Long-read DNA and cDNA sequencing identify cancer-predisposing deep intronic variation in tumor-suppressor genes.

The vast majority of deeply intronic genomic variants are benign, but some extremely rare or private deep intronic variants lead to exonification of intronic sequence with abnormal transcriptional consequences. Damaging variants of this class are likely underreported as causes of disease for several reasons: Most clinical DNA and RNA testing does not include full intronic sequences; many of these variants lie in complex repetitive regions that cannot be aligned from short-read whole-genome sequence; and, until recently, consequences of deep intronic variants were not accurately predicted by in silico tools. We evaluated the frequency and consequences of rare deep intronic variants for families severely affected with breast, ovarian, pancreatic, and/or metastatic prostate cancer, but with no causal variant identified by any previous genomic or cDNA-based approach. For 10 tumor-suppressor genes, we used multiplexed adaptive sampling long-read DNA sequencing and cDNA sequencing, based on patient-derived DNA and RNA, to systematically evaluate deep intronic variation. We identified all variants across the full genomic loci of targeted genes, applied the in silico tools SpliceAI and Pangolin to predict variants of functional consequence, and then carried out long-read cDNA sequencing to identify aberrant transcripts. For eight of the 120 (6%) previously unsolved families, rare deep intronic variants in BRCA1, PALB2, and ATM create intronic pseudoexons that are spliced into transcripts, leading to premature truncations. These results suggest that long-read DNA and cDNA sequencing can be integrated into variant discovery, with strategies for accurately characterizing pathogenic variants.

Resolving the chromatin impact of mosaic variants with targeted Fiber-seq.

Accurately quantifying the functional consequences of non-coding mosaic variants requires the pairing of DNA sequence with both accessible and closed chromatin architectures along individual DNA molecules-a pairing that cannot be achieved using traditional fragmentation-based chromatin assays. We demonstrate that targeted single-molecule chromatin fiber sequencing (Fiber-seq) achieves this, permitting single-molecule, long-read genomic and epigenomic profiling across targeted >100 kilobase loci with ~10-fold enrichment over untargeted sequencing. Targeted Fiber-seq reveals that pathogenic expansions of the DMPK CTG repeat that underlie Myotonic Dystrophy 1 are characterized by somatic instability and disruption of multiple nearby regulatory elements, both of which are repeat length-dependent. Furthermore, we reveal that therapeutic adenine base editing of the segmentally duplicated γ-globin (HBG1/HBG2) promoters in primary human hematopoietic cells induced towards an erythroblast lineage increases the accessibility of the HBG1 promoter as well as neighboring regulatory elements. Overall, we find that these non-protein coding mosaic variants can have complex impacts on chromatin architectures, including extending beyond the regulatory element harboring the variant.

Improved reference quality genome sequence of the plastic-degrading greater wax moth, Galleria mellonella.

Galleria mellonella is a pest of honeybees in many countries because its larvae feed on beeswax. However, G. mellonella larvae can also eat various plastics, including polyethylene, polystyrene, and polypropylene, and therefore, the species is garnering increasing interest as a tool for plastic biodegradation research. This paper presents an improved genome (99.3% completed lepidoptera_odb10 BUSCO; genome mode) for G. mellonella. This 472 Mb genome is in 221 contigs with an N50 of 6.4 Mb and contains 13,604 protein-coding genes. Genes that code for known and putative polyethylene-degrading enzymes and their similarity to proteins found in other Lepidoptera are highlighted. An analysis of secretory proteins more likely to be involved in the plastic catabolic process has also been carried out.

G-U base-paired hpRNA confers potent inhibition of small RNA function in plants.

MicroRNA (miRNA) target mimicry technologies, utilizing naturally occurring miRNA decoy molecules, represent a potent tool for analyzing miRNA function. In this study, we present a highly efficient small RNA (sRNA) target mimicry design based on G-U base-paired hairpin RNA (hpG:U), which allows for the simultaneous targeting of multiple sRNAs. The hpG:U constructs consistently generate high amounts of intact, polyadenylated stem-loop (SL) RNA outside the nuclei, in contrast to traditional hairpin RNA designs with canonical base pairing (hpWT), which were predominantly processed resulting in a loop. By incorporating a 460-bp G-U base-paired double-stranded stem and a 312-576 nt loop carrying multiple miRNA target mimicry sites (GUMIC), the hpG:U construct displayed effective repression of three Arabidopsis miRNAs, namely miR165/166, miR157, and miR160, both individually and in combination. Additionally, a GUMIC construct targeting a prominent cluster of siRNAs derived from cucumber mosaic virus (CMV) Y-satellite RNA (Y-Sat) effectively inhibited Y-Sat siRNA-directed silencing of the chlorophyll biosynthetic gene CHLI, thereby reducing the yellowing symptoms in infected Nicotiana plants. Therefore, the G-U base-paired hpRNA, characterized by differential processing compared to traditional hpRNA, acts as an efficient decoy for both miRNAs and siRNAs. This technology holds great potential for sRNA functional analysis and the management of sRNA-mediated diseases.

Multidisciplinary Surgical Approach to Increase Survival for Advanced Ovarian Cancer in a Tertiary Gynaecological Oncology Centre.

PURPOSE: The purpose of this paper is to report on changes in overall survival, progression-free survival, and complete cytoreduction rates in the 5-year period after the implementation of a multidisciplinary surgical team (MDT). METHODS: Two cohorts were used. Cohort A was a retrospectively collated cohort from 2006 to 2015. Cohort B was a prospectively collated cohort of patients from January 2017 to September 2021. RESULTS: This study included 146 patients in cohort A (2006-2015) and 174 patients in cohort B (2017-2021) with FIGO stage III/IV ovarian cancer. Median follow-up in cohort A was 60 months and 48 months in cohort B. The rate of primary cytoreductive surgery increased from 38% (55/146) in cohort A to 46.5% (81/174) in cohort B. Complete macroscopic resection increased from 58.9% (86/146) in cohort A to 78.7% (137/174) in cohort B (p < 0.001). At 3 years, 75% (109/144) patients had disease progression in cohort A compared with 48.8% (85/174) in cohort B (log-rank, p < 0.001). Also at 3 years, 64.5% (93/144) of patients had died in cohort A compared with 24% (42/174) of cohort B (log-rank, p < 0.001). Cox multivariate analysis demonstrated that MDT input, residual disease, and age were independent predictors of overall (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.203-0.437, p < 0.001) and progression-free survival (HR 0.31, 95% CI 0.21-0.43, p < 0.001). Major morbidity remained stable throughout both study periods (2006-2021). CONCLUSIONS: Our data demonstrate that the implementation of multidisciplinary-team, intraoperative approach allowed for a change in surgical philosophy and has resulted in a significant improvement in overall survival, progression-free survival, and complete resection rates.

Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes.

Importance: In the US, most childhood-onset bilateral sensorineural hearing loss is genetic, with more than 120 genes and thousands of different alleles known. Primary treatments are hearing aids and cochlear implants. Genetic diagnosis can inform progression of hearing loss, indicate potential syndromic features, and suggest best timing for individualized treatment. Objective: To identify the genetic causes of childhood-onset hearing loss and characterize severity, progression, and cochlear implant success associated with genotype in a single large clinical cohort. Design, Setting, and Participants: This cross-sectional analysis (genomics) and retrospective cohort analysis (audiological measures) were conducted from 2019 to 2022 at the otolaryngology and audiology clinics of Seattle Children's Hospital and the University of Washington and included 449 children from 406 families with bilateral sensorineural hearing loss with an onset younger than 18 years. Data were analyzed between January and June 2022. Main Outcomes and Measures: Genetic diagnoses based on genomic sequencing and structural variant analysis of the DNA of participants; severity and progression of hearing loss as measured by audiologic testing; and cochlear implant success as measured by pediatric and adult speech perception tests. Hearing thresholds and speech perception scores were evaluated with respect to age at implant, months since implant, and genotype using a multivariate analysis of variance and covariance. Results: Of 406 participants, 208 (51%) were female, 17 (4%) were African/African American, 32 (8%) were East Asian, 219 (54%) were European, 53 (13%) were Latino/Admixed American, and 16 (4%) were South Asian. Genomic analysis yielded genetic diagnoses for 210 of 406 families (52%), including 55 of 82 multiplex families (67%) and 155 of 324 singleton families (48%). Rates of genetic diagnosis were similar for children of all ancestries. Causal variants occurred in 43 different genes, with each child (with 1 exception) having causative variant(s) in only 1 gene. Hearing loss severity, affected frequencies, and progression varied by gene and, for some genes, by genotype within gene. For children with causative mutations in MYO6, OTOA, SLC26A4, TMPRSS3, or severe loss-of-function variants in GJB2, hearing loss was progressive, with losses of more than 10 dB per decade. For all children with cochlear implants, outcomes of adult speech perception tests were greater than preimplanted levels. Yet the degree of success varied substantially by genotype. Adjusting for age at implant and interval since implant, speech perception was highest for children with hearing loss due to MITF or TMPRSS3. Conclusions and Relevance: The results of this cross-sectional study suggest that genetic diagnosis is now sufficiently advanced to enable its integration into precision medical care for childhood-onset hearing loss.

Clinically Complex LRBA Deficiency Due to a Founder Allele in the Georgian Jewish Population.

Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin's disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.

"I'd never have that operation again" - a mixed-methods study on how patients react to adverse outcomes following foot and ankle surgery.

BACKGROUND: Adverse outcomes arising from foot and ankle surgery, including lack of pain relief, increased disability and perioperative complications are infrequent but inevitable. This mixed-methods study aims to explore the impact of adverse outcomes on patients following nonemergent foot and ankle surgery. METHODS: Patients who underwent foot and ankle surgery over a two-year period were invited to participate in this study if they reported an adverse outcome. Qualitative assessment consisted of individual semi-structured interviews, designed to explore the decision they made to have surgery and the impact of the outcome after surgery. Quantitative assessment was performed using questionnaires on demographics, current analgesia, foot pain, health-related quality of life, psychological health, and regret. RESULTS: Twelve participants (eight women) consented for inclusion in this study. Current foot pain was high in 10 participants, five met the criteria for central sensitisation syndrome and two had clinically significant pain catastrophising. Most participants regretted their decision to have surgery. The three major themes identified were expectations, communication, and alternatives. CONCLUSIONS: Self-reported adverse outcomes following foot and ankle surgery were prevalent and participants in this study consistently complained of persistent pain. Regret was common and reasons cited for their adverse outcomes centred around the feelings of inadequate communication and failure to meet expectations.

Text Messaging, Telephone, or In-Person Outpatient Visit to the Surgical Clinic: A Randomized Trial.

INTRODUCTION: Routine outpatient follow-up visits for surgical patients are a source of strain on health-care resources and patients. With the COVID-19 pandemic adding a new urgency to finding the safest follow-up arrangement, text message follow-up might prove an acceptable alternative to a phone call or an in-person clinic visit. METHODS: An open-label, three-arm, parallel randomized trial was conducted. The interventions were traditional in-person appointment, a telephone call, or a text message. The primary outcome was the number of postdischarge complications identified. The secondary outcomes were patient satisfaction with follow-up, future preference, default to follow-up, and preference to receiving medical information by text message. RESULTS: Two hundred eight patients underwent randomization: 50 in the in-person group, 80 in the telephone group, and 78 in the text message group. There was no difference in the number of reported complications: 5 (10%) patients in the in-person group, 7 (9%) patients in the text group, and 11 (14%) patients in the telephone group (P = 0.613). The preferred method of follow-up was by telephone (106, 61.6%). The least preferred was the in-person follow-up (15, 8.7%, P = 0.002), which also had the highest default rate (44%). CONCLUSIONS: There was no evidence that text messages and telephone calls are unsafe and ineffective methods of follow-up. Although most patients are happy to receive results by text message, the majority of patients would prefer a telephone follow-up and are less likely to default by this method. Health-care systems should develop telehealth initiatives when planning health-care services in the wake of the COVID-19 pandemic.

Mutational spectrum of breast cancer susceptibility genes among women ascertained in a cancer risk clinic in Northeast Brazil.

PURPOSE: There is a paucity of data on the spectrum and prevalence of pathogenic variants among women of African ancestry in the Northeast region of Brazil. METHODS: We performed BROCA panel sequencing to identify inherited loss-of-function variants in breast cancer susceptibility genes among 292 Brazilian women referred to a single institution cancer risk assessment program. RESULTS: The study included a convenient cohort of 173 women with invasive breast cancer (cases) and 119 women who were cancer-free at the time of ascertainment. The majority of the women self-reported as African-descended (67% for cases and 90.8% for unaffected volunteers). Thirty-seven pathogenic variants were found in 36 (20.8%) patients. While the spectrum of pathogenic variants was heterogeneous, the majority (70.3%) of the pathogenic variants were detected in high-risk genes BRCA1, BRCA2, PALB2, and TP53. Pathogenic variants were also found in the ATM, BARD1, BRIP1, FAM175A, FANCM, NBN, and SLX4 genes in 6.4% of the affected women. Four recurrent pathogenic variants were detected in 11 patients of African ancestry. Only one unaffected woman had a pathogenic variant in the RAD51C gene. Different risk assessment models examined performed well in predicting risk of carrying germline loss-of-function variants in BRCA1 and/or BRCA2 in breast cancer cases. CONCLUSION: The high prevalence and heterogenous spectrum of pathogenic variants identified among self-reported African descendants in Northeast Brazil is consistent with studies in other African ancestry populations with a high burden of aggressive young onset breast cancer. It underscores the need to integrate comprehensive cancer risk assessment and genomic testing in the management of newly diagnosed Black women with breast cancer across the African Diaspora, enabling improved cancer control in admixed underserved and understudied populations.

Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management.

BACKGROUND: Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes. OBJECTIVE: We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management. METHODS: Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis. RESULTS: Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation. CONCLUSIONS: Many childhood disorders now bundled as "IPEX-like" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis.

User Evaluation of a Novel Smart Insufflator for Laparoscopic Surgery-The EVA-15.

INTRODUCTION: There is resurging interest in the importance of effective, nuanced insufflation and personalised pneumoperitoneal pressure-management during laparoscopy. Here, we present user-evaluation data from a regulated, prospective, multispecialty study of a new insufflator (EVA-15, Palliare, Galway, Ireland) which provides high-frequency pressure-sensing, built-in smoke evacuation with pedal activation and highly responsive, high-flow gas provision. METHODS: With institutional ethics and regulatory body approval, a non-randomised, prospective clinical investigation was performed on 30 subjects undergoing laparoscopic surgery using an EVA-15 device. Cases were selected from a variety of specialties on a near-consecutive basis without specific exclusion criteria. Users (both surgeons and operating room nurses) completed a survey at case completion to capture ordinal categorical data on a 5-point Likert agreement scale (1 - Strongly disagree to 5 - Strongly agree) concerning (i) Settings and Setup Evaluations, (ii) Alarms and Displays Evaluations, (iii) Short Instruction Guide, and (iv) Insufflator Performance along with any additional feedback. RESULTS: Operations on 30 patients (mean age 54 y, 15 males) were studied with a questionnaire completed by operating room teams after individual consent. The procedures included general (n=13), upper (n=3) and lower (n=6) gastrointestinal surgery, bariatric (n=3), hepatobiliary (n=2) urology (n=2, both robotic prostatectomy) and gynaecology (n=1) operations. In all cases, the laparoscopic component was completed capably with the use of the EVA-15 device. The insufflator evaluation score across all categories was a median of 4, demonstrating satisfactory use and performance in all regards. CONCLUSION: The EVA-15 is a smart insufflator system that is capable of satisfactory performance across a spectrum of cases among different specialties.

Genomic insights into a population of introduced European rabbits Oryctolagus cuniculus in Australia and the development of genetic resistance to rabbit hemorrhagic disease virus.

The European rabbit (Oryctolagus cuniculus) is one of the most devastating invasive species in Australia. Since the 1950s, myxoma virus (MYXV) and rabbit haemorrhagic disease virus (RHDV) have been used to manage overabundant rabbit populations. Resistance to MYXV was observed within a few years of the release. More recently, resistance to lethal RHDV infection has also been reported, undermining the efficiency of landscape-scale rabbit control. Previous studies suggest that genetic resistance to lethal RHDV infection may differ locally between populations, yet the mechanisms of genetic resistance remain poorly understood. Here, we used genotyping by sequencing (GBS) data representing a reduced representation of the genome, to investigate Australian rabbit populations. Our aims were to understand the relationship between populations and identify possible genomic signatures of selection for RHDV resistance. One population we investigated had previously been reported to show levels of resistance to lethal RHDV infection. This population was compared to three other populations with lower or no previously reported RHDV resistance. We identified a set of novel candidate genes that could be involved in host-pathogen interactions such as virus binding and infection processes. These genes did not overlap with previous studies on RHDV resistance carried out in different rabbit populations, suggesting that multiple mechanisms are feasible. These findings provide useful insights into the different potential mechanisms of genetic resistance to RHDV virus which will inform future functional studies in this area.

In Vitro User Assessment of a Novel Wound Protection and Specimen Extraction System for Laparoscopic Procedures Involving Morcellation.

INTRODUCTION: The risk of unknowingly disseminating leiomyosarcoma by morcellation in women undergoing laparoscopic hysterectomy has massively impacted gynaecological practice. Here, we present the results of an in vitro assessment of a novel protection system developed to mitigate this hazard. METHODS: The Tissue Containment System for Manual Morcellation (Guardenia™, Advanced Surgical Concepts, Wicklow, Ireland) is an evolved wound protection/specimen extraction guarded bag system compatible with any 12mm trocar. Device use was assessed by device-naïve gynaecological and general surgeon volunteers (providing expert and inexpert morcellation cohorts, respectively) on a bench model consisting of biological tissue in a custom-built moulded rig with camera control after the operators were instructed in its use. RESULTS: Twenty surgeons (10 gynaecologists/10 general surgeons, median duration of practice experience: 8 years, median annual number of laparoscopic operative procedures: 150 and 80, respectively) completed the user assessment. All subjects understood and correctly performed each step; i.e., (i) placement of the bag through the trocar, (ii) specimen bagging, (iii) incision extension (range 25-60 mm) after tethering the bag through the port, (iv) insertion of the device guard through the mouth of the bag after trocar removal, and (v) sufficient tissue morcellation within the bag to enable complete specimen removal (mean specimen weight 390g, range 201-1800g). There was 100% bag integrity by water-leak testing following use, despite scalpel contact with the guard in 14/20 cases (70%). CONCLUSION: Among first-time clinical users, this novel device enabled complete containment of morcellation debris and removal of a laparoscopic specimen, which would support further submission for regulatory approval.

The addition of sodium thiosulphate to hyperthermic intraperitoneal chemotherapy with cisplatin in ovarian cancer.

Cisplatin based hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to prolong recurrence free and overall survival of women with ovarian cancer who have responded to neoadjuvant chemotherapy. The aim of this study was to assess the impact of cytoreductive surgery with or without the addition of HIPEC on renal function. METHOD: This is a retrospective case-controlled study at a tertiary teaching hospital in Dublin, Ireland. All patients who had interval cytoreductive surgery (CRS) and HIPEC from October 2017 to October 2020 were included. A cohort of patients who had interval CRS without HIPEC were included as a control. Sodium thiosulphate (ST) was added to the HIPEC protocol in 2019. In order to assess the impact of ST as a renal protectant, renal function and post-operative outcomes were compared between the groups. RESULTS: Sixty patients who had interval CRS were included, thirty of whom received cisplatin-based HIPEC. Seven received cisplatin 50 mg/m2 without the addition of ST. Twenty three patients received cisplatin 100 mg/m2 and ST. There were no statistically differences in age, body mass index BMI, American society of anaesthesia score, estimated blood loss or peritoneal cancer index between the cohorts (p > 0.05). The only episode of acute kidney injury (AKI) was within the HIPEC cohort, after cisplatin 50 mg/m2 (without ST) and this was sustained at three months. In contrast, no patients within the CRS cohort or cisplatin 100 mg/m2 that received the addition of ST, sustained a renal injury and all had a creatinine within the normal range at three days post operatively. CONCLUSION: The renal toxicity associated with cisplatin HIPEC and major abdominal surgery can be minimised with careful preoperative optimisation, intra operative fluid management and attention to renal function. The addition of sodium thiosulphate is a safe and effective method to minimise toxicity and should be added to any cisplatin HIPEC protocol.

Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder.

OBJECTIVES: To better distinguish NOG-related-symphalangism spectrum disorder (NOG-SSD) from chromosomal 17q22 microdeletion syndromes and to inform surgical considerations in stapes surgery for patients with NOG-SSD. BACKGROUND: Mutations in NOG cause a variety of skeletal syndromes that often include conductive hearing loss. Several microdeletions of chromosome 17q22 lead to severe syndromes with clinical characteristics that overlap NOG-SSD. Isolated deletion of NOG has not been described, and therefore the contribution of NOG deletion in these syndromes is unknown. METHODS: Two families with autosomal dominant NOG-SSD exhibited stapes ankylosis, facial dysmorphisms, and skeletal and joint anomalies. In each family, NOG was evaluated by genomic sequencing and candidate mutations confirmed as damaging by in vitro assays. Temporal bone histology of a patient with NOG-SSD was compared with temporal bones of 40 patients diagnosed with otosclerosis. RESULTS: Family 1 harbors a 555 kb chromosomal deletion encompassing only NOG and ANKFN1. Family 2 harbors a missense mutation in NOG leading to absence of noggin protein. The incus-footplate distance of the temporal bone was significantly longer in a patient with NOG-SSD than in patients with otosclerosis. CONCLUSION: The chromosomal microdeletion of family 1 led to a phenotype comparable to that due to a NOG point mutation and much milder than the phenotypes due to other chromosome 17q22 microdeletions. Severe clinical findings in other microdeletion cases are likely due to deletion of genes other than NOG. Based on temporal bone findings, we recommend that surgeons obtain longer stapes prostheses before stapes surgery in individuals with NOG-SSD stapes ankylosis.

Cisplatin +/- rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer.

Patients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0-11.5 cm) with 1 (0-38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82-4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.

A Bibliometric Analysis of 4 Major Foot and Ankle Surgery Journals.

Research publication is a central to the scientific process and comprehensive bibliometric analysis is a leading way to better understand trends within research. Currently, there are limited bibliometric analyses of literature pertaining to foot and ankle surgery. This study aims to quantify the volume of research and investigate what may affect publication and citation. Journals associated with the 3 major orthopedic foot and ankle societies (Foot & Ankle International[FAI], Foot and Ankle Surgery, and The Foot) and one podiatric college (Journal of Foot and Ankle Surgery®) were evaluated from January 2009 to December 2018 using Scopus (Elsevier, Amsterdam, the Netherlands). Descriptive statistics were used to summarize article characteristics and regression modeling was used to determine factors associated with a country's current and future productivity and an article's citation rate. A total of 4994 articles were published over the 10-year period, with the largest contributor of publications being the United States of America (USA), who produced 2096 (41.8%) publications. Regression analysis found no association between a country's productivity and gross domestic product or population. There was no significant relationship between a country's baseline publication rate and future publication rate. The variables significantly associated with an increased citation count were; the number of years since publication, the number of authors, publication in FAI and if the article was a review. To our knowledge this is the largest bibliometric analysis of foot and ankle publications. The majority of research is being produced by the USA, but there are numerous complex factors associated with citation and publication rates. Further research is required to fully assess these factors and characterize the state of foot and ankle surgery research.

Multidisciplinary Surgical Approach to Increase Complete Cytoreduction Rates for Advanced Ovarian Cancer in a Tertiary Gynecologic Oncology Center.

BACKGROUND: Surgical resection remains the cornerstone of ovarian cancer management. In 2017, the authors implemented a multi-disciplinary surgical team comprising gynecologic oncologists as well as colorectal, hepatobiliary, and upper gastrointestinal (GI) surgeons to increase gross macroscopic resection rates. This report aims to describe changes in complete cytoreduction rates and morbidity after the implementation of a multi-disciplinary surgical team comprising gynecologic oncologists as well as colorectal, hepatobiliary, and upper GI surgeons in a tertiary gynecologic oncology unit. METHODS: The study used two cohorts. Cohort A was a retrospectively collated cohort from 2006 to 2015. Cohort B was a prospectively collated cohort of patients initiated in 2017. A multidisciplinary approach to preoperative medical optimization, intraoperative management, and postoperative care was implemented in 2017. The patients in cohort B with upper abdominal disease were offered primary cytoreduction with or without hyperthermic intraperitoneal chemotherapy (HIPEC). Before 2017, the patients with upper abdominal disease received neoadjuvant chemotherapy (cohort A). RESULTS: This study included 146 patients in cohort A (2006-2015) and 93 patients in cohort B (2017-2019) with stages 3 or 4 ovarian cancer. The overall complete macroscopic resection rate (CC0) increased from 58.9 in cohort A to 67.7% in cohort B. The rate of primary cytoreductive surgery (CRS) increased from 38 (55/146) in cohort A to 42% (39/93) in cohort B. The CC0 rate for the patients who underwent primary CRS increased from 49 in cohort A to 77% in cohort B. Major morbidity remained stable throughout both study periods (2006-2019). CONCLUSIONS: The study data demonstrate that implementation of a multidisciplinary team intraoperative approach and a meticulous approach to preoperative optimization resulted in significantly improved complete resection rates, particularly for women offered primary CRS.