Diagnostic value of whole-mount crypt analysis of ileal biopsy specimens for the patients with familial small intestinal neuroendocrine tumors.

Background and Aims: Early-stage small intestinal neuroendocrine tumors (SI-NETs) are generally asymptomatic and difficult to diagnose. As a result, patients often present with late-stage incurable disease. SI-NETs originate from enterochromaffin (EC) cells, which develop enteroendocrine cell (EEC) clusters consisting of a subset of EC cells at the crypt bottom at an early stage of tumor progression. In a familial form of SI-NET, EEC clusters arise in a multifocal and polyclonal fashion. We sought to determine whether early detection and analysis of cryptal EEC clusters could provide insight into the development of SI-NETs and allow successful pre-symptomatic screening for at risk family members of patients with SI-NETs. Methods: Isolated crypts from endoscopic ileal biopsies or surgically removed specimens from 43 patients with familial SI-NET and 20 controls were formalin-fixed, immunostained for chromogranin A, and examined by confocal three-dimensional analysis for the presence of EEC cluster formations. Results: Examination of multiple areas of macroscopic tumor-free mucosa in surgically resected specimens from patients with familial SI-NET revealed widely distributed, independent, multifocal EEC micro-tumor formations of varying sizes. Consistent with this finding, randomly sampled ileal biopsy specimens identified aberrant crypt containing endocrine cell clusters (ACECs) in patients. ACECs were found exclusively in patients (23/43, 53%) and not in controls (0/20). Furthermore, analysis of positions and numbers of EECs in crypts and ACECs indicated significant increases in EECs at the crypt bottom, predominantly at positions 0 and 1' (p < 0.0001 compared to controls), suggesting the progression of EEC accumulation below +4 position as the early process of ACEC formation. These findings also suggested that ACECs were precursors in the development of micro-tumors and subsequent macro-tumors. Conclusion: This study indicates that SI-NETs develop from deep crypt EC cells to become ACECs, micro-tumors, and ultimately gross tumors. This process occurs widely throughout the distal small intestine in patients with familial SI-NETs consistent with but not exclusively explained by germline disease. Finally, analysis of crypts from ileal biopsies could contribute in part to earlier diagnostic screening processes avoiding late-stage presentation of incurable disease.

Diagnostic Accuracy of the Proton Pump Inhibitor Test in Gastroesophageal Reflux Disease and Noncardiac Chest Pain: A Systematic Review and Meta-analysis.

BACKGROUND: Response to a trial of proton pump inhibitors (PPIs) is currently accepted as a first step in the management of gastroesophageal reflux disease (GERD). However, information on the diagnostic performance of the PPI test is limited. AIM: The aim of this study was to determine the diagnostic accuracy of the PPI test in GERD and noncardiac chest pain (NCCP) and to assess the test performance in erosive reflux disease (ERD) and nonerosive reflux disease (NERD). METHODS: Web of Science, Cochrane Controlled Register of Trials (CENTRAL), and MEDLINE were searched for studies reporting the diagnostic accuracy of the PPI test in adult patients with typical GERD and NCCP who underwent evaluation using an accepted reference standard, from January 1, 1950, through February 1, 2021. Subgroup analyses were performed, and the risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS: Nineteen studies (GERD=11, NCCP=8) involving 1691 patients were included. In GERD, the PPI test had 79% pooled sensitivity [95% confidence interval (CI), 72%-84%], and 45% pooled specificity (95% CI, 40%-49%). In NCCP, pooled sensitivity and specificity were 79% (95% CI, 69%-86%) and 79% (95% CI, 69%-86%), respectively. In ERD, the PPI test had 76% pooled sensitivity (95% CI, 66%-84%) and 30% pooled specificity (95% CI, 8%-67%). In NERD, the PPI test had 79% pooled sensitivity (95% CI, 70%-86%) and 50% pooled specificity (95% CI, 39%-61%). CONCLUSIONS: The PPI test was sensitive in GERD but with suboptimal specificity. The test performed better in GERD-related NCCP. Diagnostic accuracy was comparable in ERD and NERD.

APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort.

BACKGROUND AND AIMS: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas. APPROACH AND RESULTS: Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH. CONCLUSIONS: APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.

Competition Shadow: Anchoring to Fear Versus Hope in Estimating Rivals in Competition.

We studied the effect of two inconsistent emotions, fear and hope, in strategic decision-making during a competition. We sought to examine which emotion will be more related to whether decision-makers accurately and objectively estimate their rival We developed a nuanced perspective on the effects of trait anxiety on rival estimation by integrating it with the competition shadow. Using a competition simulation and basing on data from 221 individuals across two countries, we found support for a predicted effect of trait anxiety on rival estimation. Several theoretical implications are discussed.

Contribution of substance use disorders on HIV treatment outcomes and antiretroviral medication adherence among HIV-infected persons entering jail.

HIV and substance use are inextricably intertwined. One-sixth of people living with HIV/AIDS (PLWHA) transition through the correctional system annually. There is paucity of evidence on the impact of substance use disorders on HIV treatment engagement among jail detainees. We examined correlates of HIV treatment in the largest sample of PLWHA transitioning through jail in 10 US sites from 2007 to 2011. Cocaine, alcohol, cannabis, and heroin were the most commonly used substances. Drug use severity was negatively and independently correlated with three outcomes just before incarceration: (1) having an HIV care provider (AOR = 0.28; 95 % CI 0.09-0.89); (2) being prescribed antiretroviral therapy (AOR = 0.12; 95 % CI 0.04-0.35) and (3) high levels (>95 %) of antiretroviral medication adherence (AOR = 0.18; 95 % CI 0.05-0.62). Demographic, medical and psychiatric comorbidity, and social factors also contributed to poor outcomes. Evidence-based drug treatments that include multi-faceted interventions, including medication-assisted therapies, are urgently needed to effectively engage this vulnerable population.

Post-release substance abuse outcomes among HIV-infected jail detainees: results from a multisite study.

HIV-infected individuals with substance use disorders have a high prevalence of medical and psychiatric morbidities that complicate treatment. Incarceration further disrupts healthcare access and utilization. Without appropriate diagnosis and treatment, drug relapse upon release exceeds 85 %, which contributes to poor health outcomes. A prospective cohort of 1,032 HIV-infected jail detainees were surveyed in a ten-site demonstration project during incarceration and six-months post-release, in order to examine the effect of predisposing factors, enabling resources and need factors on their subsequent drug use. Homelessness, pre-incarceration cocaine and opioid use, and high drug and alcohol severity were significantly associated with cocaine and opioid relapse. Substance abuse treatment, though poorly defined, did not influence post-release cocaine and opioid use. An approach that integrates multiple services, simultaneously using evidence-based substance abuse, psychiatric care, and social services is needed to improve healthcare outcomes for HIV-infected persons transitioning from jails to the community.

Wells' prediction rules for pulmonary embolism: valid in all clinical subgroups?

Pulmonary embolism is major cause of hospital death. Clinical prediction rules such as Wells' prediction rules can help in selection of at-risk patients who need further testing for pulmonary embolism. We evaluated the usefulness of such criteria for detection of patients with diagnosed pulmonary embolism. Patients enrolled in National Research Institute of Tuberculosis and Lung Disease (NRITLD) deep venous thrombosis (DVT) registry were evaluated and those with objective data about presence or absence of pulmonary embolism were selected for this study. Diagnosis of pulmonary embolism was based on computed tomography pulmonary angiography (CTPA). We calculated the embolic burden in those with CTPA-confirmed pulmonary embolism. Eighty-six patients entered the study (58 males, 28 females, mean age = 54.39 ± 1.74 years). Fifty-four cases had coexisting pulmonary embolism (embolic burden score: 10.77 ± 1.181). Embolic burden score was correlated to presence of massive pulmonary embolism (Pearson rho: 0.43, P = 0.002). There was no association between Wells' pulmonary embolism score and the occurrence of pulmonary embolism (Spearman's rho: 0.085, P = 0.51). Dividing the patients into two, or three, risk groups according to Wells' model did not reveal an association with occurrence of pulmonary embolism either (P = 0.99 and P = 0.261, respectively). Tachycardia and hemoptysis were the only parameters from the Wells' pulmonary embolism score correlated to presence of pulmonary embolism (Spearman's rho: 0.373, P < 0.000 and Spearman's rho: 0.297, P = 0.005, correspondingly). Wells' pulmonary embolism score could not predict the occurrence of pulmonary embolism in DVT patients suspected of having coexisting pulmonary embolism. Until further studies shed light on this patient subset, overreliance on Wells' prediction rules as the solo decision making tool should be cautioned.

Treatment outcome and mortality: Their predictors among HIV/TB co-infected patients from Iran.

BACKGROUND: The risk of death is significantly higher in TB/HIV-infected patients than in those patients with just one disease or the other. This study aims to evaluate the impact of demographic, clinical and laboratory characteristics on the treatment outcome and mortality of TB/HIV co-infected patients in a TB tertiary center in Iran. MATERIALS AND METHODS: The study was conducted at Iran's National Referral Center for Tuberculosis. In total, 111 patients were recruited between 2004 and 2007. Mycobacteriology studies were performed for all patients. Demographic, clinical, and lab data of all patients were analyzed, and predictors of unsuccessful outcomes, as well as mortality, were determined. RESULTS: The mean age for all 111 TB/HIV patients was 38±9years (range 22-70) and 107 patients (96.3%) were male; 104 patients (93.7%) had a history of drug abuse, and 96 patients (86.4%) had a history of imprisonment. The route of transmission of HIV was intravenous drug use in 88 of the patients (79.3%); 23 patients (20.7%) had a history of Category 1 (CAT-1) (5.4%) and CAT-2 treatment. Highly Active Antiretroviral Therapy (HAART) was given to 48 patients (43.2%). There was no significant association found between treatment outcome or mortality with sex, smoking, drug and alcohol abuse, imprisonment, route of transmission, history of CAT-1 and CAT-2, cluster of differentiation 4 (CD4), and adverse effects (p>0.05). Administration of HAART led to a significantly higher rate of good outcome (p<0.001). Lower Albumin levels and body weight were significantly associated with mortality. CONCLUSION: Albumin levels and weight can be predictors of mortality and an unsuccessful outcome. Administration of HAART led to a better outcome.

Dexter versus sinister deep vein thrombosis: which is the more sinister? Findings from the NRITLD DVT registry.

Deep vein thrombosis (DVT) is a major health problem. Despite the wealth of studies on its epidemiology, few have described the thrombus sidedness and particularly the association of thrombus sidedness with clinical presentation and subsequent complications. This article reviews current knowledge regarding this topic and in light of recent data from a large prospective study. This is the first report from the prospective National Research Institute of Tuberculosis and Lung Disease DVT registry. Patients with ultrasound-confirmed symptomatic DVT were enrolled, and thrombus sidedness was investigated in each case. Computed tomography pulmonary angiography was used to diagnose coexisting pulmonary embolism (PE) in DVT patients with suggestive symptoms. Embolic burden score was calculated for those with PE. From the total of 100 patients, 45 had left-sided DVT, 41 had right-sided DVT, and 14 had bilateral DVT. Presenting symptoms and comorbidities were comparable, except for cancer, which was more common in those with right-sided involvement (either right-sided or bilateral DVT; P = 0.004). Compared with those with left-sided DVT, PE happened more frequently in right-sided DVT patients. Right-sided DVT patients also had a higher rate of massive PE ( P = 0.03) and a greater mean embolic burden (13.32 ± 1.63 versus 6.05 ± 1.06; P = 0.001). These findings support raised awareness for global reconsideration of the assumption of complete identicalness of right-sided and left-sided DVT. Although future studies are needed to better elucidate epidemiological and prognostic differences based on the thrombus sidedness, our preliminary findings suggest that the two are not completely identical and right-sided DVT might be more ominous.

Revised Category II regimen as an alternative strategy for retreatment of Category I regimen failure and irregular treatment cases.

Currently, the Category (CAT) II regimen is recommended for patients who have failed the CAT I regimen. We have determined before that prevalence of multidrug-resistant tuberculosis (MDR TB) is relatively high among these patients. On the other hand, the retreatment success rate with CAT II in CAT I treatment failures and defaults is nearly 50%. Therefore, we tried to find another strategy with a higher success rate. From January 2004 to November 2007, 105 patients with pulmonary TB, who failed a prior CAT I regimen or with more than one course of irregular anti-TB treatment, were included in this study, whereas five cases with nontuberculous mycobacteria were excluded. Drug susceptibility testing (DST), for first line anti-TB drugs, and polymerase chain reaction were performed. By the time of availability of DST that took 3 to 4 months, a pilot protocol consisted of isoniazid, rifampin, ethambutol, ofloxacin, cycloserine, and amikacin was started. Then therapeutic regimen was adjusted based on four categories of DST pattern: sensitive, non-MDR pattern, MDR pattern, and culture-negative. Sensitive patients received the standard CAT I regimen, non-MDR patients an individualized regimen based on DST, MDR patients a standard second-line regimen, and culture-negatives a standard CAT I plus a 6-month injectable agent. Treatment outcomes were categorized and analyzed. Forty-eight patients with prior CAT I treatment failure and 52 with more than one irregular treatment courses were included in the analysis. Six percent of subjects had confirmed HIV infection. Seventy-two percent of subjects were assigned to a good outcome and 28% were assigned to a poor outcome group. Seventeen percent were culture-negative. Regarding DST pattern, 13% isolated strains were completely sensitive to first-line drugs. 53% strains were MDR, 10% monodrug-resistant, and 7% polydrug-resistant. There was no significant association between DST pattern and outcome (P = 0.13). The irregular regimen was associated with MDR TB as twice as CAT I regimen failure (69.2% versus 35.4%, P = 0.004). Patients with MDR TB significantly experienced more side effects than non-MDR-TBs (47% versus 27%, P = 0.102). Of 100 patients, 72% were cured, 5% abandoned treatment, 12% died, 6% were classified as treatment failures, 1% relapsed, and 5% were transferred out. Of 53 patients with MDR TB, 33 subjects were cured and seven died. All together, successful outcome was achieved in 62.2%, 76%, and 76% of MDR TB, non-MDR TB, and completely sensitive cases, respectively. A retreatment strategy based on DST and replacing the Category II regimen with an intermediate regimen called revised CAT II may improve clinical outcomes among Category I treatment failures and defaults who found to have active, infectious MDR TB. This strategy significantly reduces delays to MDR TB diagnosis and to the initiation of MDR TB therapy. Success rate of this strategy is 62.2% and 72% in MDR TB and overall CAT I failure cases and defaulters, respectively.

Utility of Gastric Lavage for Diagnosis of Tuberculosis in Patients who are Unable to Expectorate Sputum.

BACKGROUND: There are number of patients who are unable to expectorate sputum specimens. In this study, we used gastric lavage (GL) test for diagnosis of tuberculosis (TB) in patients who were unable to produce sputum. MATERIALS AND METHODS: Patients who were unable to produce sputum specimens were included in the study to confirm TB disease. Gastric lavage sampling was performed and sent for acid fast bacillus smear and culture under special laboratory conditions and sterilized methods. Further bronchoscopy for broncho-alveolar lavage was done on patients with negative GL smear results. Drug susceptibility tests were performed on 48 GL culture positive cases. RESULTS: Eighty-five patients were included in the study; who were hospitalized at our referral center for suspected TB. GL smears were reported to be positive in 37 cases (66.07%) and culture in 85.7%. The total number of smear and culture-positive cases in this study was 48 (85.7%). Forty cases (87%) of drug-sensitive, 1 case (2.2%) of isoniazid and rifampin-resistant TB (multi-drug resistant; MDR), and 5 cases of resistant to one drug were detected. There have not been observed any complications after the GL method. CONCLUSION: It seems that regarding the high number of positive GL cultures (85.7%), GL can be effective for diagnosis of patients who have suspicious tuberculosis symptoms and are unable to produce sputum especially in resource limited areas.

Impact of extensively drug-resistant tuberculosis on treatment outcome of multidrug-resistant tuberculosis patients with standardized regimen: report from Iran.

The limited experience in treating patients with extensively drug-resistant tuberculosis (XDR-TB) shows a therapeutic success rate under 50-60% and there are no publications regarding the outcome of these patients treated with standardized regimens. All multidrug-resistant tuberculosis (MDR-TB) patients hospitalized at the Masih Daneshvari Hospital in Tehran, Iran, during 2004-2007 were recruited. Drug susceptibility testing to 14 drugs (including eight second-line drugs) was performed and a standardized regimen with ofloxacin, cycloserine, prothionamide, and amikacin was administered for all patients. Outcome of the patients was studied, comparing between the MDR-TB non-XDR-TB and the XDR-TB. Fifty-one patients were included, 12 with XDR-TB criteria. Of 51, 48 were HIV negative and HIV status was unknown in three cases. All 12 were HIV negative. XDR-TB infection was significantly associated only with age (p = 0.039). The success rates for the total 51 MDR-TB, the 39 MDR-TB non-XDR-TB, and the 12 XDR-TB patients were 76.5% (39 patients), 87.2% (34 patients), and 41.7% (5 patients), respectively. Resistance to ofloxacin, ciprofloxacin, and amikacin were found to be significantly associated with unsuccessful outcome. In this setting, a standardized second-line drugs regimen produces high treatment success rates in MDR-TB patients unless XDR-TB is present.