bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular alterations and clinical prognostic factors in resectable non-small cell lung cancer
Authors: Thamrongjirapat T. , Muntham D. , Incharoen P. , Trachu N. , Sae-Lim P. , Sarachai N. , Khiewngam K. , Monnamo N. , Kantathut N. , Ngodngamthaweesuk M. , Ativitavas T. , Chansriwong P. , Nitiwarangkul C. , Ruangkanchanasetr R. , Kositwattanarerk A. , Sirachainan E. , Dejthevaporn T. , Reungwetwattana T.
Published: February 2024

Background

EGFR inhibitor and immunotherapy have been approved for adjuvant treatment in resectable non-small cell lung cancer (NSCLC). Limited reports of molecular and clinical characteristics as prognostic factors in NSCLC have been published.

Methods

Medical records of patients with resectable NSCLC stage I–III diagnosed during 2015–2020 were reviewed. Real time-PCR (RT-PCR) was performed for EGFR mutations (EGFRm). Immunohistochemistry staining was conducted for ALK and PD-L1 expression. Categorical variables were compared using chi-square test and Fisher’s exact test. Survival analysis was done by cox-regression method.

Results

Total 441 patients were included. The prevalence of EGFRm, ALK fusion, and PD-L1 expression were 57.8%, 1.9%, and 20.5% (SP263), respectively. The most common EGFRm were Del19 (43%) and L858R (41%). There was no significant difference of recurrence free survival (RFS) by EGFRm status whereas patients with PD-L1 expression (PD-L1 positive patients) had lower RFS compared to without PD-L1 expression (PD-L1 negative patients) (HR = 1.75, P = 0.036). Patients with both EGFRm and PD-L1 expression had worse RFS compared with EGFRm and PD-L1 negative patients (HR = 3.38, P = 0.001). Multivariable analysis showed higher CEA at cut-off 3.8 ng/ml, pT4, pN2, pStage II, and margin were significant poor prognostic factors for RFS in the overall population, which was similar to EGFRm population (exception of pT and pStage). Only pStage was a significant poor prognostic factor for PD-L1 positive patients. The predictive score for predicting of recurrence were 6 for all population (63% sensitivity and 86% specificity) and 5 for EGFRm population (62% sensitivity and 93% specificity).

Conclusion

The prevalence and types of EGFRm were similar between early stage and advanced stage NSCLC. While lower prevalence of PD-L1 expression was found in early stage disease. Patients with both EGFRm and PD-L1 expression had poorer outcome. Thus PD-L1 expression would be one of the prognostic factor in EGFRm patients. Validation of the predictive score should be performed in a larger cohort.
From variant of uncertain significance to likely pathogenic in two siblings with atypical RAG2 Deficiency: a case report and review of the literature
Authors: Taghizadeh Mortezaei Nima , Mohammadi Soha , Abolhassani Hassan , Shokri Sima , Nabavi Mohammad , Fallahpour Morteza , Bemanian Mohammad Hassan
Published: February 2024

Background

Severe combined immunodeficiencies (SCIDs) are hereditary disorders characterized by impaired T and B cell function, resulting in significant immune system dysfunction. Recombination-activating gene (RAG) mutations account for a substantial proportion of SCID cases. Here, we present two sibling cases of SCID caused by a novel RAG2 gene mutation.

Case Presentation

The index case was an 8-year-old boy who had a history of recurring infections. After a comprehensive immunological workup, the initial diagnosis of agammaglobulinemia was revised to combined immunodeficiency (CID). The patient underwent hematopoietic stem cell transplantation (HSCT) but succumbed to cytomegalovirus (CMV) infection. His brother, a 4-month-old boy, presented with CMV chorioretinitis. Leaky SCID was diagnosed based on genetic tests and immunological findings. The patient received appropriate treatment and was considered for HSCT. Both siblings had a homozygous RAG2 gene variant, with the first case classified as a variant of uncertain significance (VUS). The presence of the same mutation in the second brother, and the clinical phenotype, supports considering the mutation as likely pathogenic.

Conclusions

This case report highlights a novel RAG2 gene mutation associated with CID. The classification of a VUS may evolve with accumulating evidence, and additional studies are warranted to establish its pathogenicity. Proper communication between genetic counselors and immunologists, accurate documentation of patient information, increased public awareness, and precise utilization of genetic techniques are essential for optimal patient management.
Landscaping tuberculosis multimorbidity: findings from a cross-sectional study in India
Authors: Chauhan A. , Parmar M. , Rajesham J. D. , Shukla S. , Sahoo K. C. , Chauhan S. , Chitiboyina S. , Sinha A. , Srigana G. , Gorla M. , Pati Sanghamitra
Published: February 2024

Background

Multimorbidity, the concurrent presence of two or more chronic conditions is an emerging public health challenge. Till date, most of the research have focused on the presence and interaction of selected co-morbidities in tuberculosis (TB). There exist a critical knowledge gap on the magnitude of multimorbidity among TB patients and its impact on health outcomes.

Methods

We undertook a cross-sectional study to assess the prevalence and patterns of multimorbidity among newly diagnosed TB patients in two states of India. A total of 323 patients were interviewed using a structured multimorbidity assessment questionnaire for primary care (MAQ-PC). MAQ-PC is already validated for Indian population and elicits 22 chronic conditions. We defined TB multimorbidity as the co-existence of TB with one or more chronic conditions and identified commonly occurring dyads (TB + single condition) and triads (TB + two conditions).

Results

More than half (52%) of TB patients reported multimorbidity. Among dyads, depression, diabetes mellitus (DM), acid peptic disease (APD), hypertension, chronic alcoholism, arthritis and chronic back ache (CBA) were the most common co-occurring conditions while ‘DM + arthritis’, ‘depression + APD’, ‘depression + DM’ were the most commonly occurring triads among TB patients. Factors such as increasing age, low levels of education, alcohol abusers, drug-resistant TB and having health insurance were significantly associated with multimorbidity among TB patients.

Conclusions

Our findings suggest high prevalence of multimorbidity among newly diagnosed TB patients in India. The presence of concordant and discordant conditions with TB may increase the health complexity, thus necessitating appropriate care protocols. Given, the current situation, wherein TB and non-communicable diseases (NCD) services are delivered through collaborative framework between programmes, there is a need for addressing multimorbidity at the healthcare delivery level.
An integrated FoodNet in North East India: fostering one health approach to fortify public health
Authors: Das Madhuchhanda , Albert Venencia , Das Samaresh , Dolma Karma Gurmey , Majumdar Tapan , Baruah Pranjal Jyoti , Hazarika Suranjana Chaliha , Apum Basumoti , Ramamurthy Thandavarayan
Published: February 2024

Background

Food safety is a critical factor in promoting public health and nutrition, especially in developing countries like India, which experience several foodborne disease outbreaks, often with multidrug-resistant pathogens. Therefore, implementing regular surveillance of enteric pathogens in the human-animal-environment interface is necessary to reduce the disease burden in the country.

Objective

To establish a network of laboratories for the identification of major food and waterborne pathogens prevailing in the northeast region of India through integrated surveillance of animal, food, human, and environment and investigate the antimicrobial susceptibility pattern of the pathogens of public health significance.

Methods

The Indian Council of Medical Research (ICMR) has identified FoodNet laboratories; based on their geographical location, inclination to undertake the study, preparedness, proficiency, and adherence to quality assurance procedures, through an 8-step process to systematically expand to cover the Northeastern Region (NER) with comprehensive diagnostic capacities for foodborne pathogens and diarrhea outbreak investigations. Network initiated in the NER given the unique food habits of the ethnic population.

Findings

This surveillance network for foodborne enteric pathogens was established in Assam, Arunachal Pradesh, Tripura, and Sikkim, and expanded to other four states, i.e., Manipur, Mizoram, Meghalaya, and Nagaland, thereby covering the entire NER by including nine medical and three veterinary centers. All these centers are strengthened with periodic training, technical support, funding, capacity building, quality assurance, monitoring, centralized digital data management, and website development.

Results

The ICMR-FoodNet will generate NER-specific data with close to real-time reporting of foodborne disease and outbreaks, and facilitate the updating of food safety management protocols, policy reforms, and public health outbreak response. During 2020-2023, 13,981 food samples were tested and the detection of enteric pathogens ranged from 3 to 4%. In clinical samples, the detection rate of the pathogens was high in the diarrheal stools (8.9%) when 3,107 samples were tested. Thirteen outbreaks were investigated during the study period.

Conclusion

Foodborne diseases and outbreaks are a neglected subject. Given the frequent outbreaks leading to the deaths of children, it is crucial to generate robust data through well-established surveillance networks so that a strong food safety policy can be developed for better public health.
Hospitalizations and re-hospitalizations at the end-of-life among cancer patients; a retrospective register data study
Authors: Singh J. , Grov E. K. , Turzer M. , Stensvold A.
Published: February 2024

Background

Patients with incurable cancer are frequently hospitalized within their last 30 days of life (DOL) due to numerous symptoms and concerns. These hospitalizations can be burdensome for the patient and the caregivers and are therefore considered a quality indicator of end-of-life care. This retrospective cohort study aims to investigate the rates and potential predictors of hospitalizations and re-hospitalizations within the last 30 DOL.

Methods

This register data study included 383 patients with non-curable cancer who died in the pre-covid period between July 2018 and December 2019. Descriptive statistics with Chi-squared tests for the categorical data and logistic regression analysis were used to identify factors associated with hospitalization within the last 30 DOL.

Results

A total of 272 (71%) had hospitalizations within the last 30 days of life and 93 (24%) had > 1 hospitalizations. Hospitalization was associated with shorter time from palliative care unit (PCU) referral to death, male gender, age < 80 years and systemic anticancer therapy (SACT) within the last 30 DOL. The most common treatment approaches initiated during re-hospitalizations remained treatment for suspected or confirmed infection (45%), pleural or abdominal paracentesis (20%) and erythrocytes transfusion (18%).

Conclusion

Hospitalization and re-hospitalization within the last 30 DOL were associated with male gender, age below 80, systemic anticancer therapy and suspected or confirmed infection.
The Burnout PRedictiOn Using Wearable aNd ArtIficial IntelligEnce (BROWNIE) study: a decentralized digital health protocol to predict burnout in registered nurses
Authors: Wilton Angelina R. , Sheffield Katharine , Wilkes Quantia , Chesak Sherry , Pacyna Joel , Sharp Richard , Croarkin Paul E. , Chauhan Mohit , Dyrbye Liselotte N. , Bobo William V. , Athreya Arjun P.
Published: February 2024

Background

When job demand exceeds job resources, burnout occurs. Burnout in healthcare workers extends beyond negatively affecting their functioning and physical and mental health; it also has been associated with poor medical outcomes for patients. Data-driven technology holds promise for the prediction of occupational burnout before it occurs. Early warning signs of burnout would facilitate preemptive institutional responses for preventing individual, organizational, and public health consequences of occupational burnout. This protocol describes the design and methodology for the decentralized Burnout PRedictiOn Using Wearable aNd ArtIficial IntelligEnce (BROWNIE) Study. This study aims to develop predictive models of occupational burnout and estimate burnout-associated costs using consumer-grade wearable smartwatches and systems-level data.

Methods

A total of 360 registered nurses (RNs) will be recruited in 3 cohorts. These cohorts will serve as training, testing, and validation datasets for developing predictive models. Subjects will consent to one year of participation, including the daily use of a commodity smartwatch that collects heart rate, step count, and sleep data. Subjects will also complete online baseline and quarterly surveys assessing psychological, workplace, and sociodemographic factors. Routine administrative systems-level data on nursing care outcomes will be abstracted weekly.

Discussion

The BROWNIE study was designed to be decentralized and asynchronous to minimize any additional burden on RNs and to ensure that night shift RNs would have equal accessibility to study resources and procedures. The protocol employs novel engagement strategies with participants to maintain compliance and reduce attrition to address the historical challenges of research using wearable devices.

Trial Registration

NCT05481138.
Filial piety and older adult caregiving among Chinese and Chinese-American families in the United States: a concept analysis
Authors: Xiao Chunhong , Patrician Patricia A. , Montgomery Aoyjai P. , Wang Youhua , Jablonski Rita , Markaki Adelais
Published: February 2024

Background

The culturally sensitive nursing practice has not embedded filial piety as a cultural value and stance pertaining to caregiving among aging Chinese and Chinese-American (CCA) families in the United States, yet it is critical for healthy aging among CCAs.

Purpose

To understand filial piety when caring for aging CCAs and conceptualize an operational definition and framework.

Methods

A systematic search was conducted in CINAHL, PubMed, Scopus, and PsycINFO databases. Analysis of the concept of filial piety among CCAs used Walker and Avant’s methods. Twenty-six studies were selected in the final full-text analysis.

Findings

Synthesis of evidence identified four antecedents: (a) filial obligation as a ‘cultural gene’, (b) sense of altruism, (c) familial solidarity, and (d) societal expectation of ‘birth right’. Attributes included familial material and emotional support, obedience, pious reverence, and societal norms. Consequences were related to caregiver burden, psychological and physical well-being, quality of life, and health equity.

Conclusion

Filial piety is an intrinsic desire to support aging parents and an extrinsic desire to adhere to Chinese societal moral tenets. The proposed operational framework “Caregiving for aging CCAs in the United States” merits further study.
Facilitators and barriers to the implementation of prehabilitation for frail patients into routine health care: a realist review
Authors: Sontag Anna Frederike , Kiselev Jörn , Schaller Stefan J , Spies Claudia , Rombey Tanja
Published: February 2024

Background

Despite evidence supporting the effectiveness of prehabilitation as a new preoperative care pathway to optimise perioperative outcomes, its implementation into routine health care is widely pending. Frail patients might particularly benefit from prehabilitation interventions, but facilitating and hindering factors need to be considered in the implementation process. Thus, our aim was to derive a programme theory on what prehabilitation programmes work for frail patients in what circumstances and why.

Methods

Following Pawson’s realist review approach, preliminary programme theories on facilitators and barriers were established. General and topic-specific databases were searched systematically for facilitators and barriers to the implementation of prehabilitation for frail patients. Articles were included if they dealt with multimodal prehabilitation programmes prior to surgery in a frail population and if they contained information on facilitators and barriers during the implementation process in the full text. Based on these articles, refined programme theories were generated.

Results

From 2,609 unique titles, 34 were retained for the realist synthesis. Facilitating factors included the individualisation of prehabilitation programmes to meet the patients’ needs and abilities, multimodality, adaption to the local setting and health care system, endorsement by an ambassador and sharing of responsibilities among a multidisciplinary team. Central barriers for frail patients were transportation, lack of social support, and inadequate, overwhelming information provision.

Conclusions

Implementing prehabilitation as a new care pathway for frail patients requires organisational readiness and adaptability to the local setting. On an individual level, a clear understanding of responsibilities and of the intervention’s goal among patients and providers are necessary. Added attention must be paid to the individualisation to fit the needs and restrictions of frail patients. This makes prehabilitation a resource-intense, but promising intervention for frail surgery patients.

Trial registration

PROSPERO (CRD42022335282).
Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan
Authors: Cheng Siao Muk , Su Yung-Yeh , Chiang Nai-Jung , Wang Chih-Jung , Chao Ying-Jui , Huang Chien-Jui , Tsai Hui-Jen , Chen Shang-Hung , Chang Chi-Yen , Tsai Chia-Rung , Li Yi-Jie , Yen Chia-Jui , Chuang Shih-Chang , Chang Jeffrey Shu-Ming , Shan Yan-Shen , Hwang Daw-Yang , Chen Li-Tzong
Published: February 2024

Background

Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population.

Methods

Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy.

Results

Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0–43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7–33.7) versus 9.6 months (95% CI 5.9–17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2–16.9) and 12.6 months (95% CI 10.8–14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis.

Conclusions

Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.
DNA methylation risk score for type 2 diabetes is associated with gestational diabetes
Authors: Linares-Pineda Teresa M. , Fragoso-Bargas Nicolas , Picón María José , Molina-Vega Maria , Jenum Anne Karen , Sletner Line , Lee-Ødegård Sindre , Opsahl Julia O. , Moen Gunn-Helen , Qvigstad Elisabeth , Prasad Rashmi B. , Birkeland Kåre I. , Morcillo Sonsoles , Sommer Christine
Published: February 2024

Background

Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share many pathophysiological factors including genetics, but whether epigenetic marks are shared is unknown. We aimed to test whether a DNA methylation risk score (MRS) for T2DM was associated with GDM across ancestry and GDM criteria.

Methods

In two independent pregnancy cohorts, EPIPREG (n = 480) and EPIDG (n = 32), DNA methylation in peripheral blood leukocytes was measured at a gestational age of 28 ± 2. We constructed an MRS in EPIPREG and EPIDG based on CpG hits from a published epigenome-wide association study (EWAS) of T2DM.

Results

With mixed models logistic regression of EPIPREG and EPIDG, MRS for T2DM was associated with GDM: odd ratio (OR)[95% CI]: 1.3 [1.1–1.8], P = 0.002 for the unadjusted model, and 1.4 [1.1–1.7], P = 0.00014 for a model adjusted by age, pre-pregnant BMI, family history of diabetes and smoking status. Also, we found 6 CpGs through a meta-analysis (cg14020176, cg22650271, cg14870271, cg27243685, cg06378491, cg25130381) associated with GDM, and some of their methylation quantitative loci (mQTLs) were related to T2DM and GDM.

Conclusion

For the first time, we show that DNA methylation marks for T2DM are also associated with GDM, suggesting shared epigenetic mechanisms between GDM and T2DM.
Diversity in randomized clinical trials for peripheral artery disease: a systematic review
Authors: Long Chandler , Williams Abimbola O. , McGovern Alysha M. , Jacobsen Caroline M. , Hargens Liesl M. , Duval Sue , Jaff Michael R.
Published: February 2024

Background

Significant race and sex disparities exist in the prevalence, diagnosis, and outcomes of peripheral artery disease (PAD). However, clinical trials evaluating treatments for PAD often lack representative patient populations. This systematic review aims to summarize the demographic representation and enrollment strategies in clinical trials of lower-extremity endovascular interventions for PAD.

Methods

Following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched multiple sources (Medline, EMBASE, Cochrane, Clinicaltrials.gov, WHO clinical trial registry) for randomized controlled trials (RCTs), RCT protocols, and peer-reviewed journal publications of RCTs conducted between January 2012 and December 2022. Descriptive analysis was used to summarize trial characteristics, publication or study protocol characteristics, and the reporting of demographic characteristics. Meta-regression was used to explore associations between demographic characteristics and certain trial characteristics.

Results

A total of 2,374 records were identified. Of these, 59 met the inclusion criteria, consisting of 35 trials, 14 publications, and 10 protocols. Information regarding demographic representation was frequently missing. While all 14 trial publications reported age and sex, only 4 reported race/ethnicity, and none reported socioeconomic or marital status. Additionally, only 4 publications reported clinical outcomes by demographic characteristics. Meta-regression analysis revealed that 6% more women were enrolled in non-European trials (36%) than in European trials (30%).

Conclusions

The findings of this review highlight potential issues that may compromise the reliability and external validity of study findings in lower-extremity PAD RCTs when applied to the real-world population. Addressing these issues is crucial to enhance the generalizability and impact of clinical trial results in the field of PAD, ultimately leading to improved clinical outcomes for patients in underrepresented populations.

Registration

The systematic review methodology was published in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022378304).
Factors of success, barriers, and the role of frontline workers in Indigenous maternal-child health programs: a scoping review
Authors: Thompson Charlene , Million Tara , Tchir Devan , Bowen Angela , Szafron Michael
Published: February 2024

Background

Despite considerable investment in maternal-child programs in Canada, there has been little positive impact on the health of Indigenous mothers and their children. The reasons for this are unclear and there is a need to identify how such programs can be successfully implemented. Community input is essential for successful programs; however, it is unclear what the contributions of frontline workers have been in the health program process, i.e., program development, delivery, and evaluation. Based on these identified gaps, this scoping review aimed to: (1) identify factors of success and barriers to successful Indigenous maternal-child community health programs for mothers and their children aged 0–6 years; and (2) explore how frontline workers are included in the program process.

Methods

This scoping review was completed using the Arksey and O’Malley framework, informed by Levac et al. Four data bases (Medline, CINAHL, Embase, and Scopus), grey literature, and reference lists were searched for relevant materials from 1990–2019. Data was extracted from included articles and analysed using descriptive statistics, thematic analysis with the Braun and Clarke framework, and a Principal Component Analysis.

Results

Forty-five peer-reviewed and grey articles were included in the review. Factors of program success included: relationship building; cultural inclusion; knowledge transmission styles; community collaboration; client-centred approaches; Indigenous staff; and operational considerations. Barriers included: impacts of colonization; power structure and governance; client and community barriers to program access; physical and geographical challenges; lack of staff; and operational deficits. Frontline workers were found to have a role in program delivery (n = 45) and development (n = 25). Few (n = 6) had a role in program evaluation.

Conclusion

Although a better understanding of the frontline worker role in maternal-child health programs was obtained from the review, in a large proportion of literature the authors could not determine if the role went beyond program delivery. In addition, no direct input from frontline workers and their perspectives on program success or barriers were identified, suggesting areas to explore in future research. This review's findings have been applied to inform a community-based participatory research project and may also help improve the development, delivery, and evaluation of Indigenous maternal-child health programs.
‘Intracytoplasmic sperm injection (ICSI) paradox’ and ‘andrological ignorance’: AI in the era of fourth industrial revolution to navigate the blind spots
Authors: Sengupta Pallav , Dutta Sulagna , Jegasothy Ravindran , Slama Petr , Cho Chak-Lam , Roychoudhury Shubhadeep
Published: February 2024

The quandary known as the Intracytoplasmic Sperm Injection (ICSI) paradox is found at the juncture of Assisted Reproductive Technology (ART) and ‘andrological ignorance’ – a term coined to denote the undervalued treatment and comprehension of male infertility. The prevalent use of ICSI as a solution for severe male infertility, despite its potential to propagate genetically defective sperm, consequently posing a threat to progeny health, illuminates this paradox. We posit that the meteoric rise in Industrial Revolution 4.0 (IR 4.0) and Artificial Intelligence (AI) technologies holds the potential for a transformative shift in addressing male infertility, specifically by mitigating the limitations engendered by ‘andrological ignorance.’ We advocate for the urgent need to transcend andrological ignorance, envisaging AI as a cornerstone in the precise diagnosis and treatment of the root causes of male infertility. This approach also incorporates the identification of potential genetic defects in descendants, the establishment of knowledge platforms dedicated to male reproductive health, and the optimization of therapeutic outcomes. Our hypothesis suggests that the assimilation of AI could streamline ICSI implementation, leading to an overall enhancement in the realm of male fertility treatments. However, it is essential to conduct further investigations to substantiate the efficacy of AI applications in a clinical setting. This article emphasizes the significance of harnessing AI technologies to optimize patient outcomes in the fast-paced domain of reproductive medicine, thereby fostering the well-being of upcoming generations.
Association of inherited thrombophilia mutations and their combinations among palestinian women with unexplained recurrent miscarriage
Authors: Najjar Ayman A. , Hassouna Imam , Srour Mahmoud A. , Ibrahim Hany M. , Assi Randa Y. , Abd El Latif Heba M.
Published: February 2024

Background

Inherited thrombophilia (IT) has a complex pathophysiology and is associated with recurrent miscarriage (RM) by causing placental insufficiency and inhibiting fetal development. However, thrombophilia screening in unexplained RM cases is still questionable. This study aimed to investigate the association between the common eight IT mutations and their combinations among Palestinian women with unexplained RM.

Methods

This is an unmatched case-control study with 200 women (100 unexplained RM cases, 100 controls). Eight common IT mutations namely Factor V Leiden (FVL), prothrombin gene (FII) G202120A, Methylenetetrahydrofolate Reductase (MTHFR) gene (C677T and A1298C), B-fibrinogen gene − 455G > A, FV HR2 A4070G, Plasminogen activator inhibitor 1 (PAI1) 5G/4G and Factor XIIIA (FXIIIA) V34L; were analyzed. The first five mutations were analyzed by Restriction Fragment Length Polymorphism PCR and the other three mutations were analyzed using Amplification Refractory Mutation System PCR.

Results

The prevalence of the eight IT mutations among the control group was in the order PAI1 5G/4G (69%), MTHFR C677T (53%) and A1298C (47%), BFG − 455G > A (35%), FVL and FV HR2 (each 18%), FXIIIA V34L (16%) and FII G20210A (3%). Patients had a higher percentage of MTHFR A1298C (heterozygotes and mutant homozygote) compared to controls (p = 0.016). Frequencies of mutant alleles MTHFR A1298C (p < 0.001) and FXIIIA V34L (p = 0.009) were higher among patients compared to controls. No significant differences were observed for all other mutations or mutant alleles. Most patients (75%) and controls (75%) have 2–4 mutant alleles out of 8 mutant alleles studied, while 1% of patients and 2% of controls have zero mutant alleles. None of the combinations of the most often studied mutations (FVL, FII G20210A, MTHFR C1677T, and MTHFR A1298C) showed a significant difference between patients and controls.

Conclusions

There was a significant association between unexplained RM and the mutant alleles of MTHFR A1298C and FXIIIA V34L. No significant association was observed between unexplained RM and the combination of both mutant alleles for the mutations studied. This study is the first Palestinian report that evaluates eight inherited thrombophilia mutations and their alleles’ combinations in unexplained RM cases.
IGFBP5 is released by senescent cells and is internalized by healthy cells, promoting their senescence through interaction with retinoic receptors
Authors: Alessio Nicola , Aprile Domenico , Peluso Gianfranco , Mazzone Valeria , Patrone Deanira , Di Bernardo Giovanni , Galderisi Umberto
Published: February 2024

Cells that are exposed to harmful genetic damage, either from internal or external sources, may undergo senescence if they are unable to repair their DNA. Senescence, characterized by a state of irreversible growth arrest, can spread to neighboring cells through a process known as the senescence-associated secretory phenotype (SASP). This phenomenon contributes to both aging and the development of cancer. The SASP comprises a variety of factors that regulate numerous functions, including the induction of secondary senescence, modulation of immune system activity, remodeling of the extracellular matrix, alteration of tissue structure, and promotion of cancer progression. Identifying key factors within the SASP is crucial for understanding the underlying mechanisms of senescence and developing effective strategies to counteract cellular senescence. Our research has specifically focused on investigating the role of IGFBP5, a component of the SASP observed in various experimental models and conditions.

Through our studies, we have demonstrated that IGFBP5 actively contributes to promoting senescence and can induce senescence in neighboring cells. We have gained valuable insights into the mechanisms through which IGFBP5 exerts its pro-senescence effects. These mechanisms include its release following genotoxic stress, involvement in signaling pathways mediated by reactive oxygen species and prostaglandins, internalization via specialized structures called caveolae, and interaction with a specific protein known as RARα. By uncovering these mechanisms, we have advanced our understanding of the intricate role of IGFBP5 in the senescence process. The significance of IGFBP5 as a pro-aging factor stems from an in vivo study we conducted on patients undergoing Computer Tomography analysis. In these patients, we observed an elevation in circulating IGFBP5 levels in response to radiation-induced organismal stress.

Globally, our findings highlight the potential of IGFBP5 as a promising therapeutic target for age-related diseases and cancer.
From the identification of actionable molecular targets to the generation of faithful neuroblastoma patient-derived preclinical models
Authors: Capasso Mario , Brignole Chiara , Lasorsa Vito A. , Bensa Veronica , Cantalupo Sueva , Sebastiani Enrico , Quattrone Alessandro , Ciampi Eleonora , Avitabile Marianna , Sementa Angela R. , Mazzocco Katia , Cafferata Barbara , Gaggero Gabriele , Vellone Valerio G. , Cilli Michele , Calarco Enzo , Giusto Elena , Perri Patrizia , Aveic Sanja , Fruci Doriana , Tondo Annalisa , Luksch Roberto , Mura Rossella , Rabusin Marco , De Leonardis Francesco , Cellini Monica , Coccia Paola , Iolascon Achille , Corrias Maria V. , Conte Massimo , Garaventa Alberto , Amoroso Loredana , Ponzoni Mirco , Pastorino Fabio
Published: February 2024

Background

Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent.

Methods

Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models.

Results

Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as “very high priority”, that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient’s tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors.

Conclusions

PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.
Comparison of standard mismatch repair deficiency and microsatellite instability tests in a large cancer series
Authors: Nádorvári Maja L. , Kenessey István , Kiss András , Barbai Tamás , Kulka Janina , Rásó Erzsébet , Tímár József
Published: February 2024

Background

The tumor-agnostic indication of immune checkpoint inhibitors to treat cancers with mismatch repair deficiency (dMMR)/microsatellite instability (MSI) increased the demand for such tests beyond Lynch syndrome. International guideline recommendations accept immunohistochemistry (IHC) for dMMR or molecular techniques (PCR or NGS) for MSI status determinations considering the two tests are equal, although there are scattered reports contradicting to this presumption.

Materials and methods

Here we have directly compared four protein MMR immunohistochemistry (IHC) to MSI Pentaplex PCR test in a large cancer patient cohort (n = 1306) of our diagnostic center where the two tests have been run parallel in 703 cases.

Results

In this study we have found a high discrepancy rate (19.3%) of the two tests which was independent of the tumor types. The MSI PCR sensitivity for MMR IHC status was found to be very low resulting in a relatively low positive and negative predicting values. As a consequence, the correlation of the two tests was low (kappa < 0.7). During analysis of the possible contributing factors of this poor performance, we have excluded low tumor percentage of the samples, but identified dMMR phenotypes (classic versus non-classic or unusual) as possible contributors.

Conclusion

Although our cohort did not include samples with identified technical errors, our data strongly support previous reports that unidentified preanalytical factors might have the major influence on the poor performance of the MSI PCR and MMR IHC. Furthermore, the case is open whether the two test types are equally powerful predictive markers of immunotherapies.
The role of CD56bright NK cells in neurodegenerative disorders
Authors: Rodriguez-Mogeda Carla , van Ansenwoude Chaja M. J. , van der Molen Lennart , Strijbis Eva M. M. , Mebius Reina E. , de Vries Helga E.
Published: February 2024

Emerging evidence suggests a potential role for natural killer (NK) cells in neurodegenerative diseases, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. However, the precise function of NK cells in these diseases remains ambiguous. The existence of two NK cell subsets, CD56bright and CD56dim NK cells, complicates the understanding of the contribution of NK cells in neurodegeneration as their functions within the context of neurodegenerative diseases may differ significantly. CD56bright NK cells are potent cytokine secretors and are considered more immunoregulatory and less terminally differentiated than their mostly cytotoxic CD56dim counterparts. Hence, this review focusses on NK cells, specifically on CD56bright NK cells, and their role in neurodegenerative diseases. Moreover, it explores the mechanisms underlying their ability to enter the central nervous system. By consolidating current knowledge, we aim to provide a comprehensive overview on the role of CD56bright NK cells in neurodegenerative diseases. Elucidating their impact on neurodegeneration may have implications for future therapeutic interventions, potentially ameliorating disease pathogenesis.
Characterization of intestinal fungal community diversity in people living with HIV/AIDS (PLWHA)
Authors: Meng Pengfei , Zhang Guichun , Ma Xiuxia , Ding Xue , Song Xiyuan , Dang Shuyuan , Yang Ruihan , Xu Liran
Published: February 2024

Acquired Immune Deficiency Syndrome (AIDS) is a highly dangerous infectious disease caused by the Human Immunodeficiency Virus (HIV), a virus that attacks the human immune system. To explore the correlation between intestinal fungal community and immune function (Immune cells and inflammatory factors) in people living with HIV/AIDS (PLWHA). The feces and blood samples were collected from two groups of subjects: PLWHA and healthy controls. High-throughput sequencing of the internal transcribed spacer 1, flow cytometry, and ELISA were performed to analyze the differences and correlations between fungal microbiota, cellular immune status and serum inflammatory factors in the two groups. There were significant differences in the composition of fungal microbiota between the two groups. The relative abundance of Candida, Bjerkandera, and Xeromyces in PLWHA was significantly higher than that of healthy volunteers (P < 0.01), while the relative abundance of Mycospaerella, Xeroxysium, Penicillium, and Glomerella in PLWHA was significantly lower than that of healthy volunteers. The correlation analysis results show that Mycospaerella and Xeromyces are significantly positively correlated with CD4+/CD8+ T cells and the anti-inflammatory cytokine IL-4. On the other hand, Candida was positively correlated with pro-inflammatory factors negatively correlated with CD4+/CD8+ T cells and the anti-inflammatory cytokine IL-4, while it is positively correlated with pro-inflammatory cytokines. The significant increase in the relative abundance of Candida may be one of the important causes of intestinal damage in PLWHA. The results of this study contribute to the understanding of the relationship between fungal microbiota structure and immune function in the gut ecology of PLWHA.
Fat accumulation in striped hamsters (Cricetulus barabensis) reflects the temperature of prior cold acclimation
Authors: Zhang Kaiyuan , Cao Jing , Zhao Zhijun
Published: February 2024

Background

Proper adjustments of metabolic thermogenesis play an important role in thermoregulation in endotherm to cope with cold and/or warm ambient temperatures, however its roles in energy balance and fat accumulation remain uncertain. Our study aimed to investigate the effect of previous cold exposure (10 and 0 °C) on the energy budgets and fat accumulation in the striped hamsters (Cricetulus barabensis) in response to warm acclimation. The body mass, energy intake, resting metabolic rate (RMR) and nonshivering thermogenesis (NST), serum thyroid hormone levels (THs: T3 and T4), and the activity of brown adipose tissue (BAT), indicated by cytochrome c oxidase (COX) activity and uncoupling protein 1 (ucp1) expression, were measured following exposure to the cold (10 °C and 0 °C) and transition to the warm temperature (30 °C).

Results

The hamsters at 10 °C and 0 °C showed significant increases in energy intake, RMR and NST, and a considerable reduction in body fat than their counterparts kept at 21 °C. After being transferred from cold to warm temperature, the hamsters consumed less food, and decreased RMR and NST, but they significantly increased body fat content. Interestingly, the hamsters that were previously exposed to the colder temperature showed significantly more fat accumulation after transition to the warm. Serum T3 levels, BAT COX activity and ucp1 mRNA expression were significantly increased following cold exposure, and were considerably decreased after transition to the warm. Furthermore, body fat content was negatively correlated with serum T3 levels, BAT COX activity and UCP1 expression.

Conclusion

The data suggest that the positive energy balance resulting from the decreased RMR and NST in BAT under the transition from the cold to the warm plays important roles in inducing fat accumulation. The extent of fat accumulation in the warm appears to reflect the temperature of the previous cold acclimation.
NSF DARE—transforming modeling in neurorehabilitation: a patient-in-the-loop framework
Authors: Cashaback Joshua G. A. , Allen Jessica L. , Chou Amber Hsiao-Yang , Lin David J. , Price Mark A. , Secerovic Natalija K. , Song Seungmoon , Zhang Haohan , Miller Haylie L.
Published: February 2024

In 2023, the National Science Foundation (NSF) and the National Institute of Health (NIH) brought together engineers, scientists, and clinicians by sponsoring a conference on computational modelling in neurorehabiilitation. To facilitate multidisciplinary collaborations and improve patient care, in this perspective piece we identify where and how computational modelling can support neurorehabilitation. To address the where, we developed a patient-in-the-loop framework that uses multiple and/or continual measurements to update diagnostic and treatment model parameters, treatment type, and treatment prescription, with the goal of maximizing clinically-relevant functional outcomes. This patient-in-the-loop framework has several key features: (i) it includes diagnostic and treatment models, (ii) it is clinically-grounded with the International Classification of Functioning, Disability and Health (ICF) and patient involvement, (iii) it uses multiple or continual data measurements over time, and (iv) it is applicable to a range of neurological and neurodevelopmental conditions. To address the how, we identify state-of-the-art and highlight promising avenues of future research across the realms of sensorimotor adaptation, neuroplasticity, musculoskeletal, and sensory & pain computational modelling. We also discuss both the importance of and how to perform model validation, as well as challenges to overcome when implementing computational models within a clinical setting. The patient-in-the-loop approach offers a unifying framework to guide multidisciplinary collaboration between computational and clinical stakeholders in the field of neurorehabilitation.