Breast Augmentation Patient Satisfaction in an Appalachian Region.

The prevalence of cosmetic plastic surgeries, including breast augmentation, has risen significantly, with breast augmentation being among the most sought-after procedures. However, there's a dearth of research on patient outcomes and satisfaction, particularly in rural areas like the Appalachian region. This retrospective study aimed to fill this gap by examining patient satisfaction and complications following breast augmentation surgery among rural Appalachian patients in the tri-state (West Virginia, Kentucky, and Ohio) area. A total of 63 patients who underwent primary breast augmentation at a regional referral center from June 2014 to December 2022 were included in the study. Patient records were reviewed and data on demographics, complications, re-operations, and satisfaction scores were analyzed. Results revealed no significant differences between rural and urban populations in terms of demographic characteristics, complication rates, re-operation rates, or satisfaction scores. Logistic regression models confirmed that rural/urban status did not significantly influence the likelihood of complications, re-operations, or satisfaction. Despite the study's limitations, including a small sample size and single-center design, the results indicate that rural Appalachian patients receive surgical care comparable to their urban counterparts and experience similar benefits from breast augmentation surgery. Recognizing the distinctive healthcare needs and obstacles faced by rural communities is essential for mitigating healthcare disparities and enhancing overall health outcomes. Future research and healthcare initiatives should prioritize improving access to care, fostering patient-centered approaches, and addressing systemic challenges in healthcare delivery across rural Appalachia.

Age-Related Patterns of Traumatic Facial Fractures in the Appalachian Tri-state Area: A Five-Year Retrospective Study.

Introduction Traumatic facial injuries, leading to facial fractures represent a significant subset of traumatic events, with age emerging as a crucial determinant influencing both their etiology and outcomes. Understanding the age-related patterns of traumatic facial fractures is essential for developing targeted prevention and management strategies. In this context, the Appalachian tri-state area stands as an underexplored region concerning this issue, necessitating comprehensive research to elucidate the nuances of age-related traumatic facial fractures within this geographic context. Methods This retrospective study delves into the age-related patterns of traumatic facial fractures within the Appalachian tri-state area, drawing upon patient records from Cabell Huntington Hospital and Saint Mary's Medical Center spanning a five-year period. The study cohort encompasses 623 patients categorized into three age groups: individuals aged <22 years, those aged 22-65 years, and individuals over 65 years. Data analysis involves meticulous examination of mechanisms of injury, injury severity scores (ISSs), hospital length of stay, and the prevalence of surgical interventions across different age cohorts. Results Out of 623 patients, 104 (16.7%) were under 22 years old, 367 (58.9%) were between 22 and 65 years old, and 152 (24.4%) were over 65 years old. The majority were male (70%). Falls were the most common cause of facial fractures in patients over 65 (78%), while assaults were predominant in the 22-65 age group (24%), and motor vehicle collisions (MCVs) in those under 22 (34%). The median ISS and hospital stay durations were similar across age groups. 28% of patients underwent surgery, with significant variation among age groups (p<0.001): 38% for <22 years, 33% for 22-65 years, and 11% for >65 years. Mandibular fractures were more prevalent in younger patients, with rates of 12% for <22 years compared to 5.3% for >65 years. Logistic regression analysis revealed that patients aged 22-65 had 4.10 times higher odds (95% CI=2.38, 7.45, p<0.001) of undergoing surgery, while those under 22 had 5.14 times higher odds (95% CI=2.73, 10.0, p<0.001) compared to those over 65. Significant associations were found for mandibular and bilateral mandibular outcomes in patients aged 22-65 years. Discussion These findings underscore the imperative for tailored prevention strategies and age-specific treatment protocols to optimize patient outcomes. Fall prevention initiatives for the elderly and interventions addressing sports-related injuries for younger individuals are paramount. Moreover, the study highlights the necessity of specialized care protocols for elderly patients to minimize hospital stay durations and manage age-related comorbidities effectively. Moving forward, further research should address limitations, validate findings, and explore the efficacy of specific interventions, thereby paving the way for enhanced preventive measures and management strategies tailored to the diverse age cohorts affected by traumatic facial fractures in the Appalachian region.

A Comparative American Board of Surgery In-Training Examination (ABSITE) Performance Analysis Between International vs. Domestic Graduates and Doctor of Medicine (MD) vs. Doctor of Osteopathic Medicine (DO) Medical Degrees.

Introduction The American Board of Surgery (ABS) plays a pivotal role in certifying surgeons in the United States, with the American Board of Surgery In-Training Examination (ABSITE) serving as a critical assessment tool for general surgery residents aspiring for certification. The aim of this study is to compare the performance of international medical graduates (IMGs) to their domestic counterparts and assess the impact of different medical degrees on ABSITE scores. Notably, ABSITE scores often dictate the trajectory of a surgical career, including opportunities for fellowship placements in specialized fields such as plastic surgery. Methods This study focused on general surgery residents enrolled at Marshall University from 2014 to 2022. Data encompassing ABSITE scores, TrueLearn quiz percentages, and TrueLearn mock exam results were collected for analysis. Descriptive statistics summarized sample characteristics, and linear mixed models were employed to address correlations. Statistical analyses were conducted using the Statistical Analysis System (SAS) (version 9.4; SAS Institute Inc., Cary, NC, USA), with significance defined by a two-sided test with p < 0.05. Results Among the 48 participants, comprising 24 non-international medical graduates (nIMGs) and 24 IMGs, IMGs demonstrated superior performance across various metrics. They exhibited higher quiz percentages (67% vs. 61%; p = 0.0029), mock Exam 1 scores (64% vs. 58%; p = 0.0021), mock Exam 2 scores (66% vs. 58%; p = 0.0015), ABSITE scores (560 vs. 505; p = 0.010), and ABSITE percentages (74% vs. 68%; p = 0.0077) compared to nIMGs. Analysis between Doctor of Osteopathic Medicine (DO) and Doctor of Medicine (MD) participants revealed no statistically significant differences in performance metrics, highlighting the comparability of these medical degrees in the context of ABSITE scores and related assessments. Discussion/conclusion This study underscores the superior performance of IMGs over nIMGs in ABSITE examinations, shedding light on the critical role of ABSITE scores in shaping surgical careers. Higher scores correlate with enhanced opportunities for coveted fellowship placements, particularly in specialized fields like plastic surgery. Understanding these dynamics is crucial for resident training and navigating the competitive landscape of surgical sub-specialization. Future research endeavors can delve deeper into the factors influencing ABSITE performance, thereby facilitating the development of targeted interventions to support residents in achieving their career aspirations.

Navigating the American Board of Surgery In-Training Examination (ABSITE) Success: Insights From Pre-assessment Practices in Preparing Surgical Residents for Competitive Sub-specialties.

Introduction The American Board of Surgery In-Training Examination (ABSITE) is a critical tool in assessing surgical residents' readiness for board certification and clinical practice. While various factors influencing ABSITE performance have been examined, the impact of innovative educational resources, such as TrueLearn, remains underexplored. TrueLearn's adaptive learning algorithms and comprehensive question banks offer a promising adjunct to traditional study methods. This study investigates the relationship between TrueLearn utilization and ABSITE performance among general surgery residents. Methods This retrospective study, ethically approved by the Marshall University Institutional Review Board (IRB No. 2097669-1), analyzed the performance of general surgery residents at Marshall University from 2014 to 2022. Data were collected on ABSITE scores. Additionally, quiz percentages (Quiz %) and scores from two mock exams (Exam 1 and Exam 2), all provided by the TrueLearn platform, were included in the analysis. Descriptive statistics summarized the sample characteristics. Linear mixed models were employed to examine the associations between TrueLearn engagement and ABSITE performance, accounting for the correlated nature of the data and addressing any missing data at random. Statistical analyses were conducted using the Statistical Analysis System (SAS, version 9.4; SAS Institute Inc., Cary, NC), with significance defined as a p-value < 0.05. Results The study cohort included 58 residents from 2016 to 2022. Linear mixed model analysis revealed significant positive correlations between TrueLearn Quiz %, Exam 1 scores, and Exam 2 scores with ABSITE performance. A 1% increase in Quiz % was associated with a 0.77-point rise in ABSITE scores (95% CI: 0.65, 0.89; p < 0.0001). For Exam 1, each point increase corresponded to a 6.36-point increase in ABSITE scores (95% CI: 5.01, 7.7; p < 0.0001), while Exam 2 scores showed a 3.8-point increase per point (95% CI: 2.74, 4.86; p < 0.0001). Discussion and conclusion Our findings underscore the significant impact of TrueLearn engagement on ABSITE performance, with higher quiz percentages and mock exam scores predictive of better ABSITE outcomes. This suggests that regular use of TrueLearn's educational resources enhances residents' knowledge and exam readiness. These results advocate for the integration of innovative educational tools such as TrueLearn into surgical training programs to optimize study strategies and improve exam performance. However, the study's retrospective design and single-institution focus limit the generalizability of the findings. Future research should explore these relationships in diverse settings and specialties and consider additional factors influencing ABSITE performance. This study highlights the positive association between TrueLearn utilization and ABSITE performance among general surgery residents, emphasizing the importance of innovative educational resources in surgical training. By enhancing engagement with platforms such as TrueLearn, surgical programs can improve residents' readiness for high-stakes examinations, ultimately contributing to the development of proficient surgical practitioners.

Evidence-Based Performance Measures for Reconstruction after Skin Cancer Resection: A Multidisciplinary Performance Measure Set.

BACKGROUND: The American Society of Plastic Surgeons commissioned the multidisciplinary Performance Measure Development Work Group on Reconstruction after Skin Cancer Resection to identify and draft quality measures for the care of patients undergoing skin cancer reconstruction. Included stakeholders were the American Academy of Otolaryngology-Head and Neck Surgery, the American Academy of Facial Plastic and Reconstructive Surgery, the American Academy of Dermatology, the American Society of Dermatologic Surgery, the American College of Mohs Surgery, the American Society for Mohs Surgery, and a patient representative. METHODS: Two outcome measures and five process measures were identified. The outcome measures included the following: (1) patient satisfaction with information provided by their surgeon before their facial procedure, and (2) postprocedural urgent care or emergency room use. The process measures focus on antibiotic stewardship, anticoagulation continuation and/or coordination of care, opioid avoidance, and verification of clear margins. RESULTS: All measures in this report were approved by the American Society of Plastic Surgeons Quality and Performance Measures Work Group and Executive Committee, and the stakeholder societies. CONCLUSION: The work group recommends the use of these measures for quality initiatives, Continuing Medical Education, Continuous Certification, Qualified Clinical Data Registry reporting, and national quality reporting programs.

A Rare Case of Extensive Basal Cell Carcinoma With Invasion of the Humerus: Excision and Immediate Reconstruction With Fibula Allograft, Plating, and Latissimus Dorsi Flap.

Basal cell carcinoma (BCC) is the most common skin cancer, and most of the reports have involved the head and neck, but it is rare for it to be highly invasive, with an invasion of long bone being extremely rare. A 73 year old woman presented with a giant BCC on her right arm. Magnetic resonance imaging suggested the involvement of the right humerus. Biopsy confirmed the nodular type of BCC. The patient underwent BCC excision including hemicortical humerus excision with fibula allograft and latissimus dorsi flap with a split-thickness skin graft. Excluding a transient radial nerve palsy, the patient's postoperative course was otherwise uncomplicated. Although BCC invasion into the long bone is extremely rare, the gold standard treatment is, as a rule, en bloc surgical resection with a wide variety of reconstructive techniques. This treatment is only possible through the collaboration of general surgery, orthopedics, and plastic surgery.

Targeting Mycobacterium tuberculosis CoaBC through Chemical Inhibition of 4'-Phosphopantothenoyl-l-cysteine Synthetase (CoaB) Activity.

Coenzyme A (CoA) is a ubiquitous cofactor present in all living cells and estimated to be required for up to 9% of intracellular enzymatic reactions. Mycobacterium tuberculosis (Mtb) relies on its own ability to biosynthesize CoA to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the pathway to CoA biosynthesis is recognized as a potential source of novel tuberculosis drug targets. In prior work, we genetically validated CoaBC as a bactericidal drug target in Mtb in vitro and in vivo. Here, we describe the identification of compound 1f, a small molecule inhibitor of the 4'-phosphopantothenoyl-l-cysteine synthetase (PPCS; CoaB) domain of the bifunctional Mtb CoaBC, and show that this compound displays on-target activity in Mtb. Compound 1f was found to inhibit CoaBC uncompetitively with respect to 4'-phosphopantothenate, the substrate for the CoaB-catalyzed reaction. Furthermore, metabolomic profiling of wild-type Mtb H37Rv following exposure to compound 1f produced a signature consistent with perturbations in pantothenate and CoA biosynthesis. As the first report of a direct small molecule inhibitor of Mtb CoaBC displaying target-selective whole-cell activity, this study confirms the druggability of CoaBC and chemically validates this target.

Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.

Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.

Incidence of delayed intracranial hypertension in children with isolated sagittal synostosis following open calvarial vault reconstruction.

PURPOSE: Delayed intracranial hypertension (DIH) occurs most frequently in children with syndromic or multi-suture synostosis after surgical correction. The rarity of DIH in children with isolated non-syndromic sagittal synostosis (ISS) warrants follow-up evaluation by large craniofacial centers until skeletal maturity. This study reports the incidence of DIH in children following open repair for ISS by our center's craniofacial team. METHODS: A single-center retrospective study of patients who underwent open calvarial vault remodeling (CVR) for ISS at our institution between November 2000 and November 2012 was performed. Syndromic and multi-suture synostosis patients were excluded. Demographic and follow-up data were extracted from the medical record for analysis until July 2017. RESULTS: One hundred five patients with ISS were identified who had undergone CVR in the aforementioned timeframe. Average age at initial surgery was 11.7 ± 15.32 months. Mean follow-up in our craniofacial clinic was 4.94 ± 3.53 years, with 69 patients (65.7%) having follow-up in craniofacial clinic ≥ 3 years and 74 (70.5%) having follow-up ≥ 3 years in any clinic at our institution. Four patients (3.8%) had intracranial pressure (ICP) monitors placed for symptoms concerning for DIH, one of which (0.95%) had confirmed DIH and underwent a second surgical procedure at 7.4 years of age. The patient presented late initially, having his first operation at 1.56 years of age. CONCLUSION: One patient out of 105 (0.95%) developed DIH, confirmed by ICP monitoring, and required reoperation. The occurrence of DIH, albeit rare, remains an important topic to include in parental discussions and mandates long-term follow-up in this population.

A Rare Transformation of Epidermoid Cyst into Squamous Cell Carcinoma: A Case Report with Literature Review.

BACKGROUND Epidermoid cysts are the most common benign skin lesions that can occur anywhere on the body, and frequently occur on the face, scalp, neck, and trunk. Typically, patients are asymptomatic, and the lesions present as firm skin-colored nodules filled with keratinous or sebaceous materials that are formed by cystic expansion of the epidermal epithelium. Malignant transformation is rare in epidermoid cysts. CASE REPORT This is a case report of a 77-year-old male Caucasian patient who presented with an epidermoid cyst on the left parietal area. Due to high suspicion, the cyst was surgically excised and sent to pathology which resulted in discovery of malignant squamous cell carcinoma with unclear margins. Aimed at obtaining clear margins, a wide excision was performed, which revealed clean margins and absence of residual cancerous cells. The patient recovered well without major complications. CONCLUSIONS Although the prevalence of epidermoid cysts is high, malignant transformation of epidermoid cysts into squamous cell carcinoma is rare. Due to its scarcity, the exact pathophysiology of malignant transformation is still poorly understood. The differential diagnosis should include the possibility of malignancy for highly suspicious lesions, and proper management guidelines should be established. Surgical resection should be the treatment of choice, and once removed, all surgically excised cysts should undergo pathologic evaluation. As clinicians, it is crucial to stay vigilant and have a low threshold for excision and thorough histological examination of specimens to allow early diagnosis and interventions which can significantly improve patient outcomes. Through the suggested guidelines, we hope to aid in better management and intervention in case of malignant transformation of epidermoid cysts.

Comparison of Geriatric Trauma Outcomes When Admitted to a Medical or Surgical Service After a Fall.

BACKGROUND: Blunt trauma in the geriatric population is fraught with poor outcomes, with injury severity and comorbidities impacting morbidity and mortality. METHODS: We retrospectively reviewed 2172 patients aged ≥65 y who fell, requiring hospital admission between January 2012 and December 2016. There were 403 patients in the surgical arm (SA) and 1769 patients in the medical arm (MA). Ground-level falls were the only mechanism of injury included. We excluded all ICU admissions and deaths within 24 h. RESULTS: There were 5 deaths (1.24%) in the SA and 16 deaths (0.90%) in the MA (P = 0.57). The mean trauma injury severity score survival probability prediction in the SA was 96.9% versus 97.1% in the MA. MA patients had more comorbidities overall than SA patients. There was no difference in mortality between the SA and MA groups in multiple logistic regression models that accounted for trauma injury severity scores (TRISS) and comorbidities. Unadjusted hospital length of stay was 1 d shorter (median; 95% CI -1.4 to -0.6) in the SA and 0.5 d shorter (median; 95% CI -0.8 to -0.1) when adjusted for TRISS and comorbidities using multiple quantile regression. Finally, patients in the SA were 2.1 (95% CI 1.7 to 2.6) times more likely to be discharged home compared with patients in the MA, and this remained significant (OR 1.9; 95% CI 1.5 to 2.5) with simultaneous adjustment for TRISS and comorbidities using multiple logistic regression. CONCLUSIONS: Geriatric blunt trauma patients admitted to surgical services after mechanical falls have no difference in survival, a shorter median length of stay, and increased likelihood of being discharged home compared with patients admitted to medical services.

Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy.

LonP1 is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. We identified a novel homozygous missense LONP1 variant, c.2282 C > T, (p.Pro761Leu), by whole-exome and Sanger sequencing in two siblings born to healthy consanguineous parents. Both siblings presented with stepwise regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability and progressive cerebellar atrophy on brain imaging. Muscle biopsy revealed the absence of ragged-red fibers, however, scattered cytochrome c oxidase-negative staining and electron dense mitochondrial inclusions were observed. Primary cultured fibroblasts from the siblings showed normal levels of mtDNA and mitochondrial transcripts, and normal activities of oxidative phosphorylation complexes I through V. Interestingly, fibroblasts of both siblings showed glucose-repressed oxygen consumption compared to their mother, whereas galactose and palmitic acid utilization were similar. Notably, the siblings' fibroblasts had reduced pyruvate dehydrogenase (PDH) activity and elevated intracellular lactate:pyruvate ratios, whereas plasma ratios were normal. We demonstrated that in the siblings' fibroblasts, PDH dysfunction was caused by increased levels of the phosphorylated E1α subunit of PDH, which inhibits enzyme activity. Blocking E1α phosphorylation activated PDH and reduced intracellular lactate concentrations. In addition, overexpressing wild-type LonP1 in the siblings' fibroblasts down-regulated phosphoE1α. Furthermore, in vitro studies demonstrated that purified LonP1-P761L failed to degrade phosphorylated E1α, in contrast to wild-type LonP1. We propose a novel mechanism whereby homozygous expression of the LonP1-P761L variant leads to PDH deficiency and energy metabolism dysfunction, which promotes severe neurologic impairment and neurodegeneration.

Outcomes After Open Reduction With Internal Fixation of Mandible Fractures.

INTRODUCTION/HYPOTHESIS: Mandible fractures contribute substantially to morbidity after blunt trauma. Controversy exists surrounding the appropriate timing of surgical intervention and benefit from routine postreduction imaging. METHODS: The authors retrospectively reviewed 146 patients who sustained traumatic mandible fractures at a level 2 trauma center over a 5-year period, between January 2012 and December 2016. The authors excluded all patients who did not undergo surgery, underwent operative closed reduction only, sustained other significant maxillofacial injuries, penetrating mechanisms, and other major injuries based on injury severity scores (ISS) over 15. There were 51 patients meeting inclusion criteria. The authors reviewed admission face computed tomography (CT) scans and Panorex x-rays. Patients were divided into early (<72 hours) and late (>72 hours) open reduction with internal fixation (ORIF) groups. The authors reviewed demographics, mechanism of injury, postreduction imaging, and ISS. All statistical analyses were performed using Stata 15. RESULTS: There were 39 males (76%) and 12 females (24%) in the authors' study, with a mean age of 32 years. Twenty-eight patients (55%) underwent early ORIF and 23 patients (45%) underwent late ORIF, with no mortalities. There was no statistically significant difference in ISS between the 2 groups (P = 0.081). Preoperative face CT scans were performed in 49 patients (96%) and Panorex in 2 patients (4%). Eight patients (16%) had both modalities, with CT face identifying fractures in 5 patients not seen on Panorex, resulting in a change in operative approach. Postreduction imaging was obtained in 33 patients (65%), of whom 26 were Panorex X-rays. These demonstrated adequate reduction in 31 patients (94%) and did not change management in any instance. Complications occurred in 19 patients (37%), of whom there were 11 with uncontrolled pain after 1 week, 6 abscesses, 5 nonunions/malunions, 2 hardware extrusions, and 1 incisional dehiscence. A positive urine drug screen predicted uncontrolled pain (P < 0.05). There was no statistically significant difference in complications between the 2 groups. CONCLUSION: The authors' data suggest that CT scans of the face are superior to panoramic radiographs in traumatic mandible fracture evaluation, with no apparent benefit from routine postreduction imaging in detecting complications. Open reduction with internal fixation remains an effective treatment with favorable outcomes, and operative delays > 72 hours do not appear to increase complication rates.

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.

BACKGROUND: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers. METHODS: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant. RESULTS: Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set (n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants - associated with cancer, cardiac or neurodegenerative phenotypes - remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual. INTERPRETATION: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care.

Orkambi® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue.

The combination therapy of lumacaftor and ivacaftor (Orkambi®) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508 It has been predicted that Orkambi® could treat patients with rarer mutations of similar "theratype"; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function-similar to ΔF508-CFTR, are unlikely to yield a robust Orkambi® response. While in silico and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient-derived tissue. A CRISPR/Cas9-edited bronchial epithelial cell line bearing this mutation enabled studies showing that an "amplifier" compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi® response. Importantly, this "amplifier" effect was recapitulated in patient-derived nasal cultures-providing the first evidence for its efficacy in augmenting Orkambi® in tissues harboring a rare CF-causing mutation. We propose that this multi-disciplinary approach, including creation of CRISPR/Cas9-edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations.

Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines.

Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome caused by a variety of molecular changes on chromosome 11p15.5. Children with BWS have a significant risk of developing Wilms tumours with the degree of risk being dependent on the underlying molecular mechanism. In particular, only a relatively small number of children with loss of methylation at the centromeric imprinting centre (IC2) were reported to have developed Wilms tumour. Discontinuation of tumour surveillance for children with BWS and loss of methylation at IC2 has been proposed in several recent publications. We report here three children with BWS reported to have loss of methylation at IC2 on clinical testing who developed Wilms tumour or precursor lesions. Using multiple molecular approaches and multiple tissues, we reclassified one of these cases to paternal uniparental disomy for chromosome 11p15.5. These cases highlight the current challenges in definitively assigning tumour risk based on molecular classification in BWS. The confirmed cases of loss of methylation at IC2 also suggest that the risk of Wilms tumour in this population is not as low as previously thought. Therefore, we recommend that for now, all children with a clinical or molecular diagnosis of BWS be screened for Wilms tumour by abdominal ultrasonography until the age of eight years regardless of the molecular classification.

Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB.

Mutations of the cystatin B gene (CSTB; OMIM 601145) are known to cause Unverricht-Lundborg disease or progressive myoclonic epilepsy-1A (EPM1A, MIM #254800). Most patients are homozygous for an expanded (>30) dodecamer repeat in the promoter region of CSTB, or are compound heterozygotes for the dodecamer repeat and a point mutation. We report two adolescent sisters born to consanguineous parents of Sri Lankan descent who presented with profound global developmental delay, microcephaly, cortical blindness and axial hypotonia with appendicular hypertonia. Neither sibling ever developed head control, independent sitting or ambulation, and never developed speech. The elder sister had a seizure disorder. Both sisters had profound microcephaly and distinct facial features. On serial brain imaging, they had progressive atrophy of the corpus callosum and supratentorial brain, and diffuse hypomyelination with progressive loss of myelin signal. Exome sequencing revealed both siblings to be homozygous for a c.218dupT (p.His75Serfs*2) mutation in exon 3 of CSTB. The neuroimaging features of our patients are consistent with those observed in Cstb-knockout mice, which supports the hypothesis that disease severity is inversely correlated with the amount of residual functional cystatin B protein.

Congenital myopathy with "corona" fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A.

We describe two brothers with lower facial weakness, highly arched palate, scaphocephaly due to synostosis of the sagittal and metopic sutures, axial hypotonia, proximal muscle weakness, and mild scoliosis. The muscle MRI of the younger sibling revealed a selective pattern of atrophy of the gluteus maximus, adductor magnus and soleus muscles. Muscle biopsy of the younger sibling revealed myofibres with internalized nuclei, myofibrillar disarray, and "corona" fibres. Both affected siblings were found to be compound heterozygous for c.3425G>A (p.Arg1142Gln) and c.1123T>C (p.Cys375Arg) mutations in SCN4A on exome sequencing, and the parents were confirmed carriers of one of the mutations. Electrophysiological characterization of the mutations revealed the Cys375Arg confers full and Arg1142Gln mild partial loss-of-function. Loss of function of the Nav1.4 channel leads to a decrement of the action potential and subsequent reduction of muscle contraction. The unusual muscle biopsy features suggest a more complex pathomechanism, and broaden the phenotype associated with SCN4A mutations.

Prediction of Drug Penetration in Tuberculosis Lesions.

The penetration of antibiotics in necrotic tuberculosis lesions is heterogeneous and drug-specific, but the factors underlying such differential partitioning are unknown. We hypothesized that drug binding to macromolecules in necrotic foci (or caseum) prevents passive drug diffusion through avascular caseum, a critical site of infection. Using a caseum binding assay and MALDI mass spectrometry imaging of tuberculosis drugs, we showed that binding to caseum inversely correlates with passive diffusion into the necrotic core. We developed a high-throughput assay relying on rapid equilibrium dialysis and a caseum surrogate designed to mimic the composition of native caseum. A set of 279 compounds was profiled in this assay to generate a large data set and explore the physicochemical drivers of free diffusion into caseum. Principle component analysis and modeling of the data set delivered an in silico signature predictive of caseum binding, combining 69 molecular descriptors. Among the major positive drivers of binding were high lipophilicity and poor solubility. Determinants of molecular shape such as the number of rings, particularly aromatic rings, number of sp(2) carbon counts, and volume-to-surface ratio negatively correlated with the free fraction, indicating that low-molecular-weight nonflat compounds are more likely to exhibit low caseum binding properties and diffuse effectively through caseum. To provide simple guidance in the property-based design of new compounds, a rule of thumb was derived whereby the sum of the hydrophobicity (clogP) and aromatic ring count is proportional to caseum binding. These tools can be used to ensure desirable lesion partitioning and guide the selection of optimal regimens against tuberculosis.

A Novel Mutation in DMD (c.10797+5G>A) Causes Becker Muscular Dystrophy Associated with Intellectual Disability.

BACKGROUND: Severe intellectual disability has been reported in a subgroup of patients with Duchenne muscular dystrophy but is not typically associated with Becker muscular dystrophy. PATIENT: The authors report a 13-year-old boy, with severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile), attention-deficit hyperactivity disorder, and mild muscle weakness. He had elevated serum creatine kinase and dystrophic changes on muscle biopsy. Dystrophin immunohistochemistry revealed decreased staining with the C-terminal and mid-rod antibodies and essentially absent staining of the N-terminal immunostain. Sequencing of muscle mRNA revealed aberrant splicing due to a c.10797+5G > A mutation in DMD. CONCLUSION: Dystrophinopathy may be associated with predominantly cognitive impairment and neurobehavioral disorder, and should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males.