O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum.

BACKGROUND: O'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O'Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility. METHODS: Affected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible. RESULTS: We report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances. CONCLUSION: Our study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

The Return on Investment of a Province-Wide Quality Improvement Initiative for Reducing In-Hospital Sepsis Rates and Mortality in British Columbia, Canada.

OBJECTIVES: Sepsis is a life-threatening medical emergency. There is a paucity of information on whether quality improvement approaches reduce the in-hospital sepsis caseload or save lives and decrease the healthcare system and society's cost at the provincial/national levels. This study aimed to assess the outcomes and economic impact of a province-wide quality improvement initiative in Canada. DESIGN: Retrospective population-based study with interrupted time series and return on investment analyses. SETTING: The sepsis cases and deaths averted over time for British Columbia were calculated and compared with the rest of Canada (excluding Quebec and three territories). PATIENTS: Aggregate data were obtained from the Canadian Institute for Health Information on risk-adjusted in-hospital sepsis rates and sepsis mortality in acute care sites across Canada. INTERVENTIONS: In 2012, the British Columbia Sepsis Network was formed to reduce sepsis occurrence and mortality through education, knowledge translation, and quality improvement. MEASUREMENTS AND MAIN RESULTS: A return on investment analysis compared the financial investment for the British Columbia Sepsis Network with the savings from averted sepsis occurrence and mortality. An estimated 981 sepsis cases and 172 deaths were averted in the post-British Columbia Sepsis Network period (2014-2018). The total cost, including the development and implementation of British Columbia Sepsis Network, was $449,962. Net savings due to cases averted after program costs were considered were $50.6 million in 2018. This translates into a return of $112.5 for every dollar invested. CONCLUSIONS: British Columbia Sepsis Network appears to have averted a greater number of sepsis cases and deaths in British Columbia than the national average and yielded a positive return on investment. Our findings strengthen the policy argument for targeted quality improvement initiatives for sepsis care and provide a model of care for other provinces in Canada and elsewhere globally.

Expanding the phenotype of PIK3C2A related syndrome: Report of two siblings with novel features and genotype.

A pair of siblings was ascertained due to multiple congenital anomalies, including strikingly similar facial, skeletal, and ocular abnormalities. Exome sequencing of both the children and their mother revealed two novel PIK3C2A variants in the siblings, c.4381delC (p.Arg1461Glufs*31) and c.1555C > T (p.Arg519Ter). PIK3C2A belongs to the Class IIa family of Phosphatidylinositol-3-kinases, which create second messenger lipids that regulate a wide range of downstream signaling pathways involved in cell growth, survival and migration. Tiosano et al. (2019) identified the first monogenic disorder associated with biallelic PIK3C2A loss-of-function variants (oculoskeletodental syndrome). The novel syndrome was characterized by short stature, coarse facial features, ocular and skeletal abnormalities. This report describes two additional siblings affected by the PIK3C2A-related syndrome, confirms core clinical features, establishes intrafamilial variability and expands the phenotype to include proteinuria.

Exploring distributed leadership in the BC Sepsis Network.

Commissioned research was undertaken to explore the role of networks in supporting large-scale change and improvement. Participatory action research and social network analysis were used to study the BC Sepsis Network. Findings of this research include insights into distributed leadership, enablers and barriers within a network approach; the importance of relationships and trust; and the need for meaningful and timely data. Recommendations are made for health leaders who are considering utilizing networks for improving patient quality and safety.

Gastroparesis: an evidence-based review for the bariatric and foregut surgeon.

Gastroparesis is a gastric motility disorder characterized by delayed gastric emptying. It is a rare disease and difficult to treat effectively; management is a dilemma for gastroenterologists and surgeons alike. We conducted a systematic review of the literature to evaluate current diagnostic tools as well as treatment options. We describe key elements in the pathophysiology of the disease, in addition to current evidence on treatment alternatives, including nutritional considerations, medical and surgical options, and related outcomes.

Current state of the definition and terminology related to weight recurrence after metabolic surgery: review by the POWER Task Force of the American Society for Metabolic and Bariatric Surgery.

Bariatric surgery continues to be the most reliable treatment for the disease of obesity. Despite excellent results, some patients experience weight recurrence with or without concomitant recurrence of co-morbidities. There is currently no standard definition for clinically significant weight recurrence after bariatric surgery so that patients and clinicians have a platform from which to plan treatment. The Post-Operative Weight Recurrence (POWER) Task Force was formed by the American Society for Metabolic and Bariatric Surgery to address this aspect of the disease of obesity. This article reviews the literature of existing definitions for weight recurrence and their limitations. Furthermore, the term weight recurrence is introduced to replace weight regain or recidivism, and the term nonresponder is introduced to replace inadequate weight loss after surgery.

Analysis of detergent-free lipid rafts isolated from CD4+ T cell line: interaction with antigen presenting cells promotes coalescing of lipid rafts.

BACKGROUND: Lipid rafts present on the plasma membrane play an important role in spatiotemporal regulation of cell signaling. Physical and chemical characterization of lipid raft size and assessment of their composition before, and after cell stimulation will aid in developing a clear understanding of their regulatory role in cell signaling. We have used visual and biochemical methods and approaches for examining individual and lipid raft sub-populations isolated from a mouse CD4+ T cell line in the absence of detergents. RESULTS: Detergent-free rafts were analyzed before and after their interaction with antigen presenting cells. We provide evidence that the average diameter of lipid rafts isolated from un-stimulated T cells, in the absence of detergents, is less than 100 nm. Lipid rafts on CD4+ T cell membranes coalesce to form larger structures, after interacting with antigen presenting cells even in the absence of a foreign antigen. CONCLUSIONS: Findings presented here indicate that lipid raft coalescence occurs during cellular interactions prior to sensing a foreign antigen.

Cost-effectiveness of a Province-wide Quality Improvement Initiative for Reducing Potentially Inappropriate Use of Antipsychotics in Long-Term Care in British Columbia, Canada.

BACKGROUND: Potentially inappropriate use of antipsychotics (PIUA) raises serious concerns about safety, quality, and cost of care for residents in long-term care (LTC). OBJECTIVE: This study aimed to estimate the cost-effectiveness of the Call for Less Antipsychotics in Long-Term Care (Clear) initiative compared with the status quo (pre-Clear, baseline). METHODS: A model-based cost-utility analysis, from a public-payer perspective in British Columbia, was conducted using secondary data of residents in LTC homes from 2013 to 2019. Residents' health resource utilization and quality-adjusted life-year (QALY) measures were extracted from multiple administrative databases. Six Markov states were modelled for post-antipsychotic progression representing PIUA, appropriate use of antipsychotic, complete withdrawal, and death. The primary outcome was the incremental cost per QALY gained. RESULTS: A cohort of 35,669 residents was included in the primary analysis. The Clear initiative, over 10 years, was estimated to have an incremental cost-effectiveness ratio (ICER) of CA$26,055 (2020 Canadian dollars) per QALY gained at an incremental cost of CA$5211 per resident and a QALY gain of 0.20. In the subgroup analyses, our findings were even more favourable for Clear wave 2 (ICER of CA$24,447 per QALY gained) and Clear wave 3 (ICER of CA$25,933 per QALY gained). At a willingness-to-pay of CA$50,000 per QALY gained, the probabilities of Clear waves 2 and 3 were 82% cost-effective. CONCLUSION: This study demonstrated incremental costs and yielded favourable ICERs for Clear compared with the baseline. More research is needed to understand the level of support for individual care homes to sustain the Clear initiative in the long run.

Vaginal microbiota of women with frequent vulvovaginal candidiasis.

Vulvovaginal candidiasis (VVC) is an insidious infection that afflicts a large proportion of women of all ages, and 5 to 8% of affected women experience recurrent VVC (RVVC). The aim of this study was to explore the possible importance of vaginal bacterial communities in reducing the risk of RVVC. The species composition and diversity of microbial communities were evaluated for 42 women with and without frequent VVC based on profiles of terminal restriction fragment polymorphisms of 16S rRNA genes and phylogenetic analysis of cloned 16S rRNA gene sequences from the numerically dominant microbial populations. The data showed that there were no significant differences between the vaginal microbial communities of women in the two groups (likelihood score, 5.948; bootstrap P value, 0.26). Moreover, no novel bacteria were found in the communities of women with frequent VVC. The vaginal communities of most women in both groups (38/42; 90%) were dominated by species of Lactobacillus. The results of this study failed to provide evidence for the existence of altered or unusual vaginal bacterial communities in women who have frequent VVC compared to women who do not have frequent VVC. The findings suggest that commensal vaginal bacterial species may not be able to prevent VVC.

Carriage of the Toxic Shock Syndrome Toxin Gene by Contemporary Community-Associated Staphylococcus aureus Isolates.

We report here the prevalence of the tst-1 gene among 252 methicillin-susceptible Staphylococcus aureus (MSSA) isolates and 458 methicillin-resistant S aureus (MRSA) isolates collected from 531 subjects between 2008 and 2017, one of which was recovered from a child with MRSA toxic shock syndrome. tst-1 was encoded by 43 (6%) S aureus isolates overall: 42 (16.7%) MSSA isolates and 1 (0.2%) MRSA isolate (P < .001).

Cell-free antibody capture method for analysis of detergent-resistant membrane rafts.

Cholesterol-rich microdomains present on the plasma membrane appear to play an important role in spatio-temporal regulation of cell signaling and cell adhesion processes. Compositional heterogeneity of these microdomains and their coalescence during cell-cell interactions may provide one mechanism for triggering and/or regulating signaling cascades from the plasma membrane to the cell interior. Biochemical analyses of distinct lipid microdomain subpopulations and single-rafts obtained from unstimulated and ligand-stimulated cells are critical for deciphering functional role of lipid rafts. We have designed a cell-free assay that captures detergent-resistant lipid rafts with an antibody against a raft-resident molecule and detects the presence of another lipid raft molecule. Moreover, this cell-free assay provides a simple and quick way to examine the simultaneous presence of two proteins in the lipid rafts, and has the potential to estimate trafficking of molecules in and out of the lipid microdomains during cell signaling on a single lipid raft-basis.

Management of atypical squamous cells, low-grade squamous intraepithelial lesions, and cervical intraepithelial neoplasia 1.

In the American Society for Colposcopy and Cervical Pathology 2006 Consensus Guidelines, several changes in the management of mildly abnormal cervical cytology and histology were made. The most notable changes involve the management of adolescents, pregnant women, and postmenopausal women. For adolescents, management of atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions is conservative, eliminating the need for immediate colposcopy. For pregnant women, options have been made to allow for deferral of colposcopy until pregnancy completion, whereas for postmenopausal women, the new guidelines call for the option to rely on human papillomavirus DNA testing or repeat cytology to manage mild cytologic abnormalities. The guidelines for cervical intraepithelial neoplasia 1 now focus on conservative management. The goal of this article is to review the 2006 Guidelines, elaborating on the changes and providing the rationale for management decisions.

New approaches to external genital warts and vulvar intraepithelial neoplasia.

Human papillomavirus is the most common sexually transmitted disease in the United States. For the majority of affected individuals, the virus remains subclinical. However, human papillomavirus infection may result in a broad spectrum of vulvar disease including genital warts, dysplasia, and invasive carcinoma. We review the evaluation and currently available therapies to assist in patient management.

Erosive vulvar lichen planus: a cohort at risk for cancer?

OBJECTIVE: To determine the occurrence of cancer, including vulvovaginal squamous cell carcinoma (SCC), among women after diagnosis of erosive vulvar lichen planus (LP). STUDY DESIGN: Retrospective review of 113 patients diagnosed with erosive vulvar LP over an 8-year period (average follow-up, 5 years). RESULTS: A diagnosis of cancer was made in 5 women after diagnosis of erosive vulvar LP. Of these, 1 had stage II vulvar SCC after treatment for stage IIB cervical cancer, and 2 with oral LP had subsequent diagnoses of oral or esophageal SCC. The remaining 2 cancer diagnoses included cervical adenocarcinoma in situ and rectal adenocarcinoma. CONCLUSION: Of 113 women with erosive vulvar LP, 1 had subsequent development of vulvar SCC. Estimating the risk of SCC among women with vulvar LP is difficult because of the low prevalence of each disorder. Additionally, given the age of the patient and multifocal involvement, association with human papillomavirus was likely. Rather, this cohort exemplifies the need for long-term evaluation in the management of vulvar LP.

Escape Room Recruitment Event: Description and Lessons Learned.

BACKGROUND: The U.S. nursing workforce is facing a severe shortage of professionals due to an anticipated retirement of more than 500,000 RNs in the next 5 years. METHOD: An Escape to Nursing event was created and delivered in a rural medical center college of nursing in the spring of 2017. This faculty team developed four distinct rooms that were designed with key nursing concepts and patient health conditions. Recruits worked in teams to solve the patient health care puzzle, which then enabled them to proceed to the next room. RESULTS: Feedback was positive from the recruits, including comments about expanding the game to more health care scenarios and reaching out to more recruits. Additional recruitment may lead to better turnout of recruits. CONCLUSION: Linear, sequential formatting for the escape room game design is recommended for use with recruits into nursing. The use of escape rooms for recruitment is a positive activity. [J Nurs Educ. 2018;57(3):184-187.].

Constipation in pregnancy: prevalence, symptoms, and risk factors.

OBJECTIVE: To prospectively estimate constipation prevalence and risk factors in pregnancy. METHODS: We enrolled healthy pregnant women in this longitudinal study during the first trimester. At each trimester and 3 months postpartum, participants completed a self-administered bowel symptom questionnaire, physical activity and dietary fiber intake measures, and a prospective 7-day stool diary. Constipation was defined using the Rome II criteria (presence of at least two of the following symptoms for at least one quarter of defecations: straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction, manual maneuvers to facilitate defecation, and fewer than three defecations per week). Generalized linear logistic models explored factors associated with constipation during pregnancy. RESULTS: One hundred three women were enrolled with mean (+/-standard deviation) age of 28 (+/-5) years; 54% were nulliparous and 92% white. Constipation prevalence rates were 24% (95% confidence interval [CI] 16-33%), 26% (95% CI 17-38%), 16% (95% CI 8-26%), and 24% (95% CI 13-36%) in the first, second, and third trimesters and 3 months postpartum, respectively. Additionally, irritable bowel syndrome (by Rome II criteria) prevalence rates were 19% (95% CI 12-28%), 13% (95% CI 6-23%), 13% (95% CI 6-23%) and 5% (95% CI 1-13%) in the first, second, and third trimesters and 3 months postpartum, respectively. In multivariable longitudinal analysis, iron supplements (OR 3.5, 95% CI 1.04-12.10) and past constipation treatment (OR 3.58, 95% CI 1.50-8.57) were associated with constipation during pregnancy. CONCLUSION: Constipation measured using the Rome II criteria affects up to one fourth of women throughout pregnancy and at 3 months postpartum. LEVEL OF EVIDENCE: II.

Advanced laparoscopic skills decrease the learning curve for laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: The reported learning curve for laparoscopic Roux-en-Y gastric bypass (LRYGB) is 20-100 cases. Our aim was to investigate whether advanced laparoscopic skills could decrease the learning curve for LRYGB with regard to major morbidity. METHODS: The senior author performed all operations in this series. His training included a laparoscopic fellowship without bariatric surgery, six years in surgical practice focusing on upper abdominal laparoscopic surgery, two courses on bariatric surgery at national meetings, one week of observing a bariatric program, and two mentored LRGBY cases. A comprehensive obesity program was put in place before the program began. Data were collected prospectively and reviewed at the series' end. Results are presented as mean +/- standard deviation and standard statistical analysis was applied. RESULTS: Between December 2003 and February 2005, 107 LRYGB operations were performed. Mean operative time decreased significantly with experience (p < 0.0001) and was 154 +/- 29, 132 +/- 40, 127 +/- 29, and 114 +/- 30 min by quartile. Mean length of stay was 2.9 +/- 1.6 days. Mean excess weight loss was 45.3% (n = 41) at six months. There were no conversions to an open procedure, no anastomotic leaks, no pulmonary embolisms, and no bowel obstructions. The five major complications (3 in the first 50 and 2 in the last 57 cases, p = NS) were two cases of biliopancreatic limb obstruction, two cases of significant gastrointestinal bleeding from anastomotic ulcer, and one case of gastric volvulus of the remnant stomach. CONCLUSIONS: A bariatric fellowship and/or extended mentoring are not required to safely initiate a bariatric program for surgeons with advanced laparoscopic skills. Operative time decreases significantly with experience, but morbidity and mortality remain low even early in the learning curve. A comprehensive obesity program seems necessary for success.

Erosive vulvar lichen planus: retrospective review of characteristics and outcomes in 113 patients seen in a vulvar specialty clinic.

OBJECTIVE: To describe the characteristics of women diagnosed with erosive vulvar lichen planus and the outcome of treatment utilized by a single practitioner. STUDY DESIGN: A retrospective review of 113 women with erosive vulvar lichen planus. Data were abstracted, including demographic information, medical history, vulvar symptom scores and treatments utilized. Dyspareunia and vulvar symptom scores before and following treatment were compared. RESULTS: The mean age at presentation for women with lichen planus was 50 years. Comorbid medical and vulvar conditions were commonly noted. Sexually active women noted an improvement in dyspareunia symptom score and report of pain-free intercourse. Other symptoms described by women at the first visit included: burning (n = 76), itching (69), pain (43) and abnormal discharge (71). While these symptoms were significantly reduced at the final visit (p < 0.05 for each), the presence of vulvovaginal symptoms commonly waxed and waned in this group. Overall, 33% had resolution of symptoms, and 19% had improvement without resolution of symptoms. CONCLUSION: This cohort extends our understanding of the characteristics of women with erosive vulvar lichen planus and emphasizes its characteristically chronic course. While the recognition of erosive vulvar lichen planus may prevent unnecessary medical and surgical procedures, continued efforts to improve treatment should be investigated.