bluuebunny/crossref_metadata_2025 huggingface dataset:
What are the experiences of team members involved in root cause analysis? A qualitative study
Authors: Willis Ruth , Jones Tracie , Hoiles Jo , Hibbert Peter D. , Schultz Timothy J.
Published: October 2023

Background

Conducting root cause analysis (RCA) is complex and challenging. The aim of this study was to better understand the experiences of RCA team members and how they value their involvement in the RCA to inform future recruitment, conduct and implementation of RCA findings into clinical practice.

Methods

The study was set in a health network in Adelaide, South Australia. A qualitative exploratory descriptive approach was undertaken to provide an in-depth understanding of team member’s experience in participating in an RCA. Eight of 27 RCA team members who conducted RCAs in the preceding 3-year period were included in one of three semi-structured focus groups. Thematic analysis was used to synthesise the transcribed data into themes.

Results

We derived four major themes: Experiences and perceptions of the RCA team, Limitations of RCA recommendations, Facilitators and barriers to conducting an RCA, and Supporting colleagues involved in the adverse event. Participants’ mixed experience of RCAs ranged from enjoyment and the perception of worth and value to concerns about workload and lack of impact. Legislative privilege protecting RCAs from disclosure was both a facilitator and a barrier. Concern and a desire to better support their colleagues was widely reported.

Conclusions

Clinicians perceived value in reviewing significant adverse events. Improvements can be made in sharing learnings to make effective improvements in health care. We have proposed a process to better support interviewees and strengthen post interview follow up.
Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell RNA sequencing of rat dorsal root ganglion neurons
Authors: Chen Qi , Zhang Xi-Yin , Wang Yu-Pu , Fu Yun-Jie , Cao Feng , Xu Yi-Nuo , Kong Jin-Ge , Tian Na-Xi , Xu Yu , Wang Yun
Published: October 2023

Background

Severe peripheral nerve injury (PNI) often leads to significant movement disorders and intractable pain. Therefore, promoting nerve regeneration while avoiding neuropathic pain is crucial for the clinical treatment of PNI patients. However, established animal models for peripheral neuropathy fail to accurately recapitulate the clinical features of PNI. Additionally, researchers usually investigate neuropathic pain and axonal regeneration separately, leaving the intrinsic relationship between the development of neuropathic pain and nerve regeneration after PNI unclear. To explore the underlying connections between pain and regeneration after PNI and provide potential molecular targets, we performed single-cell RNA sequencing and functional verification in an established rat model, allowing simultaneous study of the neuropathic pain and axonal regeneration after PNI.

Results

First, a novel rat model named spared nerve crush (SNC) was created. In this model, two branches of the sciatic nerve were crushed, but the epineurium remained unsevered. This model successfully recapitulated both neuropathic pain and axonal regeneration after PNI, allowing for the study of the intrinsic link between these two crucial biological processes. Dorsal root ganglions (DRGs) from SNC and naïve rats at various time points after SNC were collected for single-cell RNA sequencing (scRNA-seq). After matching all scRNA-seq data to the 7 known DRG types, we discovered that the PEP1 and PEP3 DRG neuron subtypes increased in crushed and uncrushed DRG separately after SNC. Using experimental design scRNA-seq processing (EDSSP), we identified Adcyap1 as a potential gene contributing to both pain and nerve regeneration. Indeed, repeated intrathecal administration of PACAP38 mitigated pain and facilitated axonal regeneration, while Adcyap1 siRNA or PACAP6-38, an antagonist of PAC1R (a receptor of PACAP38) led to both mechanical hyperalgesia and delayed DRG axon regeneration in SNC rats. Moreover, these effects can be reversed by repeated intrathecal administration of PACAP38 in the acute phase but not the late phase after PNI, resulting in alleviated pain and promoted axonal regeneration.

Conclusions

Our study reveals that Adcyap1 is an intrinsic protective factor linking neuropathic pain and axonal regeneration following PNI. This finding provides new potential targets and strategies for early therapeutic intervention of PNI.
Bladder cancer: therapeutic challenges and role of 3D cell culture systems in the screening of novel cancer therapeutics
Authors: Farouk Sameh M. , Khafaga Asmaa F. , Abdellatif Ahmed M.
Published: October 2023

Bladder cancer (BC) is the sixth most common worldwide urologic malignancy associated with elevated morbidity and mortality rates if not well treated. The muscle-invasive form of BC develops in about 25% of patients. Moreover, according to estimates, 50% of patients with invasive BC experience fatal metastatic relapses. Currently, resistance to drug-based therapy is the major tumble to BC treatment. The three-dimensional (3D) cell cultures are clearly more relevant not only as a novel evolving gadget in drug screening but also as a bearable therapeutic for different diseases. In this review, various subtypes of BC and mechanisms of drug resistance to the commonly used anticancer therapies are discussed. We also summarize the key lineaments of the latest cell-based assays utilizing 3D cell culture systems and their impact on understanding the pathophysiology of BC. Such knowledge could ultimately help to address the most efficient BC treatment.
Severe malaria burden, clinical spectrum and outcomes at Apac district hospital, Uganda: a retrospective study of routine health facility-based data
Authors: Ocen Emmanuel , Opito Ronald , Tegu Crispus , Oula Alex , Olupot-Olupot Peter
Published: October 2023

Background

Most data describing severe malaria (SM) in sub-Saharan Africa (SSA) are from research settings outside disease endemic areas. Using routinely collected data from Apac District Hospital, this study aimed at determining the burden and clinical spectrum of severe malaria.

Methods

This was a retrospective study that reviewed all paediatric admission records for malaria in the 24 months period from Jan 2019 to Dec 2020 at Apac District Hospital. Data on children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the World Health Organization clinical criteria for surveillance of severe malaria were abstracted using a customized proforma designed to capture variables on social demographic, clinical presentation, treatment, and outcomes. In addition, the tool included laboratory variables for complete blood counts, haemoglobin, and glucose levels. Data were analysed using STATA V15.0. The study had ethical approval from Mbale Regional Referral Hospital REC, Approval No. MRRH-REC 053/2019.

Results

A total of 5631 admission records were retrieved for this study period. Of these, 3649 (64.8%) were malaria admissions and 3422/3649 were children below 12years, with only 1864 (54.5%) of children having complete data. Of the 1864 children, 745 (40.0%) fulfilled the severe malaria inclusion criteria. Of the 745 children, 51.4% (n = 381) were males. The median age at admission was 31 months (IQR = 17–60). The most common clinical presentations among children with severe malaria were fever 722 (97.3%), cough 478 (64.2%), and difficulty in breathing 122 (17.9%). The median length of hospital stay was 2 (IQR; 2–4) days and 133 (17.9%) had prolonged hospital stay (> 4 days). Factors independently associated with prolonged hospital stay were, presenting with difficulty in breathing, aOR 1.83 (95% CI 1.02–3.27, P = 0.042) and prostration aOR 8.47 (95% CI 1.94–36.99, P = 0.004). A majority of admitted children, 735 (98.7%) survived, while 10 (1.3%) died of SM.

Conclusion

A high proportion (40.0%) of malaria admissions were due to SM. Prolonged Hospital stay was associated with prostration and difficulty in breathing. Overall mortality was low, 1.3% compared to mortality in the previously reported series. This study was able to use routinely collected data to describe the burden and clinical spectrum of SM. Improvement in the quality of data from such settings would improve disease descriptions for policy, monitoring of epidemics, response to interventions and to inform research.
Socioeconomic status and health-related quality of life after stroke: a systematic review and meta-analysis
Authors: Sun Yichao A. , Kalpakavadi Serah , Prior Sarah , Thrift Amanda G. , Waddingham Suzanne , Phan Hoang , Gall Seana L.
Published: October 2023

Background

Socioeconomic status (SES) is associated with stroke occurrence and survival following stroke but its association with health-related quality of life (HRQoL) following stroke remains uncertain. We performed a systematic review and meta-analysis to examine the association between SES and HRQoL after stroke.

Methods

PubMed, SCOPUS, EMBASE, and Web of Science were searched to identify relevant cohort and case–control studies between January 2000 and May 2022. Two authors screened titles, abstracts and full text articles. One author extracted data from all included studies. Meta-analyses were performed for studies with comparable measurements of SES and HRQoL. Random effects models were used to estimate pooled summary standardised mean differences in HRQoL by SES.

Results

Out of 1,876 citations, 39 studies incorporated measurement of overall HRQoL following stroke and were included in the systematic review, with 17 studies included in the meta-analyses. Overall, reports including education, income, occupation and work status effects on HRQoL after stroke were inconsistent among all included 39 studies. In the global meta-analysis of 17 studies, HRQoL among survivors of stroke was lower in the low SES group than in the high SES group (standardised mean difference (SMD) -0.36, 95% CI -0.52, -0.20, p < 0.0001). When using education and income indicators separately, summary effects were similar to those of the global analysis (low versus high education SMD -0.38, 95% CI -0.57, -0.18, p < 0.0001; low versus high income SMD -0.39, 95% CI -0.59, -0.19, p < 0.0001).

Conclusions

Across all SES indicators, people with stroke who have lower SES have poorer overall HRQoL than those with higher SES. Accessibility and affordability of poststroke support services should be taken into consideration when planning and delivering services to people with low SES.
JMJD6–BRD4 complex stimulates lncRNA HOTAIR transcription by binding to the promoter region of HOTAIR and induces radioresistance in liver cancer stem cells
Authors: Pei Ruifeng , Zhao Le , Ding Yiren , Su Zhan , Li Deqiang , Zhu Shuo , Xu Lu , Zhao Wei , Zhou Wuyuan
Published: October 2023

Background

Long non-coding RNA (lncRNA) HOTAIR acts importantly in liver cancer development, but its effect on radioresistance remains poorly understood. Here, our study probed into the possible impact of HOTAIR in radioresistance in liver cancer stem cells (LCSCs) and to elucidate its molecular basis.

Methods

Following sorting of stem and non-stem liver cancer cells, LCSCs were identified and subjected to RNA-seq analysis for selecting differentially expressed genes. Expression of HOTAIR was determined in liver cancer tissues and CSCs. The stemness, proliferation, apoptosis and radioresistance of LCSCs were then detected in response to altered expression of HOTAIR-LSD1-JMJD6-BRD4.

Results

Ectopic HOTAIR expression was found to promote radioresistance of LCSCs by maintaining its stemness. Mechanistic investigations indicated that HOTAIR recruited LSD1 to the MAPK1 promoter region and reduced the level of H3K9me2 in the promoter region, thus elevating ERK2 (MAPK1) expression. JMJD6–BRD4 complex promoted HOTAIR transcription by forming a complex and positively regulated ERK2 (MAPK1) expression, maintaining the stemness of LCSCs, and ultimately promoting their radioresistance in vitro and in vivo.

Conclusion

Collectively, our work highlights the promoting effect of the JMJD6–BRD4 complex on the radioresistance of LCSCs through a HOTAIR-dependent mechanism.
The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab
Authors: Mallardo Domenico , Woodford Rachel , Menzies Alexander M. , Zimmer Lisa , williamson Andrew , Ramelyte Egle , Dimitriou Florentia , Wicky Alexandre , Wallace Roslyn , Mallardo Mario , Cortellini Alessio , Budillon Alfredo , Atkinson Victoria , Sandhu Shahneen , Olivier Michielin , Dummer Reinhard , Lorigan Paul , Schadendorf Dirk , Long Georgina V. , Simeone Ester , Ascierto Paolo A.
Published: October 2023

Background

The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes.

Method

To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study.

Results

Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61–27.81) in patients without diabetes, 10.23 months (95% CI: 5.81–14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04–78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02–44.85) in patients without diabetes, 22.12 months (95% CI: 14.41–29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29–72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose (< 137 mg/dl) and 36.27 months in those with high levels (hazard ratio 0.16, 95% CI: 0.04–0.58; p = 0.005). The patients whose glucose blood level increased after 3 months of treatment with nivolumab + relatinib compared to baseline (ratio of blood level at baseline/after 3 months > 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes.

Conclusions

LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained.
Alterations in pathogen-specific cellular and humoral immunity associated with acute peripheral facial palsy of infectious origin
Authors: Mohammad Leyla , Fousse Mathias , Wenzel Gentiana , Flotats Bastardas Marina , Faßbender Klaus , Dillmann Ulrich , Schick Bernhard , Zemlin Michael , Gärtner Barbara C. , Sester Urban , Schub David , Schmidt Tina , Sester Martina
Published: October 2023

Background

Peripheral facial palsy (PFP) is a common neurologic symptom which can be triggered by pathogens, autoimmunity, trauma, tumors, cholesteatoma or further local conditions disturbing the peripheral section of the nerve. In general, its cause is often difficult to identify, remaining unknown in over two thirds of cases. As we have previously shown that the quantity and quality of pathogen-specific T cells change during active infections, we hypothesized that such changes may also help to identify the causative pathogen in PFPs of unknown origin.

Methods

In this observational study, pathogen-specific T cells were quantified in blood samples of 55 patients with PFP and 23 healthy controls after stimulation with antigens from varicella-zoster virus (VZV), herpes-simplex viruses (HSV) or borrelia. T cells were further characterized by expression of the inhibitory surface molecule CTLA-4, as well as markers for differentiation (CD27) and proliferation (Ki67). Pathogen-specific antibody responses were analyzed using ELISA. Results were compared with conventional diagnostics.

Results

Patients with PFP were more often HSV-seropositive than controls (p = 0.0003), whereas VZV- and borrelia-specific antibodies did not differ between groups. Although the quantity and general phenotypical characteristics of antigen-specific T cells did not differ either, expression of CTLA-4 and Ki67 was highly increased in VZV-specific T cells of 9 PFP patients, of which 5 showed typical signs of cutaneous zoster. In the remaining 4 patients, a causal relationship with VZV was possible but remained unclear by clinical standard diagnostics. A similar CTLA-4- and Ki67-expression profile of borrelia-specific T cells was also found in a patient with acute neuroborreliosis.

Discussion

In conclusion, the high prevalence of HSV-seropositivity among PFP-patients may indicate an underestimation of HSV-involvement in PFP, even though HSV-specific T cell characteristics seem insufficient to identify HSV as a causative agent. In contrast, striking alterations in VZV- and borrelia-specific T cell phenotype and function may allow identification of VZV- and borrelia-triggered PFPs. If confirmed in larger studies, antigen-specific immune-phenotyping may have the potential to improve specificity of the clinical diagnosis.
Trends in HIV-1 pretreatment drug resistance and HIV-1 variant dynamics among antiretroviral therapy-naive Ethiopians from 2003 to 2018: a pooled sequence analysis
Authors: Kiros Mulugeta , Biset Sirak , Gebremariam Birhane , Yalew Gebrehiwet Tesfay , Abegaz Woldaregay Erku , Geteneh Alene
Published: October 2023

Background

Ethiopia is among the highly HIV-affected countries, with reported 12,000 and 12,000 AIDS-related deaths and incidents as per reports from 2021. Although the country has made a promising progress in antiretroviral therapy, recent studies have indicated that pretreatment drug resistance (PDR) is alarmingly increasing, which has become a challenge for the effectiveness of HIV treatment. Epidemiologic data on PDR is necessary to help establish ART regimens with good efficacy. Thus, this systematic review aimed to determine the trend analysis of PDR among ART-naïve individuals along with HIV variant dynamics in Ethiopia.

Method

HIV-1 pol sequences from studies conducted between 2003 and 2018 among ART-naïve Ethiopian individuals were retrieved from GenBank and analyzed for the presence of PDR mutations (PDRM) along with the analysis of HIV-1 variant dynamics. The Calibrated Population Resistance (CPR) tool Version 8.1 and the REGA HIV-1 Subtyping Tool Version 3 were used to determine the PDRM and HIV-1 genetic diversity, respectively.

Result

We identified nine studies and analyzed 1070 retrieved HIV-1 pol sequences in this systematic review. The pooled prevalence of PDR was 4.8% (51/1070), including 1.4% (15/1070), 2.8% (30/1070), and 0.8% (9/1070) for nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI (NNRTI), and protease inhibitor (PI) resistance, respectively. NRTI and NNRTI concurrent PDRM were observed among 0.2% (2/799) of the analyzed sequences. The overall PDR prevalence has been increasing over the years. Though the prevalence of the NNRTI, NRTI, and PI PDR also increased over the years, the NNRTI increment was more pronounced than the others, reaching 7.84% in 2018 from 2.19% in 2003. The majority (97%; 1038/1070) of the genetic diversity was HIV-1 subtype C virus, followed by subtype C’ (2%; 20/1038) and other subtypes (1%; 10/1038).

Conclusions

According to this systematic review, the overall pooled prevalence of PDR is low. Despite the low prevalence, there has been an increasing trend of PDR over the years, which implies the need for routine surveillance of PDRMs along with preventive measures. Hence, this supports the recently endorsed transition of ART regimens from NNRTI to integrase strand transfer inhibitor-based regimens recommended by the WHO. In addition, this finding underscores the need for routine baseline genotypic drug resistance testing for all newly diagnosed HIV-infected patients before initiating treatment to halt the upward trend of PDR.
A plant protein farnesylation system in prokaryotic cells reveals Arabidopsis AtJ3 produced and farnesylated in E. coli maintains its function of protecting proteins from heat inactivation
Authors: Wu Jia-Rong , Zohra Rida , Duong Ngoc Kieu Thi , Yeh Ching-Hui , Lu Chung-An , Wu Shaw-Jye
Published: October 2023

Background

Protein farnesylation involves the addition of a 15-carbon polyunsaturated farnesyl group to proteins whose C-terminus ends with a CaaX motif. This post-translational protein modification is catalyzed by a heterodimeric protein, i.e., farnesyltransferase (PFT), which is composed of an α and a β subunit. Protein farnesylation in plants is of great interest because of its important roles in the regulation of plant development, responses to environmental stresses, and defense against pathogens. The methods traditionally used to verify whether a protein is farnesylated often require a specific antibody and involve isotope labeling, a tedious and time-consuming process that poses hazardous risks.

Results

Since protein farnesylation does not occur in prokaryotic cells, we co-expressed a known PFT substrate (i.e., AtJ3) and both the α and β subunits of Arabidopsis PFT in E. coli in this study. Farnesylation of AtJ3 was detected using electrophoretic mobility using SDS-PAGE and confirmed using mass spectrometry. AtJ3 is a member of the heat shock protein 40 family and interacts with Arabidopsis HSP70 to protect plant proteins from heat-stress-induced denaturation. A luciferase-based protein denaturation assay demonstrated that farnesylated AtJ3 isolated from E. coli maintained this ability. Interestingly, farnesylated AtJ3 interacted with E. coli HSP70 as well and enhanced the thermotolerance of E. coli. Meanwhile, AtFP3, another known PFT substrate, was farnesylated when co-expressed with AtPFTα and AtPFTβ in E. coli. Moreover, using the same strategy to co-express rice PFT α and β subunit and a potential PFT target, it was confirmed that OsDjA4, a homolog of AtJ3, was farnesylated.

Conclusion

We developed a protein farnesylation system for E. coli and demonstrated its applicability and practicality in producing functional farnesylated proteins from both mono- and dicotyledonous plants.
Investigating social deprivation and comorbid mental health diagnosis as predictors of treatment access among patients with an opioid use disorder using substance use services: a prospective cohort study
Authors: Adams Emma A , Yang Justin C , O’Donnell Amy , Minot Sarah , Osborn David , Kirkbride James B
Published: October 2023

Background

Opioid use is a major public health concern across the globe. Opioid use and subsequent access to care is often shaped by co-occurring issues faced by people using opioids, such as deprivation, mental ill-health, and other forms of substance use. We investigated the role of social deprivation and comorbid mental health diagnoses in predicting re-engagement with substance use services or contact with crisis and inpatient services for individuals with opioid use disorder in secondary mental health care in inner-city London.

Methods

We conducted a prospective cohort study which followed individuals diagnosed with a first episode of opioid use disorder who accessed substance use services between September 2015 and May 2020 for up to 12 months, using anonymised electronic health records. We employed negative binominal regression and Cox proportional survival analyses to assess associations between exposures and outcomes.

Results

Comorbid mental health diagnoses were associated with higher contact rates with crisis/inpatient services among people with opioid use disorder: incidence rate ratios (IRR) and 95% confidence intervals (CI) were 3.91 (1.74–9.14) for non-opioid substance use comorbidity, 8.92 (1.81–64.4) for a single comorbid mental health diagnosis, and 15.9 (5.89–47.5) for multiple comorbid mental health diagnoses. Social deprivation was not associated with contact rates with crisis/inpatient services within this sample. Similar patterns were found with time to first crisis/inpatient contact. Social deprivation and comorbid mental health diagnoses were not associated with re-engagement with substance use services.

Conclusion

Comorbid substance and mental health difficulties amongst people with an opioid use disorder led to earlier and more frequent contact with crisis/inpatient mental health services during the first 12 months of follow up. Given the common co-occurrence of mental health and substance use disorders among those who use opioids, a better understanding of their wider needs (such as social, financial and other non-medical concerns) will ensure they are supported in their treatment journeys.
Cost of illness in inclusion body myositis: results from a cross-sectional study in Germany
Authors: Senn Katja C. , Thiele Simone , Kummer Karsten , Walter Maggie C. , Nagels Klaus H.
Published: October 2023

Background

Inclusion body myositis (IBM) is the most frequent type of myositis in elder patients with a slow chronic progression and refractory to treatment. Previous cost of illness (COI) studies in IBM used claims data to estimate direct costs in the US. No evidence exists globally on both direct and indirect costs in IBM from a societal perspective. We conducted a survey in patients registered in the German IBM patient registry. Self-developed items were used to assess the utilized healthcare resources and estimate the cost. The German Self-Administered Comorbidity Questionnaire (SCQ-D), the sIBM Physical Functioning Assessment (sIFA) and patient-reported measures for satisfaction and improvements in healthcare were applied for an explorative analysis.

Results

In total, 82 patients completed the survey. We estimated the mean total annual per capita COI of US$102,682 (95% CI US$82,763–US$123,090) in 2021. 92.7% of the total COI were direct costs. Medical costs were similar to nonmedical costs, with substantial costs for pharmacotherapy and informal care. Depending on the prevalence estimate, the total national COI per year were US$42.7 million–US$213.7 million. Significant differences in total COI were identified for the degree of disability, marital and employment status (p < 0.05).

Conclusions

We identified remarkable and heterogenous cost in IBM. As informal care costs represented the most relevant cost driver, caregiver burden is a major factor in the patient journey. For the first time, comprehensive economic potentials were identified as a basis to improve the actual care situations and prioritizing future activities for research, pharmaceutical and digital product development as well as health politics.
Genetic testing and diagnostic strategies of fetal skeletal dysplasia: a preliminary study in Wuhan, China
Authors: Liu Wanlu , Cao Jing , Shi Xinwei , Li Yuqi , Qiao Fuyuan , Wu Yuanyuan
Published: October 2023

Background

Fetal skeletal dysplasia is a diverse group of degenerative diseases of bone and cartilage disorders that can lead to movement disorder and even death. This study aims to evaluate the diagnostic yield of sonographic examination and genetic testing for fetal skeletal dysplasia.

Methods

From September 2015 to April 2021, the study investigated 24 cases with suspected short-limb fetuses, which were obtained from Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. To identify the causative gene, multiple approaches (including karyotype analysis, copy number variations and whole exome sequencing) were performed on these fetuses. And further segregation analysis of the candidate variant was performed in parents by using Sanger sequencing.

Results

① Out of 24 cases, likely pathogenic variants in FGFR3, FBN2, COL1A2, CUL7 and DYNC2H1 were detected in 6 cases; pathogenic variants in FGFR3, IMPAD1 and GORAB were identified in other 6 cases; and variants in WNT1, FBN1, OBSL1, COL1A1, DYNC2H1 and NEK1, known as Variant of Undetermined Significance, were found in 4 cases. There were no variants detected in the rest 8 cases by the whole exome sequencing. ② Of 24 cases, 12 (50%) were found to carry variants (pathogenic or likely pathogenic) in seven genes with 12 variants. Four fetuses (16.7%) had variants of uncertain significance.

Conclusion

Genetic testing combining with ultrasound scanning enhances the accurate diagnosis of fatal skeletal dysplasia in utero, and then provides appropriate genetic counseling.
Characterizing HIV status documentation among cancer patients at regional cancer centers in Malawi, Zimbabwe, and South Africa
Authors: Montaño Michalina A. , Mtisi Takudzwa , Ndlovu Ntokozo , Borok Margaret , Bula Agatha , Joffe Maureen , Bender Ignacio Rachel , Chagomerana Maganizo B.
Published: October 2023

Introduction

In East and Southern Africa, people with HIV (PWH) experience worse cancer-related outcomes and are at higher risk of developing certain cancers. Siloed care delivery pathways pose a substantial barrier to co-management of HIV and cancer care delivery.

Methods

We conducted cross-sectional studies of adult cancer patients at public radiotherapy and oncology units in Malawi (Kamuzu Central Hospital), Zimbabwe (Parirenyatwa Group of Hospitals), and South Africa (Charlotte Maxeke Hospital) between 2018 and 2019. We abstracted cancer- and HIV-related data from new cancer patient records and used Poisson regression with robust variance to identify patient characteristics associated with HIV documentation.

Results

We included 1,648 records from Malawi (median age 46 years), 1,044 records from South Africa (median age 55 years), and 1,135 records from Zimbabwe (median age 52 years). Records from all three sites were predominately from female patients; the most common cancers were cervical (Malawi [29%] and Zimbabwe [43%]) and breast (South Africa [87%]). HIV status was documented in 22% of cancer records from Malawi, 92% from South Africa, and 86% from Zimbabwe. Patients with infection-related cancers were more likely to have HIV status documented in Malawi (adjusted prevalence ratio [aPR]: 1.92, 95% confidence interval [CI]: 1.56–2.38) and Zimbabwe (aPR: 1.16, 95%CI: 1.10–1.22). Patients aged ≥ 60 years were less likely to have HIV status documented (Malawi: aPR: 0.66, 95% CI: 0.50–0.87; Zimbabwe: aPR: 0.76, 95%CI: 0.72–0.81) than patients under age 40 years. Patient age and cancer type were not associated with HIV status documentation in South Africa.

Conclusion

Different cancer centers have different gaps in HIV status documentation and will require tailored strategies to improve processes for ascertaining and recording HIV-related information in cancer records. Further research by our consortium to identify opportunities for integrating HIV and cancer care delivery is underway.
Implementing patient derived organoids in functional precision medicine for patients with advanced colorectal cancer
Authors: Cartry Jérôme , Bedja Sabrina , Boilève Alice , Mathieu Jacques R. R. , Gontran Emilie , Annereau Maxime , Job Bastien , Mouawia Ali , Mathias Pierre , De Baère Thierry , Italiano Antoine , Besse Benjamin , Sourrouille Isabelle , Gelli Maximiliano , Bani Mohamed-Amine , Dartigues Peggy , Hollebecque Antoine , Smolenschi Cristina , Ducreux Michel , Malka David , Jaulin Fanny
Published: October 2023

Background

Patient Derived Organoids (PDOs) emerged as the best technology to develop ex vivo tumor avatars. Whether drug testing on PDOs to identify efficient therapies will bring clinical utility by improving patient survival remains unclear. To test this hypothesis in the frame of clinical trials, PDO technology faces three main challenges to be implemented in routine clinical practices: i) generating PDOs with a limited amount of tumor material; ii) testing a wide panel of anti-cancer drugs; and iii) obtaining results within a time frame compatible with patient disease management. We aimed to address these challenges in a prospective study in patients with colorectal cancer (CRC).

Methods

Fresh surgical or core needle biopsies were obtained from patients with CRC. PDOs were established and challenged with a panel of 25 FDA-approved anti-cancer drugs (chemotherapies and targeted therapies) to establish a scoring method (‘chemogram’) identifying in vitro responders. The results were analyzed at the scale of the cohort and individual patients when the follow-up data were available.

Results

A total of 25 PDOs were successfully established, harboring 94% concordance with the genomic profile of the tumor they were derived from. The take-on rate for PDOs derived from core needle biopsies was 61.5%. A chemogram was obtained with a 6-week median turnaround time (range, 4–10 weeks). At least one hit (mean 6.16) was identified for 92% of the PDOs. The number of hits was inversely correlated to disease metastatic dissemination and the number of lines of treatment the patient received. The chemograms were compared to clinical data obtained from 8 patients and proved to be predictive of their response with 75% sensitivity and specificity.

Conclusions

We show that PDO-based drug tests can be achieved in the frame of routine clinical practice. The chemogram could provide clinicians with a decision-making tool to tailor patient treatment. Thus, PDO-based functional precision oncology should now be tested in interventional trials assessing its clinical utility for patients who do not harbor activable genomic alterations or have developed resistance to standard of care treatments.
Potential factors result in diminished ovarian reserve: a comprehensive review
Authors: Zhu Qinying , Li Yi , Ma Jianhong , Ma Hao , Liang Xiaolei
Published: October 2023

The ovarian reserve is defined as the quantity of oocytes stored in the ovary or the number of oocytes that can be recruited. Ovarian reserve can be affected by many factors, including hormones, metabolites, initial ovarian reserve, environmental problems, diseases, and medications, among others. With the trend of postponing of pregnancy in modern society, diminished ovarian reserve (DOR) has become one of the most common challenges in current clinical reproductive medicine. Attributed to its unclear mechanism and complex clinical features, it is difficult for physicians to administer targeted treatment. This review focuses on the factors associated with ovarian reserve and discusses the potential influences and pathogenic factors that may explain the possible mechanisms of DOR, which can be improved or built upon by subsequent researchers to verify, replicate, and establish further study findings, as well as for scientists to find new treatments.
Proarrhythmic changes in human cardiomyocytes during hypothermia by milrinone and isoprenaline, but not levosimendan: an experimental in vitro study
Authors: Selli Anders Lund , Ghasemi Mohammadreza , Watters Taylor , Burton Francis , Smith Godfrey , Dietrichs Erik Sveberg
Published: October 2023

Background

Accidental hypothermia, recognized by core temperature below 35 °C, is a lethal condition with a mortality rate up to 25%. Hypothermia-induced cardiac dysfunction causing increased total peripheral resistance and reduced cardiac output contributes to the high mortality rate in this patient group. Recent studies, in vivo and in vitro, have suggested levosimendan, milrinone and isoprenaline as inotropic treatment strategies in this patient group. However, these drugs may pose increased risk of ventricular arrhythmias during hypothermia. Our aim was therefore to describe the effects of levosimendan, milrinone and isoprenaline on the action potential in human cardiomyocytes during hypothermia.

Methods

Using an experimental in vitro-design, levosimendan, milrinone and isoprenaline were incubated with iCell2 hiPSC-derived cardiomyocytes and cellular action potential waveforms and contraction were recorded from monolayers of cultured cells. Experiments were conducted at temperatures from 37 °C down to 26 °C. One-way repeated measures ANOVA was performed to evaluate differences from baseline recordings and one-way ANOVA was performed to evaluate differences between drugs, untreated control and between drug concentrations at the specific temperatures.

Results

Milrinone and isoprenaline both significantly increases action potential triangulation during hypothermia, and thereby the risk of ventricular arrhythmias. Levosimendan, however, does not increase triangulation and the contractile properties also remain preserved during hypothermia down to 26 °C.

Conclusions

Levosimendan remains a promising candidate drug for inotropic treatment of hypothermic patients as it possesses ability to treat hypothermia-induced cardiac dysfunction and no increased risk of ventricular arrhythmias is detected. Milrinone and isoprenaline, on the other hand, appears more dangerous in the hypothermic setting.
First report of four rare strongylid species infecting endangered Przewalski’s horses (Equus ferus przewalskii) in Xinjiang, China
Authors: Jia Huiping , Gao Sijia , Tang Liping , Fu Yajun , Xiong Yu , Ente Make , Mubalake Shalitanati , Shao Changliang , Li Kai , Hu Defu , Zhang Dong
Published: October 2023

Background

The Przewalski's horse (Equus ferus przewalskii) is the only surviving wild horse species in the world. A significant population of Przewalski's horses resides in Xinjiang, China. Parasitosis poses a considerable threat to the conservation of this endangered species. Yet, there is limited information on the nematode parasites that infect these species. To deepen our understanding of parasitic fauna affecting wild horses, we identified the intestinal nematodes of Przewalski’s horses in Xinjiang and added new barcode sequences to a public database.

Methods

Between 2018 and 2021, nematodes were collected from 104 dewormed Przewalski's horses in Xinjiang. Each nematode was morphologically identified to the species level, and selected species underwent DNA extraction. The extracted DNA was used for molecular identification through the internal transcribed spacer 2 (ITS2) genetic marker.

Results

A total of 3758 strongylids were identified. To the best of our knowledge, this is the first study to identify four specific parasitic nematodes (Oesophagodontus robustus, Bidentostomum ivashkini, Skrjabinodentus caragandicus, Petrovinema skrjabini) and to obtain the ITS2 genetic marker for P. skrjabini.

Conclusions

The ITS2 genetic marker for P. skrjabini enriches our understanding of the genetic characteristics of this species and expands the body of knowledge on parasitic nematodes. Our findings extend the known host range of four strongylid species, thereby improving our understanding of the relationship between Przewalski’s horses and strongylids. This, in turn, aids in the enhanced conservation of this endangered species. This study introduces new instances of parasitic infections in wild animals and offers the DNA sequence of P. skrjabini as a valuable resource for molecular techniques in nematode diagnosis among wildlife.

Graphical Abstract
Evaluating understandability and actionability of online education materials for home-care patients with COVID-19 in Japan
Authors: Furukawa Emi , Okuhara Tsuyoshi , Okada Hiroko , Sawada Naomi , Kiuchi Takahiro
Published: October 2023

Objective

In Japan, educational materials on the home care of coronavirus disease 2019 (COVID-19) were developed owing to limited access to medical care during the pandemic. This study quantitatively evaluated the understandability, actionability, natural flow, and readability of 87 materials published by local governments in Japan for patients with COVID-19. Their understandability and actionability were rated using the Japanese version of the Patient Education Material Evaluation Tool for Printed Materials (PEMAT-P). Natural flow and readability were rated using Global Quality Score (GQS) and jReadability, respectively.

Results

Of the 87 materials, 55 (62.1%) were understandable and 33 (37.9%) were actionable according to the PEMAT-P. Regarding understandability, the materials used medical terms without providing definitions and lacked summaries. Regarding actionability, the materials did not demonstrate explicit steps or utilize visual aids to help the readers take action. The mean (SD) of GQS was 3.44 (0.98), indicating a moderate level of naturalness and comprehensiveness of the materials. The mean (SD) score for readability was 2.4 (0.6), indicating a “lower advanced” level. However, challenges regarding the materials’ plain language remained, such as defining medical terms, summarizing the content for understandability, and using charts and tables that encourage patients to act.
Ventricular septal defect associated with aortic regurgitation and ascending aortic aneurysm: a case report
Authors: Haliti Edmond , Bytyçi Besim , Henein Michael Y. , Bajraktari Gani , Bytyçi Ibadete
Published: October 2023

Introduction

Ventricular septal defect (VSD) is one of the most common congenital cardiac anomalies. Patients with perimembranous VSD may have aortic regurgitation (AR) secondary to prolapse of the aortic cusp.

Case presentation

We present a case of 23-year-old White man with VSD, AR and ascending aortic aneurysm. The patient presented to outpatient clinic with weakness and gradual worsening shortness of breath for the past 5 years. Clinical examination revealed regular heart rhythm and loud continuous systolic-diastolic murmur (Lewin’s grade 6/6), heard all over the precordium, associated with a palpable thrill. The ECG showed right axis deviation, fractionated QRS in V1 and signs of biventricular hypertrophy. The chest X-ray showed cardiomegaly. Transthoracic and transesophageal echocardiograms showed a perimembranous VSD with moderate restrictive shunt (Qp/Qs = 1.6), aortic regurgitation (AR), and ascending aortic aneurysm. Other clinical and laboratory findings were within normal limits.

Conclusions

Perimembranous VSD, may be associated with aortic regurgitation and ascending aortic aneurysm as secondary phenomenon if it is not early diagnosed and successfully treated.
Mechanisms and therapeutic prospects of mesenchymal stem cells-derived exosomes for tendinopathy
Authors: Zhang Yuxiang , Ju Wei , Zhang Hong , Mengyun Liu , Shen Weiliang , Chen Xiao
Published: October 2023

Tendinopathy is a debilitating and crippling syndrome resulting from the degeneration of tendon tissue, leading to loss of mechanical properties and function, and eventual tendon rupture. Unfortunately, there is currently no treatment for tendinopathy that can prevent or delay its progression. Exosomes are small extracellular vesicles that transport bioactive substances produced by cells, such as proteins, lipids, mRNAs, non-coding RNAs, and DNA. They can generate by mesenchymal stem cells (MSCs) throughout the body and play a role in intercellular communication and regulation of homeostasis. Recent research suggests that MSCs-derived exosomes (MSCs-exos) may serve as useful therapeutic candidates for promoting tendon healing. This review focuses on the function and mechanisms of MSCs-exos in tendinopathy treatment and discusses their potential application for treating this condition.
A new class of fractional inequalities through the convexity concept and enlarged Riemann–Liouville integrals
Authors: Hyder Abd-Allah , Barakat Mohamed A. , Soliman Ahmed H.
Published: October 2023

Fractional inequalities play a crucial role in building mathematical mechanisms and their related solution functions across the majority of practical science domains. A variety of mathematical disciplines are significantly impacted by convexity as well. In this article, we describe and verify many new fractional inequalities using a thorough kind of Riemann–Liouville integral and the convexity criterion of the functions. Our approach for dealing with fractional integral inequalities is clear and easy to use, and the current study is a new addition to the literature. Additionally, it is simple to observe that all the inequalities produced are extensive and may be broken down into several and different inequalities that were previously in the literature.
Diverse Xylaria in the Ecuadorian Amazon and their mode of wood degradation
Authors: Rajtar Nickolas N. , Kielsmeier-Cook Joshua C. , Held Benjamin W. , Toapanta-Alban Cristina E. , Ordonez Maria E. , Barnes Charles W. , Blanchette Robert A.
Published: October 2023

Background

Xylaria is a diverse and ecologically important genus in the Ascomycota. This paper describes the xylariaceous fungi present in an Ecuadorian Amazon Rainforest and investigates the decay potential of selected Xylaria species. Fungi were collected at Yasuní National Park, Ecuador during two collection trips to a single hectare plot divided into a 10-m by 10-m grid, providing 121 collection points. All Xylaria fruiting bodies found within a 1.2-m radius of each grid point were collected. Dried fruiting bodies were used for culturing and the internal transcribed spacer region was sequenced to identify Xylaria samples to species level. Agar microcosms were used to assess the decay potential of three selected species, two unknown species referred to as Xylaria 1 and Xylaria 2 and Xylaria curta, on four different types of wood from trees growing in Ecuador including balsa (Ochroma pyramidale), melina (Gmelina arborea), saman (Samanea saman), and moral (Chlorophora tinctoria). ANOVA and post-hoc comparisons were used to test for differences in biomass lost between wood blocks inoculated with Xylaria and uninoculated control blocks. Scanning electron micrographs of transverse sections of each wood and assay fungus were used to assess the type of degradation present.

Results

210 Xylaria collections were sequenced, with 106 collections belonging to 60 taxa that were unknown species, all with less than 97% match to NCBI reference sequences. Xylaria with sequence matches of 97% or greater included X. aff. comosa (28 isolates), X. cuneata (9 isolates) X. curta and X. oligotoma (7 isolates), and X. apiculta (6 isolates)., All Xylaria species tested were able to cause type 1 or type 2 soft rot degradation in the four wood types and significant biomass loss was observed compared to the uninoculated controls. Balsa and melina woods had the greatest amount of biomass loss, with as much as 60% and 25% lost, respectively, compared to the controls.

Conclusions

Xylaria species were found in extraordinary abundance in the Ecuadorian rainforest studied. Our study demonstrated that the Xylaria species tested can cause a soft rot type of wood decay and with the significant amount of biomass loss that occurred within a short incubation time, it indicates these fungi likely play a significant role in nutrient cycling in the Amazonian rainforest.
Estimating frequency-dependent shear wave velocity in near-surface sediment based on seismic interferometry
Authors: Zhang Hao , Shi Yang , He Hongjun , Ji Hanwen , Miao Yu
Published: October 2023

Near-surface seismic shear wave is a basic tool for seismic investigations. However, its frequency-dependent property is not fully investigated, especially by the in situ observation method. Here, we develop the seismic interferometry with a moving frequency window to process the natural seismic signals recorded by the KiK-net network. It is observed that the phase velocity of the shear wave decreases sharply as the frequency increases in the low-frequency range, and remains constant in the high-frequency range. The observed dispersion phenomenon presents a challenge to existing site effect prediction theories, while also providing an observational reference for understanding how the shear wave propagates in near-surface sediment.

Graphical Abstract