Tixagevimab and Cilgavimab Administration for Hemodialysis Patients at Community-Based Dialysis Centers in Singapore as Pre-Exposure Prophylaxis for SARS-CoV-2 Infection.

INTRODUCTION:  Hemodialysis patients are deemed to be immunosuppressed and may not be able to mount an adequate response to vaccination against the SARS-CoV-2 virus. Due to the higher morbidity and mortality in this vulnerable group, pre-exposure prophylaxis with monoclonal antibodies was introduced as an additional measure for protection in selected community-based hemodialysis patients in Singapore. Tixagevimab and cilgavimab, available as Evusheld, were used for this purpose. METHODS:  A government-sponsored clinical administration program with the provision of 200 doses of Evusheld at no cost to the patients was implemented. Patient selection criteria to further risk-stratify this vulnerable hemodialysis patient cohort was developed and 200 patients were finally selected. Evusheld administration was done over a period of two months, as two consecutive injections were given at two separate intramuscular sites, which constituted one administration. Data were collected as part of a retrospective clinical audit, as part of a routine quality monitoring process for this patient care program. Real-world evidence was generated to assess the impact on mortality, hospitalization rate, reason for hospitalization, and any associated morbidity. RESULTS:  No adverse events from the Evusheld administration were noted. All recipients had received COVID-19 vaccinations prior to Tixa-Cilga, with a range of one to five doses. A total of 198 (99%) completed two doses and 189 (95%) completed three doses, out of which, 14 (7%) patients contracted COVID-19 infection over three months. The overall hospitalization rate was 2% (four out of 200 patients). Severe illness that required intensive care unit stay was therefore seen in only 2 (1%) out of 200 patients. None of the infected patients died. DISCUSSION:  A significant reduction in severity of illness, hospitalization rate, and mortality was found with pre-exposure prophylaxis with tixagevimab and cilgavimab, in this real-world experience from Singapore. Evusheld administration reduced the hospitalization rate from 42.5% to 2%, which is a reduction of 95.3% (p<0.0001). Symptoms in infected patients were mild, with only 1% being admitted to the intensive care unit. The mortality rate from COVID-19 infection was reduced from 2.5% to 0% with Evusheld.  Conclusion: Mass administration of prophylactic treatments for vulnerable populations can be challenging in community-based settings and the successful implementation of such a program has been described. The findings can have health policy implications for the protection of such immunocompromised patients in the future. The combination of tixagevimab and cilgavimab, available as Evusheld in Singapore, was safe to use in hemodialysis patients, with no adverse events noted. There was a significant reduction in hospitalization rates and intensive care unit admissions with a zero-mortality rate due to COVID-19 infection, after pre-exposure prophylaxis.

Health economics of kidney replacement therapy in Singapore: Taking stock and looking ahead.

The prevalence of end-stage kidney disease (ESKD) in Singapore remains high and continues to rise. We continue to face major challenges in containing the rising incidence of ESKD and providing sustainable kidney replacement therapy. Our cost projections provide an insight into the present and future, urging a call to action to augment existing initiatives to address the emergent issues.

Multi-photon microscopy for the evaluation of interstitial fibrosis in extended criteria donor kidneys: A proof-of-concept study.

INTRODUCTION: To evaluate the initial use of label-free second harmonic generation (SHG) imaging with two-photon excitation (2PE) auto-fluorescence in multiphoton microscopy (MPM) for the quantification of collagen/fibrosis on preimplantation biopsies of extended criteria donors (ECD). MATERIALS AND METHODS: Twenty preimplantation core biopsies were extracted from 10 donor kidney samples, of which originated from seven donors. Kidney Donor Profile Index (KDPI) and Remuzzi scores of biopsies were calculated. Collagen parameters measured included quantification by the Collagen Area Ratio in Total Tissue (CART) and qualitative measurements by Collagen Reticulation Index (CRI). RESULTS: Biopsies classified with > 85% KDPI scores had significantly higher CART (p = .011) and lower CRI values (p = .025) than biopsies with ≤ 85% KDPI scores. Increase in CRI values correlated significantly with rise in recipient creatinine levels 1-year post-transplant (p = .027; 95% CI: 4.635-66.797). CONCLUSION: MPM is an evolving technology that enables the quantification of the amount (CART) and quality (CRI) of collagen deposition in unstained preimplantation biopsies of donor kidneys stratified by KDPI scores. This initial evaluation found significant differences in both parameters between donor kidneys with more or less than 85% KDPI.

Buried Bumper Syndrome: a rare complication during radical chemoradiotherapy for head and neck cancer.

Patients undergoing radical treatment particularly chemoradiotherapy for cancer of the upper aerodigestive tract frequently experience progressive deterioration in swallow during and immediately after treatment. It is important to identify patients at high risk of compromised feeding early, following diagnosis, so that alternate feeding routes, such as percutaneous endoscopic gastrostomies (PEGs), can be promptly and prophylactically instituted, in keeping with the UK Head and Neck Cancer Guidelines (2016).

Defining the structural basis for human leukocyte antigen reactivity in clinical transplantation.

The current state-of-the-art technology employed to assess anti-human leukocyte antigen antibodies (Anti-HLA Ab) for donor-recipient matching and patient risk stratification in renal transplantation is the single antigen bead (SAB) assay. However, there are limitations to the SAB assay as it is not quantitative and due to variations in techniques and reagents, there is no standardization across laboratories. In this study, a structurally-defined human monoclonal alloantibody was employed to provide a mechanistic explanation for how fundamental alloantibody biology influences the readout from the SAB assay. Performance of the clinical SAB assay was evaluated by altering Anti-HLA Ab concentration, subclass, and detection reagents. Tests were conducted in parallel by two internationally accredited laboratories using standardized protocols and reagents. We show that alloantibody concentration, subclass, laboratory-specific detection devices, subclass-specific detection reagents all contribute to a significant degree of variation in the readout. We report a significant prozone effect affecting HLA alleles that are bound strongly by the test alloantibody as opposed to those bound weakly and this phenomenon is independent of complement. These data highlight the importance for establishing international standards for SAB assay calibration and have significant implications for our understanding of discordance in previous studies that have analyzed its clinical relevance.

Mathematical processing is affected by daily but not cumulative glucocorticoid dose in patients with systemic lupus erythematosus.

OBJECTIVES: The impact of glucocorticoids on neurocognitive performance in patients with SLE is not fully addressed. We aimed to study the effect of daily and cumulative glucocorticoid dose on neurocognitive performance in SLE patients. METHODS: Consecutive SLE patients and gender- and age-matched healthy controls (HCs) underwent the computer-based Automated Neuropsychological Assessment Matric (ANAM), which evaluates eight neurocognitive domains including learning, recall, visual perception, mental rotation, short-term memory, attention, sustained attention and working memory. The total and individual-domain throughput scores (TPSs) and the presence of cognitive dysfunction (total TPS <1.5 s.d. below the mean TPS of HCs) were compared between SLE patients and HCs. Within the SLE group, univariate and independent associations between prednisolone dose (daily and cumulative) and individual-domain TPS were studied by univariate and multivariable linear regression, respectively. RESULTS: A total of 96 SLE patients and 96 HCs were studied. SLE patients scored significantly worse across all the neurocognitive domains and had a significantly lower mean total TPS (P < 0.001) and a higher prevalence of cognitive dysfunction compared with HCs (25.0 vs 7.3%, P = 0.001). In SLE patients, daily prednisolone dose was significantly and negatively correlated with mathematical-processing TPS, which probes working memory (P = 0.018). No significant correlation between cumulative prednisolone dose and any of the individual-domain TPSs was found. In multivariable regression, higher daily prednisolone dose and doses >9 mg daily remained independently associated with lower mathematical-processing TPSs (P = 0.031). CONCLUSION: Daily prednisolone dose ≥9 mg, but not cumulative glucocorticoid dose, had an independent negative impact on mathematical processing in SLE patients.

Defining the structural basis for human alloantibody binding to human leukocyte antigen allele HLA-A*11:01.

Our understanding of the conformational and electrostatic determinants that underlie targeting of human leukocyte antigens (HLA) by anti-HLA alloantibodies is principally based upon in silico modelling. Here we provide a biochemical/biophysical and functional characterization of a human monoclonal alloantibody specific for a common HLA type, HLA-A*11:01. We present a 2.4 Å resolution map of the binding interface of this antibody on HLA-A*11:01 and compare the structural determinants with those utilized by T-cell receptor (TCR), killer-cell immunoglobulin-like receptor (KIR) and CD8 on the same molecule. These data provide a mechanistic insight into the paratope-epitope relationship between an alloantibody and its target HLA molecule in a biological context where other immune receptors are concomitantly engaged. This has important implications for our interpretation of serologic binding patterns of anti-HLA antibodies in sensitized individuals and thus, for the biology of human alloresponses.

Cell-mediated and humoral acute vascular rejection and graft loss: A registry study.

AIMS: Rejection of renal allografts following transplantation continues to be a major impediment to long-term graft survival. Although acute vascular rejection (AVR) is associated with a high risk of graft loss, it remains unclear whether AVR with accompanied cellular or acute humoral rejection (AHR) have dissimilar outcomes. The aim of this registry study was to examine the association between subtypes of AVR and graft loss. METHODS: Using Australia and New Zealand Dialysis and Transplant registry, primary kidney transplant recipients between 2005 and 2012 whose first rejection episode was AVR were included and categorized into AVR-none (AVR without other rejections), AVR-CG (AVR with cellular and/or glomerular rejections), and AVR-AHR (AVR with AHR). Association between AVR groups and graft loss was examined using logistic and Cox regression models. RESULTS: Of the 274 recipients, 61 (22.3%) experienced AVR-none, 79 (28.8%) AVR-AHR and 134 (48.9%) AVR-CG. Compared with AVR-none and AVR-CG, AVR-AHR was associated with the highest incidence of overall graft loss at 3 months (12%, 10% and 27%, respectively, χ(2) = 11.88, P = 0.003). AVR-AHR was associated with almost a threefold greater risk of death-censored graft loss compared with AVR-none (adjusted hazard ratio 2.84, 95% confidence interval 1.22-2.62, P < 0.01). CONCLUSION: AVR-AHR is associated with the poorest outcome with over 25% of grafts being lost 3 months after transplantation. Future studies evaluating factors that predict graft loss in AVR-AHR may help determine prognosis and inform treatment practices.

Negative-pressure wound therapy for management of diabetic foot wounds: a review of the mechanism of action, clinical applications, and recent developments.

Negative-pressure wound therapy (NPWT) plays an important role in the treatment of complex wounds. Its effect on limb salvage in the management of the diabetic foot is well described in the literature. However, a successful outcome in this subgroup of diabetic patients requires a multidisciplinary approach with careful patient selection, appropriate surgical debridement, targeted antibiotic therapy, and optimization of healing markers. Evolving NPWT technology including instillation therapy, nanocrystalline adjuncts, and portable systems can further improve results if used with correct indications. This review article summarizes current knowledge about the role of NPWT in the management of the diabetic foot and its mode of action, clinical applications, and recent developments.

Plasma neutrophil gelatinase-associated lipocalin and kidney function decline and kidney disease-related clinical events in older women.

BACKGROUND: It is still unclear whether serum neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of renal tubular injury, is a prognostic marker for the progression of chronic kidney disease (CKD) in the general population. METHODS: A prospective-cohort study of 1,245 women aged ≥70 from the general population. Associations between plasma NGAL and change in 5-year estimated glomerular filtration rate (eGFR), rapid renal decline and 10-year risk of acute or chronic renal disease-related hospitalisations and/or mortality were examined. RESULTS: Compared to women with above-median plasma NGAL of 76.5 ng/l, women with below-median plasma NGAL had a 9.3% reduction in eGFR over a 5-year period. Among women with above-median plasma NGAL, there was over a 1.7-fold increased risk of rapid renal decline (eGFR decline of >3 ml/min/year) (adjusted odds ratio 1.76, 95% CI 1.003, 3.102, p = 0.049). Compared to women with baseline eGFR of <60 ml/min/1.73 m(2), women with above-median plasma NGAL experienced over a 2.5-fold increased risk of renal disease events at 10 years (hazard ratio 2.55, 95% CI 1.13, 5.78, p = 0.025) after adjustment of age, hypertension and diabetes. Addition of plasma NGAL in participants with eGFR of <60 ml/min/1.73 m(2) significantly improved the accuracy in predicting the 10-year risk of renal disease events (adjusted area-under-curve receiver operator characteristics without and with NGAL 0.64 and 0.71, respectively; p = 0.027) and reclassified 13% of women who experienced renal disease events into the higher risk categories (p = 0.03). CONCLUSION: Plasma NGAL is of modest clinical utility in predicting the renal function decline and risk of renal disease-related clinical events, particularly those with mild to moderate CKD.