Impact of the COVID-19 Pandemic on the Severity and Early Postoperative Outcomes of Acute Appendicitis.

Background The coronavirus disease 2019 (COVID-19) pandemic caused changes in surgical practice. For acute appendicitis (AA), measures to control the pandemic might hinder patients from seeking medical care timely, resulting in increasing severity, postoperative complications, and mortality. This study aimed to investigate whether the COVID-19 pandemic had a negative impact on the severity and postoperative outcomes of patients with AA. Methodology We retrospectively reviewed medical records of AA patients treated operatively at Nhan Dan Gia Dinh Hospital hospital from June 1st to September 30th in three consecutive years: pre-pandemic (2019)/Group 1, minor waves (2020)/Group 2, and major wave (2021)/Group 3 (2021). Data were collected focusing on the duration of symptoms, severity of AA, time from admission to operation, postoperative complications, and mortality. Results There were 1,055 patients, including 452 patients in Group 1, 409 in Group 2, and 194 in Group 3. The overall number of patients decreased mainly in non-complicated AA. The percentages of hospital admission after 24 hours gradually increased (20.8%, 27.9%, and 43.8%, p < 0.05). The percentages of complicated AA in Group 2 and Group 3 were statistically higher than in Group 1 (39% and 55% vs. 31%, p < 0.05). Waiting time for operation increased to five hours during the major wave. Laparoscopic appendectomy was performed in 98-99% of AA patients during the pandemic, with an early postoperative complication rate of 5-9% and a mortality rate of 0.2-1%. Conclusions Although the percentages of hospital admission after 24 hours and complicated AA increased, laparoscopic appendectomy was still feasible and effective and should be maintained as the standard management for AA during the COVID-19 pandemic.

Role of through-the-scope catheter-based EUS in inflammatory bowel disease diagnosis and activity assessment.

BACKGROUND AND AIMS: Distinguishing Crohn's disease (CD) from ulcerative colitis (UC) may be difficult when the disease is limited to the colon. Transmural healing is an important adjunctive measure of inflammatory bowel disease activity. The aim of this study was to examine the role of EUS in differentiating CD versus UC and evaluating transmural disease activity. METHODS: This prospective cohort study enrolled 20 patients with CD (10 active [aCD], 10 inactive), 20 patients with UC (10 active [aUC], 10 inactive), and 20 control subjects who underwent colonoscopy from 2019 to 2021 at a tertiary care center. Measurements of bowel wall layer thickness from the rectum and cecum were obtained using a through-the-scope US catheter (UM-3R-3; Olympus, Center Valley, Penn, USA) at the time of colonoscopy. RESULTS: Compared with control subjects, patients with aCD had thicker rectal submucosa and total wall layer (submucosa median, 1.80 mm [interquartile range {IQR}, 1.40-2.00] vs .60 mm [IQR, .40-.70]; total wall median, 3.70 mm [IQR, 3.52-4.62] vs 2.10 mm [IQR, 1.70-2.40], respectively; P < .01). Similar significant findings were observed for the cecal wall layers. Compared with control subjects, patients with aUC had thicker rectal mucosa and total wall but not submucosa or muscularis propria layers (mucosa median, 1.35 mm [IQR, 1.12-1.47] vs .60 mm [IQR, .57-.70]; total wall median, 3.45 mm [IQR, 2.85-3.75] vs 2.10 mm [IQR, 1.70-2.40], respectively; P < .01). Patients with aCD compared with those with aUC had a significantly thicker rectal submucosa layer (median, 1.80 mm [IQR, 1.40-2.00] vs .55 mm [IQR, .40-.75], respectively, P < .01). Cutoff values of 1.1 mm for rectal submucosa in CD (sensitivity, 1.0; specificity, 1.0) and 1.1 mm for rectal mucosa in UC (sensitivity, .8; specificity, .9) were found to differentiate active from inactive disease. CONCLUSIONS: EUS measurements of colon wall layers can help diagnose aCD versus aUC and assess transmural disease activity. (Clinical trial registration number: NCT03863886.).

Efficient, Selective Sodium and Lithium Removal by Faradaic Deionization Using Symmetric Sodium Titanium Vanadium Phosphate Intercalation Electrodes.

NASICON (sodium superionic conductor) materials are promising host compounds for the reversible capture of Na+ ions, finding prior application in batteries as solid-state electrolytes and cathodes/anodes. Given their affinity for Na+ ions, these materials can be used in Faradaic deionization (FDI) for the selective removal of sodium over other competing ions. Here, we investigate the selective removal of sodium over other alkali and alkaline-earth metal cations from aqueous electrolytes when using a NASICON-based mixed Ti-V phase as an intercalation electrode, namely, sodium titanium vanadium phosphate (NTVP). Galvanostatic cycling experiments in three-electrode cells with electrolytes containing Na+, K+, Mg2+, Ca2+, and Li+ reveal that only Na+ and Li+ can intercalate into the NTVP crystal structure, while other cations show capacitive response, leading to a material-intrinsic selectivity factor of 56 for Na+ over K+, Mg2+, and Ca2+. Furthermore, electrochemical titration experiments together with modeling show that an intercalation mechanism with a limited miscibility gap for Na+ in NTVP mitigates the state-of-charge gradients to which phase-separating intercalation electrodes are prone when operated under electrolyte flow. NTVP electrodes are then incorporated into an FDI cell with automated fluid recirculation to demonstrate up to 94% removal of sodium in streams with competing alkali/alkaline-earth cations with 10-fold higher concentration, showing process selectivity factors of 3-6 for Na+ over cations other than Li+. Decreasing the current density can improve selectivity up to 25% and reduce energy consumption by as much as ∼50%, depending on the competing ion. The results also indicate the utility of NTVP for selective lithium recovery.

FACT is recruited to the +1 nucleosome of transcribed genes and spreads in a Chd1-dependent manner.

The histone chaperone FACT occupies transcribed regions where it plays prominent roles in maintaining chromatin integrity and preserving epigenetic information. How it is targeted to transcribed regions, however, remains unclear. Proposed models include docking on the RNA polymerase II (RNAPII) C-terminal domain (CTD), recruitment by elongation factors, recognition of modified histone tails, and binding partially disassembled nucleosomes. Here, we systematically test these and other scenarios in Saccharomyces cerevisiae and find that FACT binds transcribed chromatin, not RNAPII. Through a combination of high-resolution genome-wide mapping, single-molecule tracking, and mathematical modeling, we propose that FACT recognizes the +1 nucleosome, as it is partially unwrapped by the engaging RNAPII, and spreads to downstream nucleosomes aided by the chromatin remodeler Chd1. Our work clarifies how FACT interacts with genes, suggests a processive mechanism for FACT function, and provides a framework to further dissect the molecular mechanisms of transcription-coupled histone chaperoning.

Spatiotemporal coordination of transcription preinitiation complex assembly in live cells.

Transcription initiation by RNA polymerase II (RNA Pol II) requires preinitiation complex (PIC) assembly at gene promoters. In the dynamic nucleus, where thousands of promoters are broadly distributed in chromatin, it is unclear how multiple individual components converge on any target to establish the PIC. Here we use live-cell, single-molecule tracking in S. cerevisiae to visualize constrained exploration of the nucleoplasm by PIC components and Mediator's key role in guiding this process. On chromatin, TFIID/TATA-binding protein (TBP), Mediator, and RNA Pol II instruct assembly of a short-lived PIC, which occurs infrequently but efficiently within a few seconds on average. Moreover, PIC exclusion by nucleosome encroachment underscores regulated promoter accessibility by chromatin remodeling. Thus, coordinated nuclear exploration and recruitment to accessible targets underlies dynamic PIC establishment in yeast. Our study provides a global spatiotemporal model for transcription initiation in live cells.

Wireless Capsule Endoscopy for Diagnosis and Management of Post-Operative Recurrence of Crohn's Disease.

Despite aggressive medical therapy, many patients with Crohn's disease require surgical intervention over time. After surgical resection, disease recurrence is common. Ileo-colonoscopy and the Rutgeerts score are commonly used for diagnosis and monitoring of post-operative endoscopic recurrence. The latter is the precursor of clinical recurrence and therefore it impacts prognosis and patient management. However, due to the limited length of bowel assessed by ileo-colonoscopy, this procedure can miss out-of-reach, more proximal lesions in the small bowel. This limitation introduces an important uncertainty when evaluating post-operative relapse by ileo-colonoscopy. In addition, the Rutgeerts score 'per se' bears a number of ambiguities. Here we will discuss the pros and cons of ileo-colonoscopy and other imaging studies including wireless capsule endoscopy to diagnose and manage post-operative recurrence of Crohn's disease. A number of studies provide evidence that wireless capsule endoscopy is a potentially more accurate as well as less invasive and less costly alternative to conventional techniques including ileo-colonoscopy.

Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents.

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn's disease (CD) and ulcerative colitis (UC) patients. Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD. Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3. Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

Economic impact on direct healthcare costs of missing opportunities for diagnosing HIV within healthcare settings.

BACKGROUND: The economic consequences of a missed opportunity for HIV testing at an earlier stage of infection within a healthcare setting are poorly described. METHODS: For all newly diagnosed HIV patients followed at the Southern Alberta HIV/AIDS Clinic (SAC), Calgary, Canada, between 1 April 2011 and 1 April 2016, all clinical encounters occurring < 3 years prior to diagnosis within the region were obtained. The direct costs of HIV care after diagnosis to 31 March 2019 were determined from a payers' perspective and reported as mean cost per patient per month (PPPM) in 2019 Canadian dollars (CDN$). Patients with no encounters for 3 years prior to diagnosis were compared with patients with encounters, with special attention to patients with HIV clinical indicator conditions (HCICs). RESULTS: Of 388 patients, 60% had one or more prior encounter without HIV testing; 14% had been treated for an HCIC. Females, older patients and heterosexuals were more likely to have prior encounters. At diagnosis, patients with previous encounters presented with lower CD4 counts and higher rates of AIDS. The mean PPPM costs for patients with any prior encounter or for an HCIC-based encounter were 16% and 33% higher, respectively, than for patients with no prior encounters. While mean PPPM costs for antiretroviral drugs and outpatient visits were slightly higher, in-patient costs were 10 times higher for people with HIV who had a previous HCIC encounter vs. those with no encounters (CDN$316 vs. $31, respectively). CONCLUSIONS: Any healthcare visit, especially for an HCIC, represents relatively easy opportunities for HIV testing. Not testing can result in poorer health and higher costs. Targeted clinical testing and novel interventions to correct overlooked testing opportunities within healthcare settings may be an easy way to implement cost savings.

Fecal Lactoferrin Predicts Primary Nonresponse to Biologic Agents in Inflammatory Bowel Disease.

INTRODUCTION: Fecal lactoferrin (FL) is a timely and accurate marker of inflammation in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to verify whether FL can predict primary nonresponse (PNR) to biologic agents during induction. METHODS: Retrospective outcome review in 27 patients (13 with CD and 14 with UC) tested for baseline FL and retested within a week after the first and second induction doses. Clinical/biochemical outcomes were evaluated at end of induction and at follow-up (3-24 months). RESULTS: Compared to baseline, changes of the Harvey-Bradshaw (CD) and Partial Mayo Scoring (UC) indices at end of induction separated responders (18/27 or 67%) from nonresponders (9/17 or 33%). In all patients, the initial FL value at induction decreased compared to baseline, continuing to decrease after the following dose in clinical responders while bouncing back in the others. Models targeting the 2 consecutively decreased FL values or the second FL value compared to baseline or the second FL value compared to the first were able to accurately predict response at end of induction. Follow-up assessment confirmed clinical remission in initial responders (with FL values reduced on the average by 94 ± 10% compared to baseline). CONCLUSIONS: In CD and UC patients during induction with biologic agents, early FL measurements accurately separate clinical responders from those experiencing PNR. The method described here offers several potential advantages over other strategies to assess and manage these patients.

Diagnostic Modality of Clostridioides difficile Infection Predicts Treatment Response and Outcomes in Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) patients are at increased risk of developing Clostridioides difficile infection (CDI). Common methods to diagnose CDI involve a combination of tests including the toxin A/B enzyme immunoassay (Toxin) and toxin gene polymerase chain reaction assay (PCR). Disease outcomes in Toxin+ versus Toxin-PCR+ IBD patients remain unclear. AIMS: This study aimed to examine the response to antibiotics and risk of IBD therapy escalation in Toxin+ versus Toxin-PCR+ patients. METHODS: IBD patients at an academic center with CDI diagnosis based on Toxin+ or Toxin-PCR+ from 2012 to 2017 were identified. Comparisons of response to antibiotics within 30 days and escalation of IBD therapy within 90 days of CDI diagnosis between these two groups were analyzed by Chi-square analysis. Multivariable regression analysis examined factors associated with antibiotic response. RESULTS: Among 92 patients included, 61% had Crohn's disease and 39% had ulcerative colitis. 70% tested Toxin-PCR+. 60% received vancomycin or fidaxomicin to treat CDI. 82% of Toxin+ patients responded to antibiotics compared to 25% of Toxin-PCR+ patients (p < 0.001). 21% of Toxin+ patients required IBD therapy escalation compared to 63% of Toxin-PCR+ patients (p < 0.001). When adjusted for the types of antibiotics used, IBD subtypes, and immunosuppression status, positivity to Toxin (OR 14.85, CI 4.62-47.72) was the most significant predictor of response to antibiotics. CONCLUSIONS: Toxin+ compared to Toxin-PCR+ IBD patients had a significantly higher rate of response to antibiotics and lower chances of requiring IBD therapy escalation. Future outcome studies involving CDI in IBD patients should be stratified by modality of diagnosis.

Fecal Lactoferrin and Other Stool Markers during Normal Pregnancy and in Inflammatory Bowel Diseases: A Prospective Study and Review of the Literature.

INTRODUCTION: Management of inflammatory bowel diseases (IBDs) - both Crohn's disease (CD) and ulcerative colitis (UC) - during pregnancy can be challenging since most monitoring tools available in nonpregnant patients are contraindicated. OBJECTIVES: The aim of the study was to test whether fecal inflammatory markers - specifically fecal lactoferrin - physiologically change during normal pregnancy as a prerequisite to use them to monitor IBD activity during pregnancy. METHODS: Fecal lactoferrin was tested in healthy pregnant and nonpregnant women from the same geographic area and age range (18-40 years) - all negative for clinical gastrointestinal tract inflammation. A retrospective review of fecal lactoferrin levels contrasted with the Simple Endoscopic Score for CD, and the Disease Activity Index for UC was also performed in women with active IBDs within the same age range and geographical area. RESULTS: In 30 nonpregnant subjects, fecal lactoferrin levels were 0.87 ± 1.08 µg/g. In 49 pregnant subjects, levels were 0.59 ± 0.83, 0.87 ± 1.13, and 0.85 ± 1.06 µg/g during the first, second, and third trimester, respectively (p = 0.64), with average levels for the 3 trimesters of 0.81 ± 1.04 µg/g (p = 0.61 compared to nonpregnant subjects). Sequential fecal lactoferrin levels (n = 26) did not differ from one trimester to the other in the individual subjects (p = 0.80). In 45 female IBD patients (27 with CD and 18 with UC), fecal lactoferrin levels were correlated with disease activity as defined by the endoscopic scores: 218, 688, and 1,175 µg/g for CD and 931, 2,088, and 2,509 µg/g for UC, respectively, for mild, moderate, and severe activity. CONCLUSIONS: Fecal lactoferrin levels during normal pregnancy are superimposable to those of nonpregnant women and significantly below levels in women of the same childbearing age with active IBDs. Additional published data - reviewed in this atricle - and our own indicate that fecal lactoferrin and other markers can be potentially used to monitor disease activity in pregnant IBD patients.

Tenofovir resistance in early and long-term treated patients on first-line antiretroviral therapy in eight low-income and middle-income countries.

OBJECTIVE: We aimed to assess the frequency of tenofovir (TDF) resistance in people failing tenofovir/lamivudine or emtricitabine (XTC)/nonnucleotide reverse-transcriptase inhibitor-based first-line antiretroviral treatment (ART) using data from 15 nationally representative surveys of HIV drug resistance conducted between 2014 and 2018 in Cameroon, Guatemala, Honduras, Nicaragua, Senegal, Uganda, Vietnam and Zambia. METHODS: Prevalence of nucleoside reverse-transcriptase inhibitor resistance among participants with virological nonsuppression (viral load ≥1000 copies/ml) who had received TDF-based ART for 12-24 months (early ART group) and at least 40 months (long-term ART group) was assessed using Sanger sequencing and resistance was interpreted using the Stanford HIVdb algorithm. For each group, we estimated a pooled prevalence using random effect meta-analysis. RESULTS: Of 4677 participants enrolled in the surveys, 640 (13.7%) had virological nonsuppression, 431 (67.3%) were successfully genotyped and were included in the analysis; of those, 60.3% (260) were participants in the early ART group. Overall, 39.1, 57.9, 38.5 and 3.6% patients in the early ART group and 42.9, 69.3, 42.9 and 10.0% patients on long-term ART had resistance to TDF, XTC, TDF + XTC and TDF + XTC + zidovudine, respectively. Overall, tenofovir resistance was mainly due to K65R or K70E/G/N/A/S/T/Y115F mutations (79%) but also due to thymidine analogue mutations (21%) which arise from exposure to thymidine analogues but causing cross-resistance to TDF. CONCLUSION: Dual resistance to TDF + XTC occurred in more than 40% of the people with viral nonsuppression receiving tenofovir-based first-line ART, supporting WHO recommendation to optimize the nucleoside backbone in second-line treatment and cautioning against single drug substitutions in people with unsuppressed viral load.

Live-cell single particle imaging reveals the role of RNA polymerase II in histone H2A.Z eviction.

The H2A.Z histone variant, a genome-wide hallmark of permissive chromatin, is enriched near transcription start sites in all eukaryotes. H2A.Z is deposited by the SWR1 chromatin remodeler and evicted by unclear mechanisms. We tracked H2A.Z in living yeast at single-molecule resolution, and found that H2A.Z eviction is dependent on RNA Polymerase II (Pol II) and the Kin28/Cdk7 kinase, which phosphorylates Serine 5 of heptapeptide repeats on the carboxy-terminal domain of the largest Pol II subunit Rpb1. These findings link H2A.Z eviction to transcription initiation, promoter escape and early elongation activities of Pol II. Because passage of Pol II through +1 nucleosomes genome-wide would obligate H2A.Z turnover, we propose that global transcription at yeast promoters is responsible for eviction of H2A.Z. Such usage of yeast Pol II suggests a general mechanism coupling eukaryotic transcription to erasure of the H2A.Z epigenetic signal.

Use of the Electrodiagnostic Entrustable Professional Activity for Competency Assessment in Physical Medicine and Rehabilitation Training Programs.

Entrustable professional activities have emerged as a means for the evaluation of resident competency that is expressed in terms of the assessed need for supervision. Recently, 19 physical medicine and rehabilitation-specific entrustable professional activities were published (Am J Phys Med Rehabil. 2017;96:762-764). The electrodiagnostic entrustable professional activity and six new electrodiagnostic entrustable professional activities subcategories (observable practice activities) were piloted as an entrustable professional activities/observable practice activities set within five residency programs. Survey-based (quantitative) and open-ended (qualitative) feedback was collected from participants. Participating attendings found this method feasible and generally reported satisfaction with the entrustable professional activities/observable practice activities as a means of providing feedback to residents. Residents were less clear on the added value of this approach. Qualitative data supported the need for adjustments to the entrustment scale to allow for more gradations within supervisory levels, a standardized orientation of residents to the use of observable practice activities and an increased quantity of assessments for each observable practice activities category to allow for demonstration of resident progress toward independence. Use of the electrodiagnostic entrustable professional activity/observable practice activities set shows promise as a means for observational competency assessment in the outpatient setting. However, feedback acquired through this pilot study suggests changes that could be made to improve future implementation.

The Vital Role of Professionalism in Physical Medicine and Rehabilitation.

Professionalism in medicine is universally embraced, and it is the foundation for core competencies in medical education, clinical practice, and research. Physical medicine and rehabilitation physicians must master a complex body of knowledge and use this to responsibly care for patients. Rehabilitation professionals work in various settings; however, each one must establish and maintain ethical standards consistent with the specialty and national standards. For example, the Accreditation Council for Graduate Medical Education lists professionalism as one of its six core competencies, which trainees must master. There is a growing interest in professionalism and some of the ethical issues that it encompasses. This report provides a general overview of professionalism. Future reports are needed, and there is an opportunity to consider many facets of professionalism in greater detail.

Updated direct costs of medical care for HIV-infected patients within a regional population from 2006 to 2017.

OBJECTIVES: The aim of the study was to reappraise the precise costs of HIV care and cost drivers, to determine the optimal tools for modelling costs for HIV care, and to understand the implications of changing medical management of HIV-infected patients for both subsequent outcomes and health care budgets. METHODS: We obtained all drug, laboratory, out-patient and in-patient care costs for all HIV-infected patients followed between 1 January 2006 and 31 December 2017 (2017 Cdn$). Mean cost per patient per month (PPPM) was used as the standard comparator value. Patients were stratified based on CD4 count: (1) ≤ 75, (2) 76-200, (3) 201-500 and (4) > 500 cells/µL. We determined the cost for only HIV-related expenses. We compared current costs with costs previously reported for the same population. RESULTS: The number of HIV-infected patients in care doubled from 2006 to 2017; total costs increased from $12.4 to $30.1 million, with antiretroviral (ARV) drugs accounting for 78.8% of costs by 2017. Out-patient/laboratory costs declined from 12% to 8.5%, while in-patient costs exhibited more annual variation. Mean PPPM costs increased from $1316 in 2006 to $1712 in 2014, declining to $1446 in 2017. Higher PPPM costs were associated with CD4 counts < 200 cells/µL. Costs have shifted. While the cost of ARV drugs increased by 32%, the costs of out-patient and in-patient services decreased by 80% and 71%, respectively. Most of the decrease for in-patient costs was attributable to a substantial decrease in HIV-related hospitalizations. CONCLUSIONS: Although antiretroviral therapy (ART) provides immense benefits, it is not inexpensive. ARV drugs remain the largest cost driver. Hospital costs have remained low. Substantial costs of lifelong ART necessitate innovative, locally applicable strategies for ARV selection and use.

Community-wide Screening for Tuberculosis in a High-Prevalence Setting.

BACKGROUND: The World Health Organization has set ambitious targets for the global elimination of tuberculosis. However, these targets will not be achieved at the current rate of progress. METHODS: We performed a cluster-randomized, controlled trial in Ca Mau Province, Vietnam, to evaluate the effectiveness of active community-wide screening, as compared with standard passive case detection alone, for reducing the prevalence of tuberculosis. Persons 15 years of age or older who resided in 60 intervention clusters (subcommunes) were screened for pulmonary tuberculosis, regardless of symptoms, annually for 3 years, beginning in 2014, by means of rapid nucleic acid amplification testing of spontaneously expectorated sputum samples. Active screening was not performed in the 60 control clusters in the first 3 years. The primary outcome, measured in the fourth year, was the prevalence of microbiologically confirmed pulmonary tuberculosis among persons 15 years of age or older. The secondary outcome was the prevalence of tuberculosis infection, as assessed by an interferon gamma release assay in the fourth year, among children born in 2012. RESULTS: In the fourth-year prevalence survey, we tested 42,150 participants in the intervention group and 41,680 participants in the control group. A total of 53 participants in the intervention group (126 per 100,000 population) and 94 participants in the control group (226 per 100,000) had pulmonary tuberculosis, as confirmed by a positive nucleic acid amplification test for Mycobacterium tuberculosis (prevalence ratio, 0.56; 95% confidence interval [CI], 0.40 to 0.78; P<0.001). The prevalence of tuberculosis infection in children born in 2012 was 3.3% in the intervention group and 2.6% in the control group (prevalence ratio, 1.29; 95% CI, 0.70 to 2.36; P = 0.42). CONCLUSIONS: Three years of community-wide screening in persons 15 years of age or older who resided in Ca Mau Province, Vietnam, resulted in a lower prevalence of pulmonary tuberculosis in the fourth year than standard passive case detection alone. (Funded by the Australian National Health and Medical Research Council; ACT3 Australian New Zealand Clinical Trials Registry number, ACTRN12614000372684.).

Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical Science.

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)-both ulcerative colitis (UC) and Crohn's Disease (CD)-as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage-as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients' first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.