Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

Evaluation Resources for Asthma Programs and Beyond.

Evaluation can ensure the quality of public health programs. Systematic efforts to identify and fully engage everyone involved with or affected by a program can provide critical information about asthma programs and the broader environment in which they operate. To assist evaluators working at programs funded by the Centers for Disease Control and Prevention (CDC's) National Asthma Control Program (NACP), we developed a package of tools that build on the CDC's 1999 Framework for Program Evaluation in Public Health. The resulting suite of evaluation tools guides evaluators through a structured but flexible process, engaging a diverse array of interest holders and actively involving them in evaluation planning and implementation, all while strengthening their capacity to meaningfully contribute to the evaluation process. For our newest tool, our team reviewed the recent evaluation literature to create an enhanced version of the 1999 framework that describes important elements of professional evaluation practice. Although the original framework describes the steps to take in conducting an evaluation and the standards for a high-quality evaluation, our enhanced framework includes an explanation of how evaluators should approach their work: by incorporating critical reflection, interpersonal competence, situational awareness, and cultural responsiveness. In this article, we highlight many of the evaluation resources our team has created since the NACP's inception, culminating in a free e-text called Planting the Seeds of High-Quality Program Evaluation in Public Health. Public health professionals working in many types of programs - not just asthma - may find these resources useful.

Ultrastaging of 'negative' pelvic lymph nodes in patients with low- and intermediate-risk endometrioid endometrial cancer who developed non-vaginal recurrences.

OBJECTIVE: Evidence on micrometastases and isolated tumor cells as factors associated with non-vaginal recurrence in low- and intermediate-risk endometrial cancer is limited. The goal of our study was to investigate risk factors for non-vaginal recurrence in low- and intermediate-risk endometrial cancer. METHODS: Records of all patients with endometrial cancer surgically managed at the Mayo Clinic before sentinel lymph node implementation (1999-2008) were reviewed. We identified all patients with endometrioid low-risk (International Federation of Gynecology and Obstetrics (FIGO) stage I, grade 1 or 2 with myometrial invasion <50% and negative peritoneal cytology) or intermediate-risk (FIGO stage I, grade 1 or 2 with myometrial invasion ≥50% or grade 3 with myometrial invasion <50% and negative peritoneal cytology) endometrial cancer at definitive pathology after pelvic and para-aortic lymph node assessment. All pelvic lymph nodes of patients with non-vaginal recurrence (any recurrence excluding isolated vaginal cuff recurrences) underwent ultrastaging. RESULTS: Among 1303 women, we identified 321 patients with low-risk (n=236) or intermediate-risk (n=85) endometrial cancer (median age 65.4 years; 266 (82.9%) stage IA; 55 (17.1%) stage IB). Of the total of 321, 13 patients developed non-vaginal recurrence (Kaplan-Meier rate 4.7% by 60 months; 95% CI 2.1% to 7.2%): 11 hematogenous/peritoneal and two para-aortic and distant lymphatic. Myometrial invasion and lymphovascular space invasion were univariately associated with non-vaginal recurrence. In these patients, the original hematoxylin/eosin slides review confirmed all 646 pelvic and para-aortic removed lymph nodes as negative. The ultrastaging of 463 pelvic lymph nodes did not identify any occult metastases (prevalence 0%; 95% CI 0% to 22.8% considering 13 patients; 95% CI 0% to 0.8% considering 463 pelvic lymph nodes). CONCLUSION: There were no occult metastases in pelvic lymph nodes of patients with low- or intermediate-risk endometrial cancer with non-vaginal recurrence. Myometrial invasion and lymphovascular space invasion appear to be associated with non-vaginal recurrence.

A Plain Language Summary of "Dostarlimab for primary advanced or recurrent endometrial cancer".

What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).

Optimizing the treatment of ovarian cancer: Neoadjuvant chemotherapy and interval debulking versus primary debulking surgery for epithelial ovarian cancers likely to have suboptimal resection.

OBJECTIVE: To: a) identify prognostic factors in patients with epithelial ovarian cancer treated with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS), and b) compare post-surgical survival between patients treated with NACT/IDS for presumed unresectable disease and stage IIIC/IV patients who underwent suboptimal primary debulking surgery (PDS). METHODS: This was a retrospective study of consecutive stage IIIC or IV patients undergoing IDS after NACT at Mayo Clinic from January 2007 to December 2013. A subset of patients receiving NACT/IDS for the indication of unresectable disease were matched 1:1 on age and stage to a cohort of patients who underwent suboptimal PDS between 2003 and 2011. Hazard ratios and corresponding 95% confidence intervals were estimated from Cox proportional hazards models. RESULTS: We identified 87 patients treated with NACT/IDS: the median OS and PFS following surgery was 2.4 and 1.0years, respectively. Factors associated with significantly worse OS were older age (adjusted HR 1.60 per 10-year increase in age, 95% CI 1.18, 2.16) and elevated CA-125 before IDS (adjusted HR 2.30 for CA-125 >35U/mL, 95% CI 1.25, 4.23). Number of adjuvant chemotherapy cycles administered did not have a significant effect on survival. In the matched cohort analysis of presumed unresectable cases undergoing NACT/IDS vs suboptimal PDS cases (n=45 each), the NACT/IDS group had a significant OS advantage (HR 0.53; 95% CI 0.32, 0.88), and fewer patients experienced a 30-day postoperative Accordion grade 3/4 complication (11% vs 36%, P=0.01). CONCLUSIONS: Younger age and normalization of CA-125 prior to IDS are associated with improved survival with NACT/IDS. For primary EOC where resection to residual disease of 1cm or less is unlikely, NACT/IDS is associated with improved survival and reduced perioperative morbidity compared to PDS. As these patients are likely best served by NACT/IDS, more reliable predictors of resectability would be valuable.

Through a Culturally Competent Lens: Why the Program Evaluation Standards Matter.

Program evaluation is an important tool for all health professionals as it enables us to learn what works, what does not, and how we can make improvements. In this article, we describe how both program staff and evaluators can use the program evaluation standards to ensure their work is culturally competent and stakeholder driven. When public health programs and their evaluations are responsive to culture and context, and they include meaningful-not token-stakeholder engagement, we produce better evaluations that are more likely to yield useful findings and lead to more effective programs. Effective programs are culturally competent programs that benefit communities in meaningful, respectful ways.

The use and efficacy of intra-operative stress tests in supination-external rotation IV ankle fracture fixation.

This study examines stress radiograph use in SER IV ankle fracture fixation; the efficacy of external rotation (ERST) and lateral hook (LHST) stress tests with incidence of subsequent fixation failure secondary to syndesmotic diastasis. 154 skeletally mature patients were admitted to our unit with ankle fractures in 12 months. 42 non-SER fractures and 32 SER fractures treated without ORIF were excluded, as were 14 which featured a syndesmotic screw in the primary ORIF. The remaining 66 SER IV fixations were included in the final sample (17 men, 49 women; median age 49 years). No stress test was performed in 51.5% of cases without a single subsequent failure in these fixations. ERST was the more commonly performed test (incidence 30.3%); negative predictive value (NPV) 0.95. Incidence of LHST was 18.2%; NPV 0.83. Both tests were performed in 6.1% of cases; NPV 0.75. The incidence of failure secondary to syndesmotic diastasis was 6.1% (4/66). Notably, there were no failures in the cases where no stress test was performed. Use of either or both external rotation and lateral hook stress tests resulted in failures to detect syndesmotic diastasis with consequent failure of fixation. This study suggests that syndesmotic injuries are not missed due to an absence of a stress test but that stress tests are not sufficiently sensitive or correctly interpreted. Clinical judgement in cases where syndesmotic injury is not present appears accurate. If syndesmotic injury is clinically suspected, apply caution and insert a syndesmotic screw rather than relying on stress test results.

The use of aprepitant in a case of refractory nausea and vomiting.

BACKGROUND: This case report describes a patient whose refractory nausea and vomiting significantly improved with the use of aprepitant, a neurokinin receptor antagonist currently only licensed for short-term use in chemotherapy-induced nausea and vomiting. CASE PRESENTATION: A patient with breast cancer and meningeal metastases had an 18-month history of nausea and vomiting refractory to a number of antiemetics commonly used in palliative care. The nausea and vomiting resolved after receiving two doses of the drug aprepitant. CASE MANAGEMENT AND OUTCOME: Maintenance antiemetic treatment with aprepitant was continued over a 5-month period with no recurrence of nausea and vomiting, and no observed side effects. CONCLUSIONS: Aprepitant has a potential role as an antiemetic for refractory symptoms within the palliative-care setting.

Managing Medications During "Sick Days" in Patients With Diabetes, Kidney, and Cardiovascular Conditions: A Theory-informed Approach to Intervention Design and Implementation.

OBJECTIVES: Our aim in this work was to 1) explore barriers and enablers to patient and health-care provider (HCP) behaviours related to sick-day medication guidance (SDMG), 2) identify theory-informed strategies to advise SDMG intervention design, and 3) obtain perspectives on an eHealth tool for this purpose. METHODS: A qualitative descriptive study using qualitative conventional content analysis was undertaken. Interviews and focus groups were held with patients and HCPs from January 2021 to April 2022. Data were analyzed using the Behaviour Change Wheel and Theoretical Domains Framework to inform intervention design. RESULTS: Forty-eight people (20 patients, 13 pharmacists, 12 family physicians, and 3 nurse practitioners) participated in this study. Three interventions were designed to address the identified barriers and enablers: 1) prescriptions provided by a community-based care provider, 2) pharmacists adding a label to at-risk medications, and 3) built-in prompts for prescribing and dispensing software. Most participants accepted the concept of an eHealth tool and identified pharmacists as the ideal point-of-care provider. Challenges for an eHealth tool were raised, including credibility, privacy of data, medical liability, clinician remuneration and workload impact, and equitable access to use of the tool. CONCLUSIONS: Patients and HCPs endorsed non-technology and eHealth innovations as strategies to aid in the delivery of SDMG. These findings can guide the design of future theory-informed SDMG interventions.

Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study.

PURPOSE: The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. MATERIALS AND METHODS: Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. RESULTS: Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 (P = .24). CONCLUSION: Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

Continuing routine cardiac surveillance in long-term use of pegylated liposomal doxorubicin: is it necessary?

OBJECTIVE: The objective of this study was to determine the cardiac safety of high cumulative doses of pegylated liposomal doxorubicin (PLD) in patients with gynecologic malignancies and the need for routine evaluation of left ventricular ejection fraction (LVEF). METHODS: Data were collected for all patients treated with PLD with at least one evaluation of LVEF with either Multi-Gated Acquisition (MUGA) scan or echocardiogram from January 2006 to May 2012. Evaluation of LVEF was used to detect PLD-related cardiac toxicity (defined as a decline in LVEF of greater than 10% compared to baseline measurements). RESULTS: A total of 141 patients were included. Twenty-two patients were treated with a cumulative dose of 500 mg/m(2) or more, and five patients with 1000 mg/m(2) or more. Ten patients (7%) had a reduction in LVEF of greater than 10%, 38 had no significant change or increase in LVEF throughout the duration of treatment, and 93 did not require a follow-up evaluation of LVEF. The LVEFs of two patients dropped below 50% at cumulative doses of 1110 mg/m(2) and 1670 mg/m(2); one began with a baseline of 52%. CONCLUSIONS: Only one patient had a clinically significant decrease in LVEF at a cumulative dose of 1670 mg/m(2), suggesting that PLD does not carry a significant risk of cardiotoxicity, as evidenced by the stability of LVEF even after treatment with large cumulative doses. Routine surveillance of LVEF does not seem to be necessary or cost effective in the absence of other risk factors.

Physician opinions regarding elective bilateral salpingectomy with hysterectomy and for sterilization.

STUDY OBJECTIVE: To gather opinions about the benefits and concerns of performing bilateral salpingectomy without oophorectomy during hysterectomy for benign indications and as a sterilization procedure. DESIGN: Survey study (Canadian Task Force classification III). SETTING: Practicing physicians in US institutions that have obstetrics and gynecology residency programs listed on the FREIDA website were surveyed electronically. INTERVENTION: A validated, standardized questionnaire designed to gather opinions about bilateral salpingectomy performed during hysterectomy or for sterilization was administered via SurveyMonkey to practitioners of obstetrics and gynecology. MEASUREMENTS AND MAIN RESULTS: Results were compiled and presented as percentages of total responders. A total of 234 surveys were returned. Fifty-four percent of physicians perform bilateral salpingectomy during hysterectomy, most commonly to reduce the risks of cancer (75%) and repeat operation (49.1%). Of the 45.5% of physicians who do not perform bilateral salpingectomy during hysterectomy, most (69.4%) believe there is no benefit. Fifty-eight percent of practitioners believe that bilateral salpingectomy is the most effective method of sterilization after age 35 years but choose this method only in patients in whom one sterilization procedure has failed or because of tubal disease. Only 7.2% of surgeons prefer it as an interval sterilization procedure. CONCLUSION: Most practitioners believe that bilateral salpingectomy is beneficial. Most also believe that bilateral salpingectomy is the most effective sterilization procedure; however, only 7.2% use this method as an interval procedure. More data are needed to evaluate the prophylactic effect of bilateral salpingectomy against postoperative sequelae.

The role of Gender in Operative Autonomy in orthopaedic Surgical Trainees (GOAST).

Aims: Global literature suggests that female surgical trainees have lower rates of independent operating (operative autonomy) than their male counterparts. The objective of this study was to identify any association between gender and lead/independent operating in speciality orthopaedic trainees within the UK national training programme. Methods: This was a retrospective case-control study using electronic surgical logbook data from 2009 to 2021 for 274 UK orthopaedic trainees. Total operative numbers and level of supervision were compared between male and female trainees, with correction for less than full-time training (LTFT), prior experience, and time out during training (OOP). The primary outcome was the percentage of cases undertaken as lead surgeon (supervised and unsupervised) by UK orthopaedic trainees by gender. Results: All participants gave permission for their data to be used. In total, 274 UK orthopaedic trainees submitted data (65% men (n = 177) and 33% women (n = 91)), with a total of 285,915 surgical procedures logged over 1,364 trainee-years. Males were lead surgeon (under supervision) on 3% more cases than females (61% (115,948/189,378) to 58% (50,285/86,375), respectively; p < 0.001), and independent operator (unsupervised) on 1% more cases. A similar trend of higher operative numbers in male trainees was seen for senior (ST6 to 8) trainees (+5% and +1%; p < 0.001), those with no time OOP (+6% and +8%; p < 0.001), and those with orthopaedic experience prior to orthopaedic specialty training (+7% and +3% for lead surgeon and independent operator, respectively; p < 0.001). The gender difference was less marked for those on LTFT training, those who took time OOP, and those with no prior orthopaedic experience. Conclusion: This study showed that males perform 3% more cases as the lead surgeon than females during UK orthopaedic training (p < 0.001). This may be due to differences in how cases are recorded, but must engender further research to ensure that all surgeons are treated equitably during their training.

The influence of heatwave temperatures on fracture patient presentation to hospital.

INTRODUCTION: As global warming continues at its current rate, heatwaves are likely to become an increasing phenomenon. At present, knowledge of the influence of heatwave temperatures on fracture patient presentation to hospital remains limited. METHODS: This was a retrospective descriptive epidemiology study performed through hospital database review, linked to meteorological data. Emergency Department and Fracture Patient Presentation Data was obtained for the adult (16+) South Glasgow population (population count - 525,839) and the adult (16+) population covered by the West of Scotland Major Trauma Centre (population count - 2,218,326) from May 2021 to August 2021. This was combined with maximum temperature data, along with humidity and humidex data. Humidex is a measure which quantifies the temperature experienced by the patient, through a combined score incorporating both maximum temperature and humidity RESULTS: During the study period, there was one temperature heatwave (19th to 25th July), and four humidex heatwaves (27th June to 3rd July, 15th to 17th July, 19th to 27th July, 22nd to 26th August). During the temperature heatwave, there was a significantly higher incidence of orthopaedic polytrauma patient presentation (IRR 2.37: p < 0.027), as well as ED patient presentation (IRR 1.07: p < 0.036). The humidex heatwaves were associated with a significantly higher incidence of orthopaedic polytrauma patient presentation (IRR 2.31: p < 0.002) and overall fracture patient presentation (IRR 1.18: p < 0.002). Positive correlations were found between orthopaedic polytrauma patient presentation vs temperature (R=0.217: p < 0.016), ED patient presentation vs temperature (R=0.427: p < 0.001), fracture patient presentation vs temperature (R=0.394: p < 0.001), and distal radius fracture patient presentation vs temperature (R=0.246: p < 0.006). CONCLUSION: This study finds that heatwave temperatures result in a significantly increased number of orthopaedic polytrauma patients presenting to a Major Trauma Centre. Given the significant resources these patients require for care, Major Trauma Centres should be aware of such findings, and consider staff and resources profiles in response.

Towards in vitro vascularisation of collagen-GAG scaffolds.

Collagen-glycosaminoglycan scaffolds that have been used clinically for skin regeneration have also shown significant promise for other applications in tissue engineering. However, regeneration of thicker tissues with the aid of implanted biomaterials is likely to depend on, or be accelerated by, the ability to establish rapid vascularisation of the implant. The present study aims to establish a nascent vascular network in vitro within a CG scaffold as a first step towards that goal. Mesenchymal stem cells (MSCs) were chosen as primary vasculogenic candidate cells and a culture medium that promoted maximal network formation on Matrigel by these cells was selected. MSCs seeded in the CG scaffold formed networks of cord-like structures after one to two weeks in the presence of the vasculogenic medium; similar structures were formed by aortic endothelial cells (ECs) cultured for comparison. Gene expression analysis suggested that the MSCs began to adopt an endothelial phenotype, with RNA for PECAM and VCAM rising while that for alpha-smooth muscle actin fell. However there was no increase in Tie-2 and vWF expression. Addition of smooth muscle cells (SMCs) as a potential perivascular stabilising component did not have a noticeable effect on MSC-derived networks, although it enhanced EC-derived structures.

Prenatal exposure to an environmentally relevant phthalate mixture alters ovarian steroidogenesis and folliculogenesis in the F1 generation of adult female mice.

Phthalates are a family of chemicals that can be found in plastic and personal care products used by consumers every day and they are known endocrine disrupting chemicals that can disrupt female reproduction. In previous studies, an environmentally relevant phthalate mixture was shown to affect female reproduction in a transgenerational manner. However, limited information was available on the effect of phthalate mixtures on ovarian steroidogenesis and folliculogenesis. Ovarian steroidogenesis is important for producing hormones needed for reproduction and ovarian regulation, and folliculogenesis is essential for the development of ovarian follicles and successful fertility. Thus, this study tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture adversely affects ovarian steroidogenesis and folliculogenesis in the F1 generation of adult female mice. Pregnant dams (F0 generation) were orally dosed with vehicle control or a phthalate mixture (20 µg/kg/day-500 mg/kg/day) daily from gestational day 10 to birth, and the adult F1 females were the offspring of the dosed dams. The ovaries of the F1 generation were collected at postnatal day 60. One ovary was used for histological examination of the numbers and percent of different follicle types. The other ovary was used to measure expression of theca and granulosa cell enzymes. Additionally, sera were collected for measuring hormone levels. The results indicate that prenatal exposure to the phthalate mixture decreases hormone levels and gene expression, alters the transitioning of follicle types, and leads to a higher incidence of atresia in the F1 generation offspring.

Effects of the COVID-19 lockdown on orthopaedic trauma: a multicentre study across Scotland.

AIMS: The UK government declared a national lockdown on 23 March 2020 to reduce transmission of COVID-19. This study aims to identify the effect of lockdown on the rates, types, mechanisms, and mortality of musculoskeletal trauma across Scotland. METHODS: Data for all musculoskeletal trauma requiring operative treatment were collected prospectively from five key orthopaedic units across Scotland during lockdown (23 March 2020 to 28 May 2020). This was compared with data for the same timeframe in 2019 and 2018. Data collected included all cases requiring surgery, injury type, mechanism of injury, and inpatient mortality. RESULTS: A total of 1,315 patients received operative treatment from 23 March 2020 to 28 May 2020 compared with 1,791 in 2019 and 1,719 in 2018. The numbers of all injury types decreased, but the relative frequency of hip fractures increased (36.3% in 2020 vs 30.2% in 2019, p < 0.0001 and 30.7% in 2018, p < 0.0001). Significant increases were seen in the proportion of DIY-related injuries (3.1% in 2020 vs 1.7% in 2019, p = 0.012 and 1.6% in 2018, p < 0.005) and injuries caused by falls (65.6% in 2020 vs 62.6% in 2019, p = 0.082 and 61.9% in 2018, p = 0.047). Significant decreases were seen in the proportion of road traffic collisions (2.6% in 2020 vs 5.4% in 2019, p < 0.0001 and 4.2% in 2018, p = 0.016), occupational injuries (1.8% in 2020 vs 3.0% in 2019, p = 0.025 and 2.3% in 2018, p = 0.012) and infections (6.8% in 2020 vs 7.8% in 2019, p = 0.268 and 10.3% in 2018, p < 0.012). Cycling injuries increased (78 in 2020 vs 64 in 2019 vs 42 in 2018). A significant increase in the proportion of self-harm injuries was seen (1.7% in 2020 vs 1.1% in 2019, p = 0.185 and 0.5% in 2018, p < 0.0001). Mortality of trauma patients was significantly higher in 2020 (5.0%) than in 2019 (2.8%, p = 0.002) and 2018 (1.8%, p < 0.0001). CONCLUSION: The UK COVID-19 lockdown has resulted in a marked reduction in musculoskeletal trauma patients undergoing surgery in Scotland. There have been significant changes in types and mechanisms of injury and, concerningly, mortality of trauma patients has risen significantly.Cite this article: Bone Joint Open 2020;1-9:541-548.

Evaluative Thinking in Practice: The National Asthma Control Program.

Although evaluative thinking lies at the heart of what we do as evaluators and what we hope to promote in others through our efforts to build evaluation capacity, researchers have given limited attention to measuring this concept. We undertook a research study to better understand how instances of evaluative thinking may present in practice-based settings-specifically within four state asthma control programs funded by the Centers for Disease Control and Prevention's National Asthma Control Program. Through content analyses of documents as well as interviews and a subsequent focus group with four state asthma control programs' evaluators and program managers we identified and defined twenty-two indicators of evaluative thinking. Findings provide insights about what practitioners may wish to look for when they intend to build evaluative thinking and the types of data sources that may be more or less helpful in such efforts.

Validity of the mental health component scale of the 12-item Short-Form Health Survey (MCS-12) as measure of common mental disorders in the general population.

This study assessed the screening utility of the 12-item Short-Form Health Survey's (SF-12) mental health component scale (MCS-12) for diagnosable depression and anxiety disorders in a general population sample, and thus, the validity of this scale as a measure of mental health in epidemiological research. Data were from the Australian National Survey of Mental Health and Wellbeing (N=10,504). Diagnoses were made using the Composite International Diagnostic Interview. The MCS-12 was compared to other brief scales: the RAND Mental Health Component scale (RAND MHC-12, an alternative scoring method for the MCS-12), the 12-item General Health Questionnaire (GHQ-12), the Kessler Psychological Distress Scale (K10 and K6), and an estimate of the Mental Health Inventory (MHI-5). The MCS-12 and RAND MHC-12 were equally able to discriminate respondents with the target diagnoses. The MCS-12 performed better than the GHQ-12, and equally to the K6 for diagnoses of depression, though not anxiety disorders, where the K6 showed greater utility. The K10 out-performed the MCS-12 for all diagnoses. Areas under receiver operating characteristics curves (AUC) indicated that the MCS-12 is valid measure of mental health in epidemiological research, and a useful screening tool for both depression (AUC=0.92) and anxiety disorders (AUC=0.83).

Investigation of factors affecting the efficacy of 3C23K, a human monoclonal antibody targeting MISIIR.

MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue-specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti-MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients. We selected two high expressing models and two low expressing models for in vivo testing. One xenograft model using an MISIIR over-expressing SKOV3ip cell line (Z3) was a positive control. The primary endpoint was change in tumor size. The secondary endpoint was final tumor mass. We observed no statistically significant differences between control and treated animals. The lack of response could be secondary to a number of variables including the lack of known biomarkers of response, the low membrane expression of MISIIR, and a limited ability of 3C23K to induce ADCC in PDX models. Further study is needed to determine the magnitude of ovarian cancer response to 3C23K and also if there is a threshold surface expression to predict response.