Misattributed parentage as an unanticipated finding during exome/genome sequencing: current clinical laboratory practices and an opportunity for standardization.

PURPOSE: Clinical laboratories performing exome or genome sequencing (ES/GS) are familiar with the challenges associated with proper consenting for and reporting of medically actionable secondary findings based on recommendations from the American College of Medical Genetics and Genomics (ACMG). Misattributed parentage is another type of unanticipated finding a laboratory may encounter during family-based ES/GS; however, there are currently no professional recommendations related to the proper consenting for and reporting of misattributed parentage encountered during ES/GS. METHODS: We surveyed 10 clinical laboratories offering family-based ES/GS regarding their consent language, discovery, and reporting of misattributed parentage. RESULTS: Many laboratories have already developed their own practices/policies for these issues, which do not necessarily agree with those from other labs. CONCLUSION: There are several other possibilities besides true misattributed parentage that could result in similar laboratory findings, and laboratories often feel they lack sufficient information to make formal conclusions on a report regarding the true genetic relatedness of the submitted samples. However, understanding the genetic relatedness (or lack thereof) of the samples submitted for family-based ES/GS has medical relevance. Therefore, professional recommendations for the appropriate handling of suspected misattributed parentage encountered during ES/GS are needed to help standardize current clinical laboratory practices.

Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing-based diagnostic testing and interpretation.

PURPOSE: With next generation sequencing technology improvement and cost reductions, it has become technically feasible to sequence a large number of genes in one diagnostic test. This is especially relevant for diseases with large genetic and/or phenotypic heterogeneity, such as hearing loss. However, variant interpretation remains the major bottleneck. This is further exacerbated by the lack in the clinical genetics community of consensus criteria for defining the evidence necessary to include genes on targeted disease panels or in genomic reports, and the consequent risk of reporting variants in genes with no relevance to disease. METHODS: We describe a systematic evidence-based approach for assessing gene-disease associations and for curating relevant genes for different disease aspects, including mode of inheritance, phenotypic severity, and mutation spectrum. RESULTS: By applying this approach to clinically available hearing loss gene panels with a total of 163 genes, we show that a significant number (45%) of genes lack sufficient evidence of association with disease and thus are expected to increase uncertainty and patient anxiety, in addition to intensifying the interpretation burden. Information about all curated genes is summarized. Our retrospective analysis of 539 hearing loss cases tested by our previous OtoGenomeV2 panel demonstrates the impact of including genes with weak disease association in laboratory wet-bench and interpretation processes. CONCLUSION: Our study is, to our knowledge, the first to highlight the urgent need for defining the clinical validity of gene-disease relationships for more efficient and accurate clinical testing and reporting.Genet Med 18 6, 545-553.

The spectrum of FBN1, TGFßR1, TGFßR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD).

INTRODUCTION: In this study, patients suspected of having a clinical diagnosis of Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS) and Thoracic Aortic Aneurysms and Dissections (TAAD) were referred for genetic testing and examined for mutations in the FBN1, TGFßR1, TGFßR2 and ACTA2 genes. METHODS: We examined 594 samples from unrelated individuals and different combinations of genes were sequenced, including one or more of the following: FBN1, TGFßR1, TGFßR2, ACTA2, and, in some cases, FBN1 was analyzed by MLPA to detect large deletions. RESULTS: A total of 112 patients had a positive result. Of those, 61 had a clinical diagnosis of MFS, eight had LDS, three had TAAD and 40 patients had clinical features with no specific diagnosis provided. A total of 44 patients had an inconclusive result; of these, 12 patients were referred with a clinical diagnosis of MFS, 4 with LDS and 9 with TAAD and 19 had no clinical diagnosis. A total of 89 mutations were novel. CONCLUSION: This study reveals the rate of detection of variants in several genes associated with MFS, LDS and TAAD. The evaluation of patients by individuals with expertise in the field may decrease the likelihood of ordering unnecessary molecular testing. Nevertheless, genetic testing supports the diagnosis of MFS, LDS and TAAD.

Anchors Aweigh! The History of Women Surgeons at Sea.

Throughout history, the maritime nations of the world have employed surgeons in sea-going service. The history of women in surgery and the military is well described, but no previous report exists describing the gender breakdown of past and current sea-going US Navy general surgeons. Using literature review, primary sources, personal interviews, and correspondence with Navy Medicine administrative leaders, this historical review describes the evolution of women providing surgical care at sea. During the 1800s and early 1900s, some of the earliest women surgeons in England, America, and Russia began their surgical careers in military service or providing combat casualty care. Women at sea served unpaid nursing roles in the 1700s and provided informal medical care in the 1800s. In 1913 and 1941, 2 different women held medical leadership roles aboard sea-going vessels. Four years after Congress allowed women to serve aboard combatant vessels, Dr Beth Jaklic became the first woman to serve as Ship's Surgeon aboard a US Navy warship in 1997. From 1997 to 2020, 19% of surgeons serving on aircraft carriers were women and one-half of the 20 general surgeons assigned to maritime surgical billets were women in 2022. War and the military environment historically have offered opportunities for women to break boundaries in the world of surgery. Navy Medicine's experience with women surgeons at sea serves as a positive example to the broader surgical community, especially "austere" practices and subspecialties with limited female representation.

Does Liposomal Bupivacaine Decrease Postoperative Opioid Use in Conjunction with an Enhanced Recovery After Bariatric Surgery Pathway? A Prospective, Double-blind, Randomized Controlled Trial.

BACKGROUND: Minimization of opiate use is an important focus in the setting of the severe national opioid crisis. This study evaluated the role of liposomal bupivacaine (LB) in decreasing postoperative opioid use before and after implementation of a bariatric enhanced recovery after surgery (ERAS) program. METHODS: We performed an IRB-approved, prospective, double-blind, randomized controlled trial of LB versus plain bupivacaine (PB) in patients undergoing elective, minimally invasive, weight loss surgery at a comprehensive metabolic and bariatric surgery program from November 2017 to December 2019. Primary outcomes were postoperative morphine milligram equivalents per day (MME/day) and average subjective inpatient pain level. Secondary outcomes were length of hospital stay (LOS) and adverse events (AEs). RESULTS: Of the 100 patients enrolled, 78 were randomly assigned to LB (42) or PB (36). Thirty-four received the ERAS protocol, and 44 did not. The mean MME/day use did not differ significantly by the bupivacaine group [median, IQR PB: 20.3 (40.95); LB: 33.0 (42.9); p = .314], but it did differ by the ERAS group [median, IQR no ERAS 33.2 (47.1), ERAS 24.0 (34.0); p = .049]. Length of stay, inpatient pain score, and AEs did not differ significantly by either the bupivacaine or the ERAS group. CONCLUSIONS: In our study, liposomal bupivacaine did not significantly decrease postoperative opioid use either before implementation of ERAS or as part of an enhanced recovery after surgery program for minimally invasive bariatric surgery procedures.

The GeneInsight Suite: a platform to support laboratory and provider use of DNA-based genetic testing.

The future of personalized medicine will hinge on effective management of patient genetic profiles. Molecular diagnostic testing laboratories need to track knowledge surrounding an increasingly large number of genetic variants, incorporate this knowledge into interpretative reports, and keep ordering clinicians up to date as this knowledge evolves. Treating clinicians need to track which variants have been identified in each of their patients along with the significance of these variants. The GeneInsight(SM) Suite assists in these areas. The suite also provides a basis for interconnecting laboratories and clinicians in a manner that increases the scalability of personalized medicine processes.

An Analysis of Essential Pediatric Surgical Cases Encountered During a Decade of Large-Scale Military Humanitarian Aid Missions.

INTRODUCTION: Disease Control Priorities, 3rd Edition (DCP3) is an evidence-based, published resource that outlines essential procedures recommended for developing health care systems. These systems must consider various populations and the incidence of certain surgical conditions that require treatment. In relation to pediatric patients, the prevalence of certain surgical conditions encountered remains unclear in several low- and middle-income countries. Over the past 15 years, the USNS Mercy, one of the U.S. Navy's large hospital ships, has led the Pacific Partnership missions, which provide large-scale humanitarian aid throughout Southeast Asia. The data collected during these missions provide an opportunity to analyze the scope of pediatric operations performed in resource-limited countries. This analysis may assist in future planning for specific needs during military humanitarian missions. MATERIALS AND METHODS: Surgical case data were prospectively collected during the six Pacific Partnership missions from 2006 to 2018. Demographic data were analyzed for all patients ≤8 years of age who underwent an operation. These data were retrospectively reviewed and all case logs were categorized by mission year, procedure-type, and host nation. Operations were classified based on 44 essential operations delineated in DCP3. Primary outcome was incidence of DCP3 essential operations. Secondary outcomes were perioperative complications. Standard statistical methods were performed for descriptive analysis. RESULTS: A total of 3,209 major and minor operations were performed during 24 port visits in nine countries. Pediatric cases represented 1,117 (38%) of these procedures. Pediatric surgeons performed 291 (26%) of these cases. Based on DCP3 criteria, 789 pediatric operations (71%) were considered essential procedures. The most common DCP3-aligned procedures were cleft lip repair (432, 57%), hernia repair (207, 27%), and hydrocelectomy (60, 8%). Operative volume for pediatric surgery was highest during the 2008 mission (522 cases), when two pediatric surgeons were deployed, and lowest during the 2018 mission (five cases), when the mission focus was on education rather than surgical procedures and lack of pediatric cases referred by the host nation. Overall complication rate for pediatric cases was 1%. CONCLUSIONS: This study represents the largest known analysis of military humanitarian assistance. Pediatric operations represented over one-third of the surgical volume during Pacific Partnership missions from 2006 to 2018. The majority of cases were DCP3-aligned and associated with a low complication rate. Future humanitarian aid missions and host nations should allocate appropriate medical and educational resources to treat DCP3 pediatric surgical diseases in low- and middle-income countries to support long-term capacity building while maintaining optimal surgical outcomes.

Effect of biochar amendment on sorption-desorption and dissipation of 17α­ethinylestradiol in sandy loam and clay soils.

Animal manure application in agricultural land has caused the release of steroid estrogens in the soil environment and further movement to aquatic systems. The objective of this study was to investigate the effects of biochar addition on sorption-desorption and dissipation behaviors of 17α­ethinylestradiol (EE2) in two different textured soils. A Commerce sandy loam and a Shakey clay were selected and subjected to sterilization. Soil samples with and without sterilization were reacted with a series of EE2 solutions of different concentrations for sorption followed by desorption and quantification using HPLC-MS/MS. Long-term dissipation of EE2 in the same soils was also evaluated over a 30-d incubation. Biochar amendment increased the maximum EE2 sorption capacity but decreased its water desorption in both sandy loam and clay soils. On other hand, biochar addition increased the Koc in the clay soil which had low EE2 sorption efficiency but decreased Koc in the sandy loam which had high EE2 sorption efficiency. Biochar did significantly increase both desorbable and non-extractable fractions of EE2, while it reduced the bioavailability of EE2 to microbial degradation. The dissipation of EE2 in non-sterilized soils fit to the first-order kinetic model, whereas it was better described by zero-order kinetic for sterilized soil. Biochar increased the half-life of EE2 dissipation in non-sterilized Commerce sandy loam soil by 48% (from 3.63 to 5.37 d) and in non-sterilized Sharkey clay soil by 67% (from 2.28 to 3.81 d). Overall, this study demonstrated positive impacts of biochar on the retention of estrogen hormones in soils.

Sustaining Screening, Brief Intervention and Referral to Treatment (SBIRT) services in health-care settings.

AIMS: To assess the sustainability of Screening, Brief Intervention and Referral to Treatment (SBIRT) services after cessation of initial start-up funding. DESIGN: Descriptive study with quantitative and qualitative data collected from 34 staff participants from six grantees (comprising 103 sites) funded previously through a large, federally supported SBIRT program. SETTING: Primary care out-patient clinics and hospitals in the United States. PARTICIPANTS: Thirty-four grantee-related staff members, including administrators, evaluators, key stakeholders and SBIRT service providers from six grantees. MEASUREMENTS: Changes to levels and types of service delivery activities after federal funding stopped, alternative sources of funding and obstacles to delivery of services. FINDINGS: Of the 103 original sites in the six SBIRT grantee programs, 69 sites continued providing services in some capacity (same as before, reduced, modified or expanded). Most of the 69 sites (67%) adapted and redesigned the delivery of SBIRT services post-initial grant funding. In addition, new sites were added after grant funding ended, bringing the total number of sites to 88. Analysis of participant responses identified four primary factors that influenced SBIRT sustainability: presence of champions, funding availability, systemic change and SBIRT practitioner characteristics. CONCLUSIONS: Almost 70% of the Screening, Brief Intervention and Referral to Treatment (SBIRT) services in the United States funded initially through a federal program were able to sustain operations after federal funding ceased and some expanded SBIRT services beyond the original sites. The key factors related to sustainability were securing new funding, having champions, adapting and making system changes and managing program staffing challenges.

The Spectrum of Psychiatric Pathology in a Patient with Genetically Verified Huntington's Disease.

Psychiatric and behavioral disturbances are common in Huntington's disease (HD) and contribute significantly to its morbidity and mortality. We herein present the case of a 43-year-old woman with genetically verified HD, whose deteriorating psychiatric condition necessitated multiple inpatient psychiatric hospitalizations and featured a clinical spectrum of neuropsychiatric disturbances classically associated with HD. This paper reviews the literature concerning Huntington's psychopathology and provides an illustrative case example of its clinical nature.

Systemic effects of thiamethoxam and chlorantraniliprole seed treatments on adult Lissorhoptrus oryzophilus (Coleoptera: Curculionidae) in rice.

BACKGROUND: Feeding assays using adult rice water weevils and foliage of plants treated as seeds with chlorantraniliprole and thiamethoxam at different rates were conducted to evaluate the systemic adulticidal and feeding effects. Dose-mortality relationships were determined for thiamethoxam seed treatments by combining leaf area lost due to feeding and insecticide residues analyzed by LC/MS/MS. Changes in adulticidal activity of thiamethoxam were also investigated by contrasting adult mortalities at the 5-6-leaf and tillering stages of rice. RESULTS: Adult weevil mortalities and leaf consumption rates on foliage were affected in thiamethoxam but not in chlorantraniliprole treatments when rice was at the 6-7-leaf stage. The LD(50) for weevils feeding on thiamethoxam-treated rice at the 2-3-leaf stage was 447 pg insecticide weevil(-1) (95% CL: 25-830 pg weevil(-1)) but was lower (142 pg weevil(-1); 95% CL: 102-180 pg weevil(-1)) in experiments with 3-4-leaf-stage plants. Mortalities on leaves from 5-6-leaf-stage plants were consistently higher than on leaves from tillering plants. Thiamethoxam residues measured by ELISA increased with seed treatment rate and differed between plant stages. CONCLUSION: The LD(50) values developed in this study are the first values for leaf-feeding insects on foliage of plants treated as seeds with thiamethoxam. The attrition of adulticidal activity of thiamethoxam in foliage of older plants may help to explain the reduced effectiveness of seed treatments against rice water larvae that is seen at later stages of rice growth in field studies. The differential activity of these two seed treatments on adults suggests that adult mortality contributes to the field efficacy of thiamethoxam but not to that of chlorantraniliprole.

Effect of redox potential and pH status on degradation and adsorption behavior of tylosin in dairy lagoon sediment suspension.

Veterinary antibiotics are the most heavily used pharmaceuticals in intensive animal farming operation. Their presence in the environment through application of manure and lagoon water as fertilizer in agricultural fields has generated a growing concern in recent years due to potential threat to the ecosystem and the risk they pose to human and animal health. Among the antibiotics, tylosin, a macrolide class of antibiotics, has been widely used for disease prevention and growth promotion in swine, cattle/dairy, and poultry production. To understand degradation and sorption behavior of tylosin A, a laboratory microcosm incubation study was conducted on dairy lagoon sediments suspension under different pH (5.5, 7.0, 8.5) and redox potentials (Eh at -100 mV, 0 mV, +250 mV, +350 mV). Sorption and degradation of tylosin was strongly influenced by sediment pH and redox conditions. Under acidic (pH 5.5) and reduced (Eh -100 mV) condition, tylosin persisted in the solution phase of dairy lagoon sediment suspension much longer with resident time of 77 d. Under oxidized (Eh +350 mV) condition, microbial degradation was much greater causing 68-75% of tylosin loss from the solution at pH 5.5 and 32-75% at pH 7.0 during the 20 d incubation. At pH 8.5, abiotic transformation of tylosin A into unknown degradates rather than sediment adsorption and microbial degradation was the major mechanism controlling tylosin disappearance from the solution regardless of the status of redox potentials. Overall, the results suggested that under reduced condition with low pH, tylosin will be persisted in the lagoon effluents and residue of tylosin may enter agricultural fields through the application of lagoon slurry as fertilizer.

Bioactives of Artemisia dracunculus L. mitigate the role of ceramides in attenuating insulin signaling in rat skeletal muscle cells.

Ectopic lipids in peripheral tissues have been implicated in attenuating insulin action in vivo. The botanical extract of Artemisia dracunculus L. (PMI 5011) improves insulin action, yet the precise mechanism is not known. We sought to determine whether the mechanism by which PMI 5011 improves insulin signaling is through regulation of lipid metabolism. After differentiation, cells were separately preincubated with free fatty acids (FFAs) and ceramide C2, and the effects on glycogen content, insulin signaling, and ceramide profiles were determined. The effect of PMI 5011 on ceramide accumulation and ceramide-induced inhibition of insulin signaling was evaluated. FFAs resulted in increased levels of total ceramides and ceramide species in L6 myotubes. Saturated FFAs and ceramide C2 inhibited insulin-stimulated phosphorylation of protein kinase B/Akt and reduced glycogen content. PMI 5011 had no effect on ceramide formation or accumulation but increased insulin sensitivity via restoration of Akt phosphorylation. PMI 5011 also attenuated the FFA-induced upregulation of a negative inhibitor of insulin signaling, i.e., protein tyrosine phosphatase 1B (PTP1B), and increased phosphorylation of PTP1B. PMI 5011 attenuates the reduction in insulin signaling induced by ceramide accumulation, but the mechanism of improved insulin signaling is independent of ceramide formation.

Factors That Influence HIV Risk among Hispanic Female Immigrants and Their Implications for HIV Prevention Interventions.

Hispanics are the fastest growing minority group in North Carolina with increasing incidence of HIV infection. Gender roles, cultural expectations, and acculturation of women may explain some of Hispanic women's risks. The perspectives of Hispanic female immigrants and community-based providers were sought to identify services they offer, understand HIV risk factors, and support the adaptation of a best-evidence HIV behavioural intervention for Hispanic women. Two sets of focus groups were conducted to explicate risks and the opportunities to reach women or couples and the feasibility to conduct HIV prevention in an acceptable manner. Salient findings were that Hispanic female immigrants lacked accurate HIV/AIDS and STI knowledge and that traditional gender roles shaped issues surrounding sexual behaviour and HIV risks, as well as condom use, partner communication, and multiple sexual partnerships. Intervention implications are discussed such as developing and adapting culturally appropriate HIV prevention interventions for Hispanics that address gender roles and partner communication.