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PURPOSE: We investigated the protection offered by vaccinations and previous infections for the household transmission of Omicron variant of SARS-CoV-2. METHODS: 34,666 participants of the German DigiHero cohort study with two or more household members were invited to a prospective household transmission study between June and December 2022. In case of a positive SARS-CoV-2 test in a household, symptom diaries were completed for at least 14 days. Dry blood spots (DBS) were taken from all household members at the beginning and six to eight weeks later. DBS were analyzed for SARS-CoV-2 antibodies. RESULTS: 1191 individuals from 457 households participated. The risk of acquiring a SARS-CoV-2 infection decreased with higher S-titer levels at the time of exposure (from 80% at titer of 0 binding antibody units (BAU)/ml to 20% at titer of 3000 BAU/ml) and increased linearly with the time since vaccination/previous infection (20% for less than one month to 80% at one year). Transmission probability was also reduced when the symptoms of the primary case were mild and if preventive measures were implemented. CONCLUSION: Vaccinations/previous infections offer a high protection against infection with the Omicron variant for a few months only, supporting the notion of seasonal circulation of the virus.
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This study aimed to compare different pancreatic enzyme preparations (PEPs) available in Germany regarding particle geometry and size, and to evaluate enzyme activity under physiologically relevant conditions in vitro. Pancreatic endocrine insufficiency is characterized by deficiency of pancreatic enzymes resulting in maldigestion. It is orally treated by pancreatic enzyme replacement therapy. The formulations differ in their physical properties and enzyme release behavior, potentially resulting in inconsistent dosages and poor interchangeability of products. A total of 25 products were analyzed for particle size and number of particles per capsule. Enzyme activities of lipase, amylase, and protease were measured by digestion of olive oil emulsion, starch, and casein, respectively. To analyze enzyme release, gastric environments were simulated by incubating PEPs at pH 1, 4, or 5. Duodenal conditions were simulated by subsequent incubation at pH 6. Regarding physical properties and enzyme release kinetics, considerable differences between different PEPs were found. Furthermore, compared to the label claim, excess lipase activity was observed for most products, reaching up to 148%. These in vitro results suggest poor interchangeability of PEPs, potentially explained by physical and release characteristics. Physicians and patients should be aware of the potential gap between label claims and the real-life performance of different PEPs.
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65 million people worldwide are estimated to suffer from long-term symptoms after their SARS-CoV-2 infection (Long COVID). However, there is still little information about the early recovery among those who initially developed Long COVID, i.e. had symptoms 4-12 weeks after infection but no symptoms after 12 weeks. We aimed to identify associated factors with this early recovery. We used data from SARS-CoV-2-infected individuals from the DigiHero study. Participants provided information about their SARS-CoV-2 infections and symptoms at the time of infection, 4-12 weeks, and more than 12 weeks post-infection. We performed multivariable logistic regression to identify factors associated with early recovery from Long COVID and principal component analysis (PCA) to identify groups among symptoms. 5098 participants reported symptoms at 4-12 weeks after their SARS-CoV-2 infection, of which 2441 (48%) reported no symptoms after 12 weeks. Men, younger participants, individuals with mild course of acute infection, individuals infected with the Omicron variant, and individuals who did not seek medical care in the 4-12 week period after infection had a higher chance of early recovery. In the PCA, we identified four distinct symptom groups. Our results indicate differential risk of continuing symptoms among individuals who developed Long COVID. The identified risk factors are similar to those for the development of Long COVID, so people with these characteristics are at higher risk not only for developing Long COVID, but also for longer persistence of symptoms. Those who sought medical help were also more likely to have persistent symptoms.
Subject(s)
COVID-19 , Post-Acute COVID-19 Syndrome , Male , Humans , SARS-CoV-2 , Principal Component AnalysisABSTRACT
OBJECTIVES: In winter of 2022/2023 SARS-CoV-2 had developed into one of many seasonal respiratory pathogens, causing an additional burden of acute respiratory infections (ARIs). Although testing was still widely used, many positive tests were not reported for the official statistics. Using data from a population-based cohort, we aimed to investigate the contribution of SARS-CoV-2 to the burden of ARI. METHODS: Over 70,000 participants of the German population-based DigiHero study were invited to a questionnaire about the number and time point of ARI and SARS-CoV-2 test results in winter 2022/2023. We calculated the incidence of non-severe acute respiratory syndrome (SARS) ARI, the additional contribution of SARS-CoV-2, and extrapolated the age-specific estimates to obtain the total burden of SARS-CoV-2 in Germany. RESULTS: For the winter of 2022/2023, 37,708 participants reported 54,813 ARIs, including 9358 SARS-CoV-2 infections. This translated into a cumulative incidence of 145 infections/100 persons for all ARIs, 120 infections/100 persons for non-SARS ARI, and 25 infections/100 persons for SARS ARI (+21%). CONCLUSIONS: Our estimate for ARI related to SARS-CoV-2 is consistent with the difference in all ARI between pre-pandemic years and 2022/2023. This additional burden should be considered, particularly, with respect to the implications for the work force.
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COVID-19 , Respiratory Tract Infections , SARS-CoV-2 , Seasons , Humans , COVID-19/epidemiology , Germany/epidemiology , Adult , Middle Aged , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/virology , Male , Female , Incidence , Aged , Adolescent , Young Adult , Child , Child, Preschool , Infant , Aged, 80 and over , Infant, Newborn , Acute Disease/epidemiologyABSTRACT
INTRODUCTION: This study explores how chronic pancreatitis (CP) relates to subclinical cognitive impairment (SCI) and its prevalence, characteristics, risk factors, and effects on patients' quality of life (QoL) and physical performance. METHODS: Patients with fulfilled CP criteria in imaging were prospectively enrolled. Overt encephalopathy, neurodegenerative disorders, decompensated cirrhosis, and sepsis were exclusion criteria. All patients underwent psychometric testing and assessment of health-related QoL, such as mobility and strength. SCI was diagnosed when at least 1 test of the psychometric test battery was pathological. RESULTS: Seventy-one patients were enrolled. The etiology was toxic (alcohol/smoking) in most (49%) of the cases. SCI was prevalent in 41% of the patients while 25% had only 1 and 16% had 2 or more pathological tests. Patients with SCI exhibited diminished overall QoL scores ( P = 0.048), primarily affecting physical functionality ( P < 0.001). This was reaffirmed in mobility tests, where patients with SCI were slower in the timed up-and-go test ( P = 0.008) and showed increased prevalence of abnormal chair rising tests ( P = 0.004). Among all variables analyzed, only alcohol abuse was an independent risk factor of SCI (odds ratio 3.46; P = 0.02) in a multivariable regression model together with the variables age, sex, education, and compensated cirrhosis. Despite SCI affecting global QoL, sleep disturbance seemed to be the strongest variable independently associated with impaired QoL (odds ratio 9.9; P = 0.001). DISCUSSION: The largest study to the subject to date shows that SCI is common in patients with CP and is linked to significant morbidity. These findings suggest the need for addressing modifiable risk factors in patients with CP to improve outcomes.
Subject(s)
Cognitive Dysfunction , Pancreatitis, Chronic , Quality of Life , Humans , Male , Female , Middle Aged , Pancreatitis, Chronic/complications , Pancreatitis, Chronic/psychology , Pancreatitis, Chronic/epidemiology , Risk Factors , Cognitive Dysfunction/etiology , Cognitive Dysfunction/epidemiology , Cognitive Dysfunction/diagnosis , Prospective Studies , Adult , Prevalence , Aged , Mobility Limitation , Psychometrics , Physical Functional Performance , Neuropsychological TestsABSTRACT
BACKGROUND AND AIMS: Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied. METHODS: We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test. RESULTS: Propensity score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months). CONCLUSIONS: EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.
Subject(s)
Ampulla of Vater , Common Bile Duct Neoplasms , Duodenal Neoplasms , Pancreatic Neoplasms , Humans , Treatment Outcome , Ampulla of Vater/surgery , Ampulla of Vater/pathology , Endoscopy, Gastrointestinal , Pancreatic Ducts/pathology , Pancreatic Neoplasms/pathology , Duodenal Neoplasms/pathology , Common Bile Duct Neoplasms/surgery , Common Bile Duct Neoplasms/pathology , Retrospective StudiesABSTRACT
BACKGROUND: Parameters to adapt individual treatment strategies for patients with pancreatic ductal adenocarcinoma (PDAC) are urgently needed. The present study aimed to evaluate body composition parameters as predictors of overall survival (OS) in PDAC patients. METHODS: Measurements of body composition parameters were performed on computed tomography scans at diagnosis. Height-standardized and Body Mass Index- and sex-adjusted regression formulas deriving cut-offs from a healthy population were used. The Kaplan-Meier method with the log-rank test was performed for survival analysis. Independent prognostic factors were identified with uni- and multivariable Cox regression analyses. RESULTS: In total, 354 patients were analyzed. In a multivariable Cox model, besides tumor stage and resection status, only myosteatosis (HR 1.53; 95% CI 1.10-2.14, p = 0.01) was an independent prognostic factor of OS among body composition parameters. Subgroup analyses revealed that the prognostic impact of myosteatosis was higher in patients ≤68 years of age, with advanced tumor stages and patients without curative intended resection. CONCLUSIONS: The analysis of one of the largest Caucasian cohorts to date, demonstrated myosteatosis to be an independent prognostic factor of OS in PDAC. To improve outcomes, prospective trials aiming to investigate the utility of an early assessment of myosteatosis with subsequent intervention by dieticians, sports medicine physicians, and physiotherapists are warranted.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Body Composition , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/therapy , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/therapy , Pancreatic Neoplasms/pathology , Prognosis , Prospective Studies , Male , Female , AgedABSTRACT
BACKGROUND: Genetic predisposition is crucial in the pathogenesis of early-onset chronic pancreatitis (CP). So far, several genetic alterations have been identified as risk factors, predominantly in genes encoding digestive enzymes. However, many early-onset CP cases have no identified underlying cause. Chymotrypsins are a family of serine proteases that can cleave trypsinogen and lead to its degradation. Because genetic alterations in the chymotrypsins CTRC, CTRB1, and CTRB2 are associated with CP, we genetically and functionally investigated chymotrypsin-like protease (CTRL) as a potential risk factor. METHODS: We screened 1005 non-alcoholic CP patients and 1594 controls for CTRL variants by exome sequencing. We performed Western blots and activity assays to analyse secretion and proteolytic activity. We measured BiP mRNA expression to investigate the potential impact of identified alterations on endoplasmic reticulum (ER) stress. RESULTS: We identified 13 heterozygous non-synonymous CTRL variants: five exclusively in patients and three only in controls. Functionality was unchanged in 6/13 variants. Four alterations showed normal secretion but reduced (p.G20S, p.G56S, p.G61S) or abolished (p.S208F) activity. Another three variants (p.C201Y, p.G215R and p.C220G) were not secreted and already showed reduced or no activity intracellularly. However, intracellular retention did not lead to ER stress. CONCLUSION: We identified several CTRL variants, some showing potent effects on protease function and secretion. We observed these effects in variants found in patients and controls, and CTRL loss-of-function variants were not significantly more common in patients than controls. Therefore, CTRL is unlikely to play a relevant role in the development of CP.
Subject(s)
Chymases , Pancreatitis, Chronic , Humans , Chymases/genetics , Genetic Predisposition to Disease , Mutation , Pancreatitis, Chronic/genetics , Pancreatitis, Chronic/metabolism , Risk FactorsABSTRACT
Background: Endoscopic approaches in the treatment of transmural esophageal defects, either after esophageal resection or due to perforation, have demonstrated convincing feasibility. Surgical options are limited and associated with high morbidity and mortality rates. Currently, internal endoscopic drainage with pigtail stents, self-expanding metal stent (SEMS), or endoscopic vacuum therapy (EVT) are options for first-line treatment. Here, we report the outcome of the recently developed combination of SEMS and EVT using the endoscopic Microtech®-VAC-Stent (EVS). Methods: Between June and July 2022, three consecutive patients (one female and two males) with esophageal transmural defects were treated with the Microtech®-VAC-Stent. Two patients suffered from an anastomotic leak after oncologic gastroesophageal surgery, and one patient presented with esophageal perforation due to Boerhaave syndrome. Results: Three consecutive patients were successfully treated with EVS. In one patient, one EVS treatment was sufficient, whereas the other two patients needed two and six EVS exchanges. Exchanges were scheduled every 7 days and no procedural adverse events were observed. Conclusion: In line with the former case series, EVS therapy is a promising new approach for the treatment of esophageal leaks. Exchange of the EVS seems feasible every 7 days reducing interventions for the individual patient. Prospective studies comparing EVS with other endoscopic therapies are needed to define the best therapeutic approach.
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Gastrointestinal (GI) bleeding is one of the most common complications associated with the use of direct oral anticoagulants (DOAC). Clear algorithms exist for the emergency measures in (suspected) GI bleeding, including assessing the medication history regarding anti-platelet drugs and anticoagulants as well as simple coagulation tests during pre-endoscopic management. Platelet transfusions, fresh frozen plasma (FFP), or prothrombin complex concentrate (4F-PCC) are commonly used for optimizing the coagulation status. For severe bleeding under the thrombin inhibitor dabigatran, idarucizumab is available, and for bleeding under the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa is available as specific antidotes for DOAC antagonization. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures including emergency endoscopy. Antagonization of oral anticoagulants should be considered for severe gastrointestinal bleeding in the following situations: (1) refractory hemorrhagic shock, (2) endoscopically unstoppable bleeding, or (3) nonavoidable delays until emergency endoscopy for life-threatening bleeding. After successful (endoscopic) hemostasis, anticoagulation (DOACs, vitamin K antagonist, heparin) should be resumed timely (i.e. usually within a week), taking into account individual bleeding and thromboembolic risk.
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Chymotrypsin C (CTRC) is a digestive serine protease produced by the pancreas that regulates intrapancreatic trypsin activity and provides a defensive mechanism against chronic pancreatitis (CP). CTRC exerts its protective effect by promoting degradation of trypsinogen, the precursor to trypsin. Loss-of-function missense and microdeletion variants of CTRC are found in around 4% of CP cases and increase disease risk by approximately 3-7-fold. In addition, a commonly occurring synonymous CTRC variant c.180C>T (p.Gly60=) was reported to increase CP risk in various cohorts but a global analysis of its impact has been lacking. Here, we analyzed the frequency and effect size of variant c.180C>T in Hungarian and pan-European cohorts, and performed meta-analysis of the new and published genetic association data. When allele frequency was considered, meta-analysis revealed an overall frequency of 14.2% in patients and 8.7% in controls (allelic odds ratio (OR) 2.18, 95% confidence interval (CI) 1.72-2.75). When genotypes were examined, c.180TT homozygosity was observed in 3.9% of CP patients and in 1.2% of controls, and c.180CT heterozygosity was present in 22.9% of CP patients and in 15.5% of controls. Relative to the c.180CC genotype, the genotypic OR values were 5.29 (95% CI 2.63-10.64), and 1.94 (95% CI 1.57-2.38), respectively, indicating stronger CP risk in homozygous carriers. Finally, we obtained preliminary evidence that the variant is associated with reduced CTRC mRNA levels in the pancreas. Taken together, the results indicate that CTRC variant c.180C>T is a clinically relevant risk factor, and should be considered when genetic etiology of CP is investigated.
Subject(s)
Pancreatitis, Chronic , Humans , Trypsin/genetics , Pancreatitis, Chronic/genetics , Chymotrypsin/genetics , Chymotrypsin/metabolism , Case-Control Studies , Genetic Predisposition to Disease , MutationABSTRACT
Introduction: The Russian invasion of Ukraine and the resulting consequences are in the center of political discussions, media, and likely individual thinking of the population in Germany. Yet, the impact of this prolonged exposure on mental health is not known hitherto. Methods: Using the population based cohort study DigiHero from three federal states (Saxony-Anhalt, Saxony, and Bavaria), we assessed anxiety levels (GAD-7), depressive symptoms (PHQ-9), and distress (modified PDI) in the first weeks of war and 6 months later. Results: Of those 19,432, who responded in the first weeks of war, 13,934 (71.1%) responded also 6 months later. While anxiety and emotional distress decreased during the 6 months, their average scores were still elevated, and a substantial fraction of respondents displayed clinically relevant sequelae. Persons from low-income households were especially affected, specifically by fears related to the personal financial situation. Those who reacted with a particularly strong fear in the beginning of war were more likely to have persistent clinically relevant symptoms of depression and anxiety also 6 months later. Discussion: The Russian invasion of Ukraine is accompanied by continuing impairment of mental health in the German population. Fears surrounding the personal financial situation are a strong determinant.
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Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a dismal outcome. To improve understanding of sequential microbiome changes during PDAC development we analyzed mouse models of pancreatic carcinogenesis (KC mice recapitulating pre-invasive PanIN formation, as well as KPC mice recapitulating invasive PDAC) during early tumor development and subsequent tumor progression. Diversity and community composition were analyzed depending on genotype, age, and gender. Both mouse models demonstrated concordant abundance changes of several genera influenced by one or more of the investigated factors. Abundance was significantly impacted by gender, highlighting the need to further elucidate the impact of gender differences. The findings underline the importance of the microbiome in PDAC development and indicate that microbiological screening of patients at risk and targeting the microbiome in PDAC development may be feasible in future.
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Diseases of the gastrointestinal tract present with substantial sex differences that have a potential impact on patient outcome. This fact is not sufficiently addressed either in basic research or in clinical studies. For example, most animal studies utilize male animals. Despite differences in incidence, sex may affect complication rates, prognosis, or therapeutic response. The incidence of gastrointestinal cancers is frequently higher in males, but this observation cannot solely rely on a distinct risk behaviour. Here, differences in immune response and p53 signalling may be factors responsible for this finding. Nevertheless, taking sex differences into account and improving our understanding of relevant mechanisms is crucial and will most likely have a substantial impact on disease outcome. This overview aims to highlight sex differences in the context of various gastroenterological diseases, primarily to enhance awareness. Attention to sex-specific differences is essential to improve individualized treatment.
Subject(s)
Gastrointestinal Neoplasms , Sex Characteristics , Animals , Humans , Male , Female , Incidence , Gastrointestinal Neoplasms/epidemiology , PrognosisSubject(s)
Gastric Bypass , Humans , Stents , Drainage , Endosonography , Ultrasonography, InterventionalABSTRACT
OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.