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Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis.
No full textImmune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKTREM2 and MerTKLYVE1) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTK STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK STM subpopulations could therefore be a potential treatment strategy for RA
Polypharmacy and potential drug-drug interactions for people with HIV in the UK from the Climate-HIV database.
No full textOBJECTIVES
People with HIV (PWHIV) are likely to need therapies for comorbidities as they age. We assessed risk of drug-drug interactions (DDIs) in PWHIV.
METHODS
The Climate-HIV electronic recording system was used to cross-sectionally analyse records from PWHIV aged ≥ 18 years attending four UK HIV units with a current antiretroviral (ARV) prescription in February 2018. Antiretroviral and non-ARV medications were categorized by clinical significance of DDIs (University of Liverpool DDI tool). Potential DDIs were predicted using treatment guidelines for commonly recorded comorbidities.
RESULTS
Among 4630 PWHIV (44% female), 41% were ≥ 50 years old. The average number of non-ARV comedications increased from 5 for patients aged ≥ 75 years; 65% were taking one or more non-ARV comedications. The median (interquartile range) number of non-ARVs was 1 (0-2) and 2 (1-5) for those aged < 50 and ≥ 50 years, respectively. Common comorbidities/concurrent health conditions occurred more frequently in patients aged ≥ 50 years vs. < 50 (53% vs. 34%). Boosted protease inhibitors were associated with the highest proportion of contraindicated comedications; dolutegravir and raltegravir had the fewest. For non-ARVs, sildenafil and quetiapine were most likely to result in DDIs. Guideline-recommended treatments for hepatitis C, hepatitis B, and tuberculosis had the highest proportions of contraindications when combined with ARV regimens, while treatments for hepatitis C, malignancy, and mental health conditions had the highest proportion of combinations potentially causing DDIs requiring dose monitoring or adjustment.
CONCLUSIONS
Non-ARV use by PWHIV is high and increases with age. Treatment decisions for ageing PWHIV should consider guideline recommendations for comorbidities
Optimising the value of immunomodulatory drugs during induction and maintenance in transplant ineligible patients with newly diagnosed multiple myeloma: results from Myeloma XI, a multicentre, open-label, randomised, Phase III trial.
No full textSecond-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual
Perioperative outcomes after laparoscopic cholecystectomy in elderly patients: a systematic review and meta-analysis.
No full textBACKGROUND
Laparoscopic cholecystectomy is increasingly performed in an ever ageing population; however, the risks are poorly quantified. The study aims to review the current evidence to quantify further the postoperative risk of cholecystectomy in the elderly population compared to younger patients.
METHOD
A systematic literature search of PubMed, EMBASE and the Cochrane Library databases were conducted including studies reporting laparoscopic cholecystectomy in the elderly population. A meta-analysis was reported in accordance with the recommendations of the Cochrane Library and PRISMA guidelines. Primary outcome was overall complications and secondary outcomes were conversion to open surgery, bile leaks, postoperative mortality and length of stay.
RESULTS
This review identified 99 studies incorporating 326,517 patients. Increasing age was significantly associated with increased rates of overall complications (OR 2.37, CI 2.00-2.78), major complication (OR 1.79, CI 1.45-2.20), risk of conversion to open cholecystectomy (OR 2.17, CI 1.84-2.55), risk of bile leaks (OR 1.50, CI 1.07-2.10), risk of postoperative mortality (OR 7.20, CI 4.41-11.73) and was significantly associated with increased length of stay (MD 2.21 days, CI 1.24-3.18).
CONCLUSION
Postoperative outcomes such as overall and major complications appear to be significantly higher in all age cut-offs in this meta-analysis. This study demonstrated there is a sevenfold increase in perioperative mortality which increases by tenfold in patients > 80 years old. This study appears to confirm preconceived suspicions of higher risks in elderly patients undergoing cholecystectomy and may aid treatment planning and informed consent
Defining appropriateness criteria for endoscopic sinus surgery in management of adult dental implant patients with incidental maxillary sinus findings on cone beam computed tomography.
No full textOBJECTIVES
Cone beam computed tomography (CBCT) imaging is commonly requested by dental implant surgeons, pre-operatively, for patients being considered for dental implants. Incidental maxillary sinus findings often result in otolaryngology (ENT) referral for further assessment. CBCT findings include transient and benign mucosal changes that may not require any intervention and therefore unnecessarily delay implant surgery. We aim to define appropriateness criteria for ESS in the management of adult dental implant patients with incidental maxillary sinus findings on CBCT and provide guidance to both dental implant and ENT surgeons.
DESIGN
The RAND/UCLA appropriateness methodology was used to develop and define the appropriateness criteria.
SETTING
A virtual panel of 13 international experts in ESS.
PARTICIPANTS
The expert panel completed two rounds of a modified Delphi ranking processfor nine clinical scenarios, considering various factors affecting decision-making processes.
MAIN OUTCOME MEASURES
To define appropriateness criteria for ESS in adult dental implant patients who have incidental maxillary sinus findings on CBCT.
RESULTS
Patients with clinical symptoms and endoscopic findings of chronic rhinosinusitis together with an obstructed ostiomeatal complex (OMC) and concentric mucosal thickening of the ipsilateral maxillary sinus or pansinusitis were deemed appropriate candidates for ESS prior to their dental implant. ESS was not appropriate in asymptomatic patients with a patent OMC and mucosal thickening isolated to floor of the ipsilateral maxillary sinus. For uncertain scenarios, further discussion between dental implant and ENT surgeon should be considered.
CONCLUSIONS
This study has developed and reported a list of appropriateness criteria to offer ESS in adult dental implant patients with incidental maxillary sinus findings on CBCT
Is immune checkpoint inhibitor-associated diabetes the same as fulminant type 1 diabetes mellitus?
No full textPembrolizumab is an anti-cancer drug that targets programmed cell death protein-1 (PD-1) receptors on lymphocytes resulting in their activation against tumour cells. PD-1 receptors are also interspersed in endocrine organs and pembrolizumab use has long been associated with hypophysitis and thyroiditis. Since the introduction of immune checkpoint inhibitors (ICI), several cases of fulminant type 1 diabetes mellitus (FT1DM) have been reported. However, it is unclear if FT1DM and ICI-induced diabetes are the same pathology. We review the existing literature of ICI-induced diabetes to investigate its nature and to what extent it represents type 1A diabetes and/or FT1DM (type 1B diabetes) using an example case. Our review showed that ICI-induced diabetes may be a different entity to FT1DM. Furthermore, there is limited evidence for the management of ICI-induced T1DM. Further research into its pathophysiology will improve management and possibly prevent this burdensome complication
Point-of-care serological assays for delayed SARS-CoV-2 case identification among health-care workers in the UK: a prospective multicentre cohort study.
No full textBACKGROUND
Health-care workers constitute a high-risk population for acquisition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Capacity for acute diagnosis via PCR testing was limited for individuals with mild to moderate SARS-CoV-2 infection in the early phase of the COVID-19 pandemic and a substantial proportion of health-care workers with suspected infection were not tested. We aimed to investigate the performance of point-of-care and laboratory serology assays and their utility in late case identification, and to estimate SARS-CoV-2 seroprevalence.
METHODS
We did a prospective multicentre cohort study between April 8 and June 12, 2020, in two phases. Symptomatic health-care workers with mild to moderate symptoms were eligible to participate 14 days after onset of COVID-19 symptoms, as per the Public Health England (PHE) case definition. Health-care workers were recruited to the asymptomatic cohort if they had not developed PHE-defined COVID-19 symptoms since Dec 1, 2019. In phase 1, two point-of-care lateral flow serological assays, the Onsite CTK Biotech COVID-19 split IgG/IgM Rapid Test (CTK Bitotech, Poway, CA, USA) and the Encode SARS-CoV-2 split IgM/IgG One Step Rapid Test Device (Zhuhai Encode Medical Engineering, Zhuhai, China), were evaluated for performance against a laboratory immunoassay (EDI Novel Coronavirus COVID-19 IgG ELISA kit [Epitope Diagnostics, San Diego, CA, USA]) in 300 samples from health-care workers and 100 pre-COVID-19 negative control samples. In phase 2 (n=6440), serosurveillance was done among 1299 (93·4%) of 1391 health-care workers reporting symptoms, and in a subset of asymptomatic health-care workers (405 [8·0%] of 5049).
FINDINGS
There was variation in test performance between the lateral flow serological assays; however, the Encode assay displayed reasonable IgG sensitivity (127 of 136; 93·4% [95% CI 87·8-96·9]) and specificity (99 of 100; 99·0% [94·6-100·0]) among PCR-proven cases and good agreement (282 of 300; 94·0% [91·3-96·7]) with the laboratory immunoassay. By contrast, the Onsite assay had reduced sensitivity (120 of 136; 88·2% [95% CI 81·6-93·1]) and specificity (94 of 100; 94·0% [87·4-97·8]) and agreement (254 of 300; 84·7% [80·6-88·7]). Five (7%) of 70 PCR-positive cases were negative across all assays. Late changes in lateral flow serological assay bands were recorded in 74 (9·3%) of 800 cassettes (35 [8·8%] of 400 Encode assays; 39 [9·8%] of 400 Onsite assays), but only seven (all Onsite assays) of these changes were concordant with the laboratory immunoassay. In phase 2, seroprevalence among the workforce was estimated to be 10·6% (95% CI 7·6-13·6) in asymptomatic health-care workers and 44·7% (42·0-47·4) in symptomatic health-care workers. Seroprevalence across the entire workforce was estimated at 18·0% (95% CI 17·0-18·9).
INTERPRETATION
Although a good positive predictive value was observed with both lateral flow serological assays and ELISA, this agreement only occurred if the pre-test probability was modified by a strict clinical case definition. Late development of lateral flow serological assay bands would preclude postal strategies and potentially home testing. Identification of false-negative results among health-care workers across all assays suggest caution in interpretation of IgG results at this stage; for now, testing is perhaps best delivered in a clinical setting, supported by government advice about physical distancing.
FUNDING
None
Autoantibodies in the diagnostic work-up of neuropathy: clinically useful or purely academic?
No full textThe search for autoantibodies in patients with acute and chronic neuropathies has become widespread in neurological practice. These tests are more routinely available and therefore are more commonly requested in larger hospitals with neuroscience centres, although they are now also regularly requested from district general hospital settings, including by non-neurologists. However, the clinical value of these frequently expensive tests is often unclear and their impact on management not always obviously beneficial. This article reviews the main immunological tests used to search for specific autoantibodies in the setting of neuropathy and discusses their potential diagnostic importance, together with the eventual therapeutic implications of results obtained
No difference in mortality among ALPPS, two-staged hepatectomy, and portal vein embolization/ligation: A systematic review by updated traditional and network meta-analyses.
No full textBACKGROUND
There is an ongoing debate on the feasibility, safety, and oncological efficacy of the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) technique. The aim of this study was to compare ALPPS, two-staged hepatectomy (TSH), and portal vein embolization (PVE)/ligation (PVL) using updated traditional meta-analysis and network meta-analysis (NMA).
DATA SOURCES
Electronic databases were used in a systematic literature search. Updated traditional meta-analysis and NMA were performed and compared. Mortality and major morbidity were selected as primary outcomes.
RESULTS
Nineteen studies including 1200 patients were selected from the pool of 436 studies. Of these patients, 315 (31%) and 702 (69%) underwent ALPPS and portal vein occlusion (PVO), respectively. Ninety-day mortality based on updated traditional meta-analysis, subgroup analysis of the randomized controlled trials (RCTs), and both Bayesian and frequentist NMA did not demonstrate significant differences between the ALPPS cohort and the PVE, PVL, and TSH cohorts. Moreover, analysis of RCTs did not demonstrate significant differences of major morbidity between the ALPPS and PVO cohorts. The ALPPS cohort demonstrated significantly more favorable outcomes in hypertrophy parameters, time to operation, definitive hepatectomy, and R0 margins rates compared with the PVO cohort. In contrast, 1-year disease-free survival was significantly higher in the PVO cohort compared to the ALPPS cohort.
CONCLUSIONS
This study is the first to use updated traditional meta-analysis and both Bayesian and frequentist NMA and demonstrated no significant differences in 90-day mortality between the ALPPS and other hepatic hypertrophy approaches. Furthermore, two high quality RCTs including 147 patients demonstrated no significant differences in major morbidity between the ALPPS and PVO cohorts