International Federation of Fertility Societies' Surveillance (IFFS) 2019: Global Trends in Reproductive Policy and Practice, 8th Edition

The triennial Surveillance project, initiated in 1998 by Drs. Howard Jones, Jr and Jean Cohen, continues to evolve, now with a new name, the International Federation of Fertility Societies’ Surveillance (IFFS) 2019: Global Trends in Reproductive Policy and Practice, 8th Edition. The new name more accurately reflects the scope and focus of the project, and makes the report more accessible to a global audience, particularly those seeking this information online. IFFS is a non-state actor (NSA) in official relations with the World Health Organization (WHO), and the publication of Surveillance serves as part of the IFFS’ WHO mandate. The 2019 version has several major changes. Some chapters have been expanded, and some topics have been combined to eliminate redundancies. The number of chapters has been reduced from 24 to 18, but all previous topics and questions have been retained. The 2018 online questionnaire was the sole source of data for IFFS Surveillance 2019: Global Trends in Reproductive Policy and Practice, 8th Edition. The online questionnaire was further refined, and was again administered by Medtech for Solutions®. The refined questionnaire consisted of 94 questions, in English, with translated versions available. On average, it took 90 minutes (cumulative on-site time) to complete. The survey was accessible online from February 1 through March 31, 2018. Although a few responses were accepted shortly after the deadline, they reflect the practices of assisted reproductive technology (ART) (also called assisted reproductive treatment) through that time. Respondents representing 97 countries (22 more than in 2015) registered online at the website, and all provided at least some responses to the 2018 questionnaire, enough to be included in the analysis

International Federation of Fertility Societies’ Surveillance (IFFS) 2019: Global Trends in Reproductive Policy and Practice, 8th Edition

The triennial Surveillance project, initiated in 1998 by Drs. Howard Jones, Jr and Jean Cohen, continues to evolve, now with a new name, the International Federation of Fertility Societies’ Surveillance (IFFS) 2019: Global Trends in Reproductive Policy and Practice, 8th Edition. The new name more accurately reflects the scope and focus of the project, and makes the report more accessible to a global audience, particularly those seeking this information online. IFFS is a non-state actor (NSA) in official relations with the World Health Organization (WHO), and the publication of Surveillance serves as part of the IFFS’ WHO mandate

The processing of Holliday junctions by BLM and WRN helicases is regulated by p53.

BLM, WRN, and p53 are involved in the homologous DNA recombination pathway. The DNA structure-specific helicases, BLM and WRN, unwind Holliday junctions (HJ), an activity that could suppress inappropriate homologous recombination during DNA replication. Here, we show that purified, recombinant p53 binds to BLM and WRN helicases and attenuates their ability to unwind synthetic HJ in vitro. The p53 248W mutant reduces abilities of both to bind HJ and inhibit helicase activities, whereas the p53 273H mutant loses these abilities. Moreover, full-length p53 and a C-terminal polypeptide (residues 373-383) inhibit the BLM and WRN helicase activities, but phosphorylation at Ser(376) or Ser(378) completely abolishes this inhibition. Following blockage of DNA replication, Ser(15) phospho-p53, BLM, and RAD51 colocalize in nuclear foci at sites likely to contain DNA replication intermediates in cells. Our results are consistent with a novel mechanism for p53-mediated regulation of DNA recombinational repair that involves p53 post-translational modifications and functional protein-protein interactions with BLM and WRN DNA helicases

Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression

BACKGROUND:Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1(-/-) mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1(-/-) mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit. METHODOLOGY/PRINCIPAL FINDINGS:Administration of CD to Npc1(-/-) mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/-) mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage. CONCLUSIONS/SIGNIFICANCE:Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/-) and Npc2(-/-) mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis

MicroRNA Expression Characterizes Oligometastasis(es)

Cancer staging and treatment presumes a division into localized or metastatic disease. We proposed an intermediate state defined by ≤ 5 cumulative metastasis(es), termed oligometastases. In contrast to widespread polymetastases, oligometastatic patients may benefit from metastasis-directed local treatments. However, many patients who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient selection for metastasis-directed therapy.Here, we identified patterns of microRNA expression of tumor samples from oligometastatic patients treated with high-dose radiotherapy.Patients who failed to develop polymetastases are characterized by unique prioritized features of a microRNA classifier that includes the microRNA-200 family. We created an oligometastatic-polymetastatic xenograft model in which the patient-derived microRNAs discriminated between the two metastatic outcomes. MicroRNA-200c enhancement in an oligometastatic cell line resulted in polymetastatic progression.These results demonstrate a biological basis for oligometastases and a potential for using microRNA expression to identify patients most likely to remain oligometastatic after metastasis-directed treatment

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Intervention Taxonomy (ITAX): Describing Essential Features of Interventions (HMC)

OBJECTIVES: To identify key features of interventions that need to be considered in the design, execution, and reporting of interventions. METHODS: Based on prior work on decomposing psychosocial and clinical interventions, current guidelines for describing interventions, and a review of a broad range of intervention studies, we developed a comprehensive intervention taxonomy. RESULTS: Specific recommendations, rationales, and definitions of intervention delivery and content characteristics including mode, materials, location, schedule, scripting, and sensitivity to participant characteristics, interventionist characteristics, adaptability, implementation, content strategies, and mechanisms of action are provided. CONCLUSIONS: Applying this taxonomy will advance intervention science by (a) improving intervention designs, (b) enhancing replication and follow-up of intervention studies, (c) facilitating systematic exploration of the efficacy and effectiveness of intervention components through cross-study analysis, and (d) informing decisions about the feasibility of implementation in broader community settings