bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor angiogenesis and anti-angiogenic therapy
Authors: Guo Ziheng , Jing Xu , Sun Xiaoting , Sun Shishuo , Yang Yunlong , Cao Yihai
Published: July 2024

Anti-angiogenic drugs (AADs), which mainly target the vascular endothelial growth factor-A signaling pathway, have become a therapeutic option for cancer patients for two decades. During this period, tremendous clinical experience of anti-angiogenic therapy has been acquired, new AADs have been developed, and the clinical indications for AAD treatment of various cancers have been expanded using monotherapy and combination therapy. However, improvements in the therapeutic outcomes of clinically available AADs and the development of more effective next-generation AADs are still urgently required. This review aims to provide historical and perspective views on tumor angiogenesis to allow readers to gain mechanistic insights and learn new therapeutic development. We revisit the history of concept initiation and AAD discovery, and summarize the up-to-date clinical translation of anti-angiogenic cancer therapy in this field.
Presurgical Mapping With Ultra-high Frequency Ultrasound of Hidradenitis Suppurativa Lesions Treated With Wide Local Excision and Secondary Intention Healing
Authors: Michelucci Alessandra , Fidanzi Cristian , Manzo Margiotta Flavia , Granieri Giammarco , Salvia Giorgia , Janowska Agata , Romanelli Marco , Dini Valentina
Published: July 2024

BACKGROUND

Hidradenitis suppurativa (HS) is a challenging chronic inflammatory condition often requiring surgical intervention, such as wide local excision. Preoperative mapping with ultra-high frequency ultrasound (UHFUS) enables detailed assessment of lesion extension, particularly identifying tunnels and fistulas, facilitating surgical planning.

OBJECTIVE

This study aimed to analyze recurrence rates of HS lesions previously mapped with UHFUS and treated with wide excision and secondary intention healing.

MATERIALS AND METHODS

A retrospective single-center study enrolled 40 patients with HS undergoing wide excision surgery after UHFUS mapping. Patients were assessed weekly until complete healing and then every 3 months, evaluating clinical and sonographic signs of relapse and pain using the visual analogue scale.

RESULTS

Results showed a population predominantly composed of women (65%) with a mean age of 39 years and a medium HS-Hurley score of 2.5. Over a 22-month follow-up, only 10% experienced clinical relapse, achieving an 90% total remission rate. Pain scores decreased significantly from Week 0 to Week 4.

CONCLUSION

The study highlights the clinical challenge of HS management, particularly regarding surgical planning and lesion margin definition. The remission rate observed in this study suggests the effectiveness of UHFUS-guided surgical approaches. Future studies should extend observation periods to further validate these findings.
Antidepressant-like effect of riparin I and riparin II against CUMS-induced neuroinflammation via astrocytes and microglia modulation in mice
Authors: Sales Iardja S.L. , de Souza Alana G. , Chaves Filho Adriano J.M. , Sampaio Tiago L. , da Silva Daniel M.A. , Valentim José T. , Chaves Raquell de C. , Soares Michelle V.R. , Costa Júnior Dilailson C. , Barbosa Filho José M. , Macêdo Danielle S. , de Sousa Francisca Cléa Florenço
Published: July 2024

Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28 days. From 15th to the 22nd day, the animals received RIP I or RIP II (50 mg/kg) or fluoxetine (FLU, 10 mg/kg) or vehicle, by gavage. On the 29th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 – Iba-1) and astrocyte (glial fibrillary acidic protein – GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1β) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1β levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression.
Impact of primary aldosteronism on kidney function: results from the SPAIN-ALDO registry
Authors: Araujo-Castro Marta , Paja Fano Miguel , González-Boillos Marga , Pascual-Corrales Eider , Martín Rojas-Marcos Patricia , García-Cano Ana , Ruiz-Sanchez Jorge Gabriel , Vicente Almudena , Gómez-Hoyos Emilia , Casterás Anna , Puig-Pérez Albert , García Sanz Iñigo , Recasens Mónica , Barahona San Millan Rebeca , Picón César María José , Díaz Guardiola Patricia , Perdomo Carolina M. , Manjón-Miguélez Laura , Rebollo Román Angel , Robles Lázaro Cristina , María Recio José , Morales-Ruiz Manuel , Calatayud María , Jiménez López Noemi , Meneses Diego , Sampedro Nuñez Miguel , Mena Ribas Elena , Sanmartín Sánchez Alicia , Gonzalvo Diaz Cesar , Lamas Cristina , Castillo Tous María del , Serrano Joaquín , Michalopoulou Theodora , Tenés Rodrigo Susana , Roa Chamorro Ricardo , Jaén Aguila Fernando , Moya Mateo Eva María , Gutiérrez-Medina Sonsoles , Hanzu Felicia Alexandra , Parra Ramírez Paola
Published: July 2024

Aim:

To evaluate the impact of aldosterone excess on renal function in individuals with primary aldosteronism and to compare its evolution after surgery or mineralocorticoid receptor antagonist (MRA) treatment.

Methods:

A multicentre, retrospective cohort study of primary aldosteronism patients in follow-up in 36 Spanish tertiary hospitals, who underwent specific treatment for primary aldosteronism (MRA or adrenalectomy).

Results:

A total of 789 patients with primary aldosteronism were included, with a median age of 57.5 years and 41.8% being women. At primary aldosteronism diagnosis, the prevalence of chronic kidney disease (CKD) was 10.7% (n = 84), with 75% of cases classified as state 3a (n = 63). Primary aldosteronism patients with CKD had a longer duration of hypertension, a higher prevalence of type 2 diabetes, dyslipidaemia, cardiovascular events, hypokalaemia, and albuminuria. Unilateral adrenalectomy was performed in 41.8% of cases (n = 330), and 459 patients were treated with MRA. After a median follow-up of 30.7 months (range 13.3–68.4), there was a significant decline in the estimated glomerular filtration rate (eGFR) in operated patients and those receiving MRA. During follow-up, 24.4% of patients with CKD at the time of primary aldosteronism diagnosis had normalized renal function, and 39% of those with albuminuria had albuminuria remission. There were no differences in renal function or albuminuria regression between the two therapy groups. However, development of albuminuria was less common in operated than in medically treated patients (0 vs. 6.0%, P = 0.009).

Conclusion:

CKD affects around 10% of the patients with primary aldosteronism, with a higher risk in individuals with long-term hypertension, type 2 diabetes, dyslipidaemia, cardiovascular events, hypokalaemia, and albuminuria. At short-term, both MRA and surgical treatment lead to a reduction of renal function, but adrenalectomy led to higher renal protection.
Assessing the Mental Model State of Emergency Responders in the Context of Radiological Dispersal Device (RDD) Incidents: A Multi-state Study
Authors: Leek Angela E. , Keren Nir , Shelley Mack C. , Franke Warren , Mosher Gretchen A. , Simpson Stephen A. , Rice Timothy , Hayden H. Emily
Published: July 2024

Hazardous Materials (HAZMAT) Technicians’ notions of mental model, or cognitive representations of their understanding and beliefs regarding Radiological Dispersal Devices (RDDs) incidents, have not been previously explored. A prior study developed an Expected Mental Model State (EMMS) framework specific to RDD incident response for HAZMAT technicians. The work herein presents the development of a derivative of this framework, the EMMS Diagnostic Matrix, to evaluate the actual Mental Model State (MMS) of HAZMAT technicians in the context of RDD incidents. The EMMS Diagnostic Matrix was administered via a survey and simulation activity in four U.S. states representing the Northeast, West, South, and Midwest regions. Data were collected and coded using grounded theory methodology. Reflexive thematic analysis was employed to identify themes across related areas where the notions of mental model for the HAZMAT technician responders' actual MMS differed from the EMMS. The analysis of the collected data revealed four significant themes representing incomplete notions of the mental model spanning various EMMS conceptual domains: Overestimation of Radiation Dose and Health Effects, indicating misunderstandings about the health impacts of radiation exposure, Acute Radiation Syndrome (ARS), particularly in the lower range of radiation doses; Overreliance on Responder Protection [personal protective equipment (PPE)/self-contained breathing apparatus (SCBA)], highlighting gaps in understanding radiation principles and radioactive material dispersal properties from a radiological dispersal device; Misunderstanding Radiation Detection and Units, signifying confusion about radiation units and differentiation between dose rate and accumulated dose; and Incomplete Understanding of Radiation Characteristics and Dispersal Properties, outlining a limited grasp of inhalation risks from radiation and the dispersal traits of a radiological dispersal device. The interconnectedness of these technical misunderstandings can guide the development of a strategic plan to evaluate and modify existing training, aiming at these specific themes to improve the efficiency of HAZMAT technicians in emergency situations and to identify areas for further research.
“Urological age” as a proxy of healthy longevity: analysis of prospective population-based cohorts in U.S. and China
Authors: Jin Yuming , Huang Weichao , Zeng Bin , Yang Lu , Wang Shengfeng , Manuel Colucci , Daniele Robesti , Deng Linghui , Leng Siqi , Hu Dan , Wang Daming , Jiang Zhongyuan , Yi Qinling , Zhang Li , Zeng Yuxiao , Zhu Wenjie , Li Sheng , Liu Xinyue , Wei Qiang , Qiu Shi
Published: July 2024

Background:

Assessing urinary symptoms poses a complex challenge for primary care practitioners. In evaluating urological function, authors’ approach involves constructing an urological age through the analysis of laboratory parameters and indicators of the urinary system.

Methods:

Based on the National Health and Nutrition Examination Survey (NHANES), urological laboratory tests and age-related symptoms were included in the development of urological age (UA) and urological age acceleration (UAA) through the Klemera Doubal method. In relation to mortality associated with UAA, the metric was categorized into grades (0, 1, 2) as a discrete variable. The authors investigated the correlation between UAA and its grades with mortality, conducted survival analysis based on UAA grades, and explored the correlation between multi-system ageing-related disorders and UAA grades based on the NHANES and the West China Natural Population Cohort Study.

Results:

UA was related to age with the r to 0.85 in men and 0.84 in women. Each year the increase in UAA was related to higher 1% and 4% mortality for men and women. Those with UAA grades 1 and 2 were associated with more risk of mortality than individuals with UAA grade 0 (men 8% and 40%, women 24% and 157%). The advanced UAA grades kept pace with multi-system ageing. Healthy diets and lifestyle habits are associated with lower UAA.

Conclusion:

Urological age is related to multi-system ageing and increases mortality risk, and urological age can be used to screen high-risk individuals and inform precision clinical development for ageing intervention.
Meta-analysis reveals higher intraoperative urologic complication rates in minimally invasive radical hysterectomy compared to abdominal radical hysterectomy
Authors: Hwang Jong Ha , Kim Bitnarae
Published: July 2024

Background:

Minimally invasive radical hysterectomy (MIRH) has been increasingly adopted for its benefits of reduced blood loss and shorter hospital stays. This study aims to conduct a meta-analysis to compare the incidence of intraoperative urologic complications, including bladder and ureteral injuries, between MIRH and abdominal radical hysterectomy (ARH).

Method:

The authors systematically searched PubMed, EMBASE, and the Cochrane Library for studies published up to April 2024. A total of 35 studies were analyzed to compute odds ratios (ORs) for intraoperative urologic complications, bladder injuries, and ureteral injuries, focusing on subgroup evaluations by publication year, study quality, BMI, geographic region, and surgical method.

Results:

The meta-analysis demonstrates that MIRH is associated with higher risks of intraoperative urologic complications (OR=2.412, 95% CI: 1.995–2.916, P<0.001), bladder injuries (OR=2.109, 95% CI: 1.567–2.839, P<0.01), and ureteral injuries (OR=2.549, 95% CI: 1.992–3.262, P<0.001). No publication bias was detected across the studies, ensuring the robustness of the findings. Significant differences in complication rates were also observed across geographic and procedural subgroups.

Conclusion:

The findings confirm that MIRH has a higher rate of intraoperative urologic complications, including bladder and ureteral injuries, compared to ARH. These results provide essential insights that could guide clinical decision-making and influence surgical practice guidelines.
Assessing Chronic Ear Symptoms in Bone-Conduction Hearing Implant (BCHI) Patients Using the Chronic Otitis Media Benefit Inventory (COMBI) Score
Authors: Collins Rachael , Phillips John , Hanif Junaid , Nunney Ian , Collett Amanda
Published: July 2024

Objective

This study aimed to determine improvement in health-related quality of life (HRQoL) using a validated disease-specific patient-reported outcome measure (PROM) questionnaire in patients undergoing bone-conduction hearing implant (BCHI) insertion.

Study Design

A mixed retrospective and prospective correlational study.

Setting

Single tertiary referral center in the United Kingdom.

Patients

All adult patients undergoing their first BCHI over 6 years (April 1, 2017, to March 3, 2023).

Main Outcome Measures

The Chronic Otitis Media Benefit Inventory (COMBI) score (postintervention) and the Glasgow Health Status Inventory (GHSI) (pre-and post-BCHI questionnaire).

Results

Improvements were seen across all COMBI domains. The mean total COMBI score was 46.3 (standard deviation = 5.3). Although expected significant improvements were seen in hearing and social domains, there were also notable gains in ear symptoms and reduced medical intervention post-BCHI. There was a statistically significant improvement in all GHSI scores post-BCHI (median total difference 67.1,p< 0.0001).

Conclusions

This study reports very favorable outcomes for BCHI patients using two different PROMs: COMBI and GHSI. Although these PROMs complement each other, they also offer different perspectives on the same cohort of patients, with COMBI providing a unique insight into specific ear symptoms. This is the first reported study using this complement of PROMS in BCHI patients and offers further evidence for the wide-reaching improvements BCHI can have for patients.
Proprotein convertase subtilisin/kexin type 9 as a drug target for abdominal aortic aneurysm
Authors: Golledge Jonathan , Lu Hong S. , Shah Sonia
Published: July 2024

Purpose of review

There are no current drug therapies to limit abdominal aortic aneurysm (AAA) growth. This review summarizes evidence suggesting that inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) may be a drug target to limit AAA growth.

Recent findings

Mendelian randomization studies suggest that raised LDL and non-HDL-cholesterol are causal in AAA formation. PCSK9 was reported to be upregulated in human AAA samples compared to aortic samples from organ donors. PCSK9 gain of function viral vectors promoted aortic expansion in C57BL/6 mice infused with angiotensin II. The effect of altering PCSK9 expression in the aortic perfusion elastase model was reported to be inconsistent. Mutations in the gene encoding PCSK9, which increase serum cholesterol, were associated with increased risk of human AAA. Patients with AAA also have a high risk of cardiovascular death, myocardial infarction and stroke. Recent research suggests that PCSK9 inhibition would substantially reduce the risk of these events.

Past research suggests that drugs that inhibit PCSK9 have potential as a novel therapy for AAA to both limit aneurysm growth and reduce risk of cardiovascular events. A large multinational randomized controlled trial is needed to test if PCSK9 inhibition limits AAA growth and cardiovascular events.
Validation of the Emergency Department Work Index in a Pediatric Freestanding Community Emergency Department
Authors: Chen Sarah M. , Stewart Gregory , Sentman Emily , Helwig Sara , Rust Laura , Hoffman Jeffrey , Reynolds Maegan , Bennett Berkeley
Published: July 2024

Objectives

The Emergency Department Work Index (EDWIN) is a validated overcrowding score shown to correlate well with staff assessment of adult emergency department (ED) overcrowding and the potential need for diversion. It derives from the number of staffed ED beds, attending physicians on duty, patients within each triage category, and admitted patients. To date, no study has validated EDWIN in a pediatric community ED setting. We aim to determine if EDWIN correlates with established overcrowding measures and provider perception of overcrowding within a freestanding, community-based pediatric ED.

Methods

In this prospective observational study at a freestanding, community-based pediatric ED, EDWIN was calculated hourly over 8 weeks throughout the year. EDWIN was compared with other objective and previously established ED metrics of overcrowding, including rates of patients who left without being seen (LWBS), average time from arrival to ED room, average length of stay (LOS), ED occupancy rates, and number of patients in the waiting room. Furthermore, EDWIN was compared with provider perception of overcrowding by surveying providers 6 times a day during the study period using novel, real-time, longitudinal, electronic health record-based survey distribution methodology. Spearman correlation coefficients were calculated to characterize the associations between EDWIN vs provider perception and EDWIN vs ED metrics. ANOVA and Tukey HSD were used to compare means of ED metrics of overcrowding across EDWIN severity categories.

Results

Five hundred eleven provider perception survey responses were collected from July 2022 through January 2023. EDWIN directly correlated with all measures of overcrowding, including provider perception of crowdedness (rho = 0.67), LWBS rates (rho = 0.44), average time from arrival to ED room (rho = 0.74), average LOS (rho = 0.70), ED occupancy rates (rho = 0.68), and number of patients in the waiting room (rho = 0.65). All findings were statistically significant (P < 0.05).

Conclusions

Our findings suggest that EDWIN is an accurate tool to measure overcrowding in a freestanding, community-based pediatric ED.
Leprous neuropathy
Authors: Marques Wilson
Published: July 2024

Purpose of review

Leprosy is still an important cause of neuropathy. Late diagnosis is associated with development of severe nerve impairment.

Recent findings

early diagnosis and early treatment is essential in order to avoid disability and disease transmission. Recognizing that leprosy is a neurological disease is a fundamental step to the Leprosy zero action proposed by the World Health Organization

leprosy neuropathy manifests as a mononeuropathy or a multiple mononeuropathy with a temperature-dependent distribution. Electromyography, high-resolution sonography serology and PCR help make the diagnosis. Multidrug therapy should be instituted.
Muscle ultrasound in myopathies
Authors: Vicino Alex , Veltsista Dimitra , van Alfen Nens
Published: July 2024

Purpose of review

This review highlights recent developments in the field of muscle ultrasound (MUS) for the diagnosis and follow up of muscle disorders.

Recent findings

The diagnostic screening capacity of quantitative grayscale analysis is still sufficient to assess children suspected of a neuromuscular disorder. A combination of visual and quantitative assessment is advised for optimal interpretation. MUS was more sensitive but less specific than MRI for detecting pathology in limb girdle dystrophies and inflammatory myopathies. New techniques such as shearwave elastography and artificial intelligence algorithms for automated image segmentation show promise but need further development for use in everyday practice.

Muscle ultrasound has high correlations with clinical measures of function in skeletal and respiratory muscles and the orofacial region, in most of the myopathies and dystrophies studied. Over time, imaging changes precede changes in clinical status, making them attractive for biomarker use in trials. In Duchenne muscular dystrophy MUS was also responsive to the effects of steroid treatment.

Muscle ultrasound is a sensitive technique to diagnose and follow up of skeletal, facial and respiratory muscles in neuromuscular disorders. Its role is both complementary to and partially overlapping with that of MRI.
Molecular characterization of enteroviruses circulating among pigs and goats in two Central African countries, Cameroon and the Central African Republic.
Authors: MODIYINJI Abdou Fatawou , JOFFRET Marie-Line , NOMBOT-YAZENGUET Marina Prisca de Marguerite , ENDENGUE ZANGA Marie-Claire , SADEUH-MBA Serge , NJOUOM Richard , Bessaud Mael
Published: July 2024

To date, data on animal enteroviruses (EVs) are scarce, especially in Central Africa. The aim of this study was to characterize EVs among pigs and goats in Cameroon and Central African Republic (CAR).
A total of 226 pig and goat faecal samples collected in two previous studies carried out in Cameroon and CAR were pooled and were screened with molecular assays targeting EV-Es, EV-Fs and EV-Gs. EV genomes were amplified by RT-PCR and their sequences obtained by Illumina sequencing and de novo assembly. Based on the capsid sequences, 27 EV-G sequences were identified and assigned to 11 virus types while no EV-E or EV-F was observed. Phylogenetic analysis revealed that the EV-Gs detected in this study were genetically closely related to sequences already reported worldwide. This worldwide circulation of EV-Gs is likely due the massive international trade of live animals. One human EV, EVC-99, which belongs to the species Enterovirus C, was detected in pigs. This is the third detection of such an event in a similar context, reinforcing the hypothesis that some EV-Cs could be infecting pigs. Our work provides new data on the genetic diversity of EVs circulating among domestic animals in Central Africa, and particularly in Cameroon with the first study.
The TRIPOD-LLM Statement: A Targeted Guideline For Reporting Large Language Models Use
Authors: Gallifant Jack , Afshar Majid , Ameen Saleem , Aphinyanaphongs Yindalon , Chen Shan , Cacciamani Giovanni , Demner-Fushman Dina , Dligach Dmitriy , Daneshjou Roxana , Fernandes Chrystinne , Hansen Lasse Hyldig , Landman Adam , Lehmann Lisa , McCoy Liam G. , Miller Timothy , Moreno Amy , Munch Nikolaj , Restrepo David , Savova Guergana , Umeton Renato , Gichoya Judy Wawira , Collins Gary S. , Moons Karel G. M. , Celi Leo A. , Bitterman Danielle S.
Published: July 2024

Large Language Models (LLMs) are rapidly being adopted in healthcare, necessitating standardized reporting guidelines. We present TRIPOD-LLM, an extension of the TRIPOD+AI statement, addressing the unique challenges of LLMs in biomedical applications. TRIPOD-LLM provides a comprehensive checklist of 19 main items and 50 subitems, covering key aspects from title to discussion. The guidelines introduce a modular format accommodating various LLM research designs and tasks, with 14 main items and 32 subitems applicable across all categories. Developed through an expedited Delphi process and expert consensus, TRIPOD-LLM emphasizes transparency, human oversight, and task-specific performance reporting. We also introduce an interactive website (https://tripod-llm.vercel.app/) facilitating easy guideline completion and PDF generation for submission. As a living document, TRIPOD-LLM will evolve with the field, aiming to enhance the quality, reproducibility, and clinical applicability of LLM research in healthcare through comprehensive reporting.

COI

DSB: Editorial, unrelated to this work: Associate Editor of Radiation Oncology,HemOnc.org(no financial compensation); Research funding, unrelated to this work: American Association for Cancer Research; Advisory and consulting, unrelated to this work: MercurialAI. DDF: Editorial, unrelated to this work: Associate Editor of JAMIA, Editorial Board of Scientific Data, Nature; Funding, unrelated to this work: the intramural research program at the U.S. National Library of Medicine, National Institutes of Health. JWG: Editorial, unrelated to this work: Editorial Board of Radiology: Artificial Intelligence, British Journal of Radiology AI journal and NEJM AI. All other authors declare no conflicts of interest.
Evaluating genetically-predicted causal effects of lipoprotein(a) in human diseases: a phenome-wide Mendelian randomization study
Authors: Shi Jingchunzi , Shringarpure Suyash S. , Hinds David ,   23andMe Research Team, Auton Adam , Holmes Michael V
Published: July 2024

Background

Lipoprotein(a) (Lp[a]) is a circulating plasma lipoprotein that is emerging as an important independent risk factor for vascular disease. Lp(a) levels are 75-90% heritable, predominantly determined by copy number variation and single nucleotide polymorphisms (SNPs) at theLPAgene.

Methods

Using ∼370K individuals with serum measurements of Lp(a) in the UK Biobank European cohort, we constructed a genetic risk score (GRS) consisting of 29 SNPs in the vicinity ofLPAwhich explained 68.18% of variation in Lp(a). Using theLPAGRS to instrument Lp(a), we conducted phenome-wide Mendelian randomization analysis (MR-PheWAS) across a spectrum of 489 medically-relevant phenotypes in ∼7.3M individuals from the 23andMe, Inc. database, and compared effects to those derived from a GRS for low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Through multivariable MR, we sought to assess the direct causal effect of Lp(a) on cardiovascular disease risks while keeping LDL-C or apoB constant.

Results

MR-PheWAS confirmed previously reported Lp(a) causal effects on coronary artery disease (CAD: OR = 1.199, 95% CI = [1.193, 1.205], p-value < 2.23×10-308, for every 59.632 nmol/L higher Lp(a) instrumented by theLPAGRS), and revealed additional genetically-predicted effects largely confined to cardiovascular endpoints, including a novel effect for restrictive cardiomyopathy (OR = 1.101, 95% CI = [1.068, 1.134], p-value = 3×10-10). We scaled theLPA, LDL-C and apoB GRS such that they each had the same OR for MACE (major adverse cardiovascular events). Using the scaling rubric, similar magnitudes of effect were seen for the three lipid traits for most vascular diseases, with the exception of peripheral artery disease, aortic stenosis and dilated cardiomyopathy, where Lp(a) had larger genetically–predicted effect sizes compared to LDL-C and apoB. Multivariable MR identified Lp(a) to retain a causal effect on MACE while accounting for LDL-C or apoB. To achieve the 25% relative risk reduction in major vascular events, as seen with a 1 mmol/L reduction in LDL-C from statin trials, we anticipate that Lp(a) ought to be reduced by ∼ 90 mg/dL (200 nmol/L), highlighting the importance of not only using therapies that have a profound impact on Lp(a) lowering, but also selecting individuals that have high Lp(a) concentrations at baseline.

Conclusion

Lp(a) has genetically-predicted causal effects on a broad range of cardiovascular diseases beyond CAD, with minimal effects seen for non-vascular disease.
Phrenic Neuropathy Etiologies and Recovery Trajectories in Outpatient Rehabilitation and Neuromuscular Medicine Clinics: A Retrospective Analysis
Authors: Demetriou Nicholas , Jensen Alexandra S. , Farr Ellen , Coleman John M. , Ajroud-Driss Senda , Adewuyi Adenike A. , Wolfe Lisa F. , Franz Colin K.
Published: July 2024

Introduction/Aims

Phrenic Neuropathy (PhN) impairs diaphragm muscle function, causing a spectrum of breathing disability. PhN etiologies and their natural history are ill defined. This knowledge gap hinders informed prognosis and management decisions. This study aims to help fill this knowledge gap on PhN etiologies, outcomes, and recovery patterns, especially in the context of non-surgical clinical practice.

Methods

This is a retrospective study from two interdisciplinary clinics, physiatry and neurology based. Patients were included if PhN was identified, and other causes of hemi-diaphragm muscle dysfunction excluded. Patients were followed serially per the discretion of the neuromuscular trained neurologist or physiatrist. Recovery was assessed using pulmonary function tests (PFTs), diaphragm muscle US thickening ratio, and patient-reported outcomes in patients presenting within two years of PhN onset.

Results

We identified 151 patients with PhN. The most common etiologies included idiopathic (27%), associated with cardiothoracic procedure (24%), and intensive care unit (17%). Of these patients, 117 (77%) were evaluated within two years of PhN onset. Of patients included in outcome analyses, 69% saw improvement on serial US, 50% on serial PFTs and 79% reported symptomatic improvement at an average of 13, 16, and 17 months respectively.

Conclusion

This study maps PhN etiologies and recovery. A clear majority of PhN patients show improvement in diaphragm muscle function, but on average improvements took 13-17 months depending on the assessment type. These insights are vital for developing tailored treatments and can guide physicians in prognosis and decision-making, especially if more invasive interventions are being considered.
The smallest worthwhile effect on pain and function for rotator cuff repair surgery: a benefit-harm trade-off study
Authors: Hansford Harrison J , Buchbinder Rachelle , Zadro Joshua R , McAuley James H , Ferreira Manuela L , Lewin Adriane , Page Richard S , Harris Ian A
Published: July 2024

Background

The smallest worthwhile effect (SWE) is the minimum benefit required in addition to that from a comparator, for an intervention to be considered worthwhile by patients. We aimed to estimate the SWE for rotator cuff repair (with decompression and debridement) compared to either decompression and debridement alone or to non-surgical treatment for people with atraumatic shoulder pain.

Methods

Benefit-harm trade-off study. We recruited English speaking adults aged 45-75 years with shoulder pain of intensity ≥4 (on a 0-10 scale) for ≥6 months to our online survey through paid advertising on Facebook. Participants must have sought care in the past 6-months and could not have had recent shoulder surgery or significant recent shoulder trauma. Participants were explained three treatments: rotator cuff repair (with subacromial decompression and debridement), subacromial decompression and debridement alone and non-surgical treatment. Participants completed the benefit-harm trade-off survey to determine the SWE of improvements in pain and function for rotator cuff repair compared to the other treatments and again after one week to assess reliability. We used univariable linear regression to estimate associations between baseline characteristics and SWE.

Results

We recruited 56 participants. The mean ± standard deviation age was 58.4±6.7 years and 39 (70%) were female. For rotator cuff repair to be worthwhile compared to decompression and debridement alone participants needed to see at least a median 40% (interquartile range (IQR) 20-62.5) between-group improvement in pain and function.

Compared to non-surgical treatment, the SWE was a median 40% (IQR 30-60). On the Western Ontario Rotator Cuff (WORC) Index the SWE values equate to a between-group improvement of 28/100 points (533/2100 on the raw WORC score). Female sex was associated with larger SWEs for both comparisons. Reliability analyses were underpowered, 25/56(45%) provided follow-up data; the intraclass correlation coefficient estimates ranged from 0.60-0.77.

Conclusions

This SWE indicates the benefit required by people with shoulder pain to consider the costs and risks of surgical rotator cuff repair worthwhile is larger than previously estimated minimum clinically important differences (13.5-28/100 on the WORC Index). This SWE may be used to inform the design or interpret the findings of trials of these comparisons.
Outcomes from the Victorian Healthy Homes Program: a randomised control trial of home energy upgrades
Authors: Page Katie , Hossain Lutfun , Liu Dan , Kim Yohan , Wilmot Kerryn , Kenny Patricia , Campbell Margaret , Cumming Toby , Kelly Scott , Longden Thomas , van Gool Kees , Viney Rosalie ,   VHHP team
Published: July 2024

Introduction

The Victorian Healthy Homes Program (VHHP) is the first randomised control trial (RCT) in Australia that investigates the impact of thermal home upgrades on energy and health outcomes in vulnerable individuals over winter in Victoria Australia.

Methods

A staggered parallel-group RCT design of 984 vulnerable households. The intervention group received their upgrade prior to their winter of recruitment and the control group received their upgrade after the winter of their recruitment.

Results

A relatively low-cost and simple home upgrade (average cost AU$2,809) resulted in reduced gas consumption (−25.5 MJ/day) and increased indoor winter temperatures (average daily increase of 0.33°C), and a reduction of exposure to cold conditions (<18°C) by an average of 0.71 hours (43 minutes) per day. The intervention group experienced improved mental health as measured by the SF-36 mental component summary and social care related quality of life measured by adult social care outcomes toolkit (ASCOT), and lower healthcare costs overall (an average of AU$887 per person) over the winter period.

Conclusions

The home upgrades significantly increased average winter indoor temperature, improved mental health and social care-related quality of life, and made householders more comfortable while bringing about reductions in overall healthcare use and costs.

STRENGTHS AND LIMITATIONS OF THIS STUDY

First randomised control trial of its kind in Australia to study the impact of thermal home upgrades on energy and health outcomes.

The use of RCTs for such interventions is uncommon but provides a powerful approach to evaluation that can minimise the effects of confounding.

The program was specifically designed to target vulnerable populations. These are groups with the most potential to benefit from home upgrades, either because of their socio-economic status or because of their chronic health conditions, or both.

The retrofitted upgrade was tailored to each home based on need and delivered for a modest budget (up to AU$3,500)

COVID-19 impacted the power of the study because not all upgrades were able to be delivered prior to winter. This was particularly relevant for the secondary health outcome measures.
MultiOmicsAgent: Guided extreme gradient-boosted decision trees-based approaches for biomarker-candidate discovery in multi-omics data
Authors: Settelmeier Jens , Goetze Sandra , Boshart Julia , Fu Jianbo , Steiner Sebastian N. , Gesell Martin , Schüffler Peter J. , Salimova Diyora , Pedrioli Patrick G. A. , Wollscheid Bernd
Published: July 2024

MultiOmicsAgent (MOAgent) is an innovative, Python based open-source tool for biomarker discovery, utilizing machine learning techniques specifically extreme gradient-boosted decision trees to process multi-omics data. With its cross-platform compatibility, user-oriented graphical interface and a well-documented API, MOAgent not only meets the needs of both coding professionals and those new to machine learning but also addresses common data analysis challenges like data incompleteness, class imbalances and data leakage between disjoint data splits. MOAgent’s guided data analysis strategy opens up data-driven insights from digitized clinical biospecimen cohorts and makes advanced data analysis accessible and reliable for a wide audience.

Biographical Note

Jens Settelmeier, Julia Boshart, Martin Gesell are Ph.D. candidates, Jianbo Fu, Sebastian N. Steiner are Post Doc candidates and Sandra Goetze, Patrick Pedrioli senior scientists at the Institute of Translational Medicine at Health Sciences and Technology department at ETH Zürich, Switzerland, within Professor Bernd Wollscheid’s research group who has been working in the fields of bioinformatics, clinical multi-omics with a focus on spatial cell surface proteomics.

Peter J. Schüffler is professor at the institute of Pathology at the TU Munich, Germany and has been working in the field of digital pathology and clinical multi-modal studies.

Diyora Salimova is junior professor at the department of Applied Mathematics at the Albert-Ludwigs-University of Freibug, Germany and has been working in the field of stochastic processes, approximation theory and machine learning related topics.

Key Points

MOAgent enables a guided biomarker-candidate discovery in multi-omics studies, providing a graphical interface and well-documented API.

A user can run MOAgent on a personal computer without the requirement of coding a single line.

MOAgent is a Python-based solution for biomarker-candidate discovery, using machine learning to analyze multi-omics data.

MOAgent can address challenges like data incompleteness and class imbalances, ensuring reliable analysis.

MOAgent makes advanced data analysis accessible, enhancing insights from clinical data.
Somatic hypermutation-mediated paratope flexibility improves the cross-reactivity of human malaria antibodies
Authors: Murugan Rajagopal , Hanke Anton , Oludada Opeyemi Ernest , Costa Giulia , Flores-Garcia Yevel , Mustafa Ghulam , Li Kan , Huntwork Richard H. C. , Horn Gillian Q. , Dennison S. Moses , Tomaras Georgia D , Zavala Fidel , Levashina Elena A. , Ketchem Randal R. , Wade Rebecca C. , Wardemann Hedda
Published: July 2024

The protective capacity of antibodies targeting circumsporozoite protein on sporozoites of the malaria parasitePlasmodium falciparum(PfCSP) is linked to high affinity and cross-reactivity with the PfCSP central repeat domain and N-terminal junction. However, the role of somatic hypermutation (SHM) in the development of such antibodies remains unclear. Here we define the contributions of SHM to the high affinity and strong repeat and N-junction cross-reactivity of the potent anti-PfCSP monoclonal antibody (mAb) 4493 and of similar antibodies with shared SHM and affinity maturation trajectories. Molecular dynamics simulations reveal that SHM reduces the flexibility of the unbound mAb 4493 but increases the flexibility of the antigen-bound complex, thereby lowering the entropic cost for antigen binding. Furthermore, we identify an inverse relation between antibody affinity and serum stability, which limits the protective capacity of these antibodies. Our study provides molecular level evidence for the different roles that the SHM process plays in increasing VH3-49+Vκ3-20 antibody affinity and cross-reactivity and demonstrates how antibody affinity maturation can negatively impact antibody stability and thereby function.
Drug-induced cis-regulatory elements in human hepatocytes affect molecular phenotypes associated with adverse reactions
Authors: Gotoh-Saito Saki , Wada Ryoko , Kawaji Hideya
Published: July 2024

Background

Genomic variations contribute to the phenotypic diversity of individuals. A number of polymorphisms in protein-coding regions that alter drug efficacy or lead to adverse reactions have been characterized; however, noncoding regions that affect drug responses are largely overlooked, except for a limited number of well-studied enhancers.

Results

We conducted a quantitative assessment ofcis-regulatory elements (CREs) based on transcription initiation profiling of mRNAs and noncoding RNAs, including enhancer RNAs, by using CAGE (Cap Analysis of Gene Expression). Candidate CREs identified in a hepatocellular carcinoma HepG2 cell line with stable expression of drug-responsive transcription factor pregnane X receptor (PXR) were further narrowed down by integrating data of PXR-binding sites in human primary hepatocytes and genome-wide association studies. We found more than 100-fold enrichments of the candidates to genetically associated loci with circulating levels of bilirubin and vitamin D, which implicated a link to adverse reactions of PXR ligands. We uncovered novel enhancers ofUGT1A1andTSKUthrough CRISPR/Cas9 knockout experiments. We identified alleles altering regulatory activities ofUGT1A1andCYP24A1enhancers by using luciferase reporter assay. Furthermore, our siRNA experiments revealed an unexpected impact of TSKU on the expression of vitamin D-metabolizing enzymes.

Conclusions

Our transcriptome-based assessment of CREs expanded the list of drug-inducible and PXR-mediated enhancers and super-enhancers. We identified regulatory alleles that alter drug-induced gene expressions, and discovered a novel molecular cascade associated with an adverse reaction. Our results contribute a precise understanding of the noncoding elements of the human genome underlying drug responses.
Epigenetic control of metabolic identity across cell types
Authors: Pacheco Maria Pires , Gerard Déborah , Mangan Riley J. , Chapman Alec R. , Hecker Dennis , Kellis Manolis , Schulz Marcel H. , Sinkkonen Lasse , Sauter Thomas
Published: July 2024

Background

Constraint-based network modeling is a powerful genomic-scale approach for analyzing cellular metabolism, capturing metabolic variations across tissues and cell types, and defining the metabolic identity essential for identifying disease-associated transcriptional states.

Results

Using RNA-seq and epigenomic data from the EpiATLAS resource of the International Human Epigenome Consortium (IHEC), we reconstructed metabolic networks for 1,555 samples spanning 58 tissues and cell types. Analysis of these networks revealed the distribution of metabolic functionalities across human cell types and provides a compendium of human metabolic activity. This integrative approach allowed us to define, across tissues and cell types, i) reactions that fulfil the basic metabolic processes (core metabolism), and ii) cell type-specific functions (unique metabolism), that shape the metabolic identity of a cell or a tissue. Integration with EpiATLAS-derived cell-type-specific gene-level chromatin states and enhancer-gene interactions identified enhancers, transcription factors, and key nodes controlling core and unique metabolism. Transport and first reactions of pathways were enriched for high expression, active chromatin state, and Polycomb-mediated repression in cell types where pathways are inactive, suggesting that key nodes are targets of repression.

Discussion

This integrative analysis forms the basis for identifying regulation points that control metabolic identity in human cells.
Improved accuracy of the whole body Center of Mass position through Kalman filtering
Authors: Charlotte Le Mouel
Published: July 2024

The trajectory of the body center of mass (CoM) is critical for evaluating balance. The position of the CoM can be calculated using either kinematic or kinetic methods. Each of these methods has its limitations, and it is difficult to evaluate their accuracy as there is no ground truth to which the CoM trajectory can be compared. In this paper, we use as ground truth the fact that, during the flight phase of running, the acceleration of the CoM is equal to gravity. We evaluate the accuracy of kinematic models of different complexity and find that the error ranges from 14 % to 36 % of gravity. We propose a novel method for optimally combining kinematic and force plate information. When using this proposed method, the error drops to 1.1 to 3.1 % for all kinematic models. Moreover, the proposed method provides a more reliable evaluation of foot placement control, which is commonly used as an indicator of balance during locomotion.

The code for calculating this optimal combination is available in both Python and Matlab at:https://github.com/charlotte-lemouel/center_of_mass

The documentation is available at:https://center-of-mass.readthedocs.io
Stable centromere association of the yeast histone variant Cse4 requires its essential N-terminal domain
Authors: Popchock Andrew R. , Hedouin Sabrine , Mao Yizi , Asbury Charles L. , Stergachis Andrew B , Biggins Sue
Published: July 2024

Chromosome segregation relies on kinetochores that assemble on specialized centromeric chromatin containing a histone H3 variant. In budding yeast, a single centromeric nucleosome containing Cse4 assembles at a sequence-defined 125 bp centromere. Yeast centromeric sequences are poor templates for nucleosome formationin vitro, suggesting the existence of mechanisms that specifically stabilize Cse4 nucleosomesin vivo. The extended Cse4 N-terminal tail binds to the chaperone Scm3, and a short essential region called END within the N-terminal tail binds the inner kinetochore complex OA. To address the roles of these interactions, we utilized single molecule fluorescence assays to monitor Cse4 during kinetochore assembly. We found that OA and Scm3 independently stabilize Cse4 at centromeres via their END interaction. Scm3 binding to the Cse4 END is enhanced by Ipl1/Aurora B phosphorylation, identifying a previously unknown role for Ipl1 in ensuring Cse4 stability. Strikingly, an Ipl1 phosphomimetic mutation in the Cse4 END enhances Scm3 binding and can restore Cse4 recruitment in mutants defective in OA binding. Together, these data suggest that a key function of the essential Cse4 N-terminus is to ensure Cse4 localization at centromeres.
Neuron-specific partial reprogramming in the dentate gyrus impacts mouse behavior and ameliorates age-related decline in memory and learning
Authors: Vílchez-Acosta Alba , del Carmen Maza María , Parras Alberto , Planells Alejandra , Picó Sara , Desdín-Micó Gabriela , Mrabti Calida , Branchina Clémence , Maroun Céline Yacoub , Deigin Yuri , Ocampo Alejandro
Published: July 2024

Age-associated neurodegenerative disorders represent significant challenges due to progressive neuronal decline and limited treatments. In aged mice, partial reprogramming, characterized by pulsed expression of reprogramming factors, has shown promise in improving function in various tissues, but its impact on the aging brain remains poorly understood. Here we investigated the impact ofin vivopartial reprogramming on mature neurons in the dentate gyrus of young and aged mice. Using two different approaches – a neuron-specific transgenic reprogrammable mouse model and neuron-specific targeted lentiviral delivery of OSKM reprogramming factors – we demonstrated thatin vivopartial reprogramming of mature neurons in the dentate gyrus, a neurogenic niche in the adult mouse brain, can influence animal behavior, and ameliorate age-related decline in memory and learning. These findings underscore the potential ofin vivopartial reprogramming as an important therapeutic intervention to rejuvenate the neurogenic niche and ameliorate cognitive decline associated with aging or neurodegeneration.