Explore the vast range of titles available.

Severe acute post-cesarean delivery (CD) pain has been associated with an increased risk for persistent pain and postpartum depression. Identification of women at increased risk for pain can be used to optimize post-cesarean analgesia. The impact of labor prior to CD (intrapartum CD) on acute post-operative pain and opioid use is unclear. We hypothesized that intrapartum CD, which has been associated with both increased inflammation and affective distress related to an unexpected surgical procedure, would result in higher postoperative pain scores and increased opioid intake. This is a secondary analysis of a prospective cohort study examining opioid use up to 2 weeks following CD. Women undergoing CD at six academic medical centers in the United States 9/2014-3/2016 were contacted by phone two weeks following discharge. Participants completed a structured interview that included questions about postoperative pain scores and opioid utilization. They were asked to retrospectively estimate their maximal pain score on an 11-point numeric rating scale at multiple time points, including day of surgery, during hospitalization, immediately after discharge, 1.sup.st week, and 2.sup.nd week following discharge. A total of 720 women were enrolled, 392 with and 328 without labor prior to CD. Patients with intrapartum CD were younger, less likely to undergo repeat CD or additional surgical procedures, and more likely to experience a complication of CD. Intrapartum CD is associated with worse pain on the day of surgery but not other time points. Opioid requirements following discharge were modestly increased following intrapartum CD.

BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response; however, selective small molecule inhibitors of defined mechanism are currently lacking. Here, we identify and characterise a specific inhibitor of BLM’s ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.

The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5ml blood; 26% of patients had ≥2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303–4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥2 CTCs during treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14–0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients.

The Greatwall kinase inhibits PP2A-B55 phosphatase activity during mitosis to stabilise critical Cdk1-driven mitotic phosphorylation. Although Greatwall represents a potential oncogene and prospective therapeutic target, our understanding of the cellular and molecular consequences of chemical Greatwall inactivation remains limited. To address this, we introduce C-604, a highly selective Greatwall inhibitor, and characterise both immediate and long-term cellular responses to the chemical attenuation of Greatwall activity. We demonstrate that Greatwall inhibition causes systemic destabilisation of the mitotic phosphoproteome, premature mitotic exit and pleiotropic cellular pathologies. Importantly, we show that the cellular and molecular abnormalities associated with reduced Greatwall activity are specifically dependent on the B55α isoform, rather than other B55 variants, underscoring PP2A-B55α phosphatases as key mediators of the cytotoxic effects of Greatwall-targeting agents in human cells. Additionally, we establish that sensitivity to Greatwall inhibition varies in different cell line models and that dependency on Greatwall activity reflects the balance between Greatwall and B55α expression levels. Our findings highlight Greatwall dependency as a cell-specific vulnerability and propose the B55α-to-Greatwall expression ratio as a predictive biomarker of cellular responses to Greatwall-targeted therapeutics. The authors develop and characterise a selective Greatwall inhibitor, C-604, and show that its cytotoxicity stems from PP2A-B55α hyperactivation. They identify B55α and Greatwall levels as biomarkers of responses to Greatwall-targeted therapy.

Needs assessments in patients with juvenile idiopathic arthritis (JIA) have revealed a need for disease information, self-management skills, and peer support. We previously developed and tested the acceptability of an in-person and videoconference-based self-management program (SMP) to address these needs. The aim of this pilot randomized controlled trial (RCT; the VISTA-JIA trial) is to evaluate the feasibility and preliminary effectiveness of a virtual group-based SMP for adolescents with JIA in comparison to a waitlist control group. A total of 100 participants with confirmed JIA (aged 12-17 years) will be recruited from 5 Canadian pediatric rheumatology centers and randomized 1:1 to the intervention or waitlist control groups. Adolescents in the intervention group will receive the virtual SMP. Those randomized to the control group will receive standard of care alone and will later be eligible for the SMP. The SMP includes JIA disease education, self-management strategies, and peer support. Four 60- to 90-minute sessions will be conducted over 8 weeks with a group size of 4-6 participants. The primary feasibility outcome will be adherence to the SMP (defined as completion of all 4 sessions by at least 80% of participants). Other secondary feasibility outcomes will include recruitment and withdrawal rates, the proportion of completed questionnaires, engagement and satisfaction with the SMP measured through a semistructured virtual interview, and intervention fidelity (consistent content and technology delivery). Secondary preliminary effectiveness outcomes will be assessed by completing 5 validated questionnaires at pre- and postprogram time points: (1) the Medical Issues, Exercise, Pain, and Social Support Questionnaire to assess perceived ability to manage JIA (self-management); (2) the Children's Arthritis Self-Efficacy Scale to assess self-efficacy; (3) the Pediatric Quality of Life Inventory 3.0 Rheumatology-Teen Module to assess health-related quality of life; (4) the PROMIS (Patient-Reported Outcomes Measurement Information System) Pediatric Pain Interference Scale to assess pain interference; and (5) Readiness for Adult Care in Rheumatology to assess transition readiness. Descriptive statistics and nonparametric tests will be used to analyze the data. The study setup is complete at all centers, including training of the facilitators, revising and finalizing education sessions, participant's handout guide, and fidelity checklist. Recruitment began in January 2024 and is expected to conclude by December 2025. Feasibility outcomes, including adherence and engagement, as well as preliminary effectiveness, will be analyzed post intervention. This is the first evidence-based, virtual, interactive, group-structured JIA SMP in Canada. This SMP will address needs for disease information, self-management skills, and peer support in adolescents with JIA. The results of this pilot study will inform a full-scale RCT focused on the efficacy and cost-effectiveness of the program with the goal of integration in routine clinical practice across Canada. ClinicalTrials.gov NCT06184100; https://clinicaltrials.gov/study/NCT06184100. DERR1-10.2196/69539.

Cannabidiol (CBD) is currently being investigated as a novel therapeutic for the treatment of CNS disorders like schizophrenia and epilepsy. ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) mediate pharmacoresistance in these disorders. P-gp and Bcrp are expressed at the blood brain barrier (BBB) and reduce the brain uptake of substrate drugs including various antipsychotics and anticonvulsants. It is therefore important to assess whether CBD is prone to treatment resistance mediated by P-gp and Bcrp. Moreover, it has become common practice in the drug development of CNS agents to screen against ABC transporters to help isolate lead compounds with optimal pharmacokinetic properties. The current study aimed to assess whether P-gp and Bcrp impacts the brain transport of CBD by comparing CBD tissue concentrations in wild-type (WT) mice versus mice devoid of ABC transporter genes. P-gp knockout ( Abcb1a/b −∕− ), Bcrp knockout ( Abcg2 −∕− ), combined P-gp/Bcrp knockout ( Abcb1a/b −∕− Abcg2 −∕− ) and WT mice were injected with CBD, before brain and plasma samples were collected at various time-points. CBD results were compared with the positive control risperidone and 9-hydroxy risperidone, antipsychotic drugs that are established ABC transporter substrates. Brain and plasma concentrations of CBD were not greater in P-gp, Bcrp or P-gp/Bcrp knockout mice than WT mice. In comparison, the brain/plasma concentration ratios of risperidone and 9-hydroxy risperidone were profoundly higher in P-gp knockout mice than WT mice. These results suggest that CBD is not a substrate of P-gp or Bcrp and may be free from the complication of reduced brain uptake by these transporters. Such findings provide favorable evidence for the therapeutic development of CBD in the treatment of various CNS disorders.

A Code White (CW) activation is a hospital-wide alert for postpartum hemorrhage (PPH) and acute care surgeons (ACS) were added to the response team to assist in resuscitation. A multidisciplinary training program was also implemented. This study aimed to evaluate the impact of ACS involvement and training on maternal outcomes. A retrospective review was performed on all CW activations from 1/1/2015–8/31/2022. Three groups—pre-ACS response, ACS response, and ACS response ​+ ​training (R&T)—were compared. 218 patients had CW activations. ACS response increased MTP activations (50.0%vs76.5%vs76.2%, p ​= ​0.014) and TXA administration (50.0%vs96.5%vs93.3%, p ​< ​0.0001). The ACS R&T had the highest ACS presence (53.6%vs72.9%vs96.2%, p ​< ​0.0001), shortest operation (99 vs 67 vs 53min, p ​= ​0.002), lowest crystalloid use (2000 vs 1110 vs 800 ​ml, p ​= ​0.003), and lowest transfusion requirements. Mortality decreased from 17.9% in pre-ACS to 2.4% in ACS response and 0% in ACS R&T (p ​< ​0.0001). ACS assistance in CW activations and multidisciplinary PPH education led to the prevention of maternal mortality. ACS are a valuable resource in this unique population. •The involvement of ACS in the management of severe PPH increased the use of TXA and MTP activation.•The institutional PPH training improved hemorrhage control and correcting coagulopathy.•The combination of ACS and PPH training improved maternal mortality.

Rationale Preclinical studies suggest that lithium carbonate (lithium) can reduce precipitated cannabinoid withdrawal in rats by stimulating release of the neuropeptide oxytocin, while two open-label studies indicate lithium may ameliorate cannabis withdrawal symptoms in humans. Objectives This study was conducted to examine the efficacy and safety of lithium in the inpatient management of cannabis withdrawal and to determine whether lithium affects plasma oxytocin and the rate of elimination of plasma cannabinoids during abstinence. Methods Treatment-seeking cannabis-dependent adults ( n  = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo given twice a day under double-blind randomized controlled trial (RCT) conditions. Primary outcomes included withdrawal severity [cannabis withdrawal scale (CWS)], rates of detoxification completion, and adverse events. Plasma cannabinoids, plasma oxytocin and serum lithium levels were measured repeatedly over admission. Follow-up research interviews were conducted at 14, 30, and 90 days postdischarge. Results Lithium did not significantly affect total CWS scores relative to placebo, although it significantly reduced individual symptoms of “loss of appetite,” “stomach aches,” and “nightmares/strange dreams.” No significant group differences were found in treatment retention or adverse events. Lithium did not increase plasma oxytocin levels nor influence the rate of elimination of cannabinoids. Both placebo- and lithium-treated participants showed reduced levels of cannabis use (verified by urinalysis) and improved health and psychosocial outcomes at 30- and 90-day follow-up relative to pretreatment baselines. Conclusions Despite the strong rationale for the present study, the efficacy of lithium over placebo in the management of cannabis withdrawal was not demonstrated.