General Hospital Cohort Research Articles

Do Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio Need to Be Stratified for Age and Comorbidities in COVID-19 Disease? A Subgroup Analysis of Two Distinct Cohorts over Disease Course.

Several studies described neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) as markers of COVID-19 severity. In a recently published study, age and frailty affected NLR and PLR more than disease severity. The study compared two distinct cohorts. The first comprised older frailer patients positive for SARS-CoV-2, with mild or asymptomatic disease, admitted to designated COVID-19 departments in a large geriatric medical center (GMC). The second cohort comprised COVID-19 patients admitted to a large general hospital (GH) for symptomatic disease. This was a follow-up study comparing a subgroup of patients who had NLR and PLR values measured a week after admission. Only 100 of 177 patients in the original GMC cohort had a second NLR test compared to almost all (287 of 289) patients in the general hospital (GH) cohort. The subgroup baseline characteristics did not change significantly from that of the original cohort. Disease symptoms were more prevalent in the GH cohort. In the GMC group, the median second NLR rose from 3.9 to 4.6, while in the GH cohort, the NLR value dropped from 3.5 to 2.8, enhancing the NLR differences between the groups. Smaller changes were observed in the second PLR. These results strengthen the prior results that age and frailty seem to have a stronger impact on NLR and PLR than disease severity.

Machine learning approaches for the genomic prediction of rheumatoid arthritis and systemic lupus erythematosus

BackgroundRheumatoid arthritis (RA) and systemic lupus erythematous (SLE) are autoimmune rheumatic diseases that share a complex genetic background and common clinical features. This study’s purpose was to construct machine learning (ML) models for the genomic prediction of RA and SLE.MethodsA total of 2,094 patients with RA and 2,190 patients with SLE were enrolled from the Taichung Veterans General Hospital cohort of the Taiwan Precision Medicine Initiative. Genome-wide single nucleotide polymorphism (SNP) data were obtained using Taiwan Biobank version 2 array. The ML methods used were logistic regression (LR), random forest (RF), support vector machine (SVM), gradient tree boosting (GTB), and extreme gradient boosting (XGB). SHapley Additive exPlanation (SHAP) values were calculated to clarify the contribution of each SNPs. Human leukocyte antigen (HLA) imputation was performed using the HLA Genotype Imputation with Attribute Bagging package.ResultsCompared with LR (area under the curve [AUC] = 0.8247), the RF approach (AUC = 0.9844), SVM (AUC = 0.9828), GTB (AUC = 0.9932), and XGB (AUC = 0.9919) exhibited significantly better prediction performance. The top 20 genes by feature importance and SHAP values included HLA class II alleles. We found that imputed HLA-DQA1*05:01, DQB1*0201 and DRB1*0301 were associated with SLE; HLA-DQA1*03:03, DQB1*0401, DRB1*0405 were more frequently observed in patients with RA.ConclusionsWe established ML methods for genomic prediction of RA and SLE. Genetic variations at HLA-DQA1, HLA-DQB1, and HLA-DRB1 were crucial for differentiating RA from SLE. Future studies are required to verify our results and explore their mechanistic explanation.

Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status

IntroductionSTK11 and KEAP1 mutations (STK11 mutant [STK11MUT] and KEAP1MUT) are among the most often mutated genes in lung adenocarcinoma (LUAD). Although STK11MUT has been associated with resistance to programmed death-(ligand)1 (PD-[L]1) inhibition in KRASMUT LUAD, its impact on immunotherapy efficacy in KRAS wild-type (KRASWT) LUAD is currently unknown. Whether KEAP1MUT differentially affects outcomes to PD-(L)1 inhibition in KRASMUT and KRASWT LUAD is also unknown. MethodsClinicopathologic and genomic data were collected from September 2013 to September 2020 from patients with advanced LUAD at the Dana-Farber Cancer Institute/Massachusetts General Hospital cohort and the Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center cohort. Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS, STK11, and KEAP1 mutation status in two independent cohorts. The Cancer Genome Atlas transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 comutation status. ResultsIn the combined cohort (Dana-Farber Cancer Institute/Massachusetts General Hospital + Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center) of 1261 patients (median age = 61 y [range: 22–92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 cases (42.5%), and deleterious STK11 and KEAP1 mutations were found in 20.6% (260 of 1261) and 19.2% (231 of 1202) of assessable cases, respectively. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free (STK11 hazard ratio [HR] = 2.04, p < 0.0001; KEAP1 HR = 2.05, p < 0.0001) and overall (STK11 HR = 2.09, p < 0.0001; KEAP1 HR = 2.24, p < 0.0001) survival to immunotherapy uniquely among KRASMUT but not KRASWT LUADs. Gene expression ontology and immune cell enrichment analyses revealed that the presence of STK11 or KEAP1 mutations results in distinct immunophenotypes in KRASMUT, but not in KRASWT, lung cancers. ConclusionsSTK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRASMUT but not among KRASWT LUAD. Tumors harboring concurrent KRAS/STK11 and KRAS/KEAP1 mutations display distinct immune profiles in terms of gene expression and immune cell infiltration.

Clinical significance of anti-NOR90 antibodies in systemic sclerosis and idiopathic interstitial pneumonia.

Anti-NOR90 antibodies are usually found in patients with SSc; however, their clinical relevance remains obscure. We developed an ELISA for measuring them to investigate the clinical features of patients with anti-NOR90 antibodies. Serum samples from 1252 patients with various conditions from Nagoya University Hospital and 244 patients with idiopathic interstitial pneumonia (IIP) from Tosei General Hospital were included. Anti-NOR90 antibodies were assayed by an ELISA using the recombinant protein produced by in vitro transcription/translation. Five (0.4%) patients in the Nagoya University Hospital cohort had anti-NOR90 antibodies. One patient with diffuse cutaneous SSc, three with limited cutaneous SSc, and one with Raynaud's disease were positive for anti-NOR90 antibodies. Anti-NOR90 antibodies were found more frequently in patients with systemic scleroderma-spectrum disorders (SSDs) than without SSDs (5/316 vs 0/936, P <0.00101) and were found more frequently in patients with SSc than without SSc (4/249 vs 0/528, P <0.0104) in the systemic autoimmune rheumatic diseases cohort. Three of the four anti-NOR90-positive SSc patients had interstitial lung disease (ILD), and two of those four had cancer. Three (1.2%) patients in the Tosei General Hospital cohort had anti-NOR90 antibodies. All three of the anti-NOR90-positive IIP patients had gastrointestinal tract involvement, and two of those three had cancer or skin lesions observed in SSc. Although anti-NOR90 antibodies are rarely found in clinics, our ELISA is useful for their detection. Further studies are needed to confirm the association of anti-NOR90 antibodies with ILD and cancer in SSc and IIP patients.

Triglyceride is an independent predictor of type 2 diabetes among middle-aged and older adults: a prospective study with 8-year follow-ups in two cohorts

BackgroundAlthough there is abundant evidence indicating the connection between triglyceride and type 2 diabetes mellitus (T2DM), few reports or cohort studies confirm that high TG concentration may predict the incidence of T2DM independently. Thus, we studied the association between triglyceride (TG) and T2DM in a male-dominated, middle and older aged cohort, Tianjin General Hospital Cohort. And we further verified our results in the China Health and Retirement Longitudinal Study (CHARLS).MethodsWe conducted an 8-year retrospective cohort study (2009–2017) with 7241 participants who were free from T2DM at baseline. Three groups were constructed based on baseline TG levels (normal, borderline-high, and high). We used a Cox proportional hazards model to evaluate the relationship between TG and T2DM after adjusting for possible risk factors. A Kaplan–Meier survival analysis was performed to compare the incidence of T2DM among subjects in each TG group. We also tested the association between TG and T2DM in the CHARLS cohort.ResultsIn Tianjin General Hospital Cohort, 7241 participants (male 75.8%, female 24.2%) were included, mean age was 61.49 ± 13.85 years at baseline. The cumulative incidence of T2DM in our cohort study was 8.6% (9.2% in men and 6.6% in women). Compared with the normal TG group, the hazard ratios in the borderline and high group were 1.30 (95% CI 1.04–1.62) and 1.54 (95% CI 1.24–1.90). The Kaplan–Meier survival analysis indicated that higher TG levels may predict higher onset of T2DM. These results were verified in the CHARLS cohort, the hazard ratio with T2DM (95% CI) for logTG was 3.94 (2.64–5.87).ConclusionsOur findings suggest that the TG level may be an independent risk factor and predictor for T2DM.

A conceptually-derived, normally-distributed overall liver dysfunction index (OLDI) predicts short- and long-term outcomes after hepatectomy for hepatocellular carcinoma: Single-institution validation in 844 HCC patients

Introduction: We developed the OLDI index: a non-empirically-derived and normally-distributed statistic which summarizes measures of liver synthetic function and hepatocyte death using the concept of geometric averages. The geometric average is superior to the arithmetic or harmonic average for representing central tendencies as it is unit-agnostic i.e. preserves the underlying statistical distribution during scale conversion (e.g. U/L to mmol/L). Method: Most prognostic scores that have been proposed are empirically-calibrated using regression techniques (i.e. have coefficient terms), and are therefore sensitive to the sample size and representativeness of the derivation set, and often fail to be reproduced in external validation sets. We showed that the geometric average of commonly-reported liver dysfunction biomarkers (“OLDI”) can be mathematically-rearranged as: (Albumin (g/L))/((Prothrombin time (s)×Bilirubin (μmol/L)×(AST [U/L]×ALT [U/L])1/2)1/3). The OLDI index was validated in the Singapore General Hospital cohort of 844 HCC patients who underwent hepatectomy between 2001 and 2016. Result: OLDI was found to be normally-distributed in the overall cohort (mean[SD]=2.104 [0.671], median[range]=2.105[0.205-4.485]), and in clinically-partitioned subsets of our cohort. In univariable analyses, OLDI predicted Clavien-Dindo grade≥2 complications (OR=0.686, 95% CI: 0.543-0.866, P=0.0016), post-hepatectomy liver failure using the ISGLS Grade B/C criteria (OR=0.631, 95% CI: 0.444-0.897, P=0.0103) or 50-50 criteria (OR=0.520, 95% CI: 0.290-0.933, P=0.0283), length of hospital stay (beta=-1.29 days; 95% CI: -2.04 to -0.54, P=0.0008 for every additional 1-point increase in OLDI), recurrence-free survival (HR=0.700, 95% CI: 0.605-0.811, P<0.0001), and overall survival (HR=0.655, 95% CI: 0.551-0.780, P<0.0001). The OLDI score remained an independent predictor of all outcomes in multivariable models adjusted for clinically-relevant confounders. Crucially, OLDI was found to outperform popular risk-stratification systems including Child-Pugh points, MELD score, TNM staging, and albumin-bilirubin score for all outcomes examined. Conclusion: OLDI outperformed many widely-used risk-stratification systems for predicting a multitude of short-term and long-term outcomes after hepatectomy for HCC, and is also easily-interpretable because of its normal distribution.

The California HIV/AIDS Research Program: History, Impact, and HIV Cure Initiative.

This Special Issue of AIDS Research and Human Retroviruses features results from the HIV Cure Initiative, funded by the California HIV/AIDS Research Program (CHRP). As a publicly funded grant maker, CHRP has served for more than three decades as a unique resource for innovative researchers in California, whose work seeks to address all aspects of the HIV epidemic and the communities affected by it. Early initiatives at CHRP pioneered what would become enduring cornerstones of HIV science: isolation of the virus; efficacy and toxicities of the first HIV treatments; the emergence of drug resistance; the first biospecimen banks for HIV-related research; the first community-based laboratory service for HIV diagnostic serology; and the first longitudinal case-control study of progression from HIV to AIDS-The San Francisco General Hospital Cohort. More recently, CHRP-funded conceptual studies of zinc-finger nuclease-mediated disruption of CCR5 genomic sequences and the safety of solid organ transplantation for HIV-positive patients have progressed from brilliant ideas to clinical realities, and CHRP is currently funding the first multisite trial of HIV preexposure prophylaxis for transgender persons in the United States. The present article outlines the founding of CHRP, our current grantmaking process, and our impact on HIV research over time. In 2013, CHRP launched a new initiative aimed at moving the then nascent frontier of HIV cure science forward: the CHRP HIV Cure Initiative provided over $1.4 million to multiple basic biomedical research projects, and selected results are presented in this Special Issue.

PTH-008 Safety And Efficacy Of Balloon Sphincteroplasty Using Controlled Radial Expansion (cre) Balloon During Endoscopic Retrograde Cholangio Pancreatography In The Management Of Large Common Bile Duct (cbd) Stones: A District General Hospital Experience

IntroductionExtraction of large (>1 cm) CBD stones at ERCP is often difficult despite adequate sphincterotomy. Failure of extraction of stones warrants repeat ERCPs and also referral to advanced techniques such...

The development of the DCIS score: Scaling and normalization in the Marin General Hospital cohort.

190 Background: In selected low-risk patients with DCIS treated with wide local excision without radiation, the DCIS score was validated as a predictor of 10 year risk of an ipsilateral breast event (IBE - recurrence of in situ or invasive carcinoma) (p = 0.02) (Solin; SABCS 2011). As part of the development of the DCIS score, scaling from 0 to 100 and determination of risk group cutoff values was done using 100 patient DCIS samples from Marin General Hospital (MGH) selected to have a wide range of tumor characteristics. Methods: 100 patient specimens diagnosed with DCIS were provided by MGH. The Oncotype DX assay was performed, normalized expression levels for the 16 cancer related genes were determined, the DCIS Score and Recurrence Score (RS) were calculated. Distributions of the DCIS score, RS, and individual gene expression levels were described overall and by tumor characteristics. Treatment and pt outcome data were not available. Results: Samples for 96 pts had sufficient tumor and were evaluable; 47% had high nuclear grade, 52% comedo necrosis, 32% tumor size &gt;10 mm, and 9% were ER-negative by IHC. After scaling and risk group cutoff determination, the DCIS score was low risk (0-38) for 49%, intermediate risk (39-54) for 27%, and high risk (≥55) for 24% of pts (Table). The DCIS score was widely distributed within subgroups defined by each of the clinical and pathology characteristics. Proliferation gene expression levels were low in DCIS, on average, relative to prior studies in invasive breast cancer. 92% had a proliferation gene group score &lt;6.5, the threshold used when the RS is calculated; no threshold is used in calculating the DCIS score. Conclusions: Optimal scaling and risk cutoff determination for a wide range of all clinicopathologic characteristics provides for a wide distribution for the DCIS Score. [Table: see text]

Disproportionate Presentation of High Risk Prostate Cancer in a Safety Net Health System

Most prostate cancer research is based on relatively homogenous cohorts of men, often with comparatively high socioeconomic status. We describe prostate cancer characteristics in men treated in a public health system and hypothesize a disproportionate burden of high risk disease in this population. We created a clinical registry from a review of the medical records of 377 men diagnosed with prostate cancer in the San Francisco General Hospital system, which provides care to underserved, uninsured populations. We compared sociodemographic data and cancer characteristics with those in 2 large prostate cancer databases from a community (CaPSURE™) and an academic (University of California-San Francisco tumor registry) setting to assess differences in risk distribution using the D'Amico and Cancer of the Prostate Risk Assessment scoring systems. Compared to men in CaPSURE or the University of California-San Francisco tumor registry those in the San Francisco General Hospital cohort were nonwhite (76%), insured under Medicaid (31%) or uninsured (8%) and had adverse clinical characteristics, including median prostate specific antigen greater than 10 ng/ml at diagnosis and higher Gleason grade. In addition, the majority of patients (67%) had intermediate or high risk disease based on the D'Amico classification and a higher mean Cancer of the Prostate Risk Assessment score. Using ANOVA for continuous variables and the chi-square test for categorical variables, all comparisons were statistically significant (p <0.001). Men in the San Francisco General Hospital public health system bear a substantially higher burden of high risk disease that those in an academic or a community setting. Populations such as this would benefit most from targeted efforts for early detection and treatment to decrease prostate cancer morbidity and mortality.

Hyperglycemia and hospital outcomes for diabetic patients admitted to general medicine and surgery services

Diabetes mellitus is a common co-morbid condition on general hospital services. However, the effect of glycemic control on outcomes has not been investigated. This study examines the relationship between hyperglycemia and hospital length of stay (LOS) for 2,468 patients admitted to Carle Foundation Hospital in 2004. Patients were categorized according to American Diabetes Association hospital glycemic targets. One-way ANOVA showed significant correlation between average finger-stick glucose (FSG) and LOS (p = 0.0002). Glycemic variability (standard deviation of FSG) also correlated significantly with LOS (p < 0.0001). Multiple regression analysis including FSG, glycemic variability, mode of therapy, Charlson Comorbidity Index, Apache II score, age, and HbA1c was performed for a subset of patients (N=170). Glycemic variability was the only variable significantly correlated with LOS (p = 0.012). Hyperglycemia and glycemic variability are strongly associated with increased LOS in preliminary analysis of a large general hospital cohort, though correlation controlled for morbidity and severity of illness remains to be completed for all study patients. Research supported by a UIUC faculty grant.

Hypomagnesemia in trauma patients.

The objective of this study was to determine the incidence of hypomagnesemia in injured patients (versus a general hospital cohort) and to compare total and ionized values with each other and with the incidence of injury severity and ethanol level. It was a descriptive study of consecutive injured patients at a level II trauma center. For 3 months subjects underwent admission paired analysis of blood total magnesium (TMg) and ionized magnesium (IMg). IMg was determined by microanalysis of whole blood (Nova Biomedical, NovaSP9). During the same time period, all hospital samples for TMg (m = 1308) underwent simultaneous IMg testing. Pearson correlation coefficients were determined for IMg versus TMg, Injury Severity Score (ISS), Trauma Score (TS), Glasgow Coma Scale (GCS), and blood units transfused. By convention, hypomagnesemia was defined as TMg < or =1.6 mg/dl and IMg < or = 0.5 mg/dl. Altogether 43% of 113 trauma patients had low magnesium levels compared to 30% of noninjured cohorts (p<0.05). The correlation coefficient (r(2)) for TMg and IMg was 0.74 for TMg values >1.6, but for TMg < or =1.6 the r(2) was 0.35. Coefficients for IMg and ISS, TS, GCS, units transfused, and ethanol level were 0.06, 0.08, 0.10, 0.04, and 0.01, respectively. Mean IMg was 0.57+/-0.09 mg/dl with ethanol ingestion and 0.56+/-0.06 mg/dl without ethanol ingestion (mean +/- SD, p>0.05). It was concluded that hypomagnesia is common in injured patients but does not correlate with indices of injury severity or ethanol level. TMg is not a good predictor of IMg at low levels. Trauma patients may benefit from determination of IMg for accurate diagnosis of a low Mg level to facilitate repletion.

Effect of new AIDS case definition on numbers of cases among homosexual and bisexual men in San Francisco

ABSTRACT To the Editor. —On January 1,1992, the Centers for Disease Control (CDC) is expected to propose that a CD4+ T-lymphocyte cell count of 200 × 106 cells/L or less in a person seropositive for the human immunodeficiency virus (HIV), in the absence of other clinical findings, be added to the list of the acquired immunodeficiency syndrome (AIDS) defining conditions. Some of the consequences of this action can be estimated from data collected in the San Francisco (Calif) Men's Health Study and the San Francisco General Hospital Cohort. These cohorts comprise approximately 1250 homosexual and bisexual men recruited in 1983 and 1984 by a combination of sampling and volunteer procedures. Both cohorts have been examined regularly since recruitment and CD4+ T-lymphocyte counts have been determined at each examination.By the end of 1990,271 cases of AIDS meeting the 1987 criteria defined by the CDC had been diagnosed. If the proposed

Effect of New AIDS Case Definition on Numbers of Cases Among Homosexual and Bisexual Men in San Francisco

<h3>To the Editor.</h3> —On January 1,1992, the Centers for Disease Control (CDC) is expected to propose that a CD4⁺T-lymphocyte cell count of 200 × 10⁶cells/L or less in a person seropositive for the human immunodeficiency virus (HIV), in the absence of other clinical findings, be added to the list of the acquired immunodeficiency syndrome (AIDS) defining conditions. Some of the consequences of this action can be estimated from data collected in the San Francisco (Calif) Men's Health Study and the San Francisco General Hospital Cohort. These cohorts comprise approximately 1250 homosexual and bisexual men recruited in 1983 and 1984 by a combination of sampling and volunteer procedures. Both cohorts have been examined regularly since recruitment and CD4⁺T-lymphocyte counts have been determined at each examination. By the end of 1990,271 cases of AIDS meeting the 1987 criteria defined by the CDC had been diagnosed. If the proposed

Seropositivity for HIV and the development of AIDS in AIDS-related condition: Three year follow-up on the San Francisco General Hospital Cohort: Moss AR, Bacchetti P, Osmond D, et al: Br Med J 296:745–750, 1988

Seropositivity for HIV and the development of AIDS in AIDS-related condition: Three year follow-up on the San Francisco General Hospital Cohort: Moss AR, Bacchetti P, Osmond D, et al: Br Med J 296:745–750, 1988

Seropositivity for HIV and the development of AIDS or AIDS related condition: three year follow up of the San Francisco General Hospital cohort.

The three year actuarial progression rate to the acquired immune deficiency syndrome (AIDS) in a cohort of men in San Francisco who were seropositive for the human immunodeficiency virus (HIV) was 22%. An additional 26 (19%) developed AIDS related conditions. Beta 2 Microglobulin concentration, packed cell volume, HIV p24 antigenaemia, and the proportion and number of T4 lymphocytes each independently predicted progression to AIDS. Beta 2 Microglobulin was the most powerful predictor. The 111 subjects tested who were normal by all predictors (40%) had a three year progression of 7%, and the 68 subjects who were abnormal by two or more predictors (24%) had a progression rate of 57%. Two thirds of all men who progressed to AIDS were in the last group. The median T4 lymphocyte count in subjects who did not progress to AIDS fell from 626 x 10(6) to 327 x 10(6)/l. HIV p24 antigenaemia developed in 7% of the subjects per year. The proportion who were abnormal by two or more predictive variables rose to 41%. At three years an estimated two thirds of the seropositive subjects showed clinical AIDS, an AIDS related condition, or laboratory results that were highly predictive of AIDS. It is concluded from the observed rates and the distribution of predictive variables at three years that half of the men who were seropositive for HIV will develop AIDS by six years after the start of the study, and three quarters will develop AIDS or an AIDS related condition.