bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the COVID-19 pandemic on the education and procedural volume of fellows in critical care medicine – a cross-sectional survey
Authors: Garner Orlando , Velamuri Kanta , Staggers Kristen , Braun Andrea Barbara
Published: May 2023

Background

The COVID-19 pandemic has changed the way medical education is delivered. The purpose of this study was to assess the impact of the COVID-19 pandemic on the education and procedural volume of critical care and pulmonary critical care fellows.

Methods

We conducted a cross-sectional, internet-based, voluntary, anonymous, national survey of adult critical care fellows and academic attending physicians in critical care and pulmonary critical care fellowship programs in the United States between December 2020 and February 2021. Survey questions covered both didactic and non-didactic aspects of education and procedural volumes. Answers were ranked on a 5-point Likert scale. Survey responses were summarized by frequency with percentage. Differences between the responses of fellows and attendings were assessed with the Fisher’s exact or Chi-Square test, using Stata 16 software (StataCorp LLC, College Station, TX).

Results

Seventy four individuals responded to the survey; the majority (70.3%) were male; less than one-third (28.4%) female. Respondents were evenly split among fellows (52.7%) and attendings (47.3%). 41.9% of survey respondents were from the authors’ home institution, with a response rate of 32.6%. Almost two-thirds (62.2%) reported that fellows spend more time in the ICU since the onset of the pandemic. The majority noted that fellows insert more central venous catheters (52.7%) and arterial lines (58.1%), but perform fewer bronchoscopies (59.5%). The impact on endotracheal intubations was mixed: almost half of respondents (45.9%) reported fewer intubations, about one-third (35.1%) more intubations. Almost all respondents (93.0%) described fewer workshops; and one-third (36.1%) fewer didactic lectures. The majority (71.2%) noted less time available for research and quality improvement projects; half (50.7%) noted less bedside teaching by faculty and more than one-third (37.0%) less fellow interaction with faculty. Almost one-half of respondents (45.2%) reported an increase in fellows’ weekly work hours.

Conclusion

The pandemic has caused a decrease in scholarly and didactic activities of critical care and pulmonary critical care fellows. Fellows spend more time in ICU rotations, insert more central and arterial lines, but perform fewer intubations and bronchoscopies. This survey provides insights into changes that have occurred in the training of critical care and pulmonary critical care fellows since the onset of the COVID-19 pandemic.
Epistasis and evolution: recent advances and an outlook for prediction
Authors: Johnson Milo S. , Reddy Gautam , Desai Michael M.
Published: May 2023

As organisms evolve, the effects of mutations change as a result of epistatic interactions with other mutations accumulated along the line of descent. This can lead to shifts in adaptability or robustness that ultimately shape subsequent evolution. Here, we review recent advances in measuring, modeling, and predicting epistasis along evolutionary trajectories, both in microbial cells and single proteins. We focus on simple patterns of global epistasis that emerge in this data, in which the effects of mutations can be predicted by a small number of variables. The emergence of these patterns offers promise for efforts to model epistasis and predict evolution.
Balancing selection on an MYB transcription factor maintains the twig trichome color variation in Melastoma normale
Authors: Huang Guilian , Wu Wei , Chen Yongmei , Zhi Xueke , Zou Peishan , Ning Zulin , Fan Qiang , Liu Ying , Deng Shulin , Zeng Kai , Zhou Renchao
Published: May 2023

Background

The factors that maintain phenotypic and genetic variation within a population have received long-term attention in evolutionary biology. Here the genetic basis and evolution of the geographically widespread variation in twig trichome color (from red to white) in a shrubMelastoma normalewas investigated using Pool-seq and evolutionary analyses.

Results

The results show that the twig trichome coloration is under selection in different light environments and that a 6-kb region containing an R2R3 MYB transcription factor gene is the major region of divergence between the extreme red and white morphs. This gene has two highly divergent groups of alleles, one of which likely originated from introgression from another species in this genus and has risen to high frequency (> 0.6) within each of the three populations under investigation. In contrast, polymorphisms in other regions of the genome show no sign of differentiation between the two morphs, suggesting that genomic patterns of diversity have been shaped by homogenizing gene flow. Population genetics analysis reveals signals of balancing selection acting on this gene, and it is suggested that spatially varying selection is the most likely mechanism of balancing selection in this case.

Conclusions

This study demonstrate that polymorphisms on a single transcription factor gene largely confer the twig trichome color variation inM. normale, while also explaining how adaptive divergence can occur and be maintained in the face of gene flow.
The effect of dietary carbohydrate and calorie restriction on weight and metabolic health in overweight/obese individuals: a multi-center randomized controlled trial
Authors: Sun Jia , Ruan Yuting , Xu Ningning , Wu Peili , Lin Nie , Yuan Kun , An Shengli , Kang Pei , Li Shu , Huang Qiya , Yingzhang  , Li Yuzhong , Su Jialin , Ma Wenjun , Chen Bo , Zhang Xiuwei , Chen Xiaoming , Liang Yongqian , Lu Zeyuan , Deng Guobao , Zhang Zhen , Wang Yuqin , Wen Weiheng , Zhang Huijie , Chen Hong
Published: May 2023

Background

Both low‐carbohydrate (LC) and calorie-restricted (CR) diets have been shown to have metabolic benefits. However, the two regimens have yet to be thoroughly compared. We conducted a 12-week randomized trial to compare the effects of these diets separately and in combination on both weight loss and metabolic risk factors in overweight/obese individuals.

Methods

A total of 302 participants were randomized to LC diet (n = 76), CR diet (n = 75), LC + CR diet (n = 76), or normal control (NC) diet (n = 75) using a computer-based random number generator. The primary outcome was the change in body mass index (BMI). The secondary outcomes included body weight, waist circumference, waist-to-hip ratio, body fat, and metabolic risk factors. All participants attended health education sessions during the trial.

Results

A total of 298 participants were analyzed. BMI change over 12 weeks was − 0.6 (95% CI, − 0.8 to − 0.3) kg/m2 in NC, − 1.3 (95% CI, − 1.5 to − 1.1) kg/m2 in CR, − 2.3 (95% CI, − 2.6 to − 2.1) kg/m2 in LC, and − 2.9 (95% CI, − 3.2 to − 2.6) kg/m2 in LC + CR. LC + CR diet was more effective than LC or CR diet alone at reducing BMI (P = 0.001 and P < 0.001, respectively). Furthermore, compared with the CR diet, the LC + CR diet and LC diet further reduced body weight, waist circumference, and body fat. Serum triglycerides were significantly reduced in the LC + CR diet group compared with the LC or CR diet alone. Plasma glucose, homeostasis model assessment of insulin resistance, and cholesterol concentrations (total, LDL, and HDL) did not change significantly between the groups during the 12-week intervention.

Conclusions

The reduction of carbohydrate intake without restricting caloric intake is more potent to achieve weight loss over 12 weeks when compared to a calorie-restricted diet in overweight/obese adults. The combination of restricting carbohydrate and total calorie intake may augment the beneficial effects of reducing BMI, body weight, and metabolic risk factors among overweight/obese individuals.

Trial registration

The study was approved by the institutional review board of Zhujiang Hospital of Southern Medical University and registered at the China Clinical Trial Registration Center (registration number: ChiCTR1800015156).
Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review
Authors: Maksoud Rebekah , Magawa Chandi , Eaton-Fitch Natalie , Thapaliya Kiran , Marshall-Gradisnik Sonya
Published: May 2023

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted condition that affects most body systems. There is currently no known diagnostic biomarker; instead, diagnosis is dependent on application of symptom-based case criteria following exclusion of any other potential medical conditions. While there are some studies that report potential biomarkers for ME/CFS, their efficacy has not been validated. The aim of this systematic review is to collate and appraise literature pertaining to a potential biomarker(s) which may effectively differentiate ME/CFS patients from healthy controls.

Methods

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane review guidelines. PubMed, Embase and Scopus were systematically searched for articles containing “biomarker” and “ME/CFS” keywords in the abstract or title and if they included the following criteria: (1) were observational studies published between December 1994 and April 2022; (2) involved adult human participants; (3) full text is available in English (4) original research; (5) diagnosis of ME/CFS patients made according to the Fukuda criteria (1994), Canadian Consensus Criteria (2003), International Consensus Criteria (2011) or Institute of Medicine Criteria (2015); (6) study investigated potential biomarkers of ME/CFS compared to healthy controls. Quality and Bias were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.

Results

A total of 101 publications were included in this systematic review. Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%), endovascular/circulatory (17.82%), neurological (7.92%), ion channel (8.91%) and physical dysfunction biomarkers (8.91%). Most of the potential biomarkers reported were blood-based (79.2%). Use of lymphocytes as a model to investigate ME/CFS pathology was prominent among immune-based biomarkers. Most biomarkers had secondary (43.56%) or tertiary (54.47%) selectivity, which is the ability for the biomarker to identify a disease-causing agent, and a moderate (59.40%) to complex (39.60%) ease-of-detection, including the requirement of specialised equipment.

Conclusions

All potential ME/CFS biomarkers differed in efficiency, quality, and translatability as a diagnostic marker. Reproducibility of findings between the included publications were limited, however, several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness. The heterogeneity shown across many of the included studies highlights the need for multidisciplinary research and uniform protocols in ME/CFS biomarker research.
A combination of genetically engineered oncolytic virus and melittin-CpG for cancer viro-chemo-immunotherapy
Authors: Bahreyni Amirhossein , Liu Huitao , Mohamud Yasir , Xue Yuan Chao , Fan Yiyun Michelle , Zhang Yizhuo Lyanne , Luo Honglin
Published: May 2023

Background

Immunotherapy has emerged as an efficient therapeutic approach for cancer management. However, stimulation of host immune system against cancer cells often fails to achieve promising clinical outcomes mainly owing to the immunosuppressive characteristics of the tumor microenvironment (TME). Combination therapeutics that can trigger sustained immunogenic cell death (ICD) have provided new opportunities for cancer treatment.

Methods

In this study, we designed and applied an ICD inducer regimen, including a genetically engineered oncolytic virus (miRNA-modified coxsackieviruses B3, miR-CVB3), a pore-forming lytic peptide (melittin, found in bee venom), and a synthetic toll-like receptor 9 ligand (CpG oligodeoxynucleotides), for breast cancer and melanoma treatment. We compared the anti-tumor efficacy of miR-CVB3 and CpG-melittin (CpGMel) alone and in combination (miR-CVB3 + CpGMel) and investigated possible mechanisms involved.

Results

We demonstrated that miR-CVB3 + CpGMel had no major impact on viral growth, while enhancing the cellular uptake of CpGMel in vitro. We further showed that combination therapy led to significant increases in tumor cell death and release of damage-associated molecular patterns compared with individual treatment. In vivo studies in 4T1 tumor-bearing Balb/c mice revealed that both primary and distant tumors were significantly suppressed, and the survival rate was significantly prolonged after administration of miR-CVB3 + CpGMel compared with single treatment. This anti-tumor effect was accompanied by increased ICD and immune cell infiltration into the TME. Safety analysis showed no significant pathological abnormalities in Balb/c mice. Furthermore, the developed therapeutic regimen also demonstrated a great anti-tumor activity in B16F10 melanoma tumor-bearing C57BL/6 J mice.

Conclusions

Overall, our findings indicate that although single treatment using miR-CVB3 or CpGMel can efficiently delay tumor growth, combining oncolytic virus-based therapy can generate even stronger anti-tumor immunity, leading to a greater reduction in tumor size.
Cardiovascular complications of diabetes: role of non-coding RNAs in the crosstalk between immune and cardiovascular systems
Authors: Spinetti Gaia , Mutoli Martina , Greco Simona , Riccio Federica , Ben-Aicha Soumaya , Kenneweg Franziska , Jusic Amela , de Gonzalo-Calvo David , Nossent Anne Yaël , Novella Susana , Kararigas Georgios , Thum Thomas , Emanueli Costanza , Devaux Yvan , Martelli Fabio
Published: May 2023

Diabetes mellitus, a group of metabolic disorders characterized by high levels of blood glucose caused by insulin defect or impairment, is a major risk factor for cardiovascular diseases and related mortality. Patients with diabetes experience a state of chronic or intermittent hyperglycemia resulting in damage to the vasculature, leading to micro- and macro-vascular diseases. These conditions are associated with low-grade chronic inflammation and accelerated atherosclerosis. Several classes of leukocytes have been implicated in diabetic cardiovascular impairment. Although the molecular pathways through which diabetes elicits an inflammatory response have attracted significant attention, how they contribute to altering cardiovascular homeostasis is still incompletely understood. In this respect, non-coding RNAs (ncRNAs) are a still largely under-investigated class of transcripts that may play a fundamental role. This review article gathers the current knowledge on the function of ncRNAs in the crosstalk between immune and cardiovascular cells in the context of diabetic complications, highlighting the influence of biological sex in such mechanisms and exploring the potential role of ncRNAs as biomarkers and targets for treatments. The discussion closes by offering an overview of the ncRNAs involved in the increased cardiovascular risk suffered by patients with diabetes facing Sars-CoV-2 infection.

Graphical Abstract
Extracellular vesicles: emerging roles, biomarkers and therapeutic strategies in fibrotic diseases
Authors: Zhu Junyan , Wang Sicong , Yang Dakai , Xu Wenrong , Qian Hui
Published: May 2023

Extracellular vesicles (EVs), a cluster of cell-secreted lipid bilayer nanoscale particles, universally exist in body fluids, as well as cell and tissue culture supernatants. Over the past years, increasing attention have been paid to the important role of EVs as effective intercellular communicators in fibrotic diseases. Notably, EV cargos, including proteins, lipids, nucleic acids, and metabolites, are reported to be disease-specific and can even contribute to fibrosis pathology. Thus, EVs are considered as effective biomarkers for disease diagnosis and prognosis. Emerging evidence shows that EVs derived from stem/progenitor cells have great prospects for cell-free therapy in various preclinical models of fibrotic diseases and engineered EVs can improve the targeting and effectiveness of their treatment. In this review, we will focus on the biological functions and mechanisms of EVs in the fibrotic diseases, as well as their potential as novel biomarkers and therapeutic strategies.
Food availability positively affects the survival and somatic maintenance of hibernating garden dormice (Eliomys quercinus)
Authors: Giroud Sylvain , Ragger Marie-Therese , Baille Amélie , Hoelzl Franz , Smith Steve , Nowack Julia , Ruf Thomas
Published: May 2023

Background

Torpor is an energy saving strategy achieved by substantial reductions of metabolic rate and body temperature that enables animals to survive periods of low resource availability. During hibernation (multiday torpor), the frequency of periodic rewarming—characterised by high levels of oxidative stress—is associated with shortening of telomeres, a marker of somatic maintenance.

Objectives

In this study, we determined the impact of ambient temperature on feeding behaviour and telomere dynamics in hibernating garden dormice (Eliomys quercinus) over winter. This obligate hibernator prepares for hibernation by accumulating fat stores but can also feed during hibernation.

Methodology

Food intake, torpor pattern, changes in telomere length, and body mass change were assessed in animals housed at experimentally controlled temperatures of either 14 °C (i.e., a mild winter) or 3 °C (i.e., a cold winter) over 6 months.

Results

When hibernating at 14 °C, dormice experienced 1.7-fold more frequent and 2.4-fold longer inter-bout euthermia, and spent significantly less time torpid, compared to animals hibernating at 3 °C. Higher food intake enabled individuals to compensate for increased energetic costs when hibernating at milder temperatures (14 °C vs. 3 °C), to buffer body mass loss and thus increase winter survival. Interestingly, we observed a significant increase of telomere length over the entire hibernation period, irrespective of temperature treatment.

Conclusion

We conclude that higher temperatures during winter, if associated with sufficient food availability, can have a positive effect on the individual’s energy balance and somatic maintenance. These results suggest that winter food availability might be a crucial determinant for the survival of the garden dormouse in the context of ever-increasing environmental temperatures.
Oleoylethanolamide attenuates cocaine-primed reinstatement and alters dopaminergic gene expression in the striatum
Authors: González-Portilla Macarena , Mellado Susana , Montagud-Romero Sandra , Rodríguez de Fonseca Fernando , Pascual María , Rodríguez-Arias Marta
Published: May 2023

The lipid oleoylethanolamide (OEA) has been shown to affect reward-related behavior. However, there is limited experimental evidence about the specific neurotransmission systems OEA may be affecting to exert this modulatory effect. The aim of this study was to evaluate the effects of OEA on the rewarding properties of cocaine and relapse-related gene expression in the striatum and hippocampus. For this purpose, we evaluated male OF1 mice on a cocaine-induced CPP procedure (10 mg/kg) and after the corresponding extinction sessions, we tested drug-induced reinstatement. The effects of OEA (10 mg/kg, i.p.) were evaluated at three different timepoints: (1) Before each cocaine conditioning session (OEA-C), (2) Before extinction sessions (OEA-EXT) and (3) Before the reinstatement test (OEA-REINST). Furthermore, gene expression changes in dopamine receptor D1 gene, dopamine receptor D2 gene, opioid receptor µ, cannabinoid receptor 1, in the striatum and hippocampus were analyzed by qRT-PCR. The results obtained in the study showed that OEA administration did not affect cocaine CPP acquisition. However, mice receiving different OEA treatment schedules (OEA-C, OEA-EXT and OEA-REINST) failed to display drug-induced reinstatement. Interestingly, the administration of OEA blocked the increase of dopamine receptor gene D1 in the striatum and hippocampus caused by cocaine exposure. In addition, OEA-treated mice exhibited reduced striatal dopamine receptor gene D2 and cannabinoid receptor 1. Together, these findings suggest that OEA may be a promising pharmacological agent in the treatment of cocaine use disorder.
Reconciling art and science in the era of personalised medicine: the legacy of Georges Canguilhem
Authors: Contino Gianmarco
Published: May 2023

Background

Biomedicine, i.e. the application of basic sciences to medicine, has become the cornerstone for the study of etiopathogenesis and treatment of diseases. Biomedicine has enormously contributed to the progress of medicine and healthcare and has become the preferred approach to medical problems in the West. The developments in statistical inference and machine learning techniques have provided the foundation for personalised medicine where clinical management can be fully informed by biomedicine. The deployment of precision medicine may impact the autonomy and self-normativity of the patients. Understanding the relationship between biomedicine and medical practice can help navigate the benefits and challenges offered by precision medicine.

Methods

Conventional content analysis was applied to “Le Normal and le Pathologique” (Canguilhem G. The Normal and the Pathological. Princeton: Princeton University Press; 1991) and further investigated with respect to its relationship with techne and precision medicine using PubMed and Google Scholar and the Standford Encyclopedia of Philosophy to search for the following keywords singularly or in combination: “Canguilhem”, “techne”, “episteme”, “precision medicine”, “machine learning AND medicine”.

Results

The Hippocratic concept of techne accounts for many characteristics of medical knowledge and practice. The advances of biomedicine, experimental medicine and, more recently, machine learning offer, in contrast, the model of a medicine based purely on episteme. I argue that Canguilhem medical epistemology establishes a framework where episteme and data-driven medicine is compatible with the promotion of patient’s autonomy and self-normativity.

Conclusions

Canguilhem’s medical epistemology orders the relationship of applied medicine with experimental sciences, ethics and social sciences. It provides guidance to define the scope of medicine and the boundaries of medicalization of healthy life. Finally, it sets an agenda for a safe implementation of machine learning in medicine.
Scaling up an intervention to protect preterm infants from neurodevelopmental disabilities — findings from a qualitative process evaluation comparing standard with enhanced quality improvement support packages for maternity units in England
Authors: Redwood Sabi , Pithara-McKeown Christalla , Stone Tracey , Treloar Emma , Donovan Jenny L. , Luyt Karen
Published: May 2023

Background

A quality improvement strategy (PReCePT) was used in a standard and enhanced format to scale up a clinical intervention (administering magnesium sulphate to women in preterm labour) across all maternity units in England to protect prematurely born infants from neurodevelopmental disabilities. Formal evaluations reported the effectiveness of the standard package alone in increasing the administration of magnesium sulphate. In this paper, we focus on the findings of the process evaluations, using normalisation process theory to explain how different implementation contexts generated the observed outcomes relating to normative and relational restructuring and sustainment.

Methods

Interviews were conducted with key individuals in implementation of leadership positions nationally and locally. Interviews were analysed initially using the framework method. We then engaged recursively with NPT constructs to generate generalisable insights with pragmatic applicability in other settings.

Results

In total, 72 interviews were conducted with good representation from units across England and staff from the National Academic Health Science Network. We found that all units irrespective of whether they received a standard or enhanced QI package were successful in the ‘normative restructuring’ of their setting to enable magnesium sulphate to be administered. This suggests that this implementation outcome is necessary to achieve improvements. However, it may not be sufficient to sustain the changes once additional resources have been withdrawn. Sustainment, our findings suggest, required ‘relational restructuring’ to accommodate altered workflows and facilitate the sharing of responsibilities and tasks in daily practice. Relational restructuring was more likely to have been achieved units receiving enhanced QI support but also happened in units with standard QI support, especially in those where perinatal team working was already well established.

Conclusion

Unlike other large QI-focused spread-and-scale programmes which failed to show any impact on outcomes, the PReCePT programme in both the enhanced and standard support packages led to improvements in the uptake of magnesium sulphate. The findings suggest that QI programmes interact with the enabling factors, such as strong interprofessional team working, already present in the setting. A standard package with minimal support was therefore sufficient in settings with enabling factors, but enhanced support was required in units where these were absent.
Improving the efficacy of combined radiotherapy and immunotherapy: focusing on the effects of radiosensitivity
Authors: Gao Zhiru , Zhao Qian , Xu Yiyue , Wang Linlin
Published: May 2023

Cancer treatment is gradually entering an era of precision, with multitude studies in gene testing and immunotherapy. Tumor cells can be recognized and eliminated by the immune system through the expression of tumor-associated antigens, but when the cancer escapes or otherwise suppresses immunity, the balance between cancer cell proliferation and immune-induced cancer cell killing may be interrupted, resulting in tumor proliferation and progression. There has been significant attention to combining conventional cancer therapies (i.e., radiotherapy) with immunotherapy as opposed to treatment alone. The combination of radio-immunotherapy has been demonstrated in both basic research and clinical trials to provide more effective anti-tumor responses. However, the absolute benefits of radio-immunotherapy are dependent on individual characteristics and not all patients can benefit from radio-immunotherapy. At present, there are numerous articles about exploring the optimal models for combination radio-immunotherapy, but the factors affecting the efficacy of the combination, especially with regard to radiosensitivity remain inconclusive. Radiosensitivity is a measure of the response of cells, tissues, or individuals to ionizing radiation, and various studies have shown that the radiosensitivity index (RSI) will be a potential biomarker for predicting the efficacy of combination radio-immunotherapy. The purpose of this review is to focus on the factors that influence and predict the radiosensitivity of tumor cells, and to evaluate the impact and predictive significance of radiosensitivity on the efficacy of radio-immunotherapy combination.
Medical care of patients with Wilson disease in Germany: a multidisciplinary survey among university centers
Authors: Zimny Sebastian , Bourhis Hélène , Weber Sabine , Reiter Florian Paul , Hohenester Simon , Kraft Eduard , Mohr Isabelle , Merle Uta , Weiss Karl Heinz , Denk Gerald
Published: May 2023

Background

Wilson disease (WD) is a rare, hereditary disorder of copper metabolism. Due to its variable symptoms and manifestations, diagnosis remains challenging. Affected patients must obtain lifelong medical treatment, as the disease is fatal if untreated. Patients require continuous monitoring, but little is known about the care of these patients in Germany. Therefore, we analyzed the medical care of WD patients at German university centers. We sent a questionnaire containing 20 questions to a total of 108 departments of pediatrics, neurology and gastroenterology in 36 university hospitals. Our questions referred to the characteristics of WD patients at the different sites and internal procedures regarding diagnosis, therapy and follow-up. A descriptive statistical analysis was performed.

Results

Sixty-three departments (58%) returned our questionnaire. In total, approximately one-third of the estimated WD patients in Germany are seen annually in the outpatient clinics of these departments (approx. 950 patients). There are only a few departments which treat patients in a multidisciplinary setting (12%). Our survey revealed that for diagnosis, 51% of all departments used an algorithm based on the Leipzig score as recommended by international guidelines. Most departments apply essential parameters recommended by WD guidelines. Routine monitoring is performed at least biannually by 84% of the departments, and standard investigations for monitoring are regularly applied. A routine family screening is performed by 84% of all departments. A reduction in medical therapy during pregnancy is recommended by 46% of the departments. Only 14% suggested that WD patients should not breastfeed. Liver transplantation (LT) due to WD is a rare but repeatedly occurring event. Most departments of gastroenterology (72%) reported at least one patient with LT within the last decade.

Conclusions

Medical care of WD patients at German university centers follows the recommendations set forth by international guidelines, but only a few centers treat significant numbers of patients. The surveillance of patients does not follow specified standards, but most departments adhere to the accepted guidelines. The formation of central units and networks in a multidisciplinary setting should be evaluated to improve the care of WD patients.
Hypertension, antihypertensive drugs, and age at onset of Huntington’s disease
Authors: Zhu Yahui , Li Mao , Bai Jiongming , Wang Haoran , Huang Xusheng
Published: May 2023

Background

Associations between blood pressure (BP) with age at onset of Huntington’s disease (HD) have reported inconsistent findings. We used Mendelian randomization (MR) to assess effects of BP and lowering systolic BP (SBP) via the genes encoding targets of antihypertensive drugs on age at onset of HD.

Methods

Genetic variants from genome-wide association studies(GWAS) of BP traits and BP-lowering variants in genes encoding antihypertensive drugs targets were extracted. Summary statistics for age at onset of HD were retrieved from the GWAS meta-analysis of HD residual age at onset from the GEM-HD Consortium included 9064 HD patients of European ancestry (4417 males and 4,647 females). MR estimates were calculated using the inverse variance weighted method, supplemented by MR-Egger, weighted median, and MR-PRESSO methods.

Results

Genetically predicted SBP or diastolic BP increase was associated with a later age at onset of HD. However, after SBP/DBP was present as a covariate using multivariable MR method, no significant causal association was suggested. A 10-mm Hg reduction in SBP through variants in genes encoding targets of calcium channel blockers (CCB) was associated with an earlier age at onset of HD (β=-0.220 years, 95% CI =-0.337 to -0.102, P = 2.42 × 10− 4). We did not find a causal association between angiotensin converting enzyme inhibitors and β-blockers with the earlier HD onset. No heterogeneity and horizontal pleiotropy were identified.

Conclusions

This MR analysis provided evidence that genetically determined SBP lowering through antihypertensive drugs might be associated with an earlier age at onset of HD. The results may have a potential impact on management of hypertension in the pre-motor-manifest HD population.
Oral antibiotic prophylaxis for infection in patients with vascular anomalies receiving sirolimus treatment: a multicenter retrospective study
Authors: Qiu Tong , Li Yanan , Gong Xue , Zhou Jiangyuan , Yang Kaiying , Zhang Xuepeng , Zhang Zixin , Lan Yuru , Hu Fan , Peng Qiang , Zhang Yongbo , Kong Feiteng , Chen Siyuan , Ji Yi
Published: May 2023

Objectives

Patients with vascular anomalies (VAs) who receive oral sirolimus may be at high risk of infectious complications. Antibiotic prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) has been advocated. However, there have been few evidence-based analyses on this topic. This study assessed the effect of prophylactic TMP-SMZ on the incidence of infections in VA patients receiving sirolimus monotherapy.

Methods

A retrospective, multicenter chart review was performed on all VA patients receiving sirolimus treatment from August, 2013 to January, 2021.

Results

Before January 2017, 112 patients were treated with sirolimus without antibiotic prophylaxis. In the subsequent period, 195 patients were treated with TMP-SMZ for at least 12 months during sirolimus therapy. The percentage of patients with at least one serious infection during the initial 12 months of sirolimus treatment did not differ between the groups (difference, 1.1%; 95% CI − 7.0–8.0%). We observed no difference in the incidence of individual infection or total adverse events between the groups. The rate of sirolimus discontinuation due to adverse events did not differ significantly between groups.

Conclusions

We demonstrated that prophylactic TMP-SMZ does not decrease the incidence of infection or improve tolerance in VA patients receiving sirolimus monotherapy.
Primary seminal vesicle Burkitt lymphoma in a patient living with HIV undergoing radical prostate and seminal vesicle resection: a rare missed case report
Authors: Wu Menghua , Zheng Xin , Wang Wei , Chang Jing , Xue Meng , Zhang Yu , Song Jian , Zhao Jimao
Published: May 2023

Primary seminal vesicle Burkitt lymphoma (PSBL) is rare that is not frequently reported. Burkitt lymphoma is often associated with extranodal organs. The diagnosis of carcinoma in seminal vesical can be difficult. In this report, we present a missed case of PSBL in a male patient who underwent radical prostate and seminal vesicle resection. We retrospectively analyzed the clinical data to explore the diagnosis, pathological features, treatment, and prognosis of this rare disease. The patient visited our hospital for dysuria, and the serum prostate-specific antigen (PSA) was moderately elevated. Pelvic magnetic resonance imaging (MRI) and computed tomography (CT) scans suggested a notable enlargement of the seminal vesicle. The patient then underwent radical surgery and the pathology diagnosis revealed Burkitt lymphoma. The diagnosis of PSBL is difficult, and the prognosis is generally poorer than that of other types of lymphoma. However, earlier diagnosis and treatment may help to improve the survival rate among patients with Burkitt lymphoma.
Statistical analysis plan for HOMESIDE: a randomised controlled trial for home-based family caregiver-delivered music and reading interventions for people living with dementia
Authors: Pac Soo Vanessa , Baker Felicity A. , Sousa Tanara Vieira , Odell-Miller Helen , Stensæth Karette , Wosch Thomas , Bukowska Anna A. , Tamplin Jeanette , Lautenschlager Nicola , Braat Sabine , Lamb Karen E.
Published: May 2023

Background

Most people with dementia live in the community, not in residential care. Therefore, quality informal care for them is critical for managing behavioural and psychological symptoms of dementia (BPSD). Music therapy has been shown to reduce BPSD. However, no randomised controlled trial has examined the effects of music interventions delivered by caregivers in home settings. The HOME-based caregiver-delivered music intervention for people living with dementia (HOMESIDE) trial aims to evaluate the effectiveness of a 12-week music intervention in addition to standard care for BPSD. This article describes the statistical analysis plan.

Methods and analysis

HOMESIDE is a large, pragmatic international three-arm parallel-group randomised controlled trial. Dyads (persons with dementia and caregiver) in Australia, Germany, the UK, Poland and Norway were randomised to receive music and standard care, reading and standard care or standard care alone. The primary outcome is BPSD (proxy) of the person living with dementia, measured using the Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 90 and 180 days post-randomisation. Longitudinal analysis will compare NPI-Q severity between music and standard care versus standard care alone. Secondary outcomes include quality of life and depression (both person with dementia and caregiver), cognition (person with dementia only), distress, resilience, competence and caregiver-patient relationship (caregiver only). Treatment effects will be obtained at 90 and 180 days post-randomisation, where applicable. Safety outcomes (adverse events, hospitalisations, deaths) will be summarised.

Discussion

This statistical analysis plan provides a detailed methodology for the analysis of HOMESIDE and will improve the validity of the study and reduce the potential for bias.

Trial registration

Australian New Zealand Clinical Trials Registry ACTRN12618001799246. Registered on November 05, 2018. ClinicalTrials.gov NCT03907748. Registered on April 09, 2019.
Immortalized erythroid cells as a novel frontier for in vitro blood production: current approaches and potential clinical application
Authors: Cervellera Christian Felice , Mazziotta Chiara , Di Mauro Giulia , Iaquinta Maria Rosa , Mazzoni Elisa , Torreggiani Elena , Tognon Mauro , Martini Fernanda , Rotondo John Charles
Published: May 2023

Background

Blood transfusions represent common medical procedures, which provide essential supportive therapy. However, these procedures are notoriously expensive for healthcare services and not without risk. The potential threat of transfusion-related complications, such as the development of pathogenic infections and the occurring of alloimmunization events, alongside the donor’s dependence, strongly limits the availability of transfusion units and represents significant concerns in transfusion medicine. Moreover, a further increase in the demand for donated blood and blood transfusion, combined with a reduction in blood donors, is expected as a consequence of the decrease in birth rates and increase in life expectancy in industrialized countries.

Main body

An emerging and alternative strategy preferred over blood transfusion is the in vitro production of blood cells from immortalized erythroid cells. The high survival capacity alongside the stable and longest proliferation time of immortalized erythroid cells could allow the generation of a large number of cells over time, which are able to differentiate into blood cells. However, a large-scale, cost-effective production of blood cells is not yet a routine clinical procedure, as being dependent on the optimization of culture conditions of immortalized erythroid cells.

Conclusion

In our review, we provide an overview of the most recent erythroid cell immortalization approaches, while also describing and discussing related advancements of establishing immortalized erythroid cell lines.
A CNN-based automatic vulnerability detection
Authors: An Jung Hyun , Wang Zhan , Joe Inwhee
Published: May 2023

With the advent of the Internet, the activities of individuals and businesses have expanded into the online realm. As a result, vulnerabilities that result in actual breaches can lead to data loss and program failure. The number of breaches is increasing every year, as is the number of vulnerabilities. To address this problem, current research focuses on the detection of vulnerabilities using static analysis techniques. To prevent the propagation of vulnerabilities, a new paradigm is needed to quickly detect vulnerabilities, analyze them, and take actions such as blocking or removing them. Recently, artificial intelligence algorithms such as deep learning have been introduced for vulnerability detection. In this paper, we propose a vulnerability detection model, V-CNN, which aims to detect CWE/CVE (Common Weakness Enumeration/Common Vulnerabilities and Exposures) using CNN (convolutional neural network). We trained CWE for deep learning and redefined vulnerabilities based on CWE. We propose an experimental algorithm to improve vulnerability detection. The accuracy of the proposed V-CNN model is 98%, which exceeds the 95% of the random forest model. Therefore, our V-CNN has excellent correctness detection performance in the field of vulnerability detection. The V-CNN vulnerability detection algorithm can be used instead of static analysis to detect various security vulnerabilities.
The stability of minimal solution sets for set optimization problems via improvement sets
Authors: Li Taiyong , Wei Yanhui
Published: May 2023

In this paper we investigate the stability of solution sets for set optimization problems via improvement sets. Some sufficient conditions for the upper semicontinuity, lower semicontinuity, and compactness of E-minimal solution mappings are given for parametric set optimization under some suitable conditions. We also give some examples to illustrate our main results.
Generalized fractional calculus in Banach spaces and applications to existence results for boundary value problems
Authors: Salem Hussein A. H. , Cichoń Mieczysław , Shammakh Wafa
Published: May 2023

In this paper, we present the definitions of fractional integrals and fractional derivatives of a Pettis integrable function with respect to another function. This concept follows the idea of Stieltjes-type operators and should allow us to study fractional integrals using methods known from measure differential equations in abstract spaces. We will show that some of the well-known properties of fractional calculus for the space of Lebesgue integrable functions also hold true in abstract function spaces. In particular, we prove a general Goebel–Rzymowski lemma for the De Blasi measure of weak noncompactness and our fractional integrals.

We suggest a new definition of the Caputo fractional derivative with respect to another function, which allows us to investigate the existence of solutions to some Caputo-type fractional boundary value problems. As we deal with some Pettis integrable functions, the main tool utilized in our considerations is based on the technique of measures of weak noncompactness and Mönch’s fixed-point theorem. Finally, to encompass the full scope of this research, some examples illustrating our main results are given.
Appraisal of the costs, health effects, and cost-effectiveness of screening, prevention, treatment and policy-indicated evidence-based interventions for eating disorders: a systematic review protocol
Authors: Aouad Phillip , Ahmed Moin Uddin , Nassar Natasha , Miskovic-Wheatley Jane , Touyz Stephen , Maguire Sarah , Cunich Michelle
Published: May 2023

Background

Having reliable information to make decisions about the allocation of healthcare resources is needed to improve well-being and quality-of-life of individuals with eating disorders (EDs). EDs are a main concern for healthcare administrators globally, particularly due to the severity of health effects, urgent and complex healthcare needs, and relatively high and long-term healthcare costs. A rigorous assessment of up-to-date health economic evidence on interventions for EDs is essential for informing decision-making in this area. To date, health economic reviews on this topic lack a comprehensive assessment of the underlying clinical utility, type and amount of resources used, and methodological quality of included economic evaluations. The current review aims to (1) detail the type of costs (direct and indirect), costing approaches, health effects, and cost-effectiveness of interventions for EDs; (2) assess the nature and quality of available evidence to provide meaningful insights into the health economics associated with EDs.

Methods

All interventions for screening, prevention, treatment, and policy-based approaches for all Diagnostic and Statistics Manual (DSM-IV and DSM-5) listed EDs among children, adolescents, and adults will be included. A range of study designs will be considered, including randomised controlled trials, panel studies, cohort studies, and quasi-experimental trials. Economic evaluations will consider key outcomes, including type of resources used (time and valued in a currency), costs (direct and indirect), costing approach, health effects (clinical and quality-of-life), cost-effectiveness, economic summaries used, and reporting and quality assessments. Fifteen general academic and field-specific (psychology and economics) databases will be searched using subject headings and keywords that consolidate costs, health effects, cost-effectiveness and EDs. Quality of included clinical studies will be assessed using risk-of-bias tools. Reporting and quality of the economic studies will be assessed using the widely accepted Consolidated Health Economic Evaluation Reporting Standards and Quality of Health Economic Studies frameworks, with findings of the review presented in tables and narratively.

Discussion

Results emanating from this systematic review are expected to highlight gaps in healthcare interventions/policy-focused approaches, under-estimates of the economic costs and disease-burden, potential under-utilisation of ED-related resources, and a pressing need for more complete health economic evaluations.
Immune stimulation recruits a subset of pro-regenerative macrophages to the retina that promotes axonal regrowth of injured neurons
Authors: Andries Lien , Kancheva Daliya , Masin Luca , Scheyltjens Isabelle , Van Hove Hannah , De Vlaminck Karen , Bergmans Steven , Claes Marie , De Groef Lies , Moons Lieve , Movahedi Kiavash
Published: May 2023

The multifaceted nature of neuroinflammation is highlighted by its ability to both aggravate and promote neuronal health. While in mammals retinal ganglion cells (RGCs) are unable to regenerate following injury, acute inflammation can induce axonal regrowth. However, the nature of the cells, cellular states and signalling pathways that drive this inflammation-induced regeneration have remained elusive. Here, we investigated the functional significance of macrophages during RGC de- and regeneration, by characterizing the inflammatory cascade evoked by optic nerve crush (ONC) injury, with or without local inflammatory stimulation in the vitreous. By combining single-cell RNA sequencing and fate mapping approaches, we elucidated the response of retinal microglia and recruited monocyte-derived macrophages (MDMs) to RGC injury. Importantly, inflammatory stimulation recruited large numbers of MDMs to the retina, which exhibited long-term engraftment and promoted axonal regrowth. Ligand-receptor analysis highlighted a subset of recruited macrophages that exhibited expression of pro-regenerative secreted factors, which were able to promote axon regrowth via paracrine signalling. Our work reveals how inflammation may promote CNS regeneration by modulating innate immune responses, providing a rationale for macrophage-centred strategies for driving neuronal repair following injury and disease.