Search Results for: Probiotici: in vivo vs in vitro

Background
The potency of T cell-mediated responses is a determinant of immunotherapy effectiveness in treating malignancies; however, the clinical efficacy of T-cell therapies has been limited in hepatocellular carcinoma (HCC) owing to the extensive immunosuppressive microenvironment.

Objective
Here, we aimed to investigate the key genes contributing to immune escape in HCC and raise a new therapeutic strategy for remoulding the HCC microenvironment.

Design
The genome-wide in vivo clustered regularly interspaced short palindromic repeats (CRISPR) screen library was conducted to identify the key genes associated with immune tolerance. Single-cell RNA-seq (scRNA-seq), flow cytometry, HCC mouse models, chromatin immunoprecipitation and coimmunoprecipitation were used to explore the function and mechanism of adenylate cyclase 7 (ADCY7) in HCC immune surveillance.

Results
Here, a genome-wide in vivo CRISPR screen identified a novel immune modulator-ADCY7. The transmembrane protein ADCY7 undergoes subcellular translocation via caveolae-mediated endocytosis and then translocates to the nucleus with the help of leucine-rich repeat-containing protein 59 (LRRC59) and karyopherin subunit beta 1 (KPNB1). In the nucleus, it functions as a transcription cofactor of CCAAT/enhancer binding protein alpha (CEBPA) to induce CCL5 transcription, thereby increasing CD8+ T cell infiltration to restrain HCC progression. Furthermore, ADCY7 can be secreted as exosomes and enter neighbouring tumour cells to promote CCL5 induction. Exosomes with high ADCY7 levels promote intratumoural infiltration of CD8+ T cells and suppress HCC tumour growth.

Conclusion
We delineate the unconventional function and subcellular location of ADCY7, highlighting its pivotal role in T cell-mediated immunity in HCC and its potential as a promising treatment target.

Circulation, Ahead of Print. BACKGROUND:Ca2+mishandling in cardiac Purkinje cells is a well-known cause of cardiac arrhythmias. The Purkinje cell resident inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is believed to play an important role in Ca2+handling, and ITPR1 gain-of-function (GOF) has been implicated in cardiac arrhythmias. However, nearly all known disease-associated ITPR1 variants are loss-of-function and are primarily linked to neurological disorders. Whether ITPR1 GOF has pathological consequences, such as cardiac arrhythmias, is unclear. This study aimed to identify human ITPR1 GOF variants and determine the impact of ITPR1 GOF on Ca2+handling and arrhythmia susceptibility.METHODS:There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice).RESULTS:We showed that the ITPR1-W1447G±and recently reported ITPR1-D2594K±GOF mutant mice were susceptible to stress-induced ventricular arrhythmias. Confocal Ca2+and voltage imaging in situ in heart slices and Ca2+imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G±and ITPR1-D2594K±variants increased the occurrence of stress-induced spontaneous Ca2+release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF.CONCLUSIONS:Our studies in mice and humans reveal that enhanced function of ITPR1, a well-known movement disorder gene, increases the risk for cardiac arrhythmias.

In this narrative medicine essay, a family planning fellow discusses how undergoing an abortion, the procedure she specializes in performing, has deepened her perception of the concept of the difficult components of choice and helped her understand the difference in providing vs experiencing care.

To the Editor A recent study found that a more selective risk stratification scheme for enoxaparin thromboprophylaxis reduced the incidence of postpartum wound hematoma without increasing the risk of postpartum venous thromboembolism (VTE). However, we believe there are several key issues that may affect the interpretation of the study results.

In Reply We appreciate the Letters to the Editor in response to our retrospective cohort study.

This Viewpoint discusses enrollment in Medicare Advantage vs traditional Medicare among older adults and common reasons for plan disenrollment, including the lack of in-network physicians and hospitals.

This Danish nationwide genome-wide association study aims to identify biomarkers of severe vs less severe ulcerative colitis.

This JAMA Insights examines antibiotic selection for the treatment of acute bacterial rhinosinusitis in US pediatric patients, specifically amoxicillin vs amoxicillin-clavulanate.

To the Editor In a recent study comparing standard risk-stratified with more selective postpartum VTE chemoprophylaxis protocols, the more selective protocol was associated with decreased rates of wound hematomas without increased rates of postpartum VTE. I would like to discuss a few concerns about this study.

Objectives
The objective of this study is to explore how the UK versus the USA compare in patient characteristics, treatment patterns and overall survival (OS) of patients with advanced non-small cell lung cancer (aNSCLC) initiating first-line (1L) treatment.

Design
Retrospective cohort study.

Setting
Oncology treatment centres in the USA and UK.

Participants
People in the USA and UK diagnosed with aNSCLC and treated in the 1L setting between 2016 and 2018. The US cohort was obtained from a nationwide electronic health record-derived deidentified database. The UK cohort information was derived from a published study exploring the patient characteristics, treatments and outcomes of people with aNSCLC in the UK.

Interventions
1L chemotherapy, immunotherapy monotherapy or targeted therapy.

Primary outcome measure
The primary outcome was OS—defined as the time from treatment initiation to death from any cause.

Results
There were 1003 patients in the UK and 3819 in the US cohorts receiving 1L therapy for aNSCLC. After standardising the US cohort to the UK cohort, median OS in the USA and UK was similar across 1L drug classes: chemotherapies (7.7 (95% CI 7.1 to 8.3) vs 8.1 (95% CI 7.4 to 8.9) months), immunotherapies (13.9 (95% CI 11.0 to 17.1) vs 14.0 (95% CI 10.7 to 20.6)) and targeted therapies (21.6 (95% CI 18.5 to 23.7) vs 20.2 (95% CI 16.0 to 30.5)). OS curves for 1L immunotherapy and targeted therapy were almost overlapping after standardisation. OS after around 12 months was higher in US patients compared with UK patients receiving 1L chemotherapy regimens. Of those receiving 1L chemotherapy, the proportion receiving any second-line therapy appeared higher for patients in the USA versus UK.

Conclusions
The results suggest that in aNSCLC patients receiving 1L treatment, US data have the potential to be used in technology evaluations to understand long-term OS where UK data are unavailable or sparse.

Background
The global increase in caesarean sections (CS), currently at 21.1% of all deliveries, has led to a rise in uterine scar defects, or ‘niches’, at the hysterotomy site. These niches, detectable in 13%–84% of cases via transvaginal ultrasound (TVS) and 42%–84% through sonohysterography (SHG), may contribute to gynaecological complications, including abnormal uterine bleeding, chronic pain and secondary infertility. Niche-associated risks for in vitro fertilisation (IVF) outcomes remain underexplored, and this study aims to evaluate their impact on clinical pregnancy rates.

Methods and analysis
This multicentre, prospective, non-interventional study will involve 250 women with a history of CS and secondary infertility undergoing IVF in 14 reproductive units of French Hospital. Participants will be assessed using SHG and TVS to determine niche presence (measurements of the length, depth and width of the niche, and residual myometrial thickness (RMT)). A niche is diagnosed by an indentation of at least 2 mm at the site of the caesarean scar, with a large niche defined as RMT

Introduction
A greater choice of menstrual products may improve menstrual health (MH). This study assessed factors associated with declining consent to receive a menstrual cup by parents and female students participating in a MH intervention trial in Ugandan schools.

Methods
We analysed baseline data from a cluster-randomised trial evaluating the effectiveness of a multicomponent MH intervention among female students in 60 Ugandan secondary schools. Parental consent and student assent to receive a menstrual cup and training on its use was sought separately from consent from other trial activities. Random-effects logistic regression models were used to estimate adjusted OR (aOR) and 95% CIs for factors associated with (i) parents or guardians declining the cup and (ii) students declining the cup using hierarchical conceptual frameworks.

Results
The baseline trial population comprised 3705 post-menarchal students (mean age 15.6 (SD 0.9 years), of whom 2048 (55.3%) were day students. Among the parents of the 3635 participants aged

Objectives
Telehealth, the provision of healthcare through digital communication, has been proposed as a potential solution to meet the increasing demand for healthcare, particularly in the setting of the COVID-19 pandemic. Sweden has an established national telehealth service for triage and referral by phone (1177) since 2013 which has the potential to meet this increasing demand. However, little is known about the development and retention in demand during and after the pandemic in Sweden. The objective of this study was to investigate the utilisation of the national telehealth service in Sweden before, during and after the pandemic in relation to emergency department (ED) visits.

Methods
This was a retrospective observational study of telephone calls to the national telehealth service in Sweden. We collected the number of calls, number of answered calls and visits to ED in Sweden from 2017 through 2021, aggregated by month. The difference in number of calls and visits was analysed using Student’s t-test for related samples.

Results
Data were collected from all 21 healthcare regions in Sweden, serving 10.5 million citizens. The average number of monthly calls was 48 (SD 10) calls per 1000 citizens. The first month of the pandemic, March 2020, had the highest monthly calls per capita during the whole study period: 62 (diff 14, 95% CI 9 to 19, p

Objectives
To evaluate and compare medication adherence and persistence for patients newly initiating single-inhaler triple therapy (SITT) and multiple-inhaler triple therapy (MITT) for chronic obstructive pulmonary disease (COPD) in Japan.

Design
Retrospective, new-user, active comparator, observational cohort study using inverse probability of treatment weighting.

Setting
Health insurance claims data from the Medical Data Vision Co., Ltd, hospital claims database.

Participants
Adults diagnosed with COPD at age ≥40 years newly initiating MITT or SITT (fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) or formoterol fumarate/budesonide/glycopyrronium) from 1 September 2019 to 31 July 2021.

Primary and secondary outcome measures
The primary outcome was medication adherence compared between patients using SITT and MITT, assessed by the proportion of days covered ≥80%. Secondary outcomes included medication persistence (time from index treatment initiation to discontinuation) compared between patients using SITT and MITT and medication adherence compared before and after the switch in a subgroup of patients switching from MITT to SITT.

Results
We included 2575 MITT and 2962 SITT users with similar baseline characteristics following weighting. The proportion of adherent patients was significantly greater for SITT versus MITT users at 6 months (19.7% vs 10.2%, p

Objectives
To describe outcomes in women admitted for labour care to midwifery units with gestational or pre-existing diabetes, compare outcomes with other women admitted to the same units and describe admission and care guidance in midwifery units typically admitting women with diabetes.

Design
A national cohort study and a survey of practice.

Setting
We used the UK Midwifery Study System to collect data from midwifery units in the UK between October 2021 and February 2023.

Participants
Women with a diagnosis of diabetes admitted for labour care to a midwifery unit were compared with a cohort of women without diabetes admitted for labour care to the same units.

Primary and secondary outcome measures
The primary outcome was a composite measure of maternal outcome reflecting the need for obstetric care (one or more of augmentation, instrumental birth, caesarean birth, maternal blood transfusion, third or fourth-degree perineal tear, maternal admission to higher level care). We also investigated a number of secondary maternal and neonatal outcomes.

Results
Overall, 420 (0.7% (95% CI 0.67% to 0.82%) of the 56 648 women admitted to midwifery units in the study period were recorded as having diabetes, most (84%) with diet-controlled gestational diabetes. Women with diabetes were no more likely than comparison women to experience the composite primary outcome (18.7% vs 20.7%, adjusted relative risk=1.31, 95% CI 0.96 to 1.80). We found no statistically significant differences between the two groups for the secondary maternal and neonatal outcomes investigated: augmentation, postpartum haemorrhage >1.5 L, shoulder dystocia, maternal blood transfusion and maternal admission for higher level care, Apgar

Annals of Internal Medicine, Ahead of Print.