The Association Between Proton Pump Inhibitors and COVID-19 is Confounded by Hyperglycemia in a Population-Based Study.

Background and Aims: There is conflicting evidence regarding the association between proton pump inhibitors (PPI) and the risk of acquisition and severity of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Aim: To evaluate the association between PPI exposure and infection and development of severe disease in patients infected with SARS-CoV2in a large population-based historical cohort. Methods: Data were extracted from a health maintenance organization database in Israel that insures over 1,200,000 individuals from across the country. All patients who underwent SARS-CoV-2 testing between March and November 2020 were included. Logistic regression and matched analyses were used to compare patients prescribed and exposed to PPIs to those not prescribed PPIs regarding SARS-CoV-2 positivity. In addition, among SARS-CoV-2 positive patients (n = 44,397) the likelihood of developing severe disease, defined by a composite endpoint of death, ICU admission and prolonged hospitalization, was compared in those exposed and not exposed to PPIs. Results: Among 255,355 adult patients who underwent SARS-CoV-2 testing by PCR, 44,397 (17.4%) were positive for SARS-CoV-2 and 12,066 (4.7%) patients were prescribed PPIs in the 3 months before testing. In a multivariable logistic regression model controlling for age, gender, smoking status, BMI, diabetes mellitus, hypertension, COPD, history of ischemic heart disease and fasting blood glucose (FBG) levels, no significant association was found between PPIs and SARS-CoV-2 positivity (p = 0.09 aOR 0.94, 95% CI - 0.88-1.01). Among SARS-CoV-2 positive patients, 910 (2%) had a severe infection. Multivariate logistic regression controlling for the abovementioned confounders, showed no such association between PPIs and severe COVID-19 (p = 0.28). Elevated FBG levels were significantly associated with both PPI exposure (p < 0.001) and severe COVID-19 infection (p < 0.001). These results were reinforced by a matched analysis (n = 655 pairs). Conclusion: PPIs are spuriously associated with severe COVID-19 due to the presence of elevated FBG as a confounder. Our study accounted for the FBG levels of patients and known risk factors for severe COVID-19 infection, which may be the reason for the discrepancy in prior studies. These results may aid in understanding potential confounders when evaluating potential associations of PPIs with other respiratory or viral diseases.

The POEM bottom-up technique for achalasia.

BACKGROUND: POEM (Per Oral Endoscopic Myotomy) is rapidly becoming a valid option for surgical myotomy in achalasia patients. Several techniques to perform POEM are described, but all concentrate on the division of the circular muscle fibers in a proximal-to-distal fashion. Our aim is to present the distal-to-proximal, or the bottom-up technique using the Flush/Dual knife, which overcomes the disadvantages of the standard technique. METHODS: A retrospective study on a prospectively maintained database was performed on all patients treated by POEM in our institution. Clinical presentation, operating time, adverse events, and outcomes were studied. RESULTS: POEM was performed on 105 achalasia patients. The first 15 cases were performed using the standard technique and were compared to the next 90 cases performed using the bottom-up technique. The average preop Eckardt scores in the standard and bottom-up groups were 9.5 and 8.8, respectively, declining to 1.4 and 0.5, 3 months post myotomy (p < 0.001). The average procedure time was 111.2 min for the standard technique and 74.3 for the bottom-up technique. (p = 0.002). Perioperative adverse events included 14 instances of pneumoperitoneum, 3 tunnel leaks, and 4 patients with fever on postoperative day one. Pneumoperitoneum needing decompression and postoperative fever were more prevalent in the standard technique group. CONCLUSIONS: As POEM is becoming more common for the treatment of achalasia, refinements of the technique and instruments used are valuable. We compared our experience of the standard technique to our bottom-up technique and found the latter to be equally effective as well as safer, faster, and easier. We, therefore, suggest considering performing POEM in this technique.

G-EYE colonoscopy is superior to standard colonoscopy for increasing adenoma detection rate: an international randomized controlled trial (with videos).

BACKGROUND AND AIMS: Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy still occur. An increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device includes a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope's optics, and reduces bowel slippage. The insufflated balloon also aims to enhance visualization of the colon during withdrawal, thereby increasing the ADR. METHODS: In this randomized, controlled, international, multicenter study (11 centers), patients (aged ≥50 years) referred to colonoscopy for screening, surveillance, or changes in bowel habits were randomized to undergo either balloon-assisted colonoscopy by using an insufflated balloon during withdrawal or standard high-definition colonoscopy. The primary endpoint was the ADR. RESULTS: One thousand patients were enrolled between May 2014 and September 2016 to undergo colonoscopy by experienced endoscopists; 803 were finally analyzed (standard colonoscopy n = 396; balloon-assisted colonoscopy n = 407). Baseline parameters were similar in both groups. Balloon-assisted colonoscopy provided a 48.0% ADR compared with 37.5% in the standard colonoscopy group (28% increase; P = .0027). Additionally, balloon-assisted colonoscopy provided for a significant increase in detection of advanced (P = .0033) flat adenomas (P < .0001) and sessile serrated adenomas/polyps (P = .0026). CONCLUSION: Balloon-assisted colonoscopy yielded a higher ADR and increased the detection of advanced, flat, and sessile serrated adenomas/polyps when compared with standard colonoscopy. Improved detection by the G-EYE device could impact the quality of CRC screening by reducing miss rates and consequently reducing interval cancer incidence. (Clinical trial registration number: NCT01917513.).

Comparison of distribution of intraesophageal pH during nighttime recumbency among patients with gastroesophageal reflux disease.

BACKGROUND: Nighttime reflux has been demonstrated to be associated with a more aggressive presentation of gastroesophageal reflux disease (GERD). However, it has remained unknown until now if the difference in nighttime reflux between the different GERD groups is related to the distribution of intraesophageal pH level or duration of acid exposure. AIM: To compare distribution of intraesophageal pH during nighttime between patients with erosive esophagitis (EE) versus those with nonerosive reflux disease (NERD). METHODS: Patients with heartburn symptoms at least 3 times per week were included in this study. Patients were not receiving any antireflux treatment. All patients underwent an upper endoscopy to determine if esophageal inflammation was present or absent. Subsequently, patients underwent ambulatory 24-hour esophageal pH monitoring. Only those with NERD and EE were included in this study. Nighttime period was defined as the time from the moment patients entered the bed to fall asleep and until they woke up the next morning. Distribution of intraesophageal pH during nighttime was generated using a special computer program that analyzed all registered pH measurements. RESULTS: Nineteen patients were found to have NERD and 31 EE. Time in bed was not different between the 2 groups. The mean number of acid reflux events, mean reflux time pH<4, and mean % total time pH<4 during nighttime were significantly lower in the NERD group as compared with the EE group (13.05±4.6, 19.7±7.09, 3.6±1.2% vs. 25.44±4.4, 29.3±7.97, 5.3±1.5%, respectively, all P<0.05). Symptom index for EE was 43.8% versus 21% for NERD, P<0.05. Overall, the distribution of intraesophageal pH during nighttime was similar between NERD and EE patients for all pH ranges. CONCLUSIONS: Patients with EE demonstrated a significantly higher nighttime esophageal acid exposure as compared with NERD, but the overall distribution of the acid exposure was similar between the 2 groups. This suggests that duration rather than intensity of nighttime intraesophageal acid exposure accounts for the difference between EE and NERD.

Renal artery stenosis with significant proteinuria may be reversed after nephrectomy or revascularization in patients with the antiphospholipid antibody syndrome: a case series and review of the literature.

Renal artery stenosis (RAS) is a disease which might present as hypertension, renal insufficiency or proteinuria and even as nephrotic syndrome. While 90% of cases are secondary to atherosclerosis, the rest of the cases are usually related to fibromuscular dysplasia. Recently, RAS has also been documented in patients with the antiphospholipid syndrome (APS). Although cases of nephrotic syndrome induced by RAS have been published, cases of patients with APS and nephrotic syndrome attributed to RAS were not reported in the literature. In this paper, three young male patients with APS, hypertension and significant proteinuria secondary to RAS are presented. The patients were treated with nephrectomy or revascularization in addition to prior treatment with warfarin, with improvement of the hypertension and the proteinuria. The relationship between renal artery stenosis, nephrotic range proteinuria and APS is reviewed. We suggest that renal artery stenosis should be included in the differential diagnosis of the nephrotic syndrome and that APS should be included in the differential diagnosis of renal artery stenosis especially in young male patients with proteinuria.

Gastro-oesophageal reflux disease: beyond proton pump inhibitor therapy.

Gastro-oesophageal reflux disease (GORD or GERD) is a very common disorder, and advancement in drug development over the years has markedly improved disease management. Proton pump inhibitors (PPIs) remain the mainstay of treatment for GERD due to their profound and consistent inhibitory effect on acid secretion. However, PPIs do not reduce the number of reflux events and do not provide long-term cure for GERD. In addition, although the safety profile of PPIs is excellent, recent population-based studies have suggested that long-term PPI use may be associated with a variety of adverse events. They include osteoporosis-related hip and spine fractures, community-acquired and nosocomial pneumonia, various enteric and non-enteric infections, fundic gland polyps and many others. Consequently, there is growing interest by patients and physicians alike in current, as well as future, non-PPI-related therapeutic strategies for GERD. This includes repositioning histamine H(2) receptor antagonists and prokinetics in our current GERD therapeutic algorithms and a resurgence of non-medical therapeutic modalities for GERD, such as anti-reflux surgery, endoscopic treatment, alternative and complementary medicine and psychological interventions. Furthermore, there will be renewed efforts in further developing new medical and non-medical therapeutic modalities for GERD.

An algorithm for diagnosis and treatment of refractory GERD.

Patients with gastro-esophageal reflux disease (GERD) who are not responding to proton pump inhibitors (PPIs) given once daily are very common. These therapy-resistant patients have become the new face of GERD in clinical practice in the last decade. Upper endoscopy appears to have a limited diagnostic value. In contrast, esophageal impedance with pH testing on therapy appears to provide the most insightful information about the subsequent management of these patients. Commonly, doubling the PPI dose or switching to another PPI will be offered to patients who failed PPI once daily. Failure of such therapeutic strategies is commonly followed by assessment for weakly or residual acidic reflux. There is growing information about the potential value of compounds that can reduce transient lower esophageal sphincter relaxation rate. Esophageal pain modulators are commonly offered to patients with functional heartburn although supportive clinical studies are still missing.

Prevalence of celiac disease in an adult Jewish population in Israel.

BACKGROUND: In the last decade the frequency of celiac disease diagnosis has increased in adults. OBJECTIVES: To determine disease prevalence (including silent and potential disease) in this population group. METHODS: We performed serologic screening of celiac disease in a representative and homogenous sample of a young adult general population in Israel, namely, 18 year old military conscripts, in 2003. Serologic screening was performed on serum samples randomly obtained from 850 healthy recruits (male/female = 1.1). Immunoglobulin A anti-tissue transglutaminase was determined by enzyme-linked immunosorbent assay. In cases of IgA deficiency, lgG anti-endomysial antibodies were determined. A small intestinal biopsy was offered to all patients with positive serology. RESULTS: The prevalence of overt CD diagnosed prior to recruitment was 0.12% (0.1% in men and 0.14% in women). The overall prevalence based on positive serology was 1.1%. Six of nine subjects with positive serology agreed to undergo endoscopy and intestinal biopsies. In all cases, biopsies were compatible with celiac disease (five biopsies were graded as Marsh 3a and one as Marsh 3b). One subject previously reporting irritable bowel-like symptoms was diagnosed with overt atypical CD. The prevalence of overt CD diagnosed by screening was 0.12%. The ratio, of overt to silent CD was 1:8. No cases of potential CD were encountered. CONCLUSIONS: Our findings suggest that CD is highly prevalent in the young adult population in Israel. Serologic screening for CD is a reliable and simple method for diagnosing this disease before symptoms or complications develop.

Management of gastroesophageal reflux disease that does not respond well to proton pump inhibitors.

PURPOSE OF REVIEW: Patients with gastroesophageal reflux disease (GERD) who are not responding to proton pump inhibitors (PPIs) given once daily are very common. These therapy-resistant patients have become the new face of GERD in clinical practice in the last decade and presently pose a significant therapeutic challenge to the practicing physician. We reviewed newly accumulated information about the management of PPI failure that has been published over the past 2 years. RECENT FINDINGS: There are diverse mechanisms that contribute to the failure of PPI treatment in GERD patients and they are not limited to residual reflux. Some of the causes of PPI failure may coincide in the same patient. Upper endoscopy appears to have limited diagnostic value. In contrast, esophageal impedance with pH testing on therapy appears to provide the most insightful information about the subsequent management of these patients. Commonly, doubling the PPI dose or switching to another PPI will be offered to patients who failed PPI once daily. Failure of such therapeutic strategies is commonly followed by assessment for residual reflux. There is growing information about the potential value of compounds that can reduce transient lower esophageal sphincter relaxations. Esophageal pain modulators are commonly offered to patients with functional heartburn, although supportive clinical studies are still missing. SUMMARY: Management of refractory GERD patients remains an important clinical challenge. Recent studies have cemented the value of impedance-pH testing in pursuing proper treatment. Presently, the most promising therapeutic development for this patient population is transient lower esophageal sphincter relaxation reducers.

Bowel symptoms in nonerosive gastroesophageal reflux disease: nature, prevalence, and relation to acid reflux.

BACKGROUND: Nonerosive gastroesophageal reflux disease (NERD) patients frequently show features of the irritable bowel syndrome (IBS). AIMS: To investigate the prevalence and intensity of bowel symptoms and their relationship to esophageal acid exposure in NERD patients. METHODS: Bowel and reflux symptoms and IBS status were assessed in NERD patients (normal upper endoscopy; esophageal pH <4 for >or= 5% of the time on 24-h pH monitoring; n=326), in relation to nonpatient controls. Bowel symptoms were scored on the 3 scales: diarrhea, constipation, and pain/gas symptoms. RESULTS: NERD and age were independently associated with bowel symptoms. NERD patients scored significantly higher than controls on all bowel scales. In a multivariate analysis, the scores on the pain/gas scale were independently associated with NERD. In NERD patients, reflux symptoms independently predicted the bowel symptoms while acid exposure did not. Forty-nine percent of the NERD patients and 18% of the controls met the criteria for IBS [IBS(+)NERD]. IBS(+)NERD patients scored significantly higher than those not meeting IBS criteria [IBS(-)] on all bowel scales. Yet IBS(-) patients scored significantly higher than controls on the scales of constipation and pain/gas. IBS(+)NERD patients scored higher than IBS(-) also on the GERD symptoms scale. CONCLUSIONS: (1) NERD patients scored significantly higher than controls on all the bowel scales; (2) Bowel symptoms were associated with reflux symptom scores, but not with acid exposure. (3) The presence of IBS features in a large proportion of NERD patients reflects a high prevalence of visceral hypersensitivity that may aggravate acid reflux symptoms.

Association of hereditary hemorrhagic telangiectasia and hereditary nonpolyposis colorectal cancer in the same kindred.

Endoglin (CD105) is a proliferation-associated protein that is strongly expressed in endothelial tissue and has a role in tumor angiogenesis. Mutations in endoglin are also linked to Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), an autosomal dominant disease associated with aberrant angiogenesis. We report an unusual association of HHT1 and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) in the same kindred. Genetic analysis indicates that these 2 syndromes are genetically unrelated and separately segregated within the family. The mutation in the endoglin gene leads to a truncated protein. The mutation in the mismatch repair gene MLH1 causes a splicing defect, giving synthesis to an unstable mRNA from this mutated allele. The potential protective role of an endoglin mutation in patients with HNPCC is discussed.

The erythrocyte adhesiveness/aggregation test to reveal real-time information of rheological relevance in patients with familial and primary hypercholesterolemia before and following plasma exchange.

We applied an erythrocyte adhesiveness/aggregation test (EAAT) to a model of plasma exchange in individuals with familial and primary hypercholesterolemia. The significant (p < 0.0001) reduction in the concentration of fibrinogen by 56%, globulins by 48%, and cholesterol by 53% corresponded to the expected significant (p < 0.0001) reduction in the degree of erythrocyte adhesiveness/aggregation in the peripheral venous blood. By virtue of its being a real-time, simple, very-low-cost, and essentially bedside technique, the EAAT might have the potential of disclosing information of rheological relevance immediately before, during, as well as following apheretical procedures administered to patients with an impaired rheological profile.