93 research outputs found

    Stroke genetics informs drug discovery and risk prediction across ancestries

    Get PDF
    Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

    Laparoscopic splenectomy for metastatic squamous cell cancer of the neck

    No full text
    Squamous cell carcinoma (SCC) spreads through direct extension, lymphatic vessels, and, rarely, hematogenous routes. The most common malignancies to metastasize to the spleen include carcinomas of the breast, lung, and melanoma. We present an unusual case of SCC of the neck with splenic metastases. The patient presented with a primary solid tumor of the neck that extended into the surrounding soft tissues, including the internal jugular vein and regional lymph nodes. A metastatic work-up with a positron emission tomograph showed enhancement in the left upper quadrant. A computed tomograph (CT) was then performed. The CT revealed three distinct splenic lesions, the largest measuring 6 × 6.5 × 2.5 cm. Subsequently, the patient was scheduled for a splenectomy. At the time of operation, diagnostic laparoscopy revealed only the splenic lesions. A laparoscopic splenectomy was performed successfully and the patient was started on a regular diet on postoperative day 1. This paper describes the first documented case of SCC of the neck with splenic metastases. The lesion was diagnosed and treated laparoscopically. The case is described in detail along with the clinical implications of this rare finding. © Mary Ann Liebert, Inc

    Laparoscopic Hiatal Hernia Repair with Falciform Ligament Buttress

    No full text
    © 2018, The Society for Surgery of the Alimentary Tract (This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply). Background: Using synthetic mesh to buttress the crural repair during laparoscopic hiatal hernia repair may be associated with dysphagia and esophageal erosions, while a biologic mesh is expensive and does not decrease long-term recurrence rates. This study documents outcomes of laparoscopic paraesophageal hernia repairs using the falciform ligament to reinforce the crural repair. Methods: This is a prospective study of laparoscopic paraesophageal hernia repairs with a falciform ligament buttress. Preoperatively and at 6 and 12 months postoperatively, medications, radiologic studies, and symptom severity and frequency scores were recorded. Patients with a hiatal defect greater than 5 cm were included, while patients with recurrent hiatal hernia repairs or prior gastric surgery were excluded. Symptom scores were compared pre- and postoperatively with a p \u3c 0.05 considered significant. Results: One hundred four patients were included with a mean age of 62.4 years, and 57 patients underwent an upper gastrointestinal series at least 12 months from the initial operation with a mean follow-up of 20.6 months. The mean symptom severity score decreased from 14.32 ± 0.93 to 4.75 ± 0.97 (p \u3c 0.001), mean symptom frequency score decreased from 14.99 ± 0.97 to 5.25 ± 0.99 (p \u3c 0.001), and mean total symptom score decreased from 29.31 ± 1.88 to 10.00 ± 1.95 (p \u3c 0.001). Five patients developed recurrent hiatal hernias on upper gastrointestinal series, but only three required operative intervention. Conclusions: Laparoscopic paraesophageal hernia repair with a falciform ligament buttress is a viable option for a durable closure. Ongoing follow-up will continue to illuminate the value of this approach to decrease morbidity and recurrence rates for hiatal hernia repair

    Elective surgery for diverticular disease in U.S. veterans: A VASQIP study of national trends and outcomes from 2004 to 2018

    No full text
    © 2020 Background: Treatment for diverticular disease has evolved over time. In the United States, there has been a trend towards minimally invasive surgical approaches and fewer postoperative complications, but no study has investigated this subject in the Veterans Health Administration. Methods: This retrospective review identified patients undergoing elective surgery for diverticular disease from 2004 to 2018. Demographics, comorbidities, operative approach, rates of ostomy creation, and 30-day outcomes were compared. The 15-year time period was divided into 3-year increments to assess changes over time. Results: 4198 patients were identified. Complication rate decreased significantly over time (28.1%–15.7%, p \u3c 0.001), as did infectious complications (21.5–6.3%, p \u3c 0.001). Median hospital length-of-stay decreased from 7 to 5 days (p \u3c 0.001). Rates of laparoscopic surgery increased over time (17.7%–48.1%, p \u3c 0.001). Conclusions: Increased utilization of laparoscopy in veterans undergoing elective surgery for diverticular disease coincided with fewer complications and a shorter length-of-stay. These trends mirror outcomes reported in non-veterans

    Resistin expression correlates with steatohepatitis in morbidly obese patients

    No full text
    Background: Morbidly obese patients are at risk for nonalcoholic steatohepatitis (NASH) even in the absence of risk factors for liver disease. Unfortunately, NASH is usually not clinically evident, and a definitive, noninvasive test for NASH does not exist. Resistin, a cytokine originating from adipose tissue, is involved in insulin resistance and also initiates proinflammatory signaling from hepatic stellate cells. This study explores the relationship between resistin expression and liver pathology in bariatric surgery patients. Methods: Blood samples from 30 patients undergoing bariatric surgery were collected. Total RNA was extracted and cDNA was synthesized. Quantitative RT-PCR was used to quantify relative gene expression using 18s rRNA gene as an internal control. Wedge liver biopsies from these patients were sectioned and stained. Based on a previously published scoring method, biopsies were assigned an overall NASH severity score and subscores for steatosis, inflammation, and fibrosis. Results were analyzed by using Student\u27s t test. Results: Resistin mRNA levels ranged from 0.5 to 9.7. A group of five patients with very high resistin expression (\u3e4) was identified. These patients had a significantly higher average NASH score compared with the rest of the group (7.9 vs. 4.48, p = 0.019). Steatosis and inflammation scores were significantly higher in the high-resistin group (p \u3c 0.05 for both comparisons). There also was a trend toward higher fibrosis score in this group, which approached statistical significance (p = 0.051). Conclusions: In morbidly obese patients, high resistin expression in serum is associated with hepatic steatosis, inflammation, and fibrosis. The development of elevated resistin expression may represent a link between obesity and the onset of steatohepatitis. © 2012 Springer Science+Business Media New York

    Bispectral index monitoring of sedation during endoscopy

    No full text
    Background: No objective measure of the level of sedation is universally accepted. However, bispectral index monitoring is currently used to objectively measure sedation levels in several clinical settings. This study compares the temporal relationship of bispectral index levels versus the Observer\u27s Assessment of Alertness/Sedation (OAA/S) scale for sedation during endoscopy and proposes a functional bispectral index range for endoscopic procedures. Methods: Fifty consecutive adults undergoing endoscopic retrograde cholangiopancreatography, colonoscopy, or esophagogastroduodenoscopy by a single endoscopist were studied. Intravenous sedation was achieved with diazepam and meperidine. Bispectral index levels (0 to 100) and OAA/S scores (1 to 5) were recorded every 3 minutes by a single trained observer. Results: There were significant temporal correlations between bispectral index levels and OAA/S scores (r = 0.59, p \u3c 0.0001). Bispectral index levels and OAA/S scores corresponded with the need for additional sedation as determined clinically by the endoscopist. An OAA/S score of 3 corresponded to a bispectral index level of 81.49 ± 9.78. Conclusions: Bispectral index monitoring temporally correlates with the OAA/S scale and therefore provides an objective measure of sedation during endoscopy. This preliminary, observational study suggests that a bispectral index level near 82 corresponds with sufficient and functional sedation levels for endoscopy

    Resistin expression correlates with steatohepatitis in morbidly obese patients

    No full text
    Background: Morbidly obese patients are at risk for nonalcoholic steatohepatitis (NASH) even in the absence of risk factors for liver disease. Unfortunately, NASH is usually not clinically evident, and a definitive, noninvasive test for NASH does not exist. Resistin, a cytokine originating from adipose tissue, is involved in insulin resistance and also initiates proinflammatory signaling from hepatic stellate cells. This study explores the relationship between resistin expression and liver pathology in bariatric surgery patients. Methods: Blood samples from 30 patients undergoing bariatric surgery were collected. Total RNA was extracted and cDNA was synthesized. Quantitative RT-PCR was used to quantify relative gene expression using 18s rRNA gene as an internal control. Wedge liver biopsies from these patients were sectioned and stained. Based on a previously published scoring method, biopsies were assigned an overall NASH severity score and subscores for steatosis, inflammation, and fibrosis. Results were analyzed by using Student\u27s t test. Results: Resistin mRNA levels ranged from 0.5 to 9.7. A group of five patients with very high resistin expression (\u3e4) was identified. These patients had a significantly higher average NASH score compared with the rest of the group (7.9 vs. 4.48, p = 0.019). Steatosis and inflammation scores were significantly higher in the high-resistin group (p \u3c 0.05 for both comparisons). There also was a trend toward higher fibrosis score in this group, which approached statistical significance (p = 0.051). Conclusions: In morbidly obese patients, high resistin expression in serum is associated with hepatic steatosis, inflammation, and fibrosis. The development of elevated resistin expression may represent a link between obesity and the onset of steatohepatitis. © 2012 Springer Science+Business Media New York
    corecore