Citations

Abstract Objective: Weight gain and vasomotor symptoms (VMS) are common complaints in midlife women going through the menopause transition. A selective serotonin 2C (5-HT2C) receptor agonist, lorcaserin, which was previously approved by the Food and Drug Administration for weight loss, has unreported observational evidence suggesting improvement in VMS with its use. The goal of this pilot study was to evaluate the efficacy of lorcaserin for weight loss and management of VMS in overweight midlife women. Methods: This was a 24-week open label pilot study of 20 overweight midlife women, aged 45-60 years, who were experiencing severe VMS. Participants received lorcaserin at the standard dose of 10 mg twice daily for 12 weeks, followed by 12 weeks of observation off the drug. The primary outcomes were changes in weight and subjectively reported VMS. Results: At the end of 12 weeks, mean change in weight was −2.4 kg (90% CI, −3.2 to −1.7, P < 0.001). However, the participants returned to the baseline weight at 24 weeks. Participants also reported significant subjective improvement in VMS, with a mean ± SD change in self-reported hot flash frequency from baseline to week 12 of −5.4 ± 3.9 (decrease of 1.4 standard deviations). There was a rapid increase in the frequency of VMS within 2 weeks of discontinuation of lorcaserin with a tendency to approach the baseline frequency of VMS. Conclusions: In addition to its weight loss-inducing effect, 5-HT2C receptor modulation may have an additional beneficial effect on VMS in midlife women. A treatment option that targets both weight and VMS in midlife women is attractive. Video Summary: http://links.lww.com/MENO/A622.

Abstract Background: Chronic conditions are placing a serious burden on individuals as well as the health care system. Health coaching (HC) has emerged as a promising approach that can support effective lifestyle interventions for chronic conditions. However, until now there is no particularly comprehensive systematic review of HC impact on a chronic condition from the angle of patient improvement and detail coaching characteristics reported. Objective: To synthesize available studies on the efficacy and current status of HC interventions on the health of chronically ill adult patients. Methods: The literature search will be conducted for trials published in English within the past four years. Electronic databases CINAHL, Cochrane Library, Embase, MEDLINE, and Scopus will be searched with keywords describing HC for chronic diseases. Randomized controlled trials that compare HC interventions to conventional care or other alternative therapies will be included. Data extraction will be conducted by two reviewers independently, and enrolled trials will be evaluated for quality and bias assessment. If appropriate, meta-analysis will be conducted on the last stage of the review; otherwise, the study findings will be described narratively. The software Review Manager (Revman version 5.3.5.) provided by the Cochrane Collaboration will be applied for the meta-analysis. Results: This is the first study to comprehensively explore the effectiveness and current status of HC intervention for patients with chronic conditions. Discussion: Study findings from this review will advance the appropriate utilization of coaching practice by determining whether HC is effective and feasible among patients with chronic disease. If proven effective, this approach may be applied more broadly through public health interventions. The current status findings will also provide evidence to inform decisions for integrating HC interventions into the current management pathway for individuals with chronic conditions. Systematic review registration: PROSPERO CRD42020153280.

Abstract Asparagine‐linked glycosylation 13 homolog ( ALG13 ) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐ N ‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13‐CDG. Twenty‐four previously reported ALG13‐CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13‐CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13‐deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13 . This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

Abstract Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1‐CDG. PGM1‐CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life‐threatening cardiomyopathy. Unlike most other CDG, PGM1‐CDG has an effective treatment option, d ‐galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1‐CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow‐up, and management guidelines for PGM1‐CDG. These guidelines are based on the best available evidence‐based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1‐CDG patients.

Abstract Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li–Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G&gt;C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G&gt;C probands and one c.1000G&gt;A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G&gt;C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G&gt;C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. Significance: TP53 c.1000C&gt;G;p.G334R is a pathogenic, Ashkenazi Jewish–predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.

Abstract Background: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. Methods: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. Results: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10−4), KRT16 (PG×E = 2.3 × 10−4), CD14 (PG×E = 9.38 × 10−4), and CYP27A1 (PG×E = 1.44 × 10−3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10−5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR &lt; 0.2. Conclusions: By incorporating functional information, we discovered several novel genes that interacted with NSAID use. Impact: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.

Abstract Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring ≥2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q &lt; .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, ∼50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.

Background: Financial distress from medical treatment is an increasing concern. Healthcare organizations may have different levels of organizational commitment, existing programs, and expected outcomes of screening and management of patient financial distress. Patients and Methods: In November 2018, representatives from 17 (63%) of the 27 existing NCCN Member Institutions completed an online survey. The survey focused on screening and management practices for patient financial distress, perceived barriers in implementation, and leadership attitudes about such practices. Due to the lack of a validated questionnaire in this area, survey questions were generated after a comprehensive literature search and discussions among the study team, including NCCN Best Practices Committee representatives. Results: Responses showed that 76% of centers routinely screened for financial distress, mostly with social worker assessment (94%), and that 56% screened patients multiple times. All centers offered programs to help with drug costs, meal or gas vouchers, and payment plans. Charity care was provided by 100% of the large centers (≥10,000 unique annual patients) but none of the small centers that responded (<10,000 unique annual patients; P =.008). Metrics to evaluate the impact of financial advocacy services included number of patients assisted, bad debt/charity write-offs, or patient satisfaction surveys. The effectiveness of institutional practices for screening and management of financial distress was reported as poor/very poor by 6% of respondents. Inadequate staffing and resources, limited budget, and lack of reimbursement were potential barriers in the provision of these services. A total of 94% agreed with the need for better integration of financial advocacy into oncology practice. Conclusions: Three-fourths of NCCN Member Institutions reported screening and management programs for financial distress, although the actual practices and range of services vary. Information from this study can help centers benchmark their performance relative to similar programs and identify best practices in this area.

The vaginal microbiome is a critical component of women’s sexual and reproductive health, with variations in microbial composition, particularly the loss of Lactobacillus species, being implicated in gynecologic and obstetric diseases. Given that the vaginal microbiome is so crucial, why do vaginal microbial profiles vary strikingly from person to person and even change over time within the same person? In the present study, which tracked the daily vaginal microbiomes of young healthy women through different lifestyles, we found that use of a locally released progestin contraceptive, a vegetarian diet, and intense exercise appear to lead to vaginal microbiome alterations and loss of Lactobacillus species. The impact of these vaginal microbiome changes on immediate and long-term health remain to be investigated.