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ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

Background Black patients are diagnosed with melanoma at a later stage, as compared with their white counterparts. It is unknown if Medicaid expansion might ameliorate this disparity. Methods Using data from the 2016 National Cancer Database, we conducted a retrospective cohort study. The primary objective was to evaluate whether being diagnosed with melanoma at a Medicaid Expansion State (MES) and black race are associated with a late diagnosis of melanoma. Main exposure: Being diagnosed in a MES. Secondary exposure: Race. Main outcome: Odds of Stage IV vs Stages 0-III at diagnosis. Univariate, multivariate logistic regression, and propensity score analyses were conducted to evaluate the potential associations. Sub-group analysis was conducted according to age Results A total of 216,604 patients were included, 40-90 years of age, [Formula: see text] 64 years [SD 12.47]. In univariate analysis, patients diagnosed in MES were 15% less likely (95% CI, 0.81-0.88) to be diagnosed with Stage IV melanoma. Black race (vs white) had 3.04 increased odds (95% CI, 2.56-3.60) of late diagnosis. In multivariate analysis, adjusting for socio-economic confounders, patients Conclusions This study suggests that patients are less likely to be diagnosed with Stage IV melanoma in MES. This beneficial effect is more pronounced among Black minorities.

Heterotopic heart transplantation (HHT) is rare in the modern era. When used as a biologic left ventricular assist, HHT provides pulsatile flow, supports the left ventricle with a physiologic cardiac output, responds to humoral stimuli, and with modern immunosuppression may offer long-term untethered survival. This study was undertaken to compare survival of HHT with orthotopic heart transplantation (OHT) to assess its viability in the modern era. In the United Network for Organ Sharing database, from January 1999 to December 2020, there were 27691 bicaval OHT, 13836 biatrial OHT, 1271 total OHT, and 51 HHT with sufficient follow-up. Survival was analyzed using restricted mean survival time (RMST) through 4 years as the outcome. In the first 4 years after transplant, compared with HHT, differences in RMST were 0.1 years (99% CI: -0.4 to 0.5 years) for bicaval OHT, 0.0 years (99% CI: -0.4 to 0.5 years) for biatrial OHT, and 0.0 years (99% CI: -0.5 to 0.4 years) for total OHT. In this cohort, survival was indistinguishable between HHT and OHT recipients in the first four years. Thus, HHT might be a viable alternative to durable mechanical circulatory assist particularly with size mismatched grafts or for patients with refractory pulmonary hypertension.

Background Respiratory infections are one of the most common causes of morbidity and mortality. This study examined antimicrobial susceptibility of common respiratory isolates from veterans. Methods Sputum culture data from the Veteran Health Administration were obtained retrospectively between January 2009 and 2019. Cumulative antibiograms were constructed for bacterial isolate susceptibility. Results Sputum and bronchial cultures from approximately 10,345 veterans were included each year. Haemophilus influenzae has maintained high levels of susceptibility to third generation cephalosporins from 2009 (99.7%) to 2018 (97.2%). Third generation cephalosporin susceptibilities amongst Klebsiella pneumoniae have trended upward from 2009 to 2018 as well (79.1% vs 86.4%). In Pseudomonas aeruginosa isolates, there has been an increase in susceptibility rates to cefepime from 2009 to 2018 (79.6%, to 86.6%), gentamicin (81.5% to 89.1%), and piperacillin/tazobactam (86.5% to 90%). Fluoroquinolone susceptibilities amongst Escherichia coli have remained low but stable between 2009 and 2018. Third generation cephalosporin susceptibilities for S. pneumoniae improved slightly from 92.2% to 95% between 2009 and 2018 while susceptibility to azithromycin trended down slightly from 56.8% in 2009 to 51.7% in 2018 for S. pneumoniae. Discussion The antibiogram of sputum isolates from the VA Healthcare System were examined to determine changes in patterns of resistance over a decade of use. Conclusions This large-scale study investigated nationwide sputum culture susceptibility trends. Avoidance of macrolides for empiric treatment of community acquired pneumonia and avoidance of fluoroquinolones for empiric treatment of hospital acquired or ventilator associated pneumonia may be warranted based on susceptibility trends.

Background: Veterans have a higher incidence of sexually transmitted infections (STIs) compared to the general population. The objective of this study is to evaluate the association of societal factors on the risk of chlamydia or gonorrhea. Methods: This retrospective cohort study evaluated data from Veteran Health Administration. Patients tested for chlamydia or gonorrhea between January 2009 and January 2019 were included. Descriptive statistics and regression were used to evaluate societal factors. Results: A total of 1,232,173 tests for chlamydia or gonorrhea were performed. There were 51,987 (4.2%) positive cases with 74.18% for chlamydia and 24.96% for gonorrhea. In 13.6% of veterans with reported military sexual trauma, there was no difference in risk of positivity ( p = 0.39). Veterans with a history of combat had lower odds of testing positive (OR, 0.94; 95% CI, 0.91–0.97). Tests in veterans who were married had a 24% less chance of positivity (OR, 0.76; 95% CI, 0.74–0.79) compared to tests in divorced veterans. Positive number of cases increased each year. Conclusion: Sexually transmitted infections are a growing concern. Gender, age, ethnicity, marital status, and race are societal identifiers which influence likelihood of STI acquisition.

Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.

CONTEXT: This scoping review examines the current research on the effect of cannabis upon pain intensity in spinal cord injury (SCI) pain. Chronic pain is a significant secondary condition following SCI, and traditional treatments (e.g. opioids, NSAIDs) are often criticized for providing inadequate relief. As a result, there is increasing interest in and use of cannabis and cannabinoid-based medications as an alternative means of pain control. OBJECTIVE: The purpose of this review was to examine the scientific evidence on the effect of cannabis/cannabinoids upon pain intensity in SCI by mapping the current literature. METHODS: Two hundred and fifty-two studies were identified by searching electronic databases for articles published through February 2020. In addition, reviewers scanned the reference lists of identified articles and examined clinicaltrials.gov for unpublished data in this area. Title, abstract, and full-text reviews were completed by two independent reviewers. Data extraction was performed by a single reviewer and verified by a second reviewer. RESULTS: Six articles covering five treatment studies were included. Studies yielded mixed findings likely due to large variability in methodology, including lack of standardized dosing paradigms, modes of use, and duration of trial. CONCLUSIONS: The current quality and level of evidence is insufficient to draw reliable conclusions of the efficacy of cannabis upon SCI-related pain itensity. We identify specific limitations of past studies and present guidelines for future research. Trial registration: ClinicalTrials.gov identifier: Nct01606202..

Background The goals of this study were to determine whether serum concentrations of endocannabinoids (eCB) and related lipids predict disease status in patients with amyotrophic lateral sclerosis (ALS) relative to healthy controls, and whether concentrations correlate with disease duration and severity. Methods Serum concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), and related lipids palmitoylethanolamine (PEA), oleoylethanolamine (OEA), and 2-oleoylglycerol (2-OG), were measured in samples from 47 patients with ALS and 19 healthy adults. Hierarchical binary logistic and linear regression analyses assessed whether lipid concentrations predicted disease status (ALS or healthy control), duration, or severity. Results Binary logistic regression revealed that, after controlling for age and gender, 2-AG, 2-OG and AEA concentrations were unique predictors of the presence of ALS, demonstrating odds ratios of 0.86 (P = .039), 1.03 (P = .023), and 42.17 (P = .026), respectively. When all five lipids and covariates (age, sex, race, ethnicity, body mass index, presence of a feeding tube) were included, the resulting model had an overall classification accuracy of 92.9%. Hierarchical linear regression analyses indicated that in patients with ALS, AEA and OEA inversely correlated with disease duration (P = .030 and .031 respectively), while PEA demonstrated a positive relationship with disease duration (P = .013). None of the lipids examined predicted disease severity. Conclusions These findings support previous studies indicating significant alterations in concentrations of circulating lipids in patients with ALS. They suggest that arachidonic and oleic acid containing small lipids may serve as biomarkers for identifying the presence and duration of this disease.

Background Ampullary stenosis following Roux-en-Y gastric bypass (RYGB) is increasingly encountered. We describe cases of biliary obstruction from ampullary stenosis and choledocholithiasis to illustrate the associated diagnostic and interventional challenges with this condition. Methods We reviewed medical records of patients with prior RYGB who underwent a biliary access procedure or surgery for non-malignant disease from January 2012–December 2018. Results We identified 15 patients (4 male, 11 female; mean age 53.7 years) who had RYGB on average 11.7 years (range 1–32) years before diagnosis of biliary obstruction. Fourteen patients reported abdominal pain, 5 had nausea/emesis, 12 had elevated liver function tests, and 6 had ascending cholangitis. Mean common bile duct (CBD) diameter at presentation was 16.9 mm (range 4.0–25.0 mm). Operations included 3 transduodenal ampullectomies (2 with biliary bypass), 2 CBD explorations with stone extraction, 1 laparoscopic cholecystectomy alone, 1 Whipple procedure, 1 balloon enteroscopy with sphincterotomy, and 7 transgastric endoscopic retrograde cholangiopancreatography. All ampulla pathology was benign in patients who underwent resection. At follow-up (mean 15.4 months; range 0.23–44.5 months), 12/15 (80%) reported symptom resolution or improvement. Discussion Ampullary stenosis after RYGB presents challenges for diagnostic evaluation and intervention, often requiring multi-disciplinary expertise. The underlying pathology remains to be elucidated.

BACKGROUND Postinjury hypercoagulability occurs in >25% of injured patients, increasing risk of thromboembolic complications despite chemoprophylaxis. However, few clinically relevant animal models of posttraumatic hypercoagulability exist. We aimed to evaluate a rodent model of bilateral hindlimb injury as a preclinical model of postinjury hypercoagulability. METHODS Forty Wistar rats were anesthetized with isoflurane: 20 underwent bilateral hindlimb fibula fracture, soft tissue and muscular crush injury, and bone homogenate injection intended to mimic the physiological severity of bilateral femur fracture. Twenty sham rats underwent anesthesia only. Terminal citrated blood samples were drawn at 0, 6, 12, and 24 hours (n = 5 per timed group) for analysis by native thromboelastography in the presence and absence of taurocholic acid to augment fibrinolysis. Plasminogen activator inhibitor 1 and α-2 antiplasmin levels in plasma were assessed via enzyme-linked immunosorbent assay. RESULTS Injured rats became hypercoagulable relative to baseline by 6 hours based on thromboelastography maximal amplitude (MA) and G (p < 0.005); sham rats became hypercoagulable to a lesser degree by 24 hours (p < 0.005). Compared with sham animals, injured rats were hypercoagulable by MA and G within 6 hours of injury, remained hypercoagulable by MA and G through at least 24 hours (all p < 0.01), and showed impaired fibrinolysis by taurocholic acid LY30 at 12 hours (p = 0.019) and native LY30 at 24 hours (p = 0.045). In terms of antifibrinolytic mediators, α-2 antiplasmin was elevated in trauma animals at 24 hours (p = 0.009), and plasminogen activator inhibitor 1 was elevated in trauma animals at 6 hours (p = 0.004) and 12 hours (p < 0.001) when compared with sham. CONCLUSIONS Orthopedic injury in rodents induced platelet and overall hypercoagulability within 6 hours and fibrinolytic impairment by 12 to 24 hours, mimicking postinjury hypercoagulability in injured patients. This rodent model of orthopedic injury may serve as a preclinical testing ground for potential therapies to mitigate hypercoagulability, maintain normal fibrinolysis, and prevent thromboembolic complications.

Angelman syndrome (AS) is a genetic neurodevelopmental disorder caused by loss or deficient expression of UBE3A on the maternally inherited allele. In 10-15% of individuals with a clinical diagnosis of AS, a molecular diagnosis cannot be established with conventional testing. We describe a 13-year-old male with an atypical presentation of AS, who was found to have a novel, maternally inherited, intronic variant in UBE3A (c.3-12T>A) using genome sequencing (GS). Targeted sequencing of RNA isolated from blood confirmed the creation of a new acceptor splice site. These GS results ended a six-year diagnostic odyssey and revealed a 50% recurrence risk for the unaffected parents. This case illustrates a previously unreported splicing variant causing AS. Intronic variants identifiable by GS may account for a proportion of individuals who are suspected of having well-known genetic disorders despite negative prior genetic testing.

There is substantial and ongoing debate regarding the centrality of Fearless Dominance/Boldness (FD/B) to psychopathic personality due, in part, to its generally weak relations with externalizing behaviors. In response to these findings, proponents of FD/B have offered two hypotheses. First, FD/B may have nonlinear associations with externalizing outcomes such that FD/B may lead to resilience at moderate levels, but an overabundance of FD/B will yield maladaptive behavioral outcomes. Second, FD/B may be related to antisocial outcomes when paired with high scores on other psychopathic traits such as self-centered impulsivity, meanness, or disinhibition. The current study tests these two possibilities using two large samples (Study 1: 787 undergraduates; Study 2: 596 Amazon’s Mechanical Turk participants). An item response theory scoring approach particularly sensitive to curvilinearity was used to maximize our ability to find a true curvilinear effect, if present. No evidence in favor of the curvilinearity hypothesis was found. Only a single significant interaction predicting substance use was observed between boldness and meanness. These findings contribute to a growing literature raising concerns regarding the relevance of FD/B to psychopathy.

Tatton-Brown Rahman syndrome (TBRS) is an overgrowth-intellectual disability syndrome caused by heterozygous variants in DNMT3A. Seventy-eight individuals have been reported with a consistent phenotype of somatic overgrowth, mild to moderate intellectual disability, and similar dysmorphisms. We present six individuals with TBRS, including the youngest individual thus far reported, first individual to be diagnosed with tumor testing and two individuals with variants at the Arg882 domain, bringing the total number of reported cases to 82. Patients reported herein have additional clinical features not previously reported in TBRS. One patient had congenital diaphragmatic hernia. One patient carrying the recurrent p.Arg882His DNMT3A variant, who was previously reported as having a phenotype due to a truncating variant in the CLTC gene, developed a ganglioneuroblastoma at 18 months and T-cell lymphoblastic lymphoma at 6 years of age. Four patients manifested symptoms suggestive of autonomic dysfunction, including central sleep apnea, postural orthostatic hypotension, and episodic vasomotor instability in the extremities. We discuss the molecular and clinical findings in our patients with TBRS in context of existing literature.

Objective To examine mortality and hospital readmission rates in male veterans with dementia diagnosed with urinary tract infection (UTI) compared with patients without dementia. Design Retrospective cohort study. Setting Veterans Healthcare Systems (VA). Participants Male inpatients with a diagnosis of UTI who were treated at any VA Healthcare Center from January 1, 2009, to December 31, 2018. Interventions None. Main Outcome Measures Mortality and hospital readmission for patients with and without dementia at 30, 60, and 90 days from UTI diagnosis. Results 262,515 veterans admitted with UTI were analyzed, and 58,940 (22.5%) had dementia. The mean age for veterans with dementia was 80.0 +/- 9.7 years. Veterans with dementia experienced less mortality than patients without dementia at 30 days (8.3% vs 8.5%; P < 0.001), but more mortality at 60-day (4.9% vs 4.7%; P < 0.001) and 90-day (3.6% vs 3.3%; P < 0.001) intervals. Death was 20% less likely at 30 days in patients with dementia. Veterans with dementia were readmitted more than those without dementia at 30-day (18.4% vs 16.0%), 60-day (4.5% vs 2.8%), and 90-day (3.4% vs 2.5%) intervals; P < 0.0001. Conclusion Though patients with dementia are at an increased risk for death long-term, risk of death is less than those without dementia shortly following UTI diagnosis. This highlights the possibility that veterans with dementia may be hospitalized and diagnosed with UTIs when in actuality they have asymptomatic bacteriuria. Patients with dementia and UTI therefore represent an important group of geriatric patients that could benefit from the oversight of a senior care pharmacist to help prevent unnecessary treatment of asymptomatic bacteriuria.

While somatic mutations in colorectal cancer (CRC) are well characterized, little is known about the accumulation of cancer mutations in the normal colon prior to cancer. Here we have developed and applied an ultra-sensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (KRAS mutations in the normal colon of about one third of patients with CRC but in none of the patients without CRC. Patients with CRC also carried more TP53 mutations than patients without cancer, and these mutations were more pathogenic and formed larger clones, especially in patients with early onset CRC. Most mutations in normal colon were different from the driver mutations in tumors suggesting that the occurrence of independent clones with pathogenic KRAS and TP53 mutations is a common event in the colon of individuals that develop CRC.SIGNIFICANCEOur results suggest a prevalent process of somatic mutation and evolution in the normal colon of patients with CRC, which can be detected by ultra-sensitive sequencing of driver genes and potentially employed clinically for CRC risk prediction.

Objective: Stroke and traumatic brain injury (TBI) are among the leading causes of disability. Even after engaging in rehabilitation, nearly half of patients with severe TBI requiring hospitalization are left with major disability. Despite decades of investigation, pharmacologic treatment of brain injury is still a field in its infancy. Recent clinical trials have begun into the use of psychedelic therapeutics for treatment of brain injury. This brief review aims to summarize the current state of the science's relevance to neurorehabilitation, and may act as a resource for those seeking to understand the precedence for these ongoing clinical trials.Methods: Narrative mini-review of studies published related to psychedelic therapeutics and brain injury.Results: Recent in vitro, in vivo, and case report studies suggest psychedelic pharmacotherapies may influence the future of brain injury treatment through modulation of neuroinflammation, hippocampal neurogenesis, neuroplasticity, and brain complexity.Conclusions: Historical data on the safety of some of these substances could serve in effect as phase 0 and phase I studies. Further phase II trials will illuminate how these drugs may treat brain injury, particularly TBI and reperfusion injury from stroke.

A 22-yr-old male sulcata tortoise (Centrochelys sulcata) presented to the Veterinary Teaching Hospital at Louisiana State University for acute swelling around the eyes, lethargy, and serous oculonasal discharge. Upon physical exam, the patient had severe bilateral chemosis, was unable to open his eyes, and was dehydrated. Because of a clinical suspicion of bacterial upper respiratory infection, the patient was started on antibiotics, an anti-inflammatory, and fluid therapy. It was also hospitalized for further diagnostics and treatment. The patient was anesthetized for bloodwork, microbiological assays, diagnostic imaging, and an ophthalmic exam. During hospitalization, fluid therapy, parenteral antibiotic administration, nebulization, esophagostomy tube placement, and bilateral subpalpebral lavage system (SPLS) placement were performed. The most significant diagnostic findings were bilateral anterior uveitis and bilateral conjunctivitis. The patient was discharged 3 days following placement of the SPLS. On re-evaluation 11 days later, the patient showed marked clinical improvement and the SPLS were removed. Subpalpebral lavage systems proved to be an effective technique for treating uveitis in this animal. Without an SPLS, topical eye medications can be difficult or impossible to administer to large tortoises.

The spatiotemporal distribution profile of polymeric nanoparticles (NPs) in the eye is important as it will determine their effectiveness as topical ocular drug delivery systems for specific eye diseases. Physical stability of the nanoparticles in an ophthalmic formulation and thermal stability of the entrapped drug are critical as well to the applicability of polymeric nanoparticles as drug delivery to the eye. To investigate these characteristics, Cy5-labeled, poly(lactic-co-glycolic acid) (PLGA) NPs (ζ-potential: -14.1±1.5 mV, size: 241.7±0.6 nm) and lutein-loaded PLGA NPs (ζ-potential: -6.7±0.3 mV, size: 210.6±3.3 nm) were synthesized, and their stability and biodistribution were assessed. Lutein-loaded NPs were stable at 4°C without significant changes in size and morphology, without significant lutein degradation, and 26% release after 5 weeks in suspension. In contrast, lutein-loaded NPs stored at 25°C and 37°C experienced significant changes in size, likely due to aggregation and surfactant dissociation; these NPs showed signs of bulk degradation based on transmission electron microscopy (TEM), and had significant lutein degradation and over 40% release after 5 weeks. Lutein loaded in NPs was more resistant to photodegradation compared to a free lutein solution when exposed to UV for 6 h, degrading 5 times slower than free lutein. To test the performance of NP therapeutics in vivo, Cy5-labled NPs were applied topically to the eyes of rats and incubated for 15 min, 30 min, or 60 min. Exterior eye tissues including the cornea, episcleral tissue, and sclera showed the highest fluorescence intensity in animals that received fluorescent nanoparticles, while the choroid was the only inner eye tissue that was significantly higher in a treatment group compared to the control group. Additionally, decreases of fluorescence in all exterior eye tissues and the choroid at 1 h compared to 30 min, indicated rapid elimination of NPs from the eye.

PTPN23 is a His-domain protein-tyrosine phosphatase implicated in ciliogenesis, the endosomal sorting complex required for transport (ESCRT) pathway, and RNA splicing. Until recently, no defined human phenotype had been associated with alterations in this gene. We identified and report a cohort of seven patients with either homozygous or compound heterozygous rare deleterious variants in PTPN23. Combined with four patients previously reported, a total of 11 patients with this disorder have now been identified. We expand the phenotypic and variation spectrum associated with defects in this gene. Patients have strong phenotypic overlap, suggesting a defined autosomal recessive syndrome caused by reduced function of PTPN23. Shared characteristics of affected individuals include developmental delay, brain abnormalities (mainly ventriculomegaly and/or brain atrophy), intellectual disability, spasticity, language disorder, microcephaly, optic atrophy, and seizures. We observe a broad range of variants across patients that are likely strongly reducing the expression or disrupting the function of the protein. However, we do not observe any patients with an allele combination predicted to result in complete loss of function of PTPN23, as this is likely incompatible with life, consistent with reported embryonic lethality in the mouse. None of the observed or reported variants are recurrent, although some have been identified in homozygosis in patients from consanguineous populations. This study expands the phenotypic and molecular spectrum of PTPN23 associated disease and identifies major shared features among patients affected with this disorder, while providing additional support to the important role of PTPN23 in human nervous and visual system development and function.

Background Obesity and high breast density both increase breast cancer risk but paradoxically are inversely related. Bariatric surgery decreases breast cancer risk, but its impact on mammographic breast density is not well understood. Objectives We investigated how mammographic density changes after bariatric surgery and whether this change is related to weight loss. Setting University of California, San Francisco Medical Center. Methods We reviewed records from 349 prospectively collected patients who underwent bariatric surgery between 2013 and 2015 and identified 42 women with pre- and postoperative screening mammograms within 1.5 years of surgery. We recorded body mass index (BMI), height and Breast Imaging Reporting and Data System density and calculated BMI loss and total weight loss. Data were analyzed in Stata 14.2. Results Average age was 54.2 years, mean preoperative BMI was 43.8 kg/m2, mean BMI lost was 30.9%, and total weight loss was 31.1% at 1.3 years. Over one-third had a change in mammographic breast density, which increased 93.3% of the time (P Conclusions Most women with a mammographic change had an increase in breast density, despite bariatric surgery being associated with reduced breast cancer risk. Baseline breast density was associated with a density change, but amount of weight loss was not. These findings suggest the metabolic effects of bariatric surgery have an effect on breast parenchyma independent of absolute BMI reduction or weight loss.

Applied psychologists commonly use personality tests in employee selection systems because of their advantages regarding incremental criterion-related validity and less adverse impact relative to cognitive ability tests. Although personality tests have seen limited legal challenges in the past, we posit that the use of personality tests might see increased challenges under the Americans with Disabilities Act (ADA) and the ADA Amendments Act (ADAAA) due to emerging evidence that normative personality and personality disorders belong to common continua. This article aims to begin a discussion and offer initial insight regarding the possible implications of this research for personality testing under the ADA. We review past case law, scholarship in employment law, Equal Employment Opportunity Commission (EEOC) guidance regarding “medical examinations,” and recent literature from various psychology disciplines—including clinical, neuropsychology, and applied personality psychology—regarding the relationship between normative personality and personality disorders. More importantly, we review suggestions proposing the five-factor model (FFM) be used to diagnose personality disorders (PDs) and recent changes in theDiagnostic and Statistical Manual of Mental Disorders(DSM). Our review suggests that as scientific understanding of personality progresses, practitioners will need to exercise evermore caution when choosing personality measures for use in selection systems. We conclude with six recommendations for applied psychologists when developing or choosing personality measures.

Neuromuscular disorders encompass a wide range of conditions often associated with a genetic component. In the present study, we report a patient with severe infantile-onset amyotrophy in whom two compound heterozygous variants in the gene CACNA1H encoding for Cav3.2 T-type calcium channels were identified. Functional analysis of Cav3.2 variants revealed several alterations of the gating properties of the channel that were in general consistent with a loss-of-channel function. Taken together, these findings suggest that severe congenital amyoplasia may be related to CACNA1H and would represent a new phenotype associated with mutations in this gene.

The GTPBP2 gene encodes a guanosine triphosphate (GTP)-binding protein of unknown function. Biallelic loss-of-function variants in the GTPBP2 gene have been previously reported in association with a neuro-ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age-related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.

MC is a 42-year-old female who was in a motor vehicle accident and suffered multiple contusions as well as a fracture of the left femur, pelvic ramus, and left orbit. Due to contusion of the brain, MC has been comatose for over a week and is on mechanical ventilation to protect her airway. There is no written declaration of surrogacy. During the admission, surgery to repair the left femoral fracture was performed and was complicated by severe blood loss. Currently, MC’s hematocrit is 24% with a hemoglobin of 7.4. The trauma team asserts that a blood transfusion would be in MC’s best interests. Since MC lacks capacity for decision making, she cannot consent to blood transfusion. Her parents are Jehovah’s Witnesses and refuse to approve blood transfusion, stating that it is against their faith. MC’s brother, however, states that MC is not a practicing Jehovah’s Witness and wants the medical team to provide the blood transfusion. The parents insist that decision making is their right; MC’s brother feels he should be making decisions. The trauma teams calls for an emergency consultation with the hospital ethics committee.

ALSUntangled reviews alternative and off-label treatments for people with ALS. Here we review light therapy. We show that it has theoretically plausible mechanisms, three flawed pre-clinical data, studies, and one incompletely documented case report supporting its use. We explain why further studies are needed to determine whether any specific light therapy protocol can help people with ALS.

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Clostridium botulinum Group I and Clostridium sporogenes are closely related bacteria responsible for foodborne, infant and wound botulism. A comparative genomic study with 556 highly diverse strains of C. botulinum Group I and C. sporogenes (including 417 newly sequenced strains) has been carried out to characterise the genetic diversity and spread of these bacteria and their neurotoxin genes. Core genome single-nucleotide polymorphism (SNP) analysis revealed two major lineages, C. botulinum Group I (most strains possessed botulinum neurotoxin gene(s) of types A, B and/or F) and C. sporogenes (some strains possessed a type B botulinum neurotoxin gene). Both lineages contained strains responsible for foodborne, infant and wound botulism. A new C. sporogenes cluster was identified that included five strains with a gene encoding botulinum neurotoxin sub-type B1. There was significant evidence of horizontal transfer of botulinum neurotoxin genes between distantly related bacteria. Population structure/diversity have been characterised, and novel associations discovered between whole genome lineage, botulinum neurotoxin sub-type variant, epidemiological links to foodborne, infant and wound botulism, and geographic origin. The impact of genomic and physiological variability on the botulism risk has been assessed. The genome sequences are a valuable resource for future research (e.g., pathogen biology, evolution of C. botulinum and its neurotoxin genes, improved pathogen detection and discrimination), and support enhanced risk assessments and the prevention of botulism.

Background A routine resting echocardiography has been suggested as a means to assess cardiac functioning and predict adverse cardiopulmonary events after bariatric surgery. Objectives To describe the findings of routine resting echocardiographs in bariatric surgical candidates over a 3-year period and correlate them with observed adverse cardiopulmonary outcomes. Setting Tertiary-care university-based referral hospital. Methods We retrospectively reviewed 422 consecutive patients who underwent a laparoscopic sleeve gastrectomy or laparoscopic gastric bypass at our center over 3 years, of whom 321 (76%) received a routine resting preoperative echocardiogram. Abnormal preoperative echocardiogram findings and patient characteristics were recorded. The primary outcome measure was the number of adverse cardiopulmonary events within 30 days of surgery, a composite measure defined as any instance of myocardial infarction, sustained hypotension, stroke, new-onset arrhythmia, heart failure, intensive care admission for cardiopulmonary monitoring, or cardiac arrest. Results Routine screening preoperative echocardiograms revealed left ventricular (LV) systolic dysfunction in 7 patients (2%), LV diastolic dysfunction in 71 patients (22%), LV hypertrophy in 73 patients (23%), wall motion abnormalities in 4 patients (1%), pulmonary hypertension in 47 patients (15%), left atrial enlargement in 45 patients (14%), and LV enlargement in 6 patients (1%). Adverse cardiopulmonary events occurred in only 4 patients, all of whom had a history of coronary revascularization, and 3 of whom had a prior myocardial infarction. No finding on the routine preoperative echocardiograms was associated with adverse cardiopulmonary events. Conclusion A routine resting preoperative echocardiography added little to the cardiopulmonary risk stratification of patients who underwent bariatric surgery. High-risk patients were identifiable based on their medical history, particularly those with a known history of coronary artery disease and coronary revascularization.

The neurotoxin formed by Clostridium botulinum Group II is a major cause of foodborne botulism, a deadly intoxication. This study aims to understand the genetic diversity and spread of C. botulinum Group II strains and their neurotoxin genes. A comparative genomic study has been conducted with 208 highly diverse C. botulinum Group II strains (180 newly sequenced strains isolated from 16 countries over 80 years, 28 sequences from Genbank). Strains possessed a single type B, E, or F neurotoxin gene or were closely related strains with no neurotoxin gene. Botulinum neurotoxin subtype variants (including novel variants) with a unique amino acid sequence were identified. Core genome single-nucleotide polymorphism (SNP) analysis identified two major lineages&mdash, one with type E strains, and the second dominated by subtype B4 strains with subtype F6 strains. This study revealed novel details of population structure/diversity and established relationships between whole-genome lineage, botulinum neurotoxin subtype variant, association with foodborne botulism, epidemiology, and geographical source. Additionally, the genome sequences represent a valuable resource for the research community (e.g., understanding evolution of C. botulinum and its neurotoxin genes, dissecting key aspects of C. botulinum Group II biology). This may contribute to improved risk assessments and the prevention of foodborne botulism.

Herpes simplex virus type-1 (HSV-1) can cause severe ocular infection and blindness. We have previously shown that the HSV-1 VC2 vaccine strain is protective in mice and guinea pigs against genital herpes infection following vaginal challenge with HSV-1 or HSV-2. In this study, we evaluated the efficacy of VC2 intramuscular vaccination in mice against herpetic keratitis following ocular challenge with lethal human clinical strain HSV-1(McKrae). VC2 vaccination in mice produced superior protection and morbidity control in comparison to its parental strain HSV-1(F). Specifically, after HSV-1(McKrae) ocular challenge, all VC2 vaccinated- mice survived, while 30% of the HSV-1(F)- vaccinated and 100% of the mock-vaccinated mice died post challenge. VC2-vaccinated mice did not exhibit any symptoms of ocular infection and completely recovered from initial conjunctivitis. In contrast, HSV-1(F)-vaccinated mice developed time-dependent progressive keratitis characterized by corneal opacification, while mock-vaccinated animals exhibited more severe stromal keratitis characterized by immune cell infiltration and neovascularization in corneal stroma with corneal opacification. Cornea in VC2-immunized mice exhibited significantly increased infiltration of CD3+ T lymphocytes and decreased infiltration of Iba1+ macrophages in comparison to mock- or HSV-1(F)-vaccinated groups. VC2 immunization produced higher virus neutralization titers than HSV-1(F) post challenge. Furthermore, VC-vaccination significantly increased the CD4 T central memory (TCM) subsets and CD8 T effector memory (TEM) subsets in the draining lymph nodes following ocular HSV-1 (McKrae) challenge, then mock- or HSV-1(F)-vaccination. These results indicate that VC2 vaccination produces a protective immune response at the site of challenge to protect against HSV-1-induced ocular pathogenesis.

Hypothenar hammer syndrome (HHS) is a vascular disorder characterized by ulnar artery thrombosis or aneurysmal formation. It is most commonly reported in middle-aged males who suffer from repetitive trauma to the palm secondary to occupational or recreational activities. Most cases of HHS can be managed conservatively; however, surgical management is typically indicated for persistent symptoms following conservative measures, imminent vascular compromise, those who fail conservative treatment, or those in imminent danger of rupture. Here we present the case of a right-handed 74-year-old female with HHS who presented with a three-week history of a mass in the hypothenar eminence of the left hand. Reportedly, the mass had appeared slowly and had no associated pain, ischemia of the distal hand, numbness, paresthesia, or changes in the overlying skin. She denied any history of a blunt or penetrating hand injury. The patient was treated surgically by removing a 2.0-cm thrombosed pseudoaneurysm of a collateral branch of the ulnar artery within the left hypothenar eminence. On follow-ups at 1, 2, and 12 weeks postoperatively, the patient's pain was found to be well-controlled. Her normal range of motion was restored, and her digits remained neurovascularly intact. This was an atypical presentation of HHS, and our review of the disorder emphasizes the importance of diagnostic reasoning in rare conditions with unusual presentations of HHS.

This chapter is an overview of the diagnosis and treatment of motor neuron disorders using amyotrophic lateral sclerosis (ALS) as the prototypical disorder. ALS is a rapidly progressive neurodegenerative disease caused by the combined loss of upper and lower motor neurons. The diagnosis of ALS can be made using the Awaji-shima criteria. Diagnostic strategies to assess ALS mimickers include imaging and laboratory studies. Current practice parameters including those of the American Academy of Neurology provide the basis for recommendations for treatment of ALS. The FDA has approved disease-modifying medications and several commonly used therapeutics are available for symptomatic treatment of dysphagia, sialorrhea, spasticity, depression, and anxiety. Rehabilitation strategies include adaptive mobility equipment, treatment of impaired communication, exercise, and restrictive lung disease management. ALS is one of a group of heterogeneous disorders within the category of motor neuron diseases. While there is no cure for ALS, symptomatic treatment provides improvement in quality of life and prolongs patient survival.

Background:Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work. Intrathecal drug administration shows promise due to close proximity of cerebrospinal fluid (CSF) to affected tissues. Development of effective intrathecal pharmaceuticals will rely on accurate models of how drugs are dispersed in the CSF. Therefore, a method to quantify these dynamics and a characterization of differences across disease states is needed. Methods:Complete intrathecal 3D CSF geometry and CSF flow velocities at six axial locations in the spinal canal were collected by T2-weighted and phase-contrast MRI, respectively. Scans were completed for eight people with ALS and ten healthy controls. Manual segmentation of the spinal subarachnoid space was performed and coupled with an interpolated model of CSF flow within the spinal canal. Geometric and hydrodynamic parameters were then gen-erated at 1 mm slice intervals along the entire spine. Temporal analysis of the waveform spectral content and feature points was also completed. Results:Comparison of ALS and control groups revealed a reduction in CSF flow magnitude and increased flow propagation velocities in the ALS cohort. Other differences in spectral harmonic content and geometric comparisons may support an overall decrease in intrathecal compliance in the ALS group. Notably, there was a high degree of vari-ability between cases, with one ALS patient displaying nearly zero CSF flow along the entire spinal canal. Conclusion:While our sample size limits statistical confidence about the differences observed in this study, it was possible to measure and quantify inter-individual and cohort variability in a non-invasive manner. Our study also shows the potential for MRI based measurements of CSF geometry and flow to provide information about the hydro-dynamic environment of the spinal subarachnoid space. These dynamics may be studied further to understand the behavior of CSF solute transport in healthy and diseased states., Fluids and Barriers of the CNS, 17 (1), ISSN:2045-8118

Contemporary personality taxonomies cast personality traits as ranging from the maladaptive (e.g., low conscientiousness) to adaptive (e.g., high conscientiousness) levels. Despite philosophical and conventional wisdom dating back to the ancients, researchers have only recently begun to uncover evidence that extreme standing on “normal” or “desirable” personality traits might be maladaptive. Here, we present an emerging perspective on why and how extreme standing on “desirable” trait continua translates into maladaptive behavior and undesirable outcomes at work and in life. An overview of the literature on the topic is presented for each trait within the five-factor model. We suggest two reasons for the lack of clarity in the empirical literature: (a) problems with statistical tests resulting from measurement error and (b) lack of breadth in the conceptualization and measurement of personality traits. We suggest that a solution to this problem is to extend trait continua to reflect maladaptive levels at both ends. We close by pointing out that a major implication of this emerging perspective indicates that many more people possess optimal personality-trait levels than previously thought and that future research needs to examine whether the question is consistent with evolutionary and neurophysiological accounts of personality science.

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

AIM The Modified Checklist for Autism in Toddlers (M-CHAT) could be appropriate for universal screening for autism spectrum disorder (ASD) at 18 months and 24 months. Validation studies, however, reported differences in psychometric properties across sample populations. This meta-analysis summarized its accuracy measures and quantified their change in relation to patient and study characteristics. METHOD Four electronic databases (MEDLINE, PsycINFO, CINAHL, and Embase) were searched to identify articles published between January 2001 and May 2016. Bayesian regression models pooled study-specific measures. Meta-regressions covariates were age at screening, study design, and proportion of males. RESULTS On the basis of the 13 studies included, the pooled sensitivity was 0.83 (95% credible interval [CI] 0.75-0.90), specificity was 0.51 (95% CI 0.41-0.61), and positive predictive value was 0.53 (95% CI 0.43-0.63) in high-risk children and 0.06 (95% CI

The American Academy of Pediatrics recommends universal screening for autism spectrum disorder at 18 and 24 months. This study compared the cost-effectiveness of universal or high-risk screening to surveillance monitoring. Simulation models estimated the costs and outcomes from birth to age 6 years. The incremental cost per child diagnosed by 36 months was $41,651.6 for high-risk screening and $757,116.9 for universal screening from the societal perspective. Universal screening may not be a cost-effective approach to increase earlier treatment initiation, as most children initiated treatment after age 60 months. Eliminating wait times resulted in more children initiated treatment by 48 months, but at a high initial cost that may be offset by future cost-savings related to better outcomes.

Introduction MRI evaluation in facioscapulohumeral muscular dystrophy (FSHD) demonstrates fatty replacement and inflammation/edema in muscle. Our previous work demonstrated short T1 inversion recovery (STIR)-hyperintense (STIR+) signal in muscle 2 years before fatty replacement. We evaluated leg muscle STIR changes and fatty replacement within 14 months. Methods FSHD subjects received 2 MRI scans of thigh and calf over a 6.9- to 13.8-month interval. Quality of life measures were collected. One Radiologist rated muscle changes on a semi-quantitative scale. Results Fifteen subjects completed longitudinal imaging. Four STIR + muscles and 3 STIR-normal (STIR-) muscles were rated as progressing to fatty tissue over the study period. Discussion STIR + muscles with confluent regions of fat at baseline increased more in fat, while STIR- muscles had increases in septal-fat over the study period. These changes may reflect two phases of FSHD, demonstrating MRI sensitivity is weighted toward gross pathological phases of the disease. Muscle Nerve 57: 905-912, 2018.

Roux-en-Y gastric bypass (RYGB) surgery is a highly effective treatment for obesity but negatively affects the skeleton. Studies of skeletal effects have generally examined areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), but DXA may be inaccurate in the setting of marked weight loss. Further, as a result of modestly sized samples of mostly premenopausal women and very few men, effects of RYGB by sex and menopausal status are unknown. We prospectively studied the effects of RYGB on skeletal health, including axial and appendicular volumetric BMD and appendicular bone microarchitecture and estimated strength. Obese adults (N = 48; 27 premenopausal and 11 postmenopausal women, 10 men) with mean ± SD body mass index (BMI) 44 ± 7 kg/m2 were assessed before and 6 and 12 months after RYGB. Participants underwent spine and hip DXA, spine QCT, radius and tibia HR-pQCT, and laboratory evaluation. Mean 12-month weight loss was 37 kg (30% of preoperative weight). Overall median 12-month increase in serum collagen type I C-telopeptide (CTx) was 278% (p < 0.0001), with greater increases in postmenopausal than premenopausal women (p = 0.049). Femoral neck BMD by DXA decreased by mean 5.0% and 8.0% over 6 and 12 months (p < 0.0001). Spinal BMD by QCT decreased by mean 6.6% and 8.1% (p < 0.0001); declines were larger among postmenopausal than premenopausal women (11.6% versus 6.0% at 12 months, p = 0.02). Radial and tibial BMD and estimated strength by HR-pQCT declined. At the tibia, detrimental changes in trabecular microarchitecture were apparent at 6 and 12 months. Cortical porosity increased at the radius and tibia, with more dramatic 12-month increases among postmenopausal than premenopausal women or men at the tibia (51.4% versus 18.3% versus 3.0%, p < 0.01 between groups). In conclusion, detrimental effects of RYGB on axial and appendicular bone mass and microarchitecture are detectable as early as 6 months postoperatively. Postmenopausal women are at highest risk for skeletal consequences and may warrant targeted screening or interventions. © 2017 American Society for Bone and Mineral Research.

Cannabis (marijuana) has been used for medicinal purposes for millennia, said to be first noted by the Chinese in c. 2737 BCE. Medicinal cannabis arrived in the United States much later, burdened with a remarkably checkered, yet colorful, history. Despite early robust use, after the advent of opioids and aspirin, medicinal cannabis use faded. Cannabis was criminalized in the United States in 1937, against the advice of the American Medical Association submitted on record to Congress. The past few decades have seen renewed interest in medicinal cannabis, with the National Institutes of Health, the Institute of Medicine, and the American College of Physicians, all issuing statements of support for further research and development. The recently discovered endocannabinoid system has greatly increased our understanding of the actions of exogenous cannabis. Endocannabinoids appear to control pain, muscle tone, mood state, appetite, and inflammation, among other effects. Cannabis contains more than 100 different cannabinoids and has the capacity for analgesia through neuromodulation in ascending and descending pain pathways, neuroprotection, and anti-inflammatory mechanisms. This article reviews the current and emerging research on the physiological mechanisms of cannabinoids and their applications in managing chronic pain, muscle spasticity, cachexia, and other debilitating problems.

Objectives: This study was conducted to better understand the characteristics of chronic pain patients seeking treatment with medicinal cannabis (MC). Design: Retrospective chart reviews of 139 patients (87 males, median age 47 years; 52 females, median age 48 years); all were legally qualified for MC use in Washington State. Setting: Regional pain clinic staffed by university faculty. Participants: Inclusion criteria: age 18 years and older; having legally accessed MC treatment, with valid documentation in their medical records. All data were de-identified. Main Outcome Measures: Records were scored for multiple indicators, including time since initial MC authorization, qualifying condition(s), McGill Pain score, functional status, use of other analgesic modalities, including opioids, and patterns of use over time. Results: Of 139 patients, 15 (11 percent) had prior authorizations for MC before seeking care in this clinic. The sample contained 236.4 patientyears of authorized MC use. Time of authorized use ranged from 11 days to 8.31 years (median of 1.12 years). Most patients were male (63 percent) yet female patients averaged 0.18 years longer authorized use. There were no other gender-specific trends or factors. Most patients (n = 123, 88 percent) had more than one pain syndrome present. Myofascial pain syndrome was the most common diagnosis (n = 114, 82 percent), followed by neuropathic pain (n = 89, 64 percent), discogenic back pain (n = 72, 51.7 percent), and osteoarthritis (n = 37, 26.6 percent). Other diagnoses included diabetic neuropathy, central pain syndrome, phantom pain, spinal cord injury, fibromyalgia, rheumatoid arthritis, HIV neuropathy, visceral pain, and malignant pain. In 51 (37 percent) patients, there were documented instances of major hurdles related to accessing MC, including prior physicians unwilling to authorize use, legal problems related to MC use, and difficulties in finding an affordable and consistent supply of MC. Conclusions: Data indicate that males and females access MC at approximately the same rate, with similar median authorization times. Although the majority of patient records documented significant symptom alleviation with MC, major treatment access and delivery barriers remain.

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.

Introduction: While somatic mutations in colorectal cancer (CRC) are well characterized, little is known about the accumulation of cancer-associated mutations in normal colon. This knowledge is crucial to understand the origin and evolution of cancer and to improve cancer prevention and prediction. The study of somatic mutation within normal tissue, however, is technically challenging because these mutations exist at extremely low frequency limiting their detection by conventional next-generation sequencing (NGS). Here we used Duplex Sequencing (DS), an error correction NGS approach that enables extreme sensitivity for mutation detection, to characterize the mutational landscape of cancer-associated genes in normal colonic mucosa of patients with and without CRC. Methods: We used a DS-based method called CRISPR-DS, which employs double stranded molecular tagging for ultra-accurate sequencing and CRISPR-Cas9 target enrichment for efficient library conversion. A panel including the full coding region of TP53 and the hotspot codons of BRAF, KRAS and PIK3CA was designed to sequence at high depth (mean 2,500x) the DNA from normal colon mucosa of 47 patients, 23 of them with CRC cancer (mean age 57 years) and 24 without (mean age 59 years). Normal colon tissue from CRC patients was obtained distant from the tumor (>15cm). Mutation frequency was calculated for all target genes and for TP53 only as the number of mutated reads (overall and separately for coding and non-coding regions) divided by the total nucleotides sequenced. Results: 168 mutations (124 coding and 44 non-coding) were identified. In nearly all patients (43/47), normal colon carried at least one coding mutation in a cancer associated gene included in the panel. Compared to patients without cancer, the normal colon of patients with CRC showed higher mutation frequency overall (5.5x10-7 vs 3.6x10-7, p=0.009) and in coding regions (7.5x10-7 vs 4.2x10-7, p=0.003), but not in non-coding regions. Similar results were observed for overall TP53 mutations (6.4x10-7 vs 3.7x10-7, p=0.01) and TP53 coding mutations (9.5x10-7 vs 4.9x10-7, p=0.006). Both groups of patients carried cancer-associated TP53 mutations but in patients with CRC the proportion of common CRC mutations and pathogenic mutations was significantly higher (p=0.01 and p=0.02, respectively). KRAS hotspot mutations (codons 12 and 13) were identified in the normal colon of 30% (7/23) of patients with CRC but in none of the patients without CRC (0/24). TP53 hotspot mutations were observed in 22% (5/23) patients with CRC and in 13% (3/24) of patients without cancer. Overall, 44% (10/23) of patients with CRC carried mutations in hotspots vs 25% (6/24) of patients without cancer and half of the CRC patients with hotspot mutations carried hotspot mutations in more than one gene. Conclusions: Common CRC mutations are present in the normal colon of adult individuals but at higher frequency and with more pathogenicity in those that have developed CRC. These results indicate that somatic evolution takes place in the normal human colon but this process appears to be increased in patients with CRC. Because the biopsies analyzed were collected more than 15cm away from tumors, these results raise questions about the extension of precarcinogenic fields harboring clonal expansions and prompts to further investigation into the landscape of cancer-associated mutations in non-cancerous colonic mucosa. Citation Format: Júlia Matas Gironella, Brendan Kohrn, Jeanne Fredickson, Kelly Carter, Ting Wang, Ming Yu, William M Grady, Miguel Angel Peinado, Rosa Ana Risques. Somatic evolution in normal colon of patients with and without cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB231.

Duplication of chromosome 22q11.2 (LCR A-D) has been reported at higher frequencies in clinical samples than the general population, but phenotypes vary widely. Triplication (4 copies) is rare, but studying the associated phenotype may provide insight into dosage-sensitivity of the genes in this chromosomal interval. We describe a proband with a triplication, specifically a “double duplication” (two copies per chromosome) of the 22q11.2 region, while his parents and two siblings each have a single duplication (3 copies). The proband had a heart malformation, dysmorphic features, and learning and socialization deficits, whereas the other family members did not. This family illustrates that while duplication of the 22q11.2 may not be sufficient to cause clinically significant neurodevelopmental or health-related phenotypes, triplication of the same region may result in a phenotype characterized by a mild neurodevelopmental disorder, facial dysmorphism, and possibly cardiac anomalies.

Bone marrow fat is a unique fat depot that may regulate bone metabolism. Marrow fat is increased in states of low bone mass, severe underweight, and diabetes. However, longitudinal effects of weight loss and improved glucose homeostasis on marrow fat are unclear, as is the relationship between marrow fat and bone mineral density (BMD) changes. We hypothesized that after Roux-en-Y gastric bypass (RYGB) surgery, marrow fat changes are associated with BMD loss. We enrolled 30 obese women, stratified by diabetes status. Before and 6 months after RYGB, we measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and vertebral marrow fat content by magnetic resonance spectroscopy. At baseline, those with higher marrow fat had lower BMD. Postoperatively, total body fat declined dramatically in all participants. Effects of RYGB on marrow fat differed by diabetes status (p = 0.03). Nondiabetic women showed no significant mean change in marrow fat (+1.8%, 95% confidence interval [CI] –1.8% to +5.4%, p = 0.29), although those who lost more total body fat were more likely to have marrow fat increases (r = –0.70, p = 0.01). In contrast, diabetic women demonstrated a mean marrow fat change of –6.5% (95% CI –13.1% to 0%, p = 0.05). Overall, those with greater improvements in hemoglobin A1c had decreases in marrow fat (r = 0.50, p = 0.01). Increases in IGF-1, a potential mediator of the marrow fat-bone relationship, were associated with marrow fat declines (r = –0.40, p = 0.05). Spinal volumetric BMD decreased by 6.4% ± 5.9% (p

Background and Objectives: Plastin 3 (PLS3) mutations are associated with an X-linked osteoporosis. Here we describe two new families with novel mutations, including one with a whole gene PLS3 deletion, and review the literature on 9 previously reported cases. Results: Hemizygous male carriers presented with multiple peripheral bone fractures, low bone mineral density (BMD), and vertebral compression fractures. Heterozygous female carriers did not have a history of fragility fractures, although 1 individual presented with low BMD. Apart from greyish-tinged sclera, no other extraskeletal features of osteogenesis imperfecta were identified. Histomorphometry from a transiliac bone biopsy in one of our index patients demonstrated significantly low trabecular bone volume with increased bone turnover. Bisphosphonate treatment was associated with a reduction in the fracture rate and increased bone density. Conclusion: Hemizygous mutations in PLS3 may cause a monogenic form of X-linked osteoporosis presenting in childhood with a nonspecific phenotype. No characteristic ocular, dental, or joint abnormalities are defined. When genetic testing is undertaken to investigate for primary causes of bone fragility, we suggest PLS3 be included in order not to miss this diagnosis.

Obesity accelerates the development of osteoarthritis of the knee and hip by exerting deleterious effects on joints through both biomechanical and also systemic inflammatory changes. The objective of this review was to evaluate the impact of obesity on lower limb biomechanics and total joint arthroplasty outcomes, as well as weight changes after joint arthroplasty and the role of bariatric surgery among patients requiring joint arthroplasty. The currently published data indicate that weight loss increases swing time, stride length, gait speed, and lower extremity range of motion. Total joint arthroplasty improves pain and joint function, but does not induce significant weight loss in the majority of patients. Bariatric surgery improves gait biomechanics, and in the severely obese patient with osteoarthritis improves pain and joint function. The evidence for supporting bariatric surgery before total joint arthroplasty is limited to retrospective reports with conflicting results. Fundamental clinical questions remain regarding the optimal management of morbid obesity and lower extremity arthritis, which should be the focus of future collaborations across disciplines providing care to patients with both conditions.

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence‐associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence‐associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.