i) inferred phylogenetic relationships between 5 species of Abrocoma and 1 of Cuscomys; (ii) performed molecular species-delimitation analyses in 4 species of the ACC (A. cinerea, A. famatina, A. schistacea, and A. uspallata); and (iii) estimated divergence times using stratigraphic ages of extinct taxa. Our phylogenetic analyses recovered 3 main clades: A. bennettii (basal); C. ashaninka; and the ACC. Striking differences in habitat use, morphology, and genetics suggest that each of these main clades might represent a distinct genus. In species-delimitation analyses in the ACC, only 2 species were recognized, and we thus suggest the synonymy of A. famatina with A. cinerea and of A. uspallata with A. schistacea. The origin of extant abrocomids was estimated at the late Miocene (~5.6 million years ago, Ma) with the subsequent origin of arboreal species during the early Pliocene (~4.3 Ma) and the ACC during the late Pliocene (~3.3 Ma). We hypothesize that topographic uplift of the central Andes and associated climatic and ecological changes were the main drivers of diversification in this family.
Implications of the initial Braidwood v. Becerra ruling for colorectal cancer outcomes: a modeling study
Authors: Van Den Puttelaar Rosita , Shi Kewei Sylvia , Smith Robert , Zhao Jingxuan , Ogongo Margaret Katana , Harlass Matthias , Hahn Anne I , Zauber Ann G , Yabroff K Robin , Lansdorp-Vogelaar Iris
Published: October 2024

The Affordable Care Act (ACA) eliminated patient cost-sharing for United States Preventive Service Task Force (USPSTF) recommended services. However, if the US Court of Appeals for the Fifth Circuit fully upheld a US District Court ruling in Braidwood Management v. Becerra, 666 F. Supp. 3d 613 (N.D. Tex 2023), cost-sharing for USPSTF recommendations made after ACA passage would have been reinstated for more than 150 million people. The case would have reinstated cost-sharing for colorectal cancer (CRC) screening for ages 45-49 years and for polyp removal during (diagnostic) colonoscopy across all ages. Using the MISCAN-Colon model, we simulated the potential impact on CRC outcomes, assuming early-onset CRC trends and lower screening participation. An 8-percentage-point decline in screening participation could increase CRC incidence by 5.1% and CRC mortality by 9.1%, with slightly lower costs due to increased cost-sharing. Larger decreases in screening participation can result in higher costs from increased incidence and delayed diagnoses.
The intersection of travel burdens and financial hardship in cancer care: a scoping review
Authors: Planey Arrianna Marie , Spees Lisa P , Biddell Caitlin B , Waters Austin , Jones Emily P , Hecht Hillary K , Rosenstein Donald , Wheeler Stephanie B
Published: October 2024

Background

In addition to greater delays in cancer screening and greater financial hardship, rural-dwelling cancer patients experience greater costs associated with accessing cancer care, including higher cumulative travel costs. This study aimed to identify and synthesize peer-reviewed research on the cumulative and overlapping costs associated with care access and utilization.

Methods

A scoping review was conducted to identify relevant studies published after 1995 by searching 5 electronic databases: PubMed, Scopus, Cumulative Index of Nursing and Allied Health Literature (CINAHL), PsycInfo, and Healthcare Administration. Eligibility was determined using the PEO (Population, Exposure, and Outcomes) method, with clearly defined populations (cancer patients), exposures (financial hardship, toxicity, or distress; travel-related burdens), and outcomes (treatment access, treatment outcomes, health-related quality of life, and survival/mortality). Study characteristics, methods, and findings were extracted and summarized.

Results

Database searches yielded 6439 results, of which 3366 were unique citations. Of those, 141 were eligible for full-text review, and 98 studies at the intersection of cancer-related travel burdens and financial hardship were included. Five themes emerged as we extracted from the full texts of the included articles: 1) Cancer treatment choices, 2) Receipt of guideline-concordant care, 3) Cancer treatment outcomes, 4) Health-related quality of life, and 5) Propensity to participate in clinical trials.

Conclusions

This scoping review identifies and summarizes available research at the intersection of cancer care-related travel burdens and financial hardship. This review will inform the development of future interventions aimed at reducing the negative effects of cancer-care related costs on patient outcomes and quality of life.
Osteogenic effect of alogliptin in chemical-induced bone loss: a tri-modal in silico, in vitro, and in vivo analysis
Authors: Ahmed Faraha , Ahmad Syed Sufian , Alam Mohammad Mumtaz , Shaquiquzzaman Mohammad , Altamish Mohammad , Krishnan Anuja , Vohora Divya , Najmi Abul Kalam , Khan Mohammad Ahmed
Published: October 2024

Objective

To investigate the effects of Alogliptin in chemical-induced post-menopausal osteoporosis.

Methodology

The binding affinity of alogliptin with osteogenic proteins was analysed in silico. The effect of alogliptin on osteogenic proteins and mineralization of osteoblastic cells was evaluated in UMR-106 cells. Further, in vivo anti-osteoporotic activity of alogliptin was evaluated in postmenopausal osteoporosis. Various bone turnover markers were assayed in serum. This followed the analysis of microarchitecture of bone, histology, and immunohistochemistry (IHC) of bone tissue.

Results

Docking scores showed that alogliptin has binding affinity for bone alkaline phosphatase (BALP), osteocalcin, and bone morphogenic protein (BMP-2). Alogliptin also enhanced mineralization of osteoblast cells, evidenced with increased ALP, osteocalcin, and BMP-2. Animal studies revealed significant elevation of bone formation markers, bone ALP, osteocalcin and BMP-2, and decreased bone resorption markers, receptor activator of NF-κβ (RANKL), cathepsin K (CTSK), tartrate resistant acid phosphatase (TRAcP5b) in VCD-induced post-menopausal osteoporosis. Micro computed tomography (μCT) analysis and histology of femur bone and lumbar vertebrae demonstrated decrease in trabecular separation and improved bone density. IHC of femur showed reduced DPP4 enzyme.

Conclusions

Alogliptin increased mineralization in osteoblast cells. It had beneficial effects also altered bone turnover markers, repaired the trabecular microstructure, improved bone mineral density, and exhibited bone forming capacity targeting DPP-4 enzyme in postmenopausal osteoporosis.
Music as preternatural in Geoffrey Hill’s poetry
Authors: Docherty Tom
Published: October 2024

In Geoffrey Hill’s poetry, music, frequently tied to thoughts of the divine, is understood as preternatural: a gift from beyond (præter) the ordinary sphere of human comprehension. For Hill, there is in music a connection with God that makes it fit to restore the link, broken in Adam’s Fall, between natural and supernatural. This essay examines the origins of the idea of music’s preternaturalness, and asks both how Hill addresses the paradox of being tuned in to what is ‘[o]ver my head’; and whether his poetry, which discusses the potential restoration of nature wrought by music, also seeks to enact it.
Bilateral atypical femur fracture in a patient with breast cancer taking zoledronic acid and denosumab: A case report
Authors: Hashimoto Kazuhiko , Ito Tomohiko , Yamagishi Yuto , Goto Koji
Published: October 2024

A 54-year-old woman developed stage IV breast cancer 8 years prior. Chemotherapy was administered, and she was started on zoledronic acid treatment for her bone metastases. Her chemotherapy regimen was then switched, owing to disease progression. Fifty-seven months after starting treatment with zoledronic acid, the patient suffered an atypical femoral fracture of her right femur, for which she underwent surgery. Twenty months later, she developed another atypical femoral fracture in her left femur and underwent intramedullary nail fixation.

Zoledronic acid and denosumab use in patients with metastatic bone tumours caused by breast cancer should be done cautiously, considering atypical femoral fracture risk.
Structural mechanisms of SLF1 interactions with Histone H4 and RAD18 at the stalled replication fork
Authors: Ryder Emma L , Nasir Nazia , Durgan Amy E O , Jenkyn-Bedford Michael , Tye Stephanie , Zhang Xiaodong , Wu Qian
Published: October 2024

DNA damage that obstructs the replication machinery poses a significant threat to genome stability. Replication-coupled repair mechanisms safeguard stalled replication forks by coordinating proteins involved in the DNA damage response (DDR) and replication. SLF1 (SMC5–SMC6 complex localization factor 1) is crucial for facilitating the recruitment of the SMC5/6 complex to damage sites through interactions with SLF2, RAD18, and nucleosomes. However, the structural mechanisms of SLF1’s interactions are unclear. In this study, we determined the crystal structure of SLF1’s ankyrin repeat domain bound to an unmethylated histone H4 tail, illustrating how SLF1 reads nascent nucleosomes. Using structure-based mutagenesis, we confirmed a phosphorylation-dependent interaction necessary for a stable complex between SLF1’s tandem BRCA1 C-Terminal domain (tBRCT) and the phosphorylated C-terminal region (S442 and S444) of RAD18. We validated a functional role of conserved phosphate-binding residues in SLF1, and hydrophobic residues in RAD18 that are adjacent to phosphorylation sites, both of which contribute to the strong interaction. Interestingly, we discovered a DNA-binding property of this RAD18-binding interface, providing an additional domain of SLF1 to enhance binding to nucleosomes. Our results provide critical structural insights into SLF1’s interactions with post-replicative chromatin and phosphorylation-dependent DDR signalling, enhancing our understanding of SMC5/6 recruitment and/or activity during replication-coupled DNA repair.
Altered dNTP pools accelerate tumor formation in mice
Authors: Tran Phong , Mishra Pradeep , Williams Leonard G , Moskalenko Roman , Sharma Sushma , Nilsson Anna Karin , Watt Danielle L , Andersson Pernilla , Bergh Anders , Pursell Zachary F , Chabes Andrei
Published: October 2024

Alterations in deoxyribonucleoside triphosphate (dNTP) pools have been linked to increased mutation rates and genome instability in unicellular organisms and cell cultures. However, the role of dNTP pool changes in tumor development in mammals remains unclear. In this study, we present a mouse model with a point mutation at the allosteric specificity site of ribonucleotide reductase, RRM1-Y285A. This mutation reduced ribonucleotide reductase activity, impairing the synthesis of deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP). Heterozygous Rrm1+/Y285A mice exhibited distinct alterations in dNTP pools across various organs, shorter lifespans and earlier tumor onset compared with wild-type controls. Mutational spectrum analysis of tumors revealed two distinct signatures, one resembling a signature extracted from a human cancer harboring a mutation of the same amino acid residue in ribonucleotide reductase, RRM1Y285C. Our findings suggest that mutations in enzymes involved in dNTP metabolism can serve as drivers of cancer development.
RAD52-mediated repair of DNA double-stranded breaks at inactive centromeres leads to subsequent apoptotic cell death
Authors: Maruta Gen , Maeoka Hisanori , Tsunoda Toshiyuki , Akiyoshi Kozaburo , Takagi Satoshi , Shirasawa Senji , Ishikura Shuhei
Published: October 2024

Centromeres, where the kinetochore complex binds, are susceptible to damages including DNA double-stranded breaks (DSBs). Here, we report the functional significance and the temporally and spatially distinct regulation of centromeric DSB repair via the three pathways of non-homologous end joining (NHEJ), homologous recombination (HR) and single-strand annealing (SSA). The SSA factor RAD52 is most frequently recruited to centromeric DSB sites compared with the HR factor RAD51 and the NHEJ factor DNA ligase IV (LIG4), indicating that SSA plays predominant roles in centromeric DSB repair. Upon centromeric DSB induction, LIG4 is recruited to both active centromeres, where kinetochore complex binds, and inactive centromeres. In contrast, RAD51 and RAD52 are recruited only to inactive centromeres. These results indicate that DSBs at active centromeres are repaired through NHEJ, whereas the three pathways of NHEJ, HR and SSA are involved in DSB repair at inactive centromeres. Furthermore, siRNA-mediated depletion of either LIG4 or RAD51 promotes cell death after centromeric DSB induction, whereas RAD52 depletion inhibits it, suggesting that HR and NHEJ are required for appropriate centromeric DSB repair, whereas SSA-mediated centromeric DSB repair leads to subsequent cell death. Thus, SSA-mediated DSB repair at inactive centromeres may cause centromere dysfunction through error-prone repair.
PDCdb: the biological activity and pharmaceutical information of peptide–drug conjugate (PDC)
Authors: Sun Xiuna , Li Hanyang , Chen Zhen , Zhang Yang , Wei Zhangle , Xu Hangwei , Liao Yang , Jiang Wanghao , Ge Yichao , Zheng Lingyan , Li Teng , Wu Yuting , Luo Meiyin , Fang Luo , Dong Xiaowu , Xiao Mang , Han Lianyi , Jia Qingzhong , Zhu Feng
Published: October 2024

Peptide–drug conjugates (PDCs) have emerged as a promising class of targeted therapeutics with substantial pharmaceutical advantages and market potentials, which is a combination of a peptide (selective to the disease-relevant target), a linker (stable in circulation but cleavable at target site) and a cytotoxic/radioactive drug (efficacious/traceable for disease). Among existing PDCs, those based on radiopharmaceuticals (a.k.a. radioactive drugs) are valued due to their accurate imaging and targeted destruction of disease sites. It's demanded to accumulate the biological activity and pharmaceutical information of PDCs. Herein, a database PDCdb was thus constructed to systematically describe these valuable data. Particularly, biological activities for 2036 PDCs were retrieved from literatures, which resulted in 1684, 613 and 2753 activity data generated based on clinical trial, animal model and cell line, respectively. Furthermore, the pharmaceutical information for all 2036 PDCs was collected, which gave the diverse data of (a) ADME property, plasma half-life and administration approach of a PDC and (b) chemical modification, primary target, mode of action, conjugating feature of the constituent peptide/linker/drug. In sum, PDCdb systematically provided the biological activities and pharmaceutical information for the most comprehensive list of PDCs among the available databases, which was expected to attract broad interest from related communities and could be freely accessible at: https://idrblab.org/PDCdb/
Pediatric metastatic extracranial high-grade glioma: A case report and literature review
Authors: Ali Naba , Eaton Bree R , Fangusaro Jason R , Castellino Robert C , Velázquez Vega José E , Chern Joshua J , Schniederjan Matthew , Patil Prabhumallikarjun
Published: October 2024

We report a case of a 10-year-old male with a right frontal diffuse pediatric-type high-grade glioma (HGG), H3-wild-type (WT), and IDH-WT, diagnosed at the age of 9 years, who underwent gross total resection, 60 Gy focal proton radiation in 30 fractions to the resection cavity with concurrent temozolomide followed by maintenance chemotherapy with temozolomide and lomustine. One month after completion of maintenance chemotherapy, he developed subcutaneous swelling in the right temporal region and was treated with antibiotics for presumed lymphadenitis. Two months later, he developed a recurrent painless right parietal soft tissue mass that failed to respond to antibiotic therapy. This prompted evaluation by MRI which revealed new enhancing masses in the cerebellum and extracranial soft tissue mass in the right temporal region. He underwent gross total resection of both masses. Pathologic analysis confirmed both masses as recurrent HGG. Molecular markers, however, differed between the 2 sites of recurrence. He proceeded to complete hypofractionated proton therapy at sites of recurrence. Three months later, he was found to have tumor dissemination into the spine and brain for which he received proton therapy to the whole spine and brain. Due to the presence of CDK4 amplification at diagnosis and both sites of tumor recurrence, he then received palliative treatment with the CDK4/6 inhibitor, abemaciclib, for the final 5 months of his life. Since extracranial HGG is a rare presentation, with few cases reported in the pediatric population, we report this case and review previously published literature.
Strengthening Fungal Infection Diagnosis and Treatment: An In-depth Analysis of Capabilities in Honduras
Authors: Ortiz Bryan , Varela Diana , Fontecha Gustavo , Torres Karla , Cornely Oliver A , Salmanton-García Jon
Published: October 2024

Background

Invasive fungal infections (IFIs) are a major public health concern in low- and middle-income countries (LMICs) due to limited diagnostic and treatment resources, leading to high morbidity and mortality. Despite their significant global burden, IFIs are underrecognized and underdiagnosed in LMICs. This study evaluates the diagnostic and therapeutic capacities for managing IFI in Honduras, a country with unique health care challenges.

Methods

From March to December 2023, a comprehensive survey was conducted across multiple health care centers in Honduras. The survey, reviewed for content and clarity by local medical institutions, targeted medical microbiologists and clinicians to assess various aspects of fungal disease diagnosis and treatment. Data included the availability and use of diagnostic tools and antifungal therapies, identifying gaps and limitations in current practices.

Results

The survey revealed that Candida spp (97.4%) and Aspergillus spp (35.9%) were the most concerning pathogens. Although microscopy and culture methods were available in most institutions, their application in suspected IFI cases was inconsistent, and antifungal susceptibility testing was rarely performed. Advanced diagnostic techniques, such as antigen detection, were available in only a few institutions, while antibody detection and polymerase chain reaction testing were entirely absent. All hospitals had access to at least 1 triazole antifungal, typically fluconazole, but there was a notable scarcity of more potent antifungals, including amphotericin B formulations and echinocandins. The limited use of available diagnostic tools and the restricted availability of essential antifungals were identified as major barriers to effective IFI management.

Conclusions

This study highlights significant gaps in the diagnostic and therapeutic capabilities for managing IFI in Honduras. The underutilization of basic diagnostic tools, the inaccessibility of advanced testing methods, and the limited availability of essential antifungal medications underscore the urgent need for capacity-building initiatives, infrastructure improvements, and policy reforms. Addressing these deficiencies is critical for enhancing the management of IFI in Honduras, with broader implications for similar LMIC settings. These findings can inform targeted interventions and resource allocation to improve outcomes for patients with IFI.
A universal scaling relation incorporating the cusp-to-core transition of dark matter halos
Authors: Kaneda Yuka , Mori Masao , Otaki Koki
Published: October 2024

The dark matter halos associated with galaxies have hitherto established strong correlations within a range of observed parameters, known as scaling relations of dark matter halos. The origin of these scaling relations still contains significant ambiguities and requires comprehensive exploration for complete understanding. Utilising the correlation between the concentration and mass of dark matter halos inferred from cosmological N-body simulations based on the cold dark matter paradigm (c–M relation), we derive theoretical scaling relations among other physical quantities, such as the surface mass density, the maximum circular velocity, and the scale radius of the dark matter halo. By comparing theoretical and observed scaling relations at various mass scales, it is found that the scaling relations observed in dwarf galaxies and galaxies originate in the c–M relation of the dark matter halo. We predict that this theoretical scaling relation is also established in galaxy clusters. Moreover, we propose a novel theoretical scaling relation that incorporates the effects of the cusp-to-core transition, which is supposed to occur in cold dark matter halos. Our discussion concludes with the exploration of potential observational verification of the cusp-to-core transition process in dark matter halos.
Examining the effectiveness of a police developed cardio-pulmonary resuscitation virtual reality training program
Authors: Keningale Paige , Halford Eric , Taleb Hussain AlShaima , Condon Camie , Bullock Karen
Published: October 2024

In 2020 the Saif Bin Zayed Academy for Security & Policing Sciences in the United Arab Emirates created a Police Virtual Training Centre, known as the Abu Dhabi Police Virtual Training Centre. Since their inception they have internally developed more than 12 virtual reality simulations. This includes a Cardio-Pulmonary Resuscitation (CPR) Virtual Reality (VR) Training Program. Delivered to both police officers and civilian employees the CPR VR replicates a realistic cardiac arrest incident. The purpose of this study is to evaluate the effectiveness of this VR simulation. This is achieved by using a quantitative survey methodology to test the knowledge acquired from two groups who received CPR training using VR and a second who received it using traditional classroom tuition. Results are compared inferential statistics and identified no significant difference in test outcomes, indicating the VR simulation is safe. In addition, we surveyed both groups regarding their views and perspectives of the training environment and we used the presence scale for virtual reality to test the degree of immersion, environmental fidelity and for negative impacts. Correlational analysis identified a strong link between the immersive nature of VR, and levels of engagement and realism. Negative effects of discomfort and disorientation were strongly correlated with one another but were not linked to the level of immersion. The findings are discussed in the context of potentially using VR to supplement or replace existing police CPR training, and the wider considerations regarding developing VR within policing.
L’espace vécu and Its Perturbations in Schizophrenia: Systematic Review and Meta-analysis of Altered Body-Centric Metrics—Personal and Peripersonal Space
Authors: Raballo Andrea , Poletti Michele , Bevione Francesco , Lacidogna Maria Carla , Preti Antonio
Published: October 2024

Subtle distortions of the experience of lived space have long been associated with schizophrenia. Although a body-centric transformation of space is considered an essential component of anomalous subjective experience in schizophrenia, its impact on the 2 major body-centric spatial constructs, that is, personal space (PS) and peripersonal space (PPS), is still not clear. This systematic review and meta-analysis have been set up to: (1) summarize the evidence on putative extensional differences of PS and PPS in schizophrenia as compared with controls, and (2) evaluate the quality and the limitations of available studies on the topic. Four electronic literature databases (MEDLINE, EMBASE, PsychINFO, and CINAHL) were searched with the keywords “Personal space OR Interpersonal distance AND Schizophrenia,” “Peripersonal space AND Schizophrenia” from inception until December 31, 2023, resulting in 15 studies on PS and 5 studies on PPS included in this systematic review. The 12 studies on PS included in the meta-analysis revealed that individuals with a diagnosis of schizophrenia place a larger interpersonal distance from the stimuli than controls, with a moderate effect size in both the fixed-effect model (Hedges’ g = 0.558 [95% confidence interval, CI: 0.445–0.671]; z = 9.67; P < 0.0001) and the random effects model (0.547 [0.294–0.799]; z = 4.77; P = 0.0006). The 5 studies included in the meta-analysis on PPS showed that individuals with a diagnosis of schizophrenia exhibit a narrower PPS than the controls at the fixed-effect (Hedges’ g = 1.043 [95%CI: .739–1.348]; z = 6.72; P < .0001), but not at the random effects model (1.318 [−0.721 to 3.359]; z = 1.79; P = .147). Heterogeneity was substantial in both meta-analyses. Overall, the findings indicate that both body-centered space constructs (PS and PPS) are affected in schizophrenia, with an enlargement PS and a reduction PPS, thereby supporting the distinction of these constructs. These modifications cohere with the subjective transformation of the lived space (aka espace vécu) reported in classical psychopathology and may be promising, neurodevelopmentally grounded, biomarkers of vulnerability to schizophrenia and its spectrum conditions.