Nevin Manimala

J Immunol. 2021 Sep 27:ji2100686. doi: 10.4049/jimmunol.2100686. Online ahead of print.

ABSTRACT

Autoimmune diseases develop when autoantigens activate previously quiescent self-reactive lymphocytes. Gene-gene interaction between certain HLA class I risk alleles and variants of the endoplasmic reticulum aminopeptidase ERAP1 controls the risk for common immune-mediated diseases, including psoriasis, ankylosing spondylitis, and Behçet disease. The functional mechanisms underlying this statistical association are unknown. In psoriasis, HLA-C*06:02 mediates an autoimmune response against melanocytes by autoantigen presentation. Using various genetically modified cell lines together with an autoreactive psoriatic TCR in a TCR activation assay, we demonstrate in this study that in psoriasis, ERAP1 generates the causative melanocyte autoantigen through trimming N-terminal elongated peptide precursors to the appropriate length for presentation by HLA-C*06:02. An ERAP1 risk haplotype for psoriasis produced the autoantigen much more efficiently and increased HLA-C expression and stimulation of the psoriatic TCR by melanocytes significantly more than a protective haplotype. Compared with the overall HLA class I molecules, cell surface expression of HLA-C decreased significantly more upon ERAP1 knockout. The combined upregulation of ERAP1 and HLA-C on melanocytes in psoriasis lesions emphasizes the pathogenic relevance of their interaction in patients. We conclude that in psoriasis pathogenesis, the increased generation of an ERAP1-dependent autoantigen by an ERAP1 risk haplotype enhances the likelihood that autoantigen presentation by HLA-C*06:02 will exceed the threshold for activation of potentially autoreactive T cells, thereby triggering CD8⁺ T cell-mediated autoimmune disease. These data identify ERAP1 function as a central checkpoint and promising therapeutic target in psoriasis and possibly other HLA class I-associated diseases with a similar genetic predisposition.

PMID:34580106 | DOI:10.4049/jimmunol.2100686

BMJ Open. 2021 Sep 27;11(9):e054213. doi: 10.1136/bmjopen-2021-054213.

ABSTRACT

In a cluster randomised trial (CRT), intact groups-such as communities, clinics or schools-are randomised to the study intervention or control conditions. The issue of informed consent in CRTs has been particularly challenging for researchers and research ethics committees. Some argue that cluster randomisation is a reason not to seek informed consent from research participants. In fact, systematic reviews have found that, relative to individually randomised trials, CRTs are associated with an increased likelihood of inadequate reporting of consent procedures and inappropriate use of waivers of consent. The objective of this paper is to clarify this confusion by providing a practical and useful framework to guide researchers and research ethics committees through consent issues in CRTs. In CRTs, it is the unit of intervention-not the unit of randomisation-that drives informed consent issues. We explicate a three-step framework for thinking through informed consent in CRTs: (1) identify research participants, (2) identify the study element(s) to which research participants are exposed, and (3) determine if a waiver of consent is appropriate for each study element. We then apply our framework to examples of CRTs of cluster-level, professional-level and individual-level interventions, and provide key lessons on informed consent for each type of CRT.

PMID:34580104 | DOI:10.1136/bmjopen-2021-054213

BMJ Open. 2021 Sep 27;11(9):e052221. doi: 10.1136/bmjopen-2021-052221.

ABSTRACT

OBJECTIVE: To determine the prevalence of tuberculosis (TB) and HIV in 13 Zambian correctional facilities.

METHODS: Cross-sectional study.

SETTING: 13 correctional facilities in seven of the 10 provinces in Zambia.

PARTICIPANTS: All incarcerated individuals were eligible for TB and HIV screening and testing. Of the total study population of 9695 individuals, which represent 46.2% of total correctional population at the beginning of the study, 8267 and 8160 were screened for TB and HIV, respectively.

INTERVENTIONS: TB and HIV screening and testing was done between July 2018 and February 2019.

PRIMARY OUTCOME MEASURES: All forms of TB, bacteriologically confirmed TB, drug-resistant TB, HIV.

RESULTS: Prevalence of all forms of TB and bacteriologically confirmed TB was 1599 (1340-1894) per 100 000 population and 1056 (847-1301) per 100 000 population, respectively. Among those with bacteriologically confirmed TB, 4.6% (1.3%-11.4%) had drug-resistant TB.There was no statistically significant difference in the prevalence of all forms of TB, bacteriologically confirmed TB and drug resistant TB between adults and juveniles: (p=0.82), (p=0.23), (p=0.68) respectively. Of the bacteriologically confirmed TB cases, 28.7% were asymptomatic. The prevalence of HIV was 14.3% (13.6%-15.1%). The prevalence of HIV among females was 1.8 times the prevalence of HIV among males (p=0.01).

CONCLUSION: Compared with the study in 2011 which screened inmates representing 30% of the country’s inmate population, then the prevalence of all forms of TB and HIV in correctional facilities has reduced by about 75% and 37.6%, respectively. However, compared with the general population, the prevalence of all forms of TB and HIV was 3.5 and 1.3 times higher, respectively. TB/HIV programmes in correctional facilities need further strengthening to include aspects of juvenile-specific TB programming and gender responsive HIV programming.

PMID:34580101 | DOI:10.1136/bmjopen-2021-052221

BMJ Open. 2021 Sep 27;11(9):e046912. doi: 10.1136/bmjopen-2020-046912.

ABSTRACT

INTRODUCTION: For people with type 2 diabetes mellitus (T2DM) who require an antidiabetic drug as an add-on to metformin, there is controversy about whether newer drug classes such as dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce the risk of long-term complications compared with sulfonylureas (SU). There is widespread variation across National Health Service Clinical Commissioning Groups (CCGs) in drug choice for second-line treatment in part because National Institute for Health and Care Excellence guidelines do not specify a single preferred drug class, either overall or within specific patient subgroups. This study will evaluate the relative effectiveness of the three most common second-line treatments in the UK (SU, DPP4i and SGLT2i as add-ons to metformin) and help target treatments according to individual risk profiles.

METHODS AND ANALYSIS: The study includes people with T2DM prescribed one of the second-line treatments-of-interest between 2014 and 2020 within the UK Clinical Practice Research Datalink linked with Hospital Episode Statistics and Office of National Statistics. We will use an instrumental variable (IV) method to estimate short-term and long-term relative effectiveness of second-line treatments according to individuals’ risk profiles. This method minimises bias from unmeasured confounders by exploiting the natural variation in second-line prescribing across CCGs as an IV for the choice of prescribed treatment. The primary outcome to assess short-term effectiveness will be change in haemoglobin A1c (%) 12 months after treatment initiation. Outcome measures to assess longer-term effectiveness (maximum ~6 years) will include microvascular and macrovascular complications, all-cause mortality and hospital admissions during follow-up.

ETHICS AND DISSEMINATION: This study was approved by the Independent Scientific Advisory Committee (20-064) and the London School of Hygiene & Tropical Medicine Research Ethics Committee (21395). Results, codelists and other analysis code will be made available to patients, clinicians, policy-makers and researchers.

PMID:34580091 | DOI:10.1136/bmjopen-2020-046912

Br J Ophthalmol. 2021 Sep 27:bjophthalmol-2021-319630. doi: 10.1136/bjophthalmol-2021-319630. Online ahead of print.

ABSTRACT

AIM: To investigate the association between visual field defects and blood vessel network (BVN) formation in optic disc melanocytomas (ODMs) using optical coherence tomography angiography (OCTA).

METHODS: Single-centre, retrospective case series of 32 eyes of 32 patients with ODM, in which eyes were divided into two groups based on complete and incomplete BVN formations.

RESULTS: OCTA revealed incomplete BVN formation in 16 of 32 ODMs. The location of BVN absence corresponded to the location of hypofluorescence from fluorescein angiography (FA) in 12 (75%) and to the location of visual field defect in 13 (81%) ODMs in the incomplete BVN group. Perimetric indices were significantly worse in the incomplete BVN group than in the complete BVN group. Linear regression of mean deviation (MD) and Visual Field Index (VFI) on the area of BVN absence were statistically significant (p=0.01 and p=0.003, respectively), whereas linear regressions of MD and VFI on the tumour area were not statistically significant (both p=0.09) in the incomplete BVN group.

CONCLUSION: The location of BVN absence within ODMs corresponded to the location of visual field defect and the location of FA hypofluorescence. Visual field defect was more severe in the incomplete BVN group than in the complete BVN group. Visual field defect was more significantly associated with the area of BVN absence than the tumour area.

PMID:34580073 | DOI:10.1136/bjophthalmol-2021-319630

BMJ Glob Health. 2021 Sep;6(9):e005427. doi: 10.1136/bmjgh-2021-005427.

ABSTRACT

BACKGROUND: While it is now apparent clinical sequelae (long COVID) may persist after acute COVID-19, their nature, frequency and aetiology are poorly characterised. This study aims to regularly synthesise evidence on long COVID characteristics, to help inform clinical management, rehabilitation strategies and interventional studies to improve long-term outcomes.

METHODS: A living systematic review. Medline, CINAHL (EBSCO), Global Health (Ovid), WHO Global Research on COVID-19 database, LitCovid and Google Scholar were searched till 17 March 2021. Studies including at least 100 people with confirmed or clinically suspected COVID-19 at 12 weeks or more post onset were included. Risk of bias was assessed using the tool produced by Hoy et al. Results were analysed using descriptive statistics and meta-analyses to estimate prevalence.

RESULTS: A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case-control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function.

CONCLUSION: Long COVID is a complex condition with prolonged heterogeneous symptoms. The nature of studies precludes a precise case definition or risk evaluation. There is an urgent need for prospective, robust, standardised, controlled studies into aetiology, risk factors and biomarkers to characterise long COVID in different at-risk populations and settings.

PROSPERO REGISTRATION NUMBER: CRD42020211131.

PMID:34580069 | DOI:10.1136/bmjgh-2021-005427

Eur Urol Oncol. 2021 Sep 24:S2588-9311(21)00153-X. doi: 10.1016/j.euo.2021.09.001. Online ahead of print.

ABSTRACT

BACKGROUND: The Göteborg 2 prostate cancer (PC) screening (G2) trial evaluates screening with prostate-specific antigen (PSA) followed by magnetic resonance imaging (MRI) in case of elevated PSA levels.

OBJECTIVE: To assess the safety of using a 2-yr interval in men who were previously screened positive with PSA but had negative MRI or positive MRI with a negative biopsy.

DESIGN, SETTING, AND PARTICIPANTS: A total of 61 201 men aged 50-60 yr were randomized and 38 366 were invited for screening (years 2015-2020). Men with positive MRI (Prostate Imaging Reporting and Data System [PI-RADS] score ≥3) were scheduled for targeted biopsies. Men with negative MRI or negative biopsies were reinvited after 2 yr. Round 1 and 2 MRI scans (PI-RADS ≥3) of men not diagnosed with PC in round 1 were re-read and classified according to Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) by two radiologists. Interval PCs (detected outside the program before invitation to round 2) were identified by linking to the Regional PC Registry.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tabulation of overall detection of PC was done.

RESULTS AND LIMITATIONS: Between October 2017 and June 2020, 474 men with round 1 elevated PSA and MRI underwent a second screening. Of those, 19% had nonelevated PSA in round 2 and were not examined further. Of the remaining 376 men, 89% had negative MRI. Targeted biopsies yielded 14 PCs: nine grade group (GG) 1 and five GG 2-3. In men with PI-RADS ≥3 and PC diagnosed in round 2, only two (GG 1) progressed according to the PRECISE criteria and the remainder were stable. Ten interval PCs were diagnosed: seven GG 1, one GG 2, and two GG 5. The two GG 5 PCs were PI-RADS 4 and 5 with negative round 1 biopsy.

CONCLUSIONS: A 2-yr interval seems to be safe in men with negative MRI, while men with PI-RADS 4 and 5 lesions with negative biopsies should have a closer follow-up.

PATIENT SUMMARY: In prostate cancer screening, a 2-yr follow-up seems to be safe if magnetic resonance imaging did not show highly suspicious findings.

PMID:34580053 | DOI:10.1016/j.euo.2021.09.001

J Am Pharm Assoc (2003). 2021 Sep 11:S1544-3191(21)00373-3. doi: 10.1016/j.japh.2021.09.003. Online ahead of print.

ABSTRACT

BACKGROUND: Although community pharmacists have been actively engaged in patient care, their role in deprescribing is still restricted.

OBJECTIVES: This study aimed to assess the effectiveness of a new educational approach designed to catalyze deprescribing in community pharmacies.

METHODS: In this 4-month, randomized, controlled trial, 108 community pharmacies in Egypt were randomly and equally distributed to either the active or the control groups. Participants from the active group pharmacies received 31 deprescribing-related clinical case scenarios, designed according to the available deprescribing guideline and clinical experiences of an expert panel members, and delivered through WhatsApp. Then participants from both groups reported the incidence of potentially inappropriate medicines (PIMs), the frequency of deprescribing opportunities, and related pharmacist interventions.

RESULTS: Pharmacists from the active group reported a considerably higher incidence of PIMs (20.87%) than that reported by pharmacists from the control group (5.03%). In addition, they made 1326 deprescribing-related interventions, of which 1022 (77.07%) were accepted and 641 (48.34%) were significant interventions. The proportions of cessation of drug therapy, reducing the dose, and persuasion of patients to accept deprescribing pharmacist interventions in the active group were 37.85%, 22.09%, and 10.63%, respectively. In contrast, 150 of 268 deprescribing-related interventions (55.97%) in the active group were accepted. The clinical value and type of deprescribing decision were statistically significant determinants for the acceptance of deprescribing decisions. The mean time needed to persuade the patient about deprescribing and the cost saved per patient across the active and the control groups were 5.09 ± 3.54 minutes versus 10.03 ± 6.19 minutes and 17.88 ± 9.60 U.S. dollars versus 4.49 ± 2.44 U.S. dollars, respectively.

CONCLUSION: The intervention proposed improved the frequency and clinical value of deprescribing decisions.

PMID:34580032 | DOI:10.1016/j.japh.2021.09.003

Pancreatology. 2021 Sep 21:S1424-3903(21)00574-3. doi: 10.1016/j.pan.2021.09.010. Online ahead of print.

ABSTRACT

BACKGROUND: Maturity-onset diabetes of the young type 8 (MODY8 or CEL-MODY) is an inherited pancreatic disease characterized by chronic inflammation of the pancreas and diabetes. It is not known whether MODY8 patients have increased risk for developing pancreatic cancer. We investigated KRAS mutation load in duodenal juice from MODY8 patients, comparing with other groups of pancreatic disease.

METHODS: Droplet digital PCR (ddPCR) was used to detect KRAS codon 12/13/61 mutations in duodenal juice sampled from 11 MODY8 patients, nine healthy subjects and 100 patients clinically investigated due to suspected pancreatic disease.

RESULTS: KRAS mutations were detected in 4/11 patients with MODY8 (36%), 1/9 healthy subjects (11%), 15/44 patients with chronic pancreatitis (CP, 34%), 3/5 patients with pancreatic ductal adenocarcinoma (PDAC, 60%), 3/20 patients with acute pancreatitis (15%), 0/13 patients with other pancreatic disorders and 2/18 patients with nonpancreatic gastrointestinal disease (11%). Of the 28 positive juice samples, 25 (89%) had low-abundance mutations in codons 12/13, with a variant allele frequency (VAF) less than 1%. KRAS-positive patients with MODY8 or CP had significantly lower VAFs than patients with PDAC (Mann-Whitney U test; p = 0.041). Although the overall mutation detection rate was higher for subjects ≥50 years old (26%) than for younger subjects (15%), the difference was not statistically significant.

CONCLUSIONS: KRAS mutations were detectable in duodenal juice from MODY8 patients, but with low abundance and at the same frequency as in CP patients. The discriminative value of the analysis with regard to other pancreatic disease was limited.

PMID:34580018 | DOI:10.1016/j.pan.2021.09.010

Curr Probl Cancer. 2021 Sep 20:100792. doi: 10.1016/j.currproblcancer.2021.100792. Online ahead of print.

ABSTRACT

To assess the recurrence of high-grade vaginal intraepithelial neoplasia (VAIN) after various treatments and to determine the factors affecting recurrence. A retrospective cohort study was conducted in patients with a histologic diagnosis of high-grade VAIN who underwent treatment between 1986 and 2013. Recurrence rates, life table analysis of recurrence-free intervals following treatment, and factors affecting recurrence were analyzed. Of the 104 included patients, the mean age was 50.8± 13.4 years; 21.1% and 78.8% had VAIN2 and VAIN3, respectively. Overall, the recurrence rate of high-grade VAIN was 33.2 incidence density rate (IDR)% per year, and the median time to recurrence was 23.6 months. Observation, topical treatment, laser vaporization, electrosurgical ablation, electrosurgical excision, knife excision, and radiation were associated with recurrence rates of 65.4, 70.0, 38.0, 22.6, 43.1, 18.5, and 0 IDR% per year, respectively. The median times to recurrence for each treatment were 16.2, 18.8, 26.5, >35.8, 6.6, 39.8, and >57.3 months, respectively, but the differences in recurrence-free intervals among treatments were not statistically significant (P = 0.06). Patients in the treatment intervention group were less likely to experience recurrence than those in the untreated group (HR = 0.44, CI: 0.23-0.87, P = 0.018). A history of pelvic radiation was associated with a higher risk of recurrence (OR = 4.14, 95% CI: 1.06-16.16, P = 0.030). Although treatments for high-grade VAIN significantly decreased the risk of recurrence, approximately one-third of patients had recurrence after therapy. No treatment modality was superior to the others with respect to the recurrence rate. A history of radiation therapy was associated with higher recurrence.

PMID:34579973 | DOI:10.1016/j.currproblcancer.2021.100792