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BACKGROUND: Robotic surgical procedures continue to increase both in the United States (US) and worldwide. Several novel robotic surgical platforms are under development or undergoing regulatory approval. This review explores robotic platforms that are expected to reach US consumers within the next 2-3 years. METHODS: The SAGES Robotic Platforms Working Group identified robotic surgery platforms in various stages of development and selected multi-visceral systems nearing or completing the US Food and Drug Administration (FDA) approval process. We outline key system components including architecture, unique features, development status, regulatory approval, and expected markets. RESULTS: We identified twenty robotic platforms that met our selection criteria. Ten companies were based in North America, and ten were based in Europe or Asia. Each system is described in detail and key features are summarized in table form for easy comparison. CONCLUSION: The emergence of novel robotic surgical platforms represents an important evolution in the growth of minimally invasive surgery. Increased competition has the potential to bring value to surgical patients by stimulating innovation and driving down cost. The impact of these platforms remains to be determined, but the continued growth of robotic surgery seems to be all but assured.

PurposeMultiple myeloma is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in multiple myeloma and developed the antibody YS5, which targets a cancer-specific epitope on this protein. We further developed the CD46-targeting PET probe [89Zr]Zr-DFO-YS5 for imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of prostate cancer. These prior studies suggested the feasibility of the CD46 antigen as a theranostic target in multiple myeloma. Herein, we validate [89Zr]Zr-DFO-YS5 for immunoPET imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma in murine models.Experimental designIn vitro saturation binding was performed using the CD46 expressing MM.1S multiple myeloma cell line. ImmunoPET imaging using [89Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and systemic multiple myeloma xenografts. For radioligand therapy, [225Ac]Ac-DOTA-YS5 was prepared, and both dose escalation and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc systemic xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded to assess antitumor effect and toxicity.Results[89Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (Kd = 16.3 nmol/L). In vitro assays in multiple myeloma cell lines demonstrated high binding, and bioinformatics analysis of human multiple myeloma samples revealed high CD46 expression. [89Zr]Zr-DFO-YS5 PET/CT specifically detected multiple myeloma lesions in a variety of models, with low uptake in controls, including CD46 knockout (KO) mice or multiple myeloma mice using a nontargeted antibody. In the MM.1S systemic model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [225Ac]Ac-DOTA-YS5 in the MM.1S systemic model demonstrated a clear tumor volume and survival benefit in the treated groups.ConclusionsOur study showed that the CD46-targeted probe [89Zr]Zr-DFO-YS5 can successfully image CD46-expressing multiple myeloma xenografts in murine models, and [225Ac]Ac-DOTA-YS5 can effectively inhibit the growth of multiple myeloma. These results demonstrate that CD46 is a promising theranostic target for multiple myeloma, with the potential for clinical translation.

BACKGROUND/AIMS: The optic nerve development during the critical postnatal weeks of preterm infants is unclear. We aimed to investigate the change of retinal nerve fibre layer (RNFL) in preterm infants. METHODS: We used an investigational handheld optical coherence tomography (OCT) system to serially image awake preterm infants between 30 and 60 weeks postmenstrual age (PMA) at the bedside. We assessed RNFL thickness in the papillomacular bundle and nasal macular ganglion cell layer+inner plexiform layer (GCL+IPL) thickness. We applied a segmented mixed model to analyse the change in the thickness of RNFL and GCL+IPL as a function of PMA. RESULTS: From 631 OCT imaging sessions of 101 infants (201 eyes), RNFL thickness followed a biphasic model between 30 and 60 weeks, with an estimated transition at 37.8 weeks PMA (95% CI: 37.0 to 38.6). RNFL thickness increased at 1.8 μm/week (95% CI: 1.6 to 2.1) before 37.8 weeks and decreased at -0.3 μm/week (95% CI: -0.5 to -0.2) afterwards. GCL+IPL thickness followed a similar biphasic model, in which the thickness increased at 2.9 μm/week (95% CI: 2.5 to 3.2) before 39.5 weeks PMA (95% CI: 38.8 to 40.1) and then decreased at -0.8 μm/week (95% CI: -0.9 to -0.6). CONCLUSION: We demonstrate the feasibility of monitoring RNFL and GCL+IPL thickness from OCT during the postnatal weeks of preterm infants. Thicknesses follow a biphasic model with a transition age at 37.8 and 39.5 weeks PMA, respectively. These findings may shed light on optic nerve development in preterm infants and assist future study designs.

BACKGROUND AND AIMS: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. APPROACH AND RESULTS: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR 140 ), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR 140 + CVC), or TXR 90 μg + CVC 150 mg (TXR 90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; -13%, TXR 90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + CVC, -1.0 kg; and CVC, -0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR 140 , CVC, TXR 140 + CVC, and TXR 90 + CVC groups, respectively. CONCLUSIONS: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Many robotic procedures require active participation by assistants. Most prior work on assistants' effect on outcomes has been limited in procedural focus and scope, with studies reporting differing results. Knowing how assistant experience affects operating room time could inform operating room case scheduling and provide an impetus for additional assistant training. As such, this retrospective cohort study aimed to determine the association between assistant experience and operating room time for 2291 robotic-assisted operations performed from 2016 to 2022 at our institution. Linear regression showed a significant association between the presence of a junior resident and increased case length differential with an increase of 26.9 min (p = 0.01). There were no significant associations between the presence of a senior resident (p = 0.52), presence of a fellow (p = 0.20), or presence of a physician assistant (p = 0.43) and case length differential. The finding of increased operating room time in the presence of a junior resident during robotic cases supports consideration of the adoption of formal assistant training programs for residents to improve efficiency.

Cutaneous neurofibromas (cNFs) are the most common tumor in people with the rasopathy neurofibromatosis type 1. They number in hundreds or even thousands throughout the body, and currently, there are no effective interventions to prevent or treat these skin tumors. To facilitate the identification of novel and effective therapies, essential studies including a more refined understanding of cNF biology and the role of RAS signaling and downstream effector pathways responsible for cNF initiation, growth, and maintenance are needed. This review highlights the current state of knowledge of RAS signaling in cNF pathogenesis and therapeutic development for cNF treatment.

BackgroundColorectal cancer is a leading cause of morbidity and mortality across U.S. racial/ethnic groups. Existing studies often focus on a particular race/ethnicity or single domain within the care continuum. Granular exploration of disparities among different racial/ethnic groups across the entire colon cancer care continuum is needed. We aimed to characterize differences in colon cancer outcomes by race/ethnicity across each stage of the care continuum.MethodsWe used the 2010-2017 National Cancer Database to examine differences in outcomes by race/ethnicity across six domains: clinical stage at presentation; timing of surgery; access to minimally invasive surgery; post-operative outcomes; utilization of chemotherapy; and cumulative incidence of death. Analysis was via multivariable logistic or median regression, with select demographics, hospital factors, and treatment details as covariates.Results326,003 patients (49.6% female, 24.0% non-White, including 12.7% Black, 6.1% Hispanic/Spanish, 1.3% East Asian, 0.9% Southeast Asian, 0.4% South Asian, 0.3% AIAE, and 0.2% NHOPI) met inclusion criteria. Relative to non-Hispanic White patients: Southeast Asian (OR 1.39, p

Transanal excision of benign lesions, moderately or well-differentiated rectal T1 adenocarcinomas is typically completed via transanal endoscopic microsurgery (TEM) or laparoscopic transanal minimally invasive surgery (TAMIS). Robotic platforms provide ergonomic comfort in an enclosed space, enhanced range of motion, and superior 3D visualization. This study sought to perform a literature review of robotic TAMIS (R-TAMIS) and provide expert commentary on the technique. A Pubmed literature search was performed. Study design, robot type, indication, techniques compared, surgical margins, conversion, complications, operative time, estimated blood loss, patient positioning, and defect closure were collected from included articles. Expert opinion on pre-operative planning, technical details, and possible pitfalls was provided, with an accompanying video. Twelve articles published between 2013 and 2022 were included. Five were case reports, three case series, two prospective cohort studies, one retrospective cohort study, and one Phase II trial. The Da Vinci Si (n = 3), Xi (n = 2), single port (n = 3) and flex robotic system (n = 2) were used. Five studies reported negative surgical margins, one reported positive margins, and six did not comment. Operating room time ranged from 45 to 552 min and EBL ranged from 0 to 100 mL. Patient positioning varied based on lesion location but included supine, prone, modified lithotomy, and prone jackknife positions. 11/12 studies reported defect closure, most commonly with V-Loc absorbable suture. We recommend pre-operative MRI abdomen/pelvis, digital rectal exam, and rigid proctoscopy; prone jackknife patient positioning to avoid collisions with robotic arms; and defect closure of full-thickness excisions with backhanded running V-Loc suture.

BackgroundPerineal hernias can be secondarily acquired following abdominoperineal resection of the rectum. While transabdominal minimally invasive techniques have traditionally used laparoscopy, there are few studies published on the robotic platform, which has been gaining popularity for other types of hernia repairs. We review the existing literature, share a video vignette, and provide practical tips for surgeons interested in adopting this approach.MethodsA literature search in Pubmed was performed to include all articles in English describing robotic repair of perineal hernias with identification of variables of interest related to repair. A case presentation with an accompanying video vignette and lessons learned from the experience are provided.ResultsSeven case reports (four containing video) published between 2019 and 2022 were included. Most articles (n = 5) utilized the Da Vinci Si or Xi, and most patients (n = 5) had undergone abdominoperineal resection with neoadjuvant chemotherapy to treat rectal cancer. Patients were positioned in Trendelenburg with rightward tilt (n = 2), modified lithotomy (n = 1), or a combination of the two (n = 1). All articles (n = 7) reported closing the defect and using mesh. Three articles describe placing five ports (one camera, three robotic, one assistant). There were no significant intraoperative or postoperative complications reported, and no recurrence noted at 3-27 months follow-up. Based on our experience, as shown in the video vignette, we recommend lithotomy positioning, using porous polypropylene mesh anchored to the periosteum of the sacrum and peritoneum overlying the bladder and side wall, and placing a drain above the mesh.ConclusionsA robotic transabdominal approach to perineal hernia repair is a viable alternate to laparoscopy based on low complication rates and lack of recurrence. Prospective and longer duration data are needed to compare the techniques.

BACKGROUND/AIMS: Neonatal insults from systemic diseases have been implicated in the pathway of impaired neurodevelopment in preterm infants. We aimed to investigate the associations between systemic health factors and retinal nerve fibre layer (RNFL) thickness in preterm infants. METHODS: We prospectively enrolled infants and imaged both eyes at 36±1 weeks postmenstrual age (PMA) using a hand-held optical coherence tomography system at the bedside in the Duke intensive care nurseries. We evaluated associations between RNFL thickness and 29 systemic health factors using univariable and multivariable regression models. RESULTS: 83 infants with RNFL thickness measures were included in this study. Based on the multivariable model, RNFL thickness was positively associated with infant weight at imaging and was negatively associated with sepsis/necrotising enterocolitis (NEC). RNFL thickness was 10.4 µm (95% CI -15.9 to -4.9) lower in infants with than without sepsis/NEC in the univariable analysis (p

22q11.2 deletion syndrome, associated with congenital and neuropsychiatric anomalies, is the most common copy number variant (CNV)-associated syndrome. Patient-derived, induced pluripotent stem cell (iPS) models have provided insight into this condition. However, patient-derived iPS cells may harbor underlying genetic heterogeneity that can confound analysis. Furthermore, almost all available models reflect the commonly-found ~ 3 Mb "A-D" deletion at this locus. The ~ 1.5 Mb "A-B" deletion, a variant of the 22q11.2 deletion which may lead to different syndromic features, and is much more frequently inherited than the A-D deletion, remains under-studied due to lack of relevant models. Here we leveraged a CRISPR-based strategy to engineer isogenic iPS models of the 22q11.2 "A-B" deletion. Differentiation to excitatory neurons with subsequent characterization by transcriptomics and cell surface proteomics identified deletion-associated alterations in proliferation and adhesion. To illustrate in vivo applications of this model, we further implanted neuronal progenitor cells into the cortex of neonatal mice and found potential alterations in neuronal maturation. The isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.

Robotic proctectomy has become increasingly popular for both benign and malignant indications. The purpose of this study was to determine if the robotic approach has a distinct advantage over laparoscopy in obese patients, which has been suggested by previous subgroup analyses. We performed a retrospective review of 2016-2018 National Surgery Quality Improvement Program (NSQIP) data to compare outcomes between patients who underwent robotic versus laparoscopic proctectomy, stratified by Body Mass Index (BMI) subgroups. We also compared outcomes of converted minimally invasive proctectomy to planned open operations. Four thousand four hundred eighteen (69.3%) patients underwent laparoscopic proctectomy, and 1956 (30.7%) patients underwent robotic proctectomy. Robotic proctectomy was associated with a significantly lower conversion rate compared to laparoscopic proctectomy (5.1% vs 12.3%; p = 0.002), and this relationship was maintained on an adjusted model. Obese (BMI > 30) patients were more likely to require conversion in both laparoscopic and robotic groups with the greatest difference in the conversion rate in the obese subgroup. Patients who underwent conversion had higher composite morbidity compared to patients who underwent planned open operations (50.8% vs 41.3%; p

Crosstalk between the Hedgehog and MAPK signaling pathways occurs in several types of cancer and contributes to clinical resistance to Hedgehog pathway inhibitors. Here we show that MAP kinase-mediated phosphorylation weakens the binding of the GLI1 transcription factor to its negative regulator SUFU. ERK2 phosphorylates GLI1 on three evolutionarily conserved target sites (S102, S116, and S130) located near the high-affinity binding site for SUFU; these phosphorylations cooperate to weaken the affinity of GLI1-SUFU binding by over 25-fold. Phosphorylation of any one, or even any two, of the three sites does not result in the level of SUFU release seen when all three sites are phosphorylated. Tumor-derived mutations in R100 and S105, residues bordering S102, also diminish SUFU binding, collectively defining a novel evolutionarily conserved SUFU affinity-modulating region. In cultured mammalian cells, GLI1 variants containing phosphomimetic substitutions of S102, S116, and S130 displayed an increased ability to drive transcription. We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk.

Heterogeneity in the clinical presentation of SARS-CoV-2 infection and COVID-19 progression underscores the urgent need to identify individual-level susceptibility factors that affect infection vulnerability and disease severity. Tobacco product use is a potential susceptibility factor. In this Personal View, we provide an overview of the findings of peer-reviewed, published studies relating tobacco product use to SARS-CoV-2 infection and COVID-19 outcomes, with most studies focusing on cigarette smoking in adults. Findings pertaining to the effects of tobacco product use on the incidence of SARS-CoV-2 infection are inconsistent. However, evidence supports a role for cigarette smoking in increasing the risk of poor COVID-19 outcomes, including hospital admission, progression in disease severity, and COVID-19-related mortality. We discuss the potential effects of tobacco use behaviour on SARS-CoV-2 transmission and infection, and highlight the pathophysiological changes associated with cigarette smoking that could promote SARS-CoV-2 infection and increased disease severity. We consider the biological mechanisms by which nicotine and other tobacco product constituents might affect immune and inflammatory responses to SARS-CoV-2 infection. Finally, we identify current knowledge gaps and suggest priorities for research to address acute and post-acute health outcomes of COVID-19 during and after the pandemic.

This cross-sectional study examines factors associated with the stage at which colon cancer is diagnosed.

How basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. We use singe-cell RNA sequencing to define the human BCC ecosystem and discriminate between normal and malignant epithelial cells. We identify spatial biomarkers of tumors and their surrounding stroma that reinforce the heterogeneity of each tissue type. Combining pseudotime, RNA velocity-PAGA, cellular entropy, and regulon analysis in stromal cells reveals a cancer-specific rewiring of fibroblasts, where STAT1, TGF-β, and inflammatory signals induce a noncanonical WNT5A program that maintains the stromal inflammatory state. Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific inflammatory signaling pathways by producing heat shock proteins, whose expression we validated in situ. Last, dose-dependent treatment with an HSP70 inhibitor suppresses in vitro vismodegib-resistant BCC cell growth, Hedgehog signaling, and in vivo tumor growth in a BCC mouse model, validating HSP70's essential role in tumor growth and reinforcing the critical nature of tumor microenvironment cross-talk in BCC progression.

BackgroundWe identified commonly deficient standards across rectal cancer programs that underwent accreditation review by the National Accreditation Program for Rectal Cancer to evaluate for patterns of noncompliance.Study designWith the use of the internal database of the American College of Surgeons, programs that underwent accreditation review from 2018 to 2020 were evaluated. The occurrence and frequency of noncompliance with the standards, using the 2017 standards manual, were evaluated. Programs were further stratified based on the year of review, annual rectal cancer volume, and Commission on Cancer classification.ResultsA total of 25 programs with annual rectal cancer volume from 14 to more than 200 cases per year underwent accreditation review. Only 2 programs achieved 100% compliance with all standards. Compliance with standards ranged from 48% to 100%. The 2 standards with the lowest level of compliance included standard 2.5 and standard 2.11 that require all patients with rectal cancer to be discussed at a multidisciplinary team meeting before the initiation of definitive treatment and within 4 weeks after definitive surgical therapy, respectively. Patterns of noncompliance persisted when programs were stratified on the basis oof the year of survey, annual rectal cancer volume, and Commission on Cancer classification. The corrective action process allowed all programs to ultimately become successfully accredited.ConclusionDuring this initial phase of the National Accreditation Program for Rectal Cancer accreditation, the majority of programs undergoing review did not achieve 100% compliance and went through a corrective action process. Although the minimal multidisciplinary team meeting attendance requirements were simplified in the 2021 revised standards, noncompliance related to presentation of all patients at the multidisciplinary team meeting before and after definitive treatment highlights the need for programs seeking accreditation to implement optimized and standardized workflows to achieve compliance.

BackgroundGuidelines recommend limiting minimally invasive pancreaticoduodenectomy (MIPD) to high-volume centers. However, the definition of high-volume care remains unclear. We aimed to objectively define a minimum number of MIPD performed annually per hospital associated with improved outcomes in a contemporary patient cohort.Patients and methodsResectable pancreatic adenocarcinoma patients undergoing MIPD were included from the National Cancer Database (2010-2017). Multivariable modeling with restricted cubic splines was employed to identify an MIPD annual hospital volume threshold associated with lower 90-day mortality. Outcomes were compared between patients treated at low-volume (≤ model-identified cutoff) and high-volume (> cutoff) centers.ResultsAmong 3079 patients, 141 (5%) died within 90 days. Median hospital volume was 6 (range 1-73) cases/year. After adjustment, increasing hospital volume was associated with decreasing 90-day mortality for up to 19 (95% CI 16-25) cases/year, indicating a threshold of 20 cases/year. Most cases (82%) were done at low-volume (< 20 cases/year) centers. With adjustment, MIPD at low-volume centers was associated with increased 90-day mortality (OR 2.7; p = 0.002). Length of stay, positive surgical margins, 30-day readmission, and overall survival were similar. On analysis of the most recent two years (n = 1031), patients at low-volume centers (78.2%) were younger and had less advanced tumors but had longer length of stay (8 versus 7 days; p < 0.001) and increased 90-day mortality (7% versus 2%; p = 0.009).ConclusionsThe cutpoint analysis identified a threshold of at least 20 MIPD cases/year associated with lower postoperative mortality. This threshold should inform national guidelines and institution-level protocols aimed at facilitating the safe implementation of this complex procedure.

BackgroundRobotic transanal minimally invasive surgery (R-TAMIS) is an appealing alternative to transanal minimally invasive surgery (TAMIS) and transanal endoscopic microsurgery (TEM) for benign and early malignant rectal lesions that are not amenable to traditional open transanal excision. However, no studies to our knowledge have directly compared the three techniques. This study sought to compare peri-operative and pathologic outcomes of the three approaches.MethodsThe records of 29 consecutive patients who underwent TEM, TAMIS, or R-TAMIS at a single academic center between 2016 and 2020 were reviewed. Intra-operative details, pathological diagnosis and margins, and post-operative outcomes were recorded. The three groups were compared using chi-square and Kruskal-Wallis tests.ResultsOverall, 16/29 patients were women and the median age was 57 (interquartile range (IQR): 28-81). Thirteen patients underwent TEM, six had TAMIS, and 10 had R-TAMIS. BMI was lower in the R-TAMIS patients (24.7; IQR 23.8-28.7), than in TEM (29.3; IQR 19.9-30.2), and TAMIS (30.4; IQR 26.6-32.9) patients. High grade dysplasia and/or invasive cancer was more common in TAMIS (80%) and R-TAMIS (66.7%) patients than in TEM patients (41.7%). The three groups did not differ significantly in tumor type or distance from the anal verge. No R-TAMIS patients had a positive surgical margin compared to 23.1% in the TEM group and 16.7% in the TAMIS group. Length of stay (median 1 day for TEM and R-TAMIS patients, 0 days for TAMIS patients) and 30-day readmission rates (7.7% of TEM, 0% of TAMIS, 10% of R-TAMIS patients) also did not differ among the groups. Median operative time was 110 min for TEM, 105 min for TAMIS, and 76 min for R-TAMIS patients.ConclusionsR-TAMIS may have several advantages over other advanced techniques for transanal excisions. R-TAMIS tended to be faster and to more often result in negative surgical margins compared to the two other techniques.

ObjectiveThis prospective study evaluated perioperative lung resection outcomes after implementation of a multidisciplinary, evidence-based Thoracic Enhanced Recovery After Surgery (ERAS) Program in an academic, quaternary-care center.BackgroundERAS programs have the potential to improve outcomes, but have not been widely utilized in thoracic surgery.MethodsIn all, 295 patients underwent elective lung resection for pulmonary malignancy from 2015 to 2019 PRE (n = 169) and POST (n = 126) implementation of an ERAS program containing all major ERAS Society guidelines. Propensity score-matched analysis, based upon patient, tumor, and surgical characteristics, was utilized to evaluate outcomes.ResultsAfter ERAS implementation, there was increased minimally invasive surgery (PRE 39.6%→POST 62.7%), reduced intensive care unit utilization (PRE 70.4%→POST 21.4%), improved chest tube (PRE 24.3%→POST 54.8%) and urinary catheter (PRE 20.1%→POST 65.1%) removal by postoperative day 1, and increased ambulation ≥3× on postoperative day 1 (PRE 46.8%→POST 54.8%). Propensity score-matched analysis that accounted for minimally invasive surgery demonstrated that program implementation reduced length of stay by 1.2 days [95% confidence interval (CI) 0.3-2.0; PRE 4.4→POST 3.2), morbidity by 12.0% (95% CI 1.6%-22.5%; PRE 32.0%→POST 20.0%), opioid use by 19 oral morphine equivalents daily (95% CI 1-36; PRE 101→POST 82), and the direct costs of surgery and hospitalization by $3500 (95% CI $1100-5900; PRE $23,000→POST $19,500). Despite expedited discharge, readmission remained unchanged (PRE 6.3%→POST 6.6%; P = 0.94).ConclusionsThe Thoracic ERAS Program for lung resection reduced length of stay, morbidity, opioid use, and direct costs without change in readmission. This is the first external validation of the ERAS Society thoracic guidelines; adoption by other centers may show similar benefit.

E-cigarette use among adolescents and young adults has been associated with adverse respiratory symptoms, including symptoms of asthma and bronchitis. This investigation examined whether such associations differ by primary type of e-cigarette device used. This cross-sectional study included data from four study populations in California and Connecticut, United States, ages 13-21 years (N = 10,483), who self-reported their tobacco use behaviors and health status from 2018 to 2020. Adverse respiratory symptoms were grouped as bronchitis, asthma exacerbation, and shortness of breath. Associations with e-cigarette use were examined by frequency of e-cigarette use (regardless of device type) and most-frequently use device type in the past 30 days (pod, pen/tank, disposable, or mod). Multivariable modeling accounted for demographic variables and use of other tobacco and cannabis. Results were pooled at the study level via random-effects meta-analysis. Across the four studies, e-cigarette use >5 days/month versus never use was associated with bronchitic symptoms (summary odds ratio, sOR: 1.56; 95% confidence interval, CI: 1.37, 1.77) and shortness of breath (sOR: 1.68; 95% CI: 1.35, 2.08) but not statistically significantly with asthma exacerbations (sOR: 1.36; 95% CI; 0.95, 1.95). Among past 30-day e-cigarette users, associations with respiratory symptoms did not differ by device type. In these populations, e-cigarette use was positively associated with symptoms of bronchitis and shortness of breath, but adjusted odds of symptoms did not differ meaningfully by device type. These findings suggest that risk of these respiratory outcomes is elevated among more frequent e-cigarette users regardless of device type used.

IntroductionVarious methods have been described to create a functional neovagina with feminizing (male-to-female) gender affirming surgery. Intestinal vaginoplasty using ileal or colon segments confers natural mucus production and greater canal depth with primary vaginoplasty. In this work we describe an alternative approach to primary and salvage vaginoplasty using right colon. We focus on relative advantages compared to use of other bowel segments, and we review patient outcomes.MethodsTransgender women who had previously undergone primary vaginoplasty underwent laparoscopic right colon vaginoplasty at our center between 12/2017 and 7/2019. Demographic, medical, outcome, and satisfaction data was collected and retrospectively reviewed.ResultsTwenty-two consecutive transgender women patients underwent laparoscopic right colon vaginoplasty. Mean age was 39.3 years. There were two intraoperative complications:1 injury of the ileocolic pedicle, and 1 minor bladder injury. Four of 22 patients (18.2%) had short-term complications ( 30 days): 1 developed Crohn's (not involving the neovagina); 1 developed late small bowel obstruction (SBO) (managed conservatively); 5 developed neovagina prolapse; 4 developed stenosis (2 at the vaginal introitus, and 2 had extrinsic obstruction at the recto-vaginal junction (all underwent successful laparoscopic surgical correction); and 3 were diagnosed with diversion neovaginitis (all treated conservatively). All complications were successfully treated with conservative and/or surgical intervention. All (100%) patients reported satisfaction with neovagina function and appearance.ConclusionThis is the only outcomes series of transgender women patients who have undergone right colon vaginoplasty, to date. Our study finding suggests that laparoscopic right colon for primary or salvage vaginoplasty has several important advantages over use of Sigmoid colon or Ileum, and is a reliable technique whose complications can be managed successfully, with favorable, satisfactory long-term outcomes.

The SARS-CoV-2 pandemic has had an unprecedented impact on multiple levels of society. Not only has the pandemic completely overwhelmed some health systems but it has also changed how scientific evidence is shared and increased the pace at which such evidence is published and consumed, by scientists, policymakers and the wider public. More significantly, the pandemic has created tremendous challenges for decision-makers, who have had to implement highly disruptive containment measures with very little empirical scientific evidence to support their decision-making process. Given this lack of data, predictive mathematical models have played an increasingly prominent role. In high-income countries, there is a long-standing history of established research groups advising policymakers, whereas a general lack of translational capacity has meant that mathematical models frequently remain inaccessible to policymakers in low-income and middle-income countries. Here, we describe a participatory approach to modelling that aims to circumvent this gap. Our approach involved the creation of an international group of infectious disease modellers and other public health experts, which culminated in the establishment of the COVID-19 Modelling (CoMo) Consortium. Here, we describe how the consortium was formed, the way it functions, the mathematical model used and, crucially, the high degree of engagement fostered between CoMo Consortium members and their respective local policymakers and ministries of health.

Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.

Multiple myeloma (MM) cell lines are routinely used to model the disease. However, a long-standing question is how well these cell lines truly represent tumor cells in patients. Here, we employ a recently described method of transcriptional correlation profiling to compare similarity of 66 MM cell lines to 779 newly diagnosed MM patient tumors. We found that individual MM lines differ significantly with respect to patient tumor representation, with median R ranging from 0.35 to 0.54. ANBL-6 was the "best" line, markedly exceeding all others (p

The Consortium for Top-Down Proteomics (www.topdownproteomics.org) launched the present study to assess the current state of top-down mass spectrometry (TD MS) and middle-down mass spectrometry (MD MS) for characterizing monoclonal antibody (mAb) primary structures, including their modifications. To meet the needs of the rapidly growing therapeutic antibody market, it is important to develop analytical strategies to characterize the heterogeneity of a therapeutic product's primary structure accurately and reproducibly. The major objective of the present study is to determine whether current TD/MD MS technologies and protocols can add value to the more commonly employed bottom-up (BU) approaches with regard to confirming protein integrity, sequencing variable domains, avoiding artifacts, and revealing modifications and their locations. We also aim to gather information on the common TD/MD MS methods and practices in the field. A panel of three mAbs was selected and centrally provided to 20 laboratories worldwide for the analysis: Sigma mAb standard (SiLuLite), NIST mAb standard, and the therapeutic mAb Herceptin (trastuzumab). Various MS instrument platforms and ion dissociation techniques were employed. The present study confirms that TD/MD MS tools are available in laboratories worldwide and provide complementary information to the BU approach that can be crucial for comprehensive mAb characterization. The current limitations, as well as possible solutions to overcome them, are also outlined. A primary limitation revealed by the results of the present study is that the expert knowledge in both experiment and data analysis is indispensable to practice TD/MD MS.

The Tobacco Regulatory Science Program is a collaborative research effort between the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). In 2013, the NIH funded 14 Tobacco Centers of Regulatory Science (TCORS), which serve as partners in establishing research, training, and professional development programs to guide FDA. Each of the fourteen TCORS, and two other NIH-funded research programs, the Center for the Evaluation of Nicotine in Cigarettes (CENIC) and the Consortium on Methods Evaluating Tobacco (COMET), pursued specific research themes relevant to FDA's priorities. A key mandate for FDA is to reduce tobacco use among young people. This article is a review of the peer-reviewed research, including published and in-press manuscripts, from the TCORS, CENIC, and COMET, which provides specific data or other findings on youth (ages 10-18 years) and/or young adults (ages 18-34 years), from 2013 to 2018. Citations of all TCORS, CENIC, and COMET articles from September 2013 to December 2017 were collected by the TCORS coordinating center, the Center for Evaluation and Coordination of Training and Research. Additional citations up to April 30, 2018 were requested from the principal investigators. A scoring rubric was developed and implemented to assess study type, primary theme, and FDA priority area addressed by each article. The major subareas and findings from each priority area are presented. There were 766 articles in total, with 258 (34%) focusing on youth and/or young adults. Findings relevant to FDA from this review concern impact analysis, toxicity, health effects, addiction, marketing influences, communications, and behavior.ImplicationsThe Tobacco Centers of Regulatory Science, CENIC, and COMET have had a high output of scientific articles since 2013. These Centers are unique in that the FDA supports science specifically to guide future regulatory actions. The 258 articles that have focused on youth and/or young adults are providing data for regulatory actions by the FDA related to the key priority areas such as the addictiveness of non-cigarette products, the effects of exposure to electronic cigarette marketing on initiation and cessation, and the impact of flavored products on youth and young adult tobacco use. Future regulations to reduce tobacco use will be guided by the cumulative evidence. These Centers are one innovative mechanism to promote important outcomes to advance tobacco regulatory science.

Enthusiasm exists for the potential of diet to impact the immune system, prevent disease and its therapeutic potential. Herein, we describe the challenge to nutrition scientists in defining this relationship through case studies of diets and nutrients in the context of allergic and autoimmune diseases. Moderate-quality evidence exists from both human intervention and observational studies to suggest that diet and individual nutrients can influence systemic markers of immune function and inflammation; numerous challenges exist for demonstrating the impact of defined diets and nutrient interventions on clearly influencing immune-mediated-clinical disease endpoints. A growing body of evidence suggests that further consideration of dietary patterns, immune system and gut microbiome composition and function, and subsequent epigenetic modifications are needed to improve our understanding of diet-immune system interactions.

PurposeWe aimed to described 25-hydroxyvitamin D [25(OH)D] levels in newly diagnosed colorectal cancer (CRC) patients and to re-evaluate levels after chemotherapy.MethodsPermanent residents of the San Francisco Bay Area with a new CRC diagnosis of any stage were recruited prior to any non-surgical therapy. Serum 25(OH)D levels were measured at time of diagnosis and 6-month follow-up. Supplement use was not restricted. The primary endpoint was the frequency of vitamin D deficiency in patients with newly diagnosed CRC of all stages. The Kruskal-Wallis and Spearman correlation tests were used to evaluate associations of patient characteristics with 25(OH)D levels.ResultsMedian 25(OH)D level at baseline was 27.0 ng/mL (range 7.2, 59.0); 65% of patients had insufficient levels (25(OH)D

Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naive tumor responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains common. Although the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, and the molecular basis of tumor type and pathway selection are still obscure. Here, we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoothened inhibitor-resistant BCCs have an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared with naive or Gorlin syndrome patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature showed increased Ras/MAPK pathway activation. Tissue analysis confirmed an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiated Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines conferred resistance to both canonical (vismodegib) and noncanonical (atypical protein kinase C and MRTF inhibitors) HH pathway inhibitors and conferred sensitivity to MAPK inhibitors. Our results provide insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH-to-Ras/MAPK pathway switching.

Without haptic feedback, robotic surgeons rely on visual processing to interpret the operative field. To provide guidance for teaching in this environment, we analyzed intracorporeal actions and behaviors of a robotic surgeon. Six hours of video were captured by the intracorporeal camera during a robot-assisted lower anterior resection. After complete review, authors reduced the video to a consecutive 35 min of highly focused robotic activity and finally, a 2-min clip was subjected to microanalysis. The clip was replayed multiple times (capturing 1, 2, 10, 60 and 120 s intervals) and activities were identified, such as right and left hand motion, tissue handling and camera adjustments recorded using a software program. Activity patterns were categorized into two main themes: change in operative focus occurs when there is an inability to obtain adequate tension, and observation of robot-assisted surgery is based on an incomplete visual framework. The surgeon manipulated tissue predominantly using blunt adjustments and rarely grasped it, likely as a way to avoid tissue trauma. A magnified operative field required precise dissection, which occurs robotically with movement of a single instrument against a static field (motionless second robotic arm). This meticulous technique is unlike the bimodal manipulation often used for laparoscopic dissection. Since residents have limited active participation in robotic cases, and therefore, rely heavily on the captured image for skill acquisition, we recommend surgeons to use focus shifts as an opportunity to describe their operative decision-making and highlight instrument manipulations specific to operating with robotic technology.

Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.

In this review, we explore the rationale and history behind the practice of preoperative fasting in elective surgery including the gradual move toward longer fasting and the more recent change in direction of practice. Gastric emptying physiology and the metabolic effects of prolonged fasting and carbohydrate loading are examined. Most recent guidelines related to these topics are discussed and practical recommendations for implementing these guidelines are suggested.

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.

ImportanceTumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.ObjectiveTo determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Design, setting, and participantsFive men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.Main outcomes and measuresThe primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.ResultsOf the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.Conclusions and relevanceTargeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.

A recent innovation to help patients adhere to daily tuberculosis (TB) treatment over many months is video (or virtually) observed therapy (VOT). VOT is becoming increasingly feasible as mobile telephone applications and tablet computers become more widely available. Studies of the effectiveness of VOT in improving TB patient outcomes are being conducted.

A recent innovation to help patients adhere to daily tuberculosis (TB) treatment over many months is video (or virtually) observed therapy (VOT). VOT is becoming increasingly feasible as mobile telephone applications and tablet computers become more widely available. Studies of the effectiveness of VOT in improving TB patient outcomes are being conducted.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.

Radiation damage to the rectum following radiotherapy for pelvic malignancies can range from acute dose-limiting side effects to major morbidity affecting health-related quality of life. No standard guidelines exist for diagnosis and management of radiation proctitis. This article reviews the definitions, staging, and clinical features of radiation proctitis, and summarizes the modalities available for the treatment of acute and chronic radiation proctitis. Because of the paucity of well-controlled, blinded, randomized studies, it is not possible to fully assess the comparative efficacy of the different approaches to management. However, the evidence and rationale for use of the different strategies are presented.

Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.