Waughwagner4751

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2-M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC. buy L-NAME SIGNIFICANCE Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.

To study the extent of blinding in randomised clinical trials of psychological interventions and the interpretative considerations if randomised clinical trials are not blinded.

Retrospective study of trial reports published in six high impact factor journals within the field of psychiatry in 2017 and 2018.

Trial reports published in

,

,

,

,

, or

.

Blinding status of participants, treatment providers, outcome assessors, data managers, the data safety and monitoring committee, statisticians and conclusion makers, if trialists rejected the null hypothesis on the primary outcome measure, and if trialists discussed the potential bias risk from lack of blinding in the published trial report.

63 randomised clinical trials of psychological interventions were identified. None (0%; 95% CI 0% to 5.75%) of the trials reported blinding of all possible key persons. 37 (58.7%; 95% CI 46.42% to 70.04%) trials reported blinding of outcome assessors. Two (3.2%; 95% CI 0.87% to 10.86%) trials reported blietative limitations are only rarely considered. There is a need of randomised clinical trials of psychological interventions with documented blinding attempts of all possible key persons.Since the initial description of the SARS-CoV-2 outbreak and its declaration as a worldwide pandemic, the number of publications on the novel virus has increased rapidly. We studied the trends and quality of evidence in early SARS-CoV-2 publications. link2 A comprehensive search of MEDLINE and EMBASE was performed for papers published between 1 January 2020 and 21 April 2020. Two reviewers independently screened titles and abstracts and subsequently full texts for eligibility in this systematic review. The search yielded 2504 citations published between January and February 2020 or an unspecified date, 109 of which remained for extraction after screening. Data extracted included study design, year of publication, country of basis, journal of publication, impact factor of publishing journal, study sample size, number of citations and topic of investigation. Study design-specific critical appraisal tools were used to evaluate the scientific rigour of all included papers the Joanna Briggs Institute checklist was used for case series, Scale for the Assessment of Narrative Review Articles scale for narrative reviews, Newcastle-Ottawa scale for cohort studies and AMSTAR 2 for systematic reviews. The overall quality of the literature was low-moderate. Of 541 papers that reported clinical characteristics, 295 were commentaries/expert opinions and 36 were case reports. There were no randomised clinical trials, 45 case series studies, 58 narrative reviews, 1 cohort study and 5 systematic reviews. We encourage clinicians to be attentive to these findings when utilising early SARS-CoV-2 evidence in their practices.

Most but not all studies suggest that women with type 2 diabetes have higher relative risk (RR) for cardiovascular disease (CVD) than men. More uncertainty exists on whether the RR for CVD is higher in women with prediabetes compared with men with prediabetes.

In a cross-sectional study, in 3,540 adults with normal glucose tolerance (NGT), prediabetes, and diabetes, we compared the RR for prevalent nonfatal CVD between men and women. In a longitudinal study including 1,658 adults with NGT, prediabetes, and diabetes, we compared the RR for incidences of major adverse outcomes, including all-cause death, coronary heart disease, and cerebrovascular disease events, after 5.6 years of follow-up.

Women with prediabetes and diabetes exhibited greater relative differences in BMI, waist circumference, blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, fasting glucose, hs-CRP, and white blood cell count than men with prediabetes and diabetes when compared with their NGT counterparts. We found a higher RR for prevalent CVD in women with diabetes (RR 9.29; 95% CI 4.73-18.25;

< 0.0001) than in men (RR 4.56; 95% CI 3.07-6.77;

< 0.0001), but no difference in RR for CVD was observed comparing women and men with prediabetes. In the longitudinal study, we found that women with diabetes, but not those with prediabetes, have higher RR (RR 5.25; 95% CI 3.22-8.56;

< 0.0001) of incident major adverse outcomes than their male counterparts (RR 2.72; 95% CI 1.81-4.08;

< 0.0001).

This study suggests that women with diabetes, but not those with prediabetes, have higher RR for prevalent and incident major adverse outcomes than men.

This study suggests that women with diabetes, but not those with prediabetes, have higher RR for prevalent and incident major adverse outcomes than men.

Statins may reduce the risk of diabetic polyneuropathy (DPN) as a result of lipid-lowering and anti-inflammatory effects, but statins have also been associated with neurotoxicity. We examined whether statin therapy affects the risk of DPN.

We identified all Danish patients with incident type 2 diabetes during 2002-2016. New users initiated statins between 180 days before and 180 days after their first diabetes record, while prevalent users had initiated statins before that period. Patients were followed for incident DPN using validated hospital diagnosis codes, starting 180 days after their first diabetes record. Cox proportional hazard analysis was used to compute adjusted hazard ratios (aHRs) for DPN.

The study cohort comprised 59,255 (23%) new users, 75,528 (29%) prevalent users, and 124,842 (48%) nonusers; median follow-up time was 6.2 years (interquartile range 3.4-9.6). The incidence rate of DPN events per 1,000 person-years was similar in new users (4.0 [95% CI 3.8-4.2]), prevalent users (3.8 [3.6-3.9]), and nonusers (3.8 [3.7-4.0]). The aHR for DPN was 1.05 (0.98-1.11) in new users and 0.97 (0.91-1.04) in prevalent users compared with statin nonusers. New users had a slightly increased DPN risk during the first year (1.31 [1.12-1.53]), which vanished after >2 years of follow-up. Findings were similar in on-treatment and propensity score-matched analyses and with additional adjustment for pretreatment blood lipid levels.

Statin therapy is unlikely to increase or mitigate DPN risk in patients with type 2 diabetes, although a small acute risk of harm cannot be excluded.

Statin therapy is unlikely to increase or mitigate DPN risk in patients with type 2 diabetes, although a small acute risk of harm cannot be excluded.

To assess the association between daily carbohydrate (CHO) intake and glycemic control in adult hybrid closed-loop (HCL) users with type 1 diabetes (T1D).

Mean individual daily CHO intake (MIDC) and relative deviation from MIDC (≤80% low, 81-120% medium, >120% high CHO consumption) were compared with parameters of glycemic control assessed by continuous glucose monitoring.

Records from 36 patients (26 male, 10 female; age 36.9 ± 13.5 years; HbA

7.1 ± 0.9% [54 ± 10 mmol/mol]) provided 810 days of data (22.5 ± 6.7 days per patient). Time in range (70-180 mg/dL) for low, medium, and high CHO consumption was 77.4 ± 15.4%, 75.2 ± 16.7%, and 70.4 ± 17.8%, respectively (

< 0.001). Time above range (>180 mg/dL) was 20.1 ± 14.7%, 22.0 ± 16.9%, and 27.2 ± 18.4%, respectively (

< 0.001). There was no between-group difference for time in hypoglycemia (<70 mg/dL;

= 0.50).

Daily CHO intake was inversely associated with glycemic control in adults with T1D using an HCL system. link3 Lower CHO intake may be a strategy to optimize glucose control in HCL users.

Daily CHO intake was inversely associated with glycemic control in adults with T1D using an HCL system. Lower CHO intake may be a strategy to optimize glucose control in HCL users.

The incidence of type 1 diabetes has been rising for decades, particularly among young children. Between 2006 and 2011, the incidence rate (IR) reached a plateau in Finland. In this observational, register-based cohort study, we assess recent trends in the disease rate in Finnish children.

Based on data from the Finnish Pediatric Diabetes Register, we studied the incidence of type 1 diabetes among children younger than 15 years of age between 2003 and 2018. We assessed sex-specific IRs per 100,000 person-years (PY) by 4-year time periods in three age-groups (0.50-4.99, 5.00-9.99, and 10.00-14.99 years).

Among the 7,871 children with newly diagnosed type 1 diabetes, the median age at diagnosis increased from 7.88 to 8.33 years (

= 0.001), while the overall IR decreased from 57.9/100,000 PY in 2003-2006 to 52.2/100,000 PY in 2015-2018, yielding an IR ratio (IRR) of 0.90 (95% CI 0.85-0.96,

= 0.001). This decline was mainly due to the decrease in the youngest age-group (IRR 0.77 [95% CI 0.68-0.87];

< 0.001), being significant both among boys and girls. In the middle age-group, a significant decrease was observed only among girls. No changes were observed in the oldest children.

The incidence of type 1 diabetes decreased among young Finnish children between 2003 and 2018. Current findings imply that environmental factors driving the immune system toward islet autoimmunity are changing in young children.

The incidence of type 1 diabetes decreased among young Finnish children between 2003 and 2018. Current findings imply that environmental factors driving the immune system toward islet autoimmunity are changing in young children.Although the immune response is likely to play a pivotal role in controlling Kaposi sarcoma (KS)-associated herpesvirus (KSHV) and preventing disease development, the exact factors responsible for that control remain ill defined. T cell responses are weak and variable, and neutralizing Abs are more frequently detected in individuals with KS. This suggests a potential role for nonneutralizing Abs, which to date have been largely uninvestigated. Ab-dependent cell cytotoxicity (ADCC) is a common effector function for nonneutralizing Abs and is known to play a protective role in other herpesvirus infections; yet, ADCC has never been investigated in the context of KSHV infection. In this study, we provide, to our knowledge, the first evidence that anti-KSHV Abs are capable of mediating ADCC responses against infected human cells undergoing lytic reactivation. ADCC activity significantly higher than seronegative controls was detected in 24 of 68 KSHV-seropositive individuals tested. However, ADCC responses were not associated with KS development or progression.