bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative analysis of two methods in circumcision: a new disposable device versus classic sleeve technique
Authors: Kılıç Sinan
Published: June 2024

Purpose

Circumcision is the most common surgical procedures performed in males. Medical circumcision is recommended for diseases such as phimosis, paraphimosis, balanoposthitis and common urinary tract infections, although there is no exact indication. Conversely, Jewish and Muslim individuals commonly undergo circumcision regardless of medical necessity. Circumcision devices are designed to shorten surgery time, achieve an aesthetic appearance and ensure safe surgery. The aim of this study is to evaluate the effectiveness of the NeoAlis clamp, a disposable circumcision device, by comparing it with the sleeve technique in children.

Materials and methods

Between 2017 and 2023, retrospective evaluation of 2626 patients who underwent circumcision using either the NeoAlis clamp (group 1) or the sleeve technique (group 2) was conducted. Operation time, results, cost, complications were compared between the two groups.

Results

The study encompassed 2626 patients who fulfilled the inclusion criteria. Group 1 comprised 2403 patients, whereas Group 2 consisted of 223 patients. The overall complication rate, as denoted by n = 47, was 1.7%. Group 1 operation time was shorter than group 2. Bleeding, the most feared complication in the early period, was higher in the second group. No statistically significant difference was observed between the two groups regarding cost comparison.

Conclusion

The primary concern during circumcision is to avoid complications related to general anesthesia in newborns and infants. The use of disposable ring devices has been facilitated by the shorter operation time and the absence of the need for sutures when performing circumcision under local anesthesia. However, knowledge of advanced surgical circumcision techniques is necessary in cases of bleeding and inappropriate ring placement.
Does metabolic control of the disease related with bone turnover markers in children with type 1 diabetes mellitus in Turkey?
Authors: Topkaya Merve Sena , Akın Onur , Cömert Tuğba Küçükkasap
Published: June 2024

Background

The aim was to evaluate the effect of metabolic control on bone biomarkers in children with type I diabetes.

Materials and methods

The children were divided into two groups according to their glycated hemoglobin (HbA1c) (%) levels: a group with HbA1c levels < 8% (n = 16) and: a group with HbA1c levels > 8% (n = 18). The serum total oxidative status (TOS) (µmol/L), total antioxidant status (TAS) (mmol/L), alkaline phosphatase (ALP) (IU/L), osteocalcin (OC) (ng/ml), procollagen type-1-N-terminal peptide (P1NP) (ng/ml), and vitamin D (IU) levels and food consumption frequencies were determined.

Results

When patients were classified according to HbA1c (%) levels, those with HbA1c levels < 8% were found to have lower TOS (µmol/L) values (8.7 ± 6.16, 9.5 ± 5.60) and higher serum OC (ng/mL) (24.2 ± 16.92, 22.0 ± 6.21) levels than those with HbA1c levels > 8% (p < 0.05). Regardless of the level of metabolic control, there was a statistically significant association between serum TOS (µmol/L) and P1NP (ng/ml) (p < 0.05) levels, with no group-specific relationship (HbA1c levels <%8 or HbA1c levels >%8).

Conclusion

HbA1c and serum TOS levels had an effect on bone turnover biomarkers in individuals with type I diabetes.
For, against, and beyond: healthcare professionals’ positions on Medical Assistance in Dying in Spain
Authors: Parra Jounou Iris , Triviño-Caballero Rosana , Cruz-Piqueras Maite
Published: June 2024

Background

In 2021, Spain became the first Southern European country to grant and provide the right to euthanasia and medically assisted suicide. According to the law, the State has the obligation to ensure its access through the health services, which means that healthcare professionals’ participation is crucial. Nevertheless, its implementation has been uneven. Our research focuses on understanding possible ethical conflicts that shape different positions towards the practice of Medical Assistance in Dying, on identifying which core ideas may be underlying them, and on suggesting possible reasons for this disparity. The knowledge acquired contributes to understanding its complexity, shedding light into ambivalent profiles and creating strategies to increase their participation.

Methods

We conducted an exploratory qualitative research study by means of semi-structured interviews (1 h) with 25 physicians and nurses from primary care (12), hospital care (7), and palliative care (6), 17 women and 8 men, recruited from Madrid, Catalonia, and Andalusia between March and May 2023. Interviews were recorded, transcribed, and coded in Atlas.ti software by means of thematic and interpretative methods to develop a conceptual model.

Results

We identified four approaches to MAiD: Full Support (FS), Conditioned Support (CS), Conditioned Rejection (CR), and Full Rejection (FR). Full Support and Full Rejection fitted the traditional for and against positions on MAiD. Nevertheless, there was a gray area in between represented by conditioned profiles, whose participation cannot be predicted beforehand. The profiles were differentiated considering their different interpretations of four core ideas: end-of-life care, religion, professional duty/deontology, and patient autonomy. These ideas can intersect, which means that participants' positions are multicausal and complex. Divergences between profiles can be explained by different sources of moral authority used in their moral reasoning and their individualistic or relational approach to autonomy.

Conclusions

There is ultimately no agreement but rather a coexistence of plural moral perspectives regarding MAiD among healthcare professionals. Comprehending which cases are especially difficult to evaluate or which aspects of the law are not easy to interpret will help in developing new strategies, clarifying the legal framework, or guiding moral reasoning and education with the aim of reducing unpredictable non-participations in MAID.
Development of a CRISPR/Cas12a-based fluorescent detection method of Senecavirus A
Authors: He Wei , Liao Kai , Li Ruixue , Peng Wanqing , Qian Bingxu , Zeng Dexin , Tang Fang , Xue Feng , Jung Yong Sam , Dai Jianjun
Published: June 2024

Background

Senecavirus A (SVA), identified in 2002, is known to cause porcine idiopathic vesicular disease (PIVD), which presents with symptoms resembling other vesicular diseases. This similarity complicates field diagnosis. Conventional molecular diagnostic techniques are limited by their cost, sensitivity, and requirement for complicated instrumentation. Therefore, developing an effective and accurate diagnostic method is crucial for timely identification and isolation of affected pigs, thereby preventing further disease spread.

Methods

In this study, we developed a highly-specific and ultra-sensitive SVA detection method powered by CRISPR/Cas12a. To enhance the availability in laboratories with varied equipment conditions, microplate reader and ultraviolet light transilluminator were introduced. Moreover, PCR amplification has also been incorporated into this method to improve sensitivity. The specificity and sensitivity of this method were determined following the preparation of the recombinant Cas12a protein and optimization of the CRISPR/Cas12a-based trans-cleavage system.

Results

The method demonstrated no cross-reactivity with ten kinds of viruses of swine. The minimum template concentration required to activate substantial trans-cleavage activity was determined to be 106 copies/µL of SVA templates. However, when PCR amplification was incorporated, the method achieved a detection limit of one copy of SVA templates per reaction. It also exhibited 100% accuracy in simulated sample testing. The complete testing process does not exceed three hours.

Conclusions

Importantly, this method utilizes standard laboratory equipment, making it accessible for use in resource-limited settings and facilitating widespread and ultra-sensitive screening during epidemics. Overall, the development of this method not only broadens the array of tools available for detecting SVA but also holds significant promise for controlling the spread of PIVD.
Beyond traditional translation: ncRNA derived peptides as modulators of tumor behaviors
Authors: Wen Kang , Chen Xin , Gu Jingyao , Chen Zhenyao , Wang Zhaoxia
Published: June 2024

Within the intricate tapestry of molecular research, noncoding RNAs (ncRNAs) were historically overshadowed by a pervasive presumption of their inability to encode proteins or peptides. However, groundbreaking revelations have challenged this notion, unveiling select ncRNAs that surprisingly encode peptides specifically those nearing a succinct 100 amino acids. At the forefront of this epiphany stand lncRNAs and circRNAs, distinctively characterized by their embedded small open reading frames (sORFs). Increasing evidence has revealed different functions and mechanisms of peptides/proteins encoded by ncRNAs in cancer, including promotion or inhibition of cancer cell proliferation, cellular metabolism (glucose metabolism and lipid metabolism), and promotion or concerted metastasis of cancer cells. The discoveries not only accentuate the depth of ncRNA functionality but also open novel avenues for oncological research and therapeutic innovations. The main difficulties in the study of these ncRNA-derived peptides hinge crucially on precise peptide detection and sORFs identification. Here, we illuminate cutting-edge methodologies, essential instrumentation, and dedicated databases tailored for unearthing sORFs and peptides. In addition, we also conclude the potential of clinical applications in cancer therapy.
Nanopore sequencing for smear-negative pulmonary tuberculosis—a multicentre prospective study in China
Authors: Yan Xiaojing , Yang Guoli , Wang Yunfei , Wang Yuqing , Cheng Jie , Xu Peisong , Qiu Xiaoli , Su Lei , Liu Lina , Geng Ruixue , You Yingxia , Liu Hui , Chu Naihui , Ma Li , Nie Wenjuan
Published: June 2024

Purpose

In this prospective study, the diagnosis accuracy of nanopore sequencing-based Mycobacterium tuberculosis (MTB) detection was determined through examining bronchoalveolar lavage fluid (BALF) samples from pulmonary tuberculosis (PTB) -suspected patients. Compared the diagnostic performance of nanopore sequencing, mycobacterial growth indicator tube (MGIT) culture and Xpert MTB/rifampin resistance (MTB/RIF) assays.

Methods

Specimens collected from suspected PTB cases across China from September 2021 to April 2022 were tested then assay diagnostic accuracy rates were compared.

Results

Among the 111 suspected PTB cases that were ultimately diagnosed as PTB, the diagnostic rate of nanopore sequencing was statistically significant different from other assays (P < 0.05). Fleiss’ kappa values of 0.219 and 0.303 indicated fair consistency levels between MTB detection results obtained using nanopore sequencing versus other assays, respectively. Respective PTB diagnostic sensitivity rates of MGIT culture, Xpert MTB/RIF and nanopore sequencing of 36.11%, 40.28% and 83.33% indicated superior sensitivity of nanopore sequencing. Analysis of area under the curve (AUC), Youden’s index and accuracy values and the negative predictive value (NPV) indicated superior MTB detection performance for nanopore sequencing (with Xpert MTB/RIF ranking second), while the PTB diagnostic accuracy rate of nanopore sequencing exceeded corresponding rates of the other methods.

Conclusions

In comparison with MGIT culture and Xpert MTB/RIF assays, BALF’s nanopore sequencing provided superior MTB detection sensitivity and thus is suitable for testing of sputum-scarce suspected PTB cases. However, negative results obtained using these assays should be confirmed based on additional evidence before ruling out a PTB diagnosis.
Clinical diagnosis and treatment of 37 cases of gallbladder neuroendocrine carcinoma
Authors: Liu Feng , Miao Wentao , Nan Jiang , Shi Zhiyong , Zhang Anhong , Bo Yunfeng , Xu Jun
Published: June 2024

Objective

This study aims to investigate the clinical and pathological characteristics, treatment approaches, and prognosis of gallbladder neuroendocrine carcinoma (GB-NEC).

Methods

Retrospective analysis was conducted on the clinical data of 37 patients with GB-NEC admitted to Shanxi Cancer Hospital from January 2010 to June 2023. The study included an examination of their general information, treatment regimens, and overall prognosis.

Results

Twelve cases, either due to distant metastasis or other reasons, did not undergo surgical treatment and received palliative chemotherapy (Group 1). Two cases underwent simple cholecystectomy (Group 2); four patients underwent palliative tumor resection surgery (Group 3), and nineteen patients underwent radical resection surgery (Group 4). Among the 37 GB-NEC patients, the average pre-surgery CA19-9 level was 113.29 ± 138.45 U/mL, and the median overall survival time was 19 months (range 7.89–30.11 months). Of these, 28 cases (75.7%) received systemic treatment, 25 cases (67.6%) underwent surgical intervention, and 16 cases (64.0%) received postoperative adjuvant treatment, including combined radiochemotherapy or chemotherapy alone. The median overall survival time was 4 months (0.61–7.40 months) for Group 1 (n = 12), 8 months for Group 2 (n = 2), 21 months (14.67–43.33 months) for Group 3 (n = 4), and 19 months (range 7.89–30.11 months) for Group 4 (n = 19). A significant difference in median overall survival time was observed between Group 1 and Group 4 (P = 0.004).

Conclusion

Surgery remains the primary treatment for GB-NEC, with radical resection potentially offering greater benefits to patient survival compared to other therapeutic options. Postoperative adjuvant therapy has the potential to extend patient survival, although the overall prognosis remains challenging.
Incidence and risk factors of postoperative pulmonary complications following total hip arthroplasty revision: a retrospective Nationwide Inpatient Sample database study
Authors: Huang Liping , Huang Xinlin , Lin Junhao , Yang Qinfeng , Zhu Hailun
Published: June 2024

Background

Postoperative pulmonary complications (PPCs) are among the most severe complications following total hip arthroplasty revision (THAR), imposing significant burdens on individuals and society. This study examined the prevalence and risk factors of PPCs following THAR using the NIS database, identifying specific pulmonary complications (SPCs) and their associated risks, including pneumonia, acute respiratory failure (ARF), and pulmonary embolism (PE).

Methods

The National Inpatient Sample (NIS) database was used for this cross-sectional study. The analysis included patients undergoing THAR based on NIS from 2010 to 2019. Available data include demographic data, diagnostic and procedure codes, total charges, length of stay (LOS), hospital information, insurance information, and discharges.

Results

From the NIS database, a total of 112,735 THAR patients in total were extracted. After THAR surgery, there was a 2.62% overall incidence of PPCs. Patients with PPCs after THAR demonstrated increased LOS, total charges, usage of Medicare, and in-hospital mortality. The following variables have been determined as potential risk factors for PPCs: advanced age, pulmonary circulation disorders, fluid and electrolyte disorders, weight loss, congestive heart failure, metastatic cancer, other neurological disorders (encephalopathy, cerebral edema, multiple sclerosis etc.), coagulopathy, paralysis, chronic pulmonary disease, renal failure, acute heart failure, deep vein thrombosis, acute myocardial infarction, peripheral vascular disease, stroke, continuous trauma ventilation, cardiac arrest, blood transfusion, dislocation of joint, and hemorrhage.

Conclusions

Our study revealed a 2.62% incidence of PPCs, with pneumonia, ARF, and PE accounting for 1.24%, 1.31%, and 0.41%, respectively. A multitude of risk factors for PPCs were identified, underscoring the importance of preoperative optimization to mitigate PPCs and enhance postoperative outcomes.
Vaginal microbiota and gynecological cancers: a complex and evolving relationship
Authors: Javadi Kasra , Ferdosi-Shahandashti Elaheh , Rajabnia Mehdi , Khaledi Mansoor
Published: June 2024

The vagina hosts a community of microorganisms known as the vaginal microbiota. This community is relatively stable and straightforward, with Lactobacillus species being the most dominant members. The vaginal microbiota has various functions that are essential for maintaining human health and balance. For example, it can metabolise dietary nutrients, produce growth factors, communicate with other bacteria, modulate the immune system, and prevent the invasion of harmful pathogens. When the vaginal microbiota is disrupted, it can lead to diseases and infections. The observed disturbance is distinguished by a reduction in the prevalence of Lactobacillus and a concurrent rise in the number of other bacterial species that exhibit a higher tolerance to low oxygen levels. Gynecologic cancers are a group of cancers that affect the female reproductive organs and tissues, such as the ovaries, uterus, cervix, vagina, vulva, and endometrium. These cancers are a major global health problem for women. Understanding the complex interactions between the host and the vaginal microorganisms may provide new insights into the prevention and treatment of gynecologic cancers. This could improve the quality of life and health outcomes for women.
Three-dimensional environment sensitizes pancreatic cancer cells to the anti-proliferative effect of budesonide by reprogramming energy metabolism
Authors: Ibello Eduardo , Saracino Federica , Delle Cave Donatella , Buonaiuto Silvia , Amoroso Filomena , Andolfi Gennaro , Corona Marco , Guardiola Ombretta , Colonna Vincenza , Sainz Jr Bruno , Altucci Lucia , De Cesare Dario , Cobellis Gilda , Lonardo Enza , Patriarca Eduardo Jorge , D’Aniello Cristina , Minchiotti Gabriella
Published: June 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer with an aggressive metastatic phenotype and very poor clinical prognosis. Interestingly, a lower occurrence of PDAC has been described in individuals with severe and long-standing asthma. Here we explored the potential link between PDAC and the glucocorticoid (GC) budesonide, a first-line therapy to treat asthma.

Methods

We tested the effect of budesonide and the classical GCs on the morphology, proliferation, migration and invasiveness of patient-derived PDAC cells and pancreatic cancer cell lines, using 2D and 3D cultures in vitro. Furthermore, a xenograft model was used to investigate the effect of budesonide on PDAC tumor growth in vivo. Finally, we combined genome-wide transcriptome analysis with genetic and pharmacological approaches to explore the mechanisms underlying budesonide activities in the different environmental conditions.

Results

We found that in 2D culture settings, high micromolar concentrations of budesonide reduced the mesenchymal invasive/migrating features of PDAC cells, without affecting proliferation or survival. This activity was specific and independent of the Glucocorticoid Receptor (GR). Conversely, in a more physiological 3D environment, low nanomolar concentrations of budesonide strongly reduced PDAC cell proliferation in a GR-dependent manner. Accordingly, we found that budesonide reduced PDAC tumor growth in vivo. Mechanistically, we demonstrated that the 3D environment drives the cells towards a general metabolic reprogramming involving protein, lipid, and energy metabolism (e.g., increased glycolysis dependency). This metabolic change sensitizes PDAC cells to the anti-proliferative effect of budesonide, which instead induces opposite changes (e.g., increased mitochondrial oxidative phosphorylation). Finally, we provide evidence that budesonide inhibits PDAC growth, at least in part, through the tumor suppressor CDKN1C/p57Kip2.

Conclusions

Collectively, our study reveals that the microenvironment influences the susceptibility of PDAC cells to GCs and provides unprecedented evidence for the anti-proliferative activity of budesonide on PDAC cells in 3D conditions, in vitro and in vivo. Our findings may explain, at least in part, the reason for the lower occurrence of pancreatic cancer in asthmatic patients and suggest a potential suitability of budesonide for clinical trials as a therapeutic approach to fight pancreatic cancer.
Autoimmune thyroid disease and ovarian hypofunction: a review of literature
Authors: Wang Ru , Lv Youyuan , Dou Tao , Yang Qian , Yu Chunxiao , Guan Qingbo
Published: June 2024

Thyroid hormones(THs) are essential for the proper functioning of the ovaries, and multiple studies have shown that thyroid abnormalities, especially during adolescence and reproductive age, can lead to lifelong ovarian dysfunction. Autoimmune thyroid disease (AITD), one of the most common organ specific autoimmune diseases, is mainly mediated by cellular autoimmune reactions, and has strong inflammatory infiltration and immune active cells, including chemokines and cytokines, which are important components of ovarian aging. This suggests that autoimmune and inflammatory molecular processes may play a role in the emergence of ovarian dysfunction. The purpose of this review is to summarize recent in vivo and in vitro evidence of a complex relationship between AITD and ovarian dysfunction. AITD is closely related to the decline of ovarian function from the perspective of antibody, cytokine, oxidative stress, and genetic factors. Finally, some of the currently known treatments for AITD and hypo ovarian disease are summarized.
Modifiable risk factors for cancer among people with lynch syndrome: an international, cross-sectional survey
Authors: Power Robert F. , Doherty Damien E. , Horgan Roberta , Fahey Pat , Gallagher David J. , Lowery Maeve A. , Cadoo Karen A.
Published: June 2024

Background

Lynch syndrome is the most common cause of hereditary colorectal and endometrial cancer. Lifestyle modification may provide an opportunity for adjunctive cancer prevention. In this study, we aimed to characterise modifiable risk factors in people with Lynch syndrome and compare this with international guidelines for cancer prevention.

Methods

A cross-sectional study was carried out utilizing survey methodology. Following public and patient involvement, the survey was disseminated through patient advocacy groups and by social media. Self-reported demographic and health behaviours were collected in April 2023. Guidelines from the World Cancer Research Fund (WCRF) were used to compare percentage adherence to 9 lifestyle recommendations, including diet, physical activity, weight, and alcohol intake. Median adherence scores, as a surrogate for lifestyle risk, were calculated and compared between groups.

Results

156 individuals with Lynch syndrome participated from 13 countries. The median age was 51, and 54% were cancer survivors. The mean BMI was 26.7 and the mean weekly duration of moderate to vigorous physical activity was 90 min. Median weekly consumption of ethanol was 60 g, and 3% reported current smoking. Adherence to WCRF recommendations for cancer prevention ranged from 9 to 73%, with all but one recommendation having < 50% adherence. The median adherence score was 2.5 out of 7. There was no significant association between median adherence scores and age (p = 0.27), sex (p = 0.31), or cancer history (p = 0.75).

Conclusions

We have characterised the modifiable risk profile of people living with Lynch syndrome, outlining targets for intervention based on lifestyle guidelines for the general population. As evidence supporting the relevance of modifiable factors in Lynch syndrome emerges, behavioural modification may prove an impactful means of cancer prevention.
A do it yourself (DIY) point-of-care wrist ultrasound phantom for joint access training
Authors: Cheng Andrea , Zhou Justin , Chan Chun Hei Ryan , Chen Connie , Cheng Charlotte , Storm Kaitlyn , Zhou Anson , Mao Alan , Kuk Won Jun , Fong Tiffany C. , Villagran Ignacio , Miranda Constanza
Published: June 2024

Background

Joint access is essential for arthrocentesis, or joint aspiration of fluids. Joint treatments that are not performed properly can result in avoidable patient issues such as damage to the muscles, tendons, and blood vessels surrounding the joint. The use of ultrasound has become the gold standard for this procedure and proven to be a support in the skill learning process. However, success with this equipment, particularly in small joints like the wrist, depends on a clinician's capacity to recognize the crucial landmarks that guide these procedures. Prior to executing on a real patient, task trainers have proven to be an effective way for doctors to practice and prepare for procedures. However, shortcomings of current solutions include high purchase costs, incompatibility with ultrasound imaging, and low reusability. In addition, since this is a procedure that is not performed frequently, there may not be space or resources available in healthcare facilities to accommodate one at the point of care. This study aimed to close the existing gap by developing a DIY ultrasound compatible task trainer for wrist joint access training.

Results

We developed a novel ultrasound compatible wrist joint model that can be made from sustainable materials and reusable parts, thus reducing the costs for acquisition and environmental impact. Our model, which was produced utilizing small-batch production methods, is made up of 3D-printed bones enclosed in an ultrasound-compatible gelatin mixture. It can be easily remade after each practice session, removing needle tracks that are visible under ultrasound for conventional phantoms. The ultrasonic properties of this model were tested through pixel brightness analysis and visual inspection of simulated anatomical structures.

Conclusion

Our results report the advantages and limitations of the proposed model regarding production, practice, and ultrasound compatibility. While future work entails the transfer to patients of the same skill, this reusable and replicable model has proven, when presented to experts, to be successful in representing the physical characteristics and ultrasound profile of significant anatomical structures. This novel DIY product could be an effective alternative to teach procedures in the context of resource-restrained clinical simulation centers.
Effect of Otago exercise on fear of falling in older adults: a systematic review and meta-analysis
Authors: Han Jianlong , Wang Hongwei , Ding Yunxin , Li Qing , Zhai Huanqie , He Shuling
Published: June 2024

Background

Approximately 40–70% of older adults who have experienced falls develop fear of falling (FOF), with the incidence rate in nursing home residents reaching as high as 79.4%. An increasing number of studies have focused on the effect of the Otago Exercise Programme (OEP) on reducing FOF among older adults, yet comprehensive analysis is lacking due to regional and demographic variations. Therefore, this study integrates the relevant literature to provide evidence supporting interventions aimed at alleviating FOF among older adults.

Objective

To evaluate the impact of OEP on FOF in older adults through meta-analysis.

Methods

We searched ten databases using computer systems, covering all records up to May 1, 2024. Two researchers independently conducted the literature screening, bias risk assessment, and data extraction. We performed data analysis using RevMan 5.3 and Stata 15.0 software, assessed result stability through sensitivity analysis, and examined publication bias with funnel plots and Egger’s test.

Results

Sixteen RCTs were included. Meta-analysis revealed that the OEP significantly reduced FOF among older adults [SMD = 0.96, 95%CI (0.68, 1.23), P < 0.00001]. Subgroup analysis revealed that interventions lasting more than 16 weeks [SMD = 1.12, 95%CI (0.75, 1.49), P < 0.00001], with a frequency of more than twice a week [SMD = 0.99, 95%CI (0.64, 1.35), P < 0.00001], and for older adults in community and nursing institutions [SMD = 1.03, 95%CI (0.50, 1.57), P = 0.0002] were more effective. A comparison of the 16-week and 24-week interventions revealed that the latter had better outcomes [SMD = 0.87, 95%CI (0.66, 1.08), P = 0.0004].

Conclusion

Current evidence indicates that OEP effectively reduces FOF among older adults. It is recommended that interventions last for more than 24 weeks, occur more than twice a week, and suitable for application among older adults in community settings or elder care institutions.
Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder
Authors: Simões de Oliveira Laura , O’Leary Heather E. , Nawaz Sarfaraz , Loureiro Rita , Davenport Elizabeth C. , Baxter Paul , Louros Susana R. , Dando Owen , Perkins Emma , Peltier Julien , Trost Matthias , Osterweil Emily K. , Hardingham Giles E. , Cousin Michael A. , Chattarji Sumantra , Booker Sam A. , Benke Tim A. , Wyllie David J. A , Kind Peter C.
Published: June 2024

Background

Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5−/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5−/y rats.

Methods

To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology.

Results

Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5−/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5−/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses.

Conclusions

Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity.

Limitations

This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.
Phenotypic and ancestry-related assortative mating in autism
Authors: Zhang Jing , Weissenkampen J. Dylan , Kember Rachel L. ,   iPSYCH Consortium, Hougaard David M. , Bybjerg-Grauholm Jonas , Werge Thomas , Als Thomas D. , Rosengren Anders , Grove Jakob , Børglum Anders D. , Robinson Elise B. , Brodkin Edward S. , Almasy Laura , Bucan Maja , Sebro Ronnie
Published: June 2024

Background

Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population.

Methods

To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families).

Results

We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|> 0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3–4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D2 on the order of 1 × 10−5).

Limitations

We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification.

Conclusions

This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for < 5% of the fractional change in the estimate of the phenotypic AM. Future studies are needed to evaluate if the small increase of long-range LD induced by ancestry-related AM has impact on the downstream analysis.
Monogenic hypertriglyceridemia and recurrent pancreatitis in a homozygous carrier of a rare APOA5 mutation: a case report
Authors: Makhmudova Umidakhon , Schulze P. Christian , Lorkowski Stefan , März Winfried , Geiling J.-A. , Weingärtner Oliver
Published: June 2024

Background

Homozygous mutations in the APOA5 gene constitute a rare cause of monogenic hypertriglyceridemia, or familial chylomicronemia syndrome (FCS). We searched PubMed and identified 16 cases of homozygous mutations in the APOA5 gene. Severe hypertriglyceridemia related to monogenic mutations in triglyceride-regulating genes can cause recurrent acute pancreatitis. Standard therapeutic approaches for managing this condition typically include dietary interventions, fibrates, and omega-3-fatty acids. A novel therapeutic approach, antisense oligonucleotide volanesorsen is approved for use in patients with FCS.

Case presentation

We report a case of a 25-years old Afghani male presenting with acute pancreatitis due to severe hypertriglyceridemia up to 29.8 mmol/L caused by homozygosity in APOA5 (c.427delC, p.Arg143Alafs*57). A low-fat diet enriched with medium-chain TG (MCT) oil and fibrate therapy did not prevent recurrent relapses, and volanesorsen was initiated. Volanesorsen resulted in almost normalized triglyceride levels. No further relapses of acute pancreatitis occurred. Patient reported an improve life quality due to alleviated chronic abdominal pain and headaches.

Conclusions

Our case reports a rare yet potentially life-threatening condition—monogenic hypertriglyceridemia-induced acute pancreatitis. The implementation of the antisense drug volanesorsen resulted in improved triglyceride levels, alleviated symptoms, and enhanced the quality of life.
Wavelet analysis on a generalized helix space curves and its examples
Authors: Zhou Xiaohui
Published: June 2024

In this paper, wavelet transform on a generalized helix space curves are investigated, including of local continuous wavelet transform at some point and discrete wavelet transform on a class of helix curves. Firstly, a class of helix space curves are introduced and the parameter equations are given. Then the dilation operator and translation on the function $$\psi^{{(\xi_{{0}} )}}$$

ψ

(

ξ
0

)

is properly defined by the local projection at some point from a space curve on the unit sphere onto its tangent line. The local continuous wavelet transform and its reconstruction formula are deduced at some point of a space curve on the unit sphere. On the other hand, According to the discretization of length-preserving projection, discrete wavelet transform is lifted onto a helix space curve, such as a circular helix curve. Based on length-preserving projection, the some properties are discussed, such as two-scale sequences of scaling function and wavelet, orthogonality, decomposition formula and so on. Finally, two examples are given for our discussion. One example is illustrating the application of local continuous wavelet transform at some point of a space curve. The result shows the signal at some point of a space curve can be reconstructed by local continuous wavelet method. The norm of the error is 0.3783 between original signal and reconstructed signal in this example. The other numerical example is given for decomposing and reconstructing with the signal on a circular helix curve. The result shows the signal on a helix space curve can be decomposed and reconstructed by the length-preserving projection. The norm of the error is 8.0741 × 10−11 between original signal and reconstructed signal. The figures are shown for the simulation results.
Image quality comparison of AirDoc portable retina camera versus eyer in a diabetic retinopathy screening program
Authors: Brant Rodrigo , Nakayama Luis Filipe , de Oliveira Talita Virgínia Fernandes , de Oliveira Juliana Angelica Estevão , Ribeiro Lucas Zago , Richter Gabriela Dalmedico , Rodacki Rafael , Penha Fernando Marcondes
Published: June 2024

Background

Diabetic retinopathy (DR) stands as the foremost cause of preventable blindness in adults. Despite efforts to expand DR screening coverage in the Brazilian public healthcare system, challenges persist due to various factors including social, medical, and financial constraints. Our objective was to evaluate the quality of images obtained with the AirDoc, a novel device, compared to Eyer portable camera which has already been clinically validated.

Methods

Images were captured by two portable retinal devices: AirDoc and Eyer. The included patients had their fundus images obtained in a screening program conducted in Blumenau, Santa Catarina. Two retina specialists independently assessed image’s quality. A comparison was performed between both devices regarding image quality and the presence of artifacts.

Results

The analysis included 129 patients (mean age of 61 years), with 29 (43.28%) male and an average disease duration of 11.1 ± 8 years. In Ardoc, 21 (16.28%) images were classified as poor quality, with 88 (68%) presenting artifacts; in Eyer, 4 (3.1%) images were classified as poor quality, with 94 (72.87%) presenting artifacts.

Conclusions

Although both Eyer and AirDoc devices show potential as screening tools, the AirDoc images displayed higher rates of ungradable and low-quality images, that may directly affect the DR and DME grading. We must acknowledge the limitations of our study, including the relatively small sample size. Therefore, the interpretations of our analyses should be approached with caution, and further investigations with larger patient cohorts are warranted to validate our findings.
Direct oral anticoagulant versus low molecular weight heparin for venous thromboembolism in patients receiving immune checkpoint inhibitors.
Authors: Chiang Cho Han , Chang Yu-Cheng , Tang Zhiting , See Xin Ya , Chi Kuan-Yu , Chang Yu , Chiang Cho Hung , Gong Jingyi , Curtis Lauren Mary , Neilan Tomas G.
Published: June 2024

12127

Background: The two most common therapies for the treatment of cancer-associated venous thromboembolism (VTE) are low molecular weight heparin (LMWHs) and direct oral anticoagulants (DOACs). However, there is a paucity of data on the optimal anticoagulation strategy specifically among patients receiving immune checkpoint inhibitors (ICIs). Therefore, we aimed to evaluate the comparable safety and efficacy of DOACs versus LMWHs in the treatment of VTE among patients receiving ICIs. Methods: We conducted a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network, which contains de-identified data from over 120 healthcare institutions and 250 million patients. We included adult cancer patients who have received ICI therapy including nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, ipilimumab, dostarlimab and who also received a diagnosis of VTE. Patients treated with DOACs were matched in a 1:1 ratio to patients treated with LMWHs based on the variables: age, sex, metastatic disease, cancer therapy, underlying comorbidities, Khorana score, and history of intracranial and gastrointestinal bleeding. The primary outcome was the occurrence of a new VTE, a composite of pulmonary embolism (PE) and deep venous thrombosis (DVT). The safety outcomes included all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding within 2 years following the start of anticoagulation therapy. Results: We matched 4608 ICI-treated patients on a DOAC to 4608 ICI-treated patients on a LMWH. In a Cox proportional hazard analysis, patients receiving DOACs or LMWH had a similar risk of a subsequent VTE event (Hazard ratio (HR), 1.13 [95% CI: 0.84-1.50]). When comparing different types of VTEs, the DOAC group was associated with a lower risk of PE (HR, 0.72 [95% CI: 0.54-0.96]) and a similar risk of DVT (HR, 0.87 [95% CI: 0.70-1.09]) compared to LMWHs. Furthermore, DOACs were associated with a lower risk of intracranial hemorrhage and all-cause mortality. There were no detectable differences in the risk of gastrointestinal bleeding between the two groups. Conclusions: DOACs were associated with a similar risk for subsequent VTE events but a lower risk of intracranial bleeding as well as an improvement in mortality compared to LMWHs among ICI-treated patients with a diagnosis of VTE. Prospective trials are needed to validate these findings. [Table: see text]
Efficacy of intrathecal delivery of peptide-pulsed type 1 conventional dendritic cell vaccine for the treatment of breast cancer-associated leptomeningeal disease in preclinical models.
Authors: Law Vincent , Snyder Colin , Chen Zhihua , Kalinski Pawel , Czerniecki Brian J. , Forsyth Peter A. J.
Published: June 2024

2030

Background: Approximately 5% of advanced stage breast cancer (BC) will develop leptomeningeal disease, a rare form of metastasis in the meninges, a membrane surrounding the brain and spinal cord. The prognosis for BC-LMD is dismal and currently available treatments are ineffective. For example, intrathecal (IT) therapy such as trastuzumab, and proton cranial spinal radiotherapy have only showed modest success. Dendritic cells are a master regulator of the immune system and play a critical role in bridging the innate and adaptive immune response. Here, we used a novel preclinical model to administer MHC class II peptide-pulsed conventional Type 1 dendritic cells (cDC1s) intrathecally in mice that harbor either HER2+ or triple negative breast cancer (TBNC) LMD. Our murine BC-LMD murine data lead us to open a Phase 1 clinical trial of cDC1s in HER2+ and TNBC LMD (NCT05809752; in progress). Methods: Our lab developed a “murine Ommaya” which mimics the clinically used Ommaya reservoir and allows for repeated intrathecal (IT) injections of novel drugs at 3 – 7µl volume directly into the CSF. We next developed a pipeline for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and using these targets to generate tumor-targeting cDC1s. We tested the resulting vaccines in a preclinical model that IT delivers peptide-pulsed cDC1 cell therapy directly into the BC-LMD microenvironment. Results: We tested the efficacy of treatment in HER2+ LMD and TNBC-LMD models and found effective responses; LMD mice that received IT cDC1 therapy exhibited reduced tumor burden and prolonged survival that was significantly better than systemic therapy. Approximately 70% of mice from HER2+ LMD and 30% from TNBC LMD demonstrated complete responses. This was CD4+ T cell dependent. Notably, cured mice also showed signs of resistance against LMD recurrence upon rechallenge. Subsequent single cell RNA-seq (scRNA-seq) analyses of the CSF showed a shift in the innate immune landscape found in untreated LMD to an adaptive immune landscape. In addition, we noted the elevated secretion of Th1 proinflammatory cytokines such as IFN-γ in the CSF. This was recapitulated in the CSF samples of patients enrolled in an on-going phase 1 trial, where early data showed IT cDC1 triggered a high concentration of several proinflammatory cytokines. Conclusions: Our preclinical data suggest IT cDC1 vaccine is effective against BC-LMD and prevents LMD recurrence. We are currently investigating the mechanism(s) by which IT cDC1-initiates the CD4 Th1 adaptive immune response against LMD. By employing an scRNA-seq approach, we hope to further determine the roles of different immune cells and their subtypes in the CSF to IT cDC1s in mice and in patients. A future approach includes testing IT cDC1 platform in LMD from other cancers (e.g. melanoma etc.).
Tumor treating fields (TTFields) therapy in patients with glioblastoma: Long-term survival results from TTFields in Germany in routine clinical care (TIGER) study.
Authors: Bähr Oliver , Tabatabai Ghazaleh , Fietkau Rainer , Goldbrunner Roland , Glas Martin
Published: June 2024

2036

Background: Tumor Treating Fields (TTFields) therapy has demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) when applied with adjuvant temozolomide (TMZ) compared to TMZ alone in newly diagnosed glioblastoma (ndGBM). TTFields therapy delivers electric fields, through scalp-placed arrays, that disrupt cellular processes critical for cancer cell viability, is CE marked for WHO grade 4 glioma, and is a recommended treatment regimen for ndGBM. TTFields therapy was administered to >25,000 patients, showing no systemic toxicities and mild to moderate skin reactions being the main therapy-related adverse event. Here, we report survival and safety data from the TIGER study, the largest prospective study investigating real-world use of TTFields therapy during routine clinical care in patients with ndGBM in Germany. Methods: TIGER (NCT03258021), a prospective, non-interventional, multicenter, medical device study, screened patients ≥18 years of age with histologically confirmed ndGMB from August 2017 to November 2019 in 81 participating centers in Germany who had clinical indication for TTFields therapy and were within the first 3 cycles of maintenance chemotherapy treatment. The analysis presented here focuses on patients that accepted TTFields therapy. Endpoints included OS, PFS, safety, and quality of life. Results: In this study, 710 assessed patients agreed to participate, with 583 (82%) opting for TTFields therapy, and 429 actually commencing the treatment. This patient population represents typical GBM patients, with a median age of 58 (range 19–82) and 64.1% being male. After a total follow-up of 56.2 months, the median OS and PFS were 19.6 months (95% CI, 17.9–22.4) and 10.2 months (95% CI, 9.4–11.4), respectively. The corresponding 1, 2, 3, and 4-year OS rates stood at 79.2%, 42.4%, 31.5%, and 27.7%, while the PFS rates were 42.0%, 23.2%, 19.9%, and 17.6%, respectively. Serious AEs were observed in 68% of patients, with only 0.5% being attributed to TTFields therapy. Conclusions: TIGER is the largest prospective study to date on routine clinical practice in ndGBM. It reaffirms TTFields therapy’s positive safety profile, and its OS and PFS survival benefits are consistent with prior reports. It also reveals promising long-term survival rates. Clinical trial information: NCT03258021 .