Comparison of immunogenicity and clinical effectiveness between BNT162b2 and ChAdOx1 SARS-CoV-2 vaccines in people with end-stage kidney disease receiving haemodialysis: A prospective, observational cohort study.

Background: People with end-stage kidney disease, including people on haemodialysis, are susceptible to greater COVID-19 related morbidity and mortality. This study compares the immunogenicity and clinical effectiveness of BNT162B2 versus ChAdOx1 in haemodialysis patients. Methods: In this observational cohort study, 1021 patients were followed-up from time of vaccination until December 2021. All patients underwent weekly RT-PCR screening. Patients were assessed for nucleocapsid(anti-NP) and spike(anti-S) antibodies at timepoints after second(V2) and third(V3) vaccinations. 191 patients were investigated for T-cell responses. Vaccine effectiveness (VE) for prevention of infection, hospitalisation and mortality was evaluated using the formula VE=(1-adjustedHR)x100. Findings: 45.7% (467/1021) had evidence of prior infection. There was no difference in the proportion of infection-naïve patients who seroconverted by vaccine type, but median anti-S antibody titres were higher post-BNT162b2 compared with ChAdOx1; 462(152-1171) and 78(20-213) BAU/ml respectively, p<0.001.  Concomitant immunosuppressant use was a risk factor for non-response, OR 0.12[95% CI 0.05-0.25] p<0.001.  Post-V3 (all BNT162b2), median anti-S antibody titres remained higher in those receiving BNT162b2 versus ChAdOx1 as primary doses; 2756(187-1246) and 1250(439-2635) BAU/ml respectively, p=0.003.Anti-S antibodies waned over time. Hierarchical levels of anti-S post-V2 predicted risk of infection; patients with no/low anti-S being at highest risk. VE for preventing infection, hospitalisation and death was 53% (95% CI 6-75), 77% (95% CI 30-92) and 93% (95% CI 59-99) respectively, with no difference seen by vaccine type. Interpretation: Serum anti-S concentrations predict risk of breakthrough infection. Anti-S responses vary dependent upon clinical features, infection history and vaccine type. Monitoring of serological responses may enable individualised approaches to vaccine boosters in at risk populations. Funding: National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.

COVID-19 in patients with glomerular disease.

PURPOSE OF REVIEW: Managing patients with glomerular disease during the COVID-19 pandemic has been challenging, as the infection risk associated with immunosuppression must be balanced against the need to control severe glomerular disease that can lead to kidney failure. This review provides an overview of COVID-19 and the effectiveness of SARS-CoV-2 vaccination in patients with glomerular disease. RECENT FINDINGS: Registry data, although biased towards outcomes of hospitalized patients, suggest that the mortality from COVID-19 is higher in patients with glomerular disease than in the general population. Glucocorticoid use prior to SARS-CoV-2 infection is associated with adverse outcomes from COVID-19. Rituximab significantly attenuates serological responses to both natural infection and vaccination against SARS-CoV-2, although it is not clear whether this leads to adverse outcomes. Case reports of disease flares occurring after vaccination have been reported, but causality in any of these cases has yet to be proven and the absolute risk remains very small. SUMMARY: Patients with glomerular disease represent an at-risk group for severe COVID-19 disease and vaccination is key to reducing this risk. As immunosuppressed patients demonstrate an attenuated response to vaccination, the efficacy of a third primary dose followed by a subsequent booster is being investigated.

Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can present with life-threatening lung-kidney syndromes. However, many controlled treatment trials excluded patients with diffuse alveolar hemorrhage or severely impaired glomerular filtration rates, and so the optimum treatment in these cases is unclear. In this retrospective cohort study, we report the outcomes of 64 patients with life-threatening disease treated with a combination regimen of rituximab, low-dose intravenous cyclophosphamide, oral glucocorticoids, and plasma exchange. At entry, the median estimated glomerular filtration rate was 9 mL/min, 47% of patients required dialysis, and 52% had diffuse alveolar hemorrhage. All patients received a minimum of seven plasma exchanges, and the median cumulative doses of rituximab, cyclophosphamide, and glucocorticoid were 2, 3, and 2.6 g, respectively, at six months. A total of 94% of patients had achieved disease remission (version 3 Birmingham Vasculitis Activity Score of 0) at this time point, and 67% of patients who required dialysis recovered independent kidney function. During long-term follow-up (median duration 46 months), overall patient survival was 85%, and 69% of patients remained free from end-stage kidney disease, which compares favorably to a historic cohort with severe disease treated with a conventional induction regimen. Combination treatment was associated with prolonged B cell depletion and low rates of relapse; 87% of patients were in continuous remission at month 36. The serious infection rate during total follow-up was 0.28 infections/patient/year, suggesting that combination treatment is not associated with an enduring risk of infection. Thus, we suggest that combination immunosuppressive therapy may permit glucocorticoid avoidance and provide rapid and prolonged disease control in patients with severe ANCA-associated vasculitis.

Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression.

OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.

The Predictive Validity of a Text-Based Situational Judgment Test in Undergraduate Medical and Dental School Admissions.

PROBLEM: Situational judgment tests (SJTs) can be used to assess the nonacademic attributes necessary for medical and dental trainees to become successful practitioners. Evidence for SJTs' predictive validity, however, relates predominantly to selection in postgraduate settings or using video-based SJTs at the undergraduate level; it may not be directly transferable to text-based SJTs in undergraduate medical and dental school selection. This preliminary study aimed to address these gaps by assessing the validity of the UK Clinical Aptitude Test (UKCAT) text-based SJT. APPROACH: Study participants were 218 first-year medical and dental students from four UK undergraduate schools who completed the first UKCAT text-based SJT in 2013. Outcome measures were educational supervisor ratings of in-role performance in problem-based learning tutorial sessions-mean rating across the three domains measured by the SJT (integrity, perspective taking, and team involvement) and an overall judgment of performance-collected in 2015. OUTCOMES: There were significant correlations between SJT scores and both mean supervisor ratings (uncorrected r = 0.24, P < .001; corrected r = 0.34) and overall judgments (uncorrected rs = 0.16, P < .05; corrected rs = 0.20). SJT scores predicted 6% of variance in mean supervisor ratings across the three nonacademic domains. NEXT STEPS: The results provide evidence that a well-designed text-based SJT can be appropriately integrated, and add value to, the selection process for undergraduate medical and dental school. More evidence is needed regarding the longitudinal predictive validity of SJTs throughout medical and dental training pathways, with appropriate outcome criteria.

Evaluating the complementary roles of an SJT and academic assessment for entry into clinical practice.

Although there is extensive evidence confirming the predictive validity of situational judgement tests (SJTs) in medical education, there remains a shortage of evidence for their predictive validity for performance of postgraduate trainees in their first role in clinical practice. Moreover, to date few researchers have empirically examined the complementary roles of academic and non-academic selection methods in predicting in-role performance. This is an important area of enquiry as despite it being common practice to use both types of methods within a selection system, there is currently no evidence that this approach translates into increased predictive validity of the selection system as a whole, over that achieved by the use of a single selection method. In this preliminary study, the majority of the range of scores achieved by successful applicants to the UK Foundation Programme provided a unique opportunity to address both of these areas of enquiry. Sampling targeted high (>80th percentile) and low (<20th percentile) scorers on the SJT. Supervisors rated 391 trainees' in-role performance, and incidence of remedial action was collected. SJT and academic performance scores correlated with supervisor ratings (r = .31 and .28, respectively). The relationship was stronger between the SJT and in-role performance for the low scoring group (r = .33, high scoring group r = .11), and between academic performance and in-role performance for the high scoring group (r = .29, low scoring group r = .11). Trainees with low SJT scores were almost five times more likely to receive remedial action. Results indicate that an SJT for entry into trainee physicians' first role in clinical practice has good predictive validity of supervisor-rated performance and incidence of remedial action. In addition, an SJT and a measure of academic performance appeared to be complementary to each other. These initial findings suggest that SJTs may be more predictive at the lower end of a scoring distribution, and academic attainment more predictive at the higher end.

Situational judgment tests reliably measure professional attributes important for clinical practice.

Over the course of more than 40 years, international research has consistently shown situational judgment tests (SJTs) to be a reliable and valid selection method for assessing a range of professional attributes. However, SJTs still represent a relatively new selection method within the medical profession, and as such it is to be expected that applicant reactions will vary. In this Expert Opinion piece, we respond to Najim et al's article "The situational judgement test: a student's worst nightmare" by highlighting three key clarifications. We outline that 1) the UK Foundation Programme's SJT deliberately measures only a subset (five) of the nine professional attributes important for the role of Foundation Trainee doctor, 2) these attributes are measured in addition to academic attainment, and 3) the SJT represents a cost-effective approach to selection rather than attempting to interview approximately 8,000 candidates each year, which would be logistically impossible. We present these points to inform future research and encourage debate, and conclude that the SJT is an appropriate and fair measurement method to be used as one part of selection to the UK Foundation Programme.

Recruiting for values in healthcare: a preliminary review of the evidence.

Displaying compassion, benevolence and respect, and preserving the dignity of patients are important for any healthcare professional to ensure the provision of high quality care and patient outcomes. This paper presents a structured search and thematic review of the research evidence relating to values-based recruitment within healthcare. Several different databases, journals and government reports were searched to retrieve studies relating to values-based recruitment published between 1998 and 2013, both in healthcare settings and other occupational contexts. There is limited published research related to values-based recruitment directly, so the available theoretical context of values is explored alongside an analysis of the impact of value congruence. The implications for the design of selection methods to measure values is explored beyond the scope of the initial literature search. Research suggests some selection methods may be appropriate for values-based recruitment, such as situational judgment tests (SJTs), structured interviews and multiple-mini interviews (MMIs). Personality tests were also identified as having the potential to compliment other methods (e.g. structured interviews), as part of a values-based recruitment agenda. Methods including personal statements, references and unstructured/'traditional' interviews were identified as inappropriate for values-based recruitment. Practical implications are discussed in the context of values-based recruitment in the healthcare context. Theoretical implications of our findings imply that prosocial implicit trait policies, which could be measured by selection tools such as SJTs and MMIs, may be linked to individuals' values via the behaviours individuals consider to be effective in given situations. Further research is required to state this conclusively however, and methods for values-based recruitment represent an exciting and relatively unchartered territory for further research.

Single mutation (A162H) in human cardiac troponin I corrects acid pH sensitivity of Ca2+-regulated actomyosin S1 ATPase.

In contrast to skeletal muscle, the efficiency of the contractile apparatus of cardiac tissue has long been known to be severely compromised by acid pH as in the ischemia of myocardial infarction and other cardiac myopathies. Recent reports (Westfall, M. V., and Metzger, J. M. (2001) News Physiol. Sci. 16, 278-281; Li, G., Martin, A. F., and Solaro, R. J. (2001) J. Mol. Cell. Cardiol. 33, 1309-1320) have indicated that the reduced Ca(2+) sensitivity of cardiac contractility at low pH (