Inhibition of the Lectin Pathway of Complement Activation Reduces Acute Respiratory Distress Syndrome Severity in a Mouse Model of SARS-CoV-2 Infection.

Most patients with COVID-19 in the intensive care unit develop an acute respiratory distress syndrome characterized by severe hypoxemia, decreased lung compliance, and high vascular permeability. Activation of the complement system is a hallmark of moderate and severe COVID-19, with abundant deposition of complement proteins in inflamed tissue and on the endothelium during COVID-19. Using a transgenic mouse model of SARS-CoV-2 infection, we assessed the therapeutic utility of an inhibitory antibody (HG4) targeting MASP-2, a key enzyme in the lectin pathway. Treatment of infected mice with HG4 reduced the disease severity score and improved survival vs mice that received an isotype control antibody. Administration of HG4 significantly reduced the lung injury score, including alveolar inflammatory cell infiltration, alveolar edema, and alveolar hemorrhage. The ameliorating effect of MASP-2 inhibition on the severity of COVID-19 pathology is reflected by a significant reduction in the proinflammatory activation of brain microglia in HG4-treated mice.

Ensuring Sustainability of Continuous Kidney Replacement Therapy in the Face of Extraordinary Demand: Lessons From the COVID-19 Pandemic.

With the exponential surge in patients with coronavirus disease 2019 (COVID-19) worldwide, the resources needed to provide continuous kidney replacement therapy (CKRT) for patients with acute kidney injury or kidney failure may be threatened. This article summarizes subsisting strategies that can be implemented immediately. Pre-emptive weekly multicenter projections of CKRT demand based on evolving COVID-19 epidemiology and routine workload should be made. Corresponding consumables should be quantified and acquired, with diversification of sources from multiple vendors. Supply procurement should be stepped up accordingly so that a several-week stock is amassed, with administrative oversight to prevent disproportionate hoarding by institutions. Consumption of CKRT resources can be made more efficient by optimizing circuit anticoagulation to preserve filters, extending use of each vascular access, lowering blood flows to reduce citrate consumption, moderating the CKRT intensity to conserve fluids, or running accelerated KRT at higher clearance to treat more patients per machine. If logistically feasible, earlier transition to intermittent hemodialysis with online-generated dialysate, or urgent peritoneal dialysis in selected patients, may help reduce CKRT dependency. These measures, coupled to multicenter collaboration and a corresponding increase in trained medical and nursing staffing levels, may avoid downstream rationing of care and save lives during the peak of the pandemic.

Epoetin-ß induced pure red cell aplasia: an unintended consequence.

Pure red cell aplasia is a rare condition associated with the use of recombinant human erythropoietin preparations. It has predominantly been associated with the subcutaneous use of a particular epoetin-α product, Eprex, and is rarely associated with intravenous use or with other commercially available products. Only a few cases of pure red cell aplasia secondary to epoetin-ß have been reported. On account of its rarity, the condition can often be missed on initial presentation, leading to unnecessary investigations and delayed diagnosis. A high index of suspicion is required for timely diagnosis and proper management. We present a case of severe anaemia secondary to the subcutaneous use of epoetin-ß (Recormon) and briefly discuss the pathogenesis, diagnosis and management.

Dialysis for older adults: why should the targets be different?

The number of patients aged > 75-years treated by dialysis continues to increase, particularly in developed countries. Haemodialysis is a well-established treatment with national and international clinical guidelines designed to provide patients with optimal treatment. However, these were developed when the dialysis population was younger, and less co-morbid. This change in patient demographics questions whether these guideline targets still apply to older patients. More patients now start dialysis with residual kidney function and could benefit from a less frequent dialysis schedule. Older patients have a lower thirst drive, so lower interdialytic gains, reduced appetite, muscle mass and physical activity would potentially allow starting dialysis with less frequent sessions a practical option. Similarly, patients with residual kidney function and lower metabolic activity may not need to meet current dialyser Kt/Vurea clearance targets to remain healthy. Instead, some elderly patients may be at risk of malnutrition and might need liberalisation of the low salt, potassium and phosphate dietary restrictions, or even additional supplements to ensure adequate protein intake. Although a fistula is the preferred vascular access, a forearm fistula may not be an option due to vascular disease, while a brachial fistula can potentially compromise cardiovascular reserve, so a dialysis catheter becomes the de facto access, especially in patients with limited life expectancy. Thus, clinical guideline targets designed for a younger less co-morbid dialysis population may not be equally applicable to the older patient initiating dialysis, and so a more individualised approach to dialysis prescription and vascular access is required.

Assessing caregiver burden in advanced kidney disease: protocol for a systematic review of the measurement properties of instruments and tools.

INTRODUCTION: Caregiver burden is a significant issue in the care of patients with advanced kidney disease. Its assessment is crucial for evaluating the needs of caregivers and for the development of interventions to support them. Several instruments have been developed to measure caregiver burden in these patients. However, the measurement properties of these instruments have not been systematically reviewed. METHODS AND ANALYSIS: This systematic review will include a comprehensive search of databases including PubMed, CINAHL, Embase, Cochrane Library, SCOPUS and Web of Science by using keywords and MeSH terms to identify relevant studies starting from each database inception to 1 January 2024 and covering papers in English. The search strategy will combine relevant keywords and database-specific subject headings related to the following concepts: (1) caregivers, (2) burden, stress, distress, (3) chronic kidney disease, end-stage kidney disease, dialysis. Reference lists of eligible articles will also be hand searched. We will include quantitative and qualitative studies evaluating measurement properties of instruments assessing caregiver burden in caregivers of adult patients (aged ≥18 years). Data will be extracted from the selected studies and analysed using the COnsensus-based Standards for the selection of health Measurement INstruments checklist as the study quality assessment tool. Subsequently, the van der Vleuten utility index will be used to critique and categorise the instruments. A narrative that synthesises the utility of all instruments will be presented along with recommendations for the selection of instruments depending on specific clinical contexts. This systematic review will provide an overview of the measurement properties of available instruments, including discussion on reliability, validity and responsiveness. Results from the review may give rise to the subsequent development of most appropriate instrument that could be applied to the assessment of caregiver burden in advanced kidney disease. ETHICS AND DISSEMINATION: Ethics approval is not required as this study will merely synthesise data from published studies. The results will be disseminated through peer-reviewed publications as well as conference presentations. PROSPERO REGISTRATION NUMBER: CRD42023433906.

Re-examining the roles of generalists and specialists in healthcare.

Increasing workload and case complexity of a multimorbid ageing population have catalysed primary care transformation for general practitioners to meet these challenges. There is also a need to re-examine the role of hospital specialists as overly disease-centric, hospital-based specialist care is no longer sustainable. A new specialist-generalist model can maximise the potential of generalists and specialists to provide person-centred care, increase cost-effectiveness, improve appropriateness of referrals, decrease length of hospital stay and lower mortality.

Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice.

Acute respiratory distress syndrome (ARDS) is a life-threatening disorder with a high rate of mortality. Complement activation in ARDS initiates a robust inflammatory reaction that can cause progressive endothelial injury in the lung. Here, we tested whether inhibition of the lectin pathway of complement could reduce the pathology and improve the outcomes in a murine model of LPS-induced lung injury that closely mimics ARDS in human. In vitro, LPS binds to murine and human collectin 11, human MBL and murine MBL-A, but not to C1q, the recognition subcomponent of the classical pathway. This binding initiates deposition of the complement activation products C3b, C4b and C5b-9 on LPS via the lectin pathway. HG-4, a monoclonal antibody that targets MASP-2, a key enzyme in the lectin pathway, inhibited lectin pathway functional activity in vitro, with an IC50 of circa 10nM. Administration of HG4 (5mg/kg) in mice led to almost complete inhibition of the lectin pathway activation for 48hrs, and 50% inhibition at 60hrs post administration. Inhibition of the lectin pathway in mice prior to LPS-induced lung injury improved all pathological markers tested. HG4 reduces the protein concentration in bronchoalveolar lavage fluid (p<0.0001) and levels of myeloid peroxide (p<0.0001), LDH (p<0.0001), TNFα and IL6 (both p<0.0001). Lung injury was significantly reduced (p<0.001) and the survival time of the mice increased (p<0.01). From the previous findings we concluded that inhibition of the lectin pathway has the potential to prevent ARDS pathology.

Randomized Controlled Clinical Trial of the Effect of Treatment with Vitamin K2 on Vascular Calcification in Hemodialysis Patients (Trevasc-HDK).

Introduction: Vitamin K deficiency among patients on hemodialysis (HD) affects the function of matrix GLA protein (MGP), a potent vitamin K-dependent inhibitor of vascular calcification (VC). Methods: We conducted a single-center randomized controlled trial (RCT) on maintenance HD patients to examine if vitamin K2 supplementation can reduce progression of coronary artery calcification (CAC) over an 18-month study period. Patients were randomized to vitamin K2 group receiving menaquinone-7360 µg 3 times/wk or control group. The primary outcome was CAC scores at the end of the study period. The secondary outcomes were aortic valve calcification (AVC), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), dephosphorylated undercarboxylated MGP (dp-ucMGP) levels, major adverse cardiac events (MACE), and vascular access events. Results: Of the 178 patients randomized, follow-up was completed for 138 patients. The CAC scores between the 2 groups were not statistically different at the end of 18 months (relative mean difference [RMD] 0.85, 95% CI 0.55-1.31). The secondary outcomes did not differ significantly in AVC (RMD 0.82, 95% CI 0.34-1.98), cfPWV (absolute mean difference [AMD] 0.55, 95% CI -0.50 to 1.60), and AIx (AMD 0.13, 95% CI -3.55 to 3.80). Supplementation with vitamin K2 did reduce dp-ucMGP levels (AMD -86, 95% CI -854 to -117). The composite outcome of MACE and mortality was not statistically different between the 2 groups (Hazard ratio = 0.98, 95% CI 0.50-1.94). Conclusion: Our study did not demonstrate a beneficial effect of vitamin K2 in reducing progression of VC in this population at the studied dose and duration.

Depression and marital dissatisfaction among Indian hemodialysis patients and their spouses: a cross-sectional Study.

AIM: Interaction of patient in marital dyad may have bearing on long-term patient outcome. Depression, subjective stress, and marital discord have been reported in healthy spouses of patients with end-stage renal disease (ESRD). Depressed patients on dialysis along with their spouses can function as depressed dyad. We looked at the incidence and factors associated with depression and marital stress among Indian hemodialysis patients and their spouses. METHODS: A total of 49 (32 males, 17 females) patients on maintenance hemodialysis and their spouses were independently administered Beck Depression Inventory (BDI), Revised Dyadic Adjustment Scale, and self-rated subjective quality-of-life scale. Their demographic parameters, socioeconomic status, and type of family (nuclear or joint) were also noted. RESULTS: About 57.1% of patients were depressed compared with 42.8% of spouses (p = 0.133). In both patients and spouses, BDI correlated with quality of life and perceived marital stress. About 36.7% of patients and 24.4% of spouses reported marital stress (p = 0.69). Male spouses had more marital stress compared with female spouses (p < 0.0001). Depression and marital stress in patients and spouses was not associated with socioeconomic status, literacy levels, and employment. Depression in patients had direct correlation with depression in spouse (r = 0.572, p < 0.0001) and degree of marital dissatisfaction in spouse (r = 0.623, p < 0.0001). Patients living in nuclear family were more depressed and had more marital stress. CONCLUSION: Married ESRD patients and their spouses function as a complex psychosocial dyad with significant two-way interactions. Social support, as is seen in joint families, leads to significantly lesser depression and better marital understanding.

Back to the basics.

The history and physical examination skills are being replaced by the tools of technology in establishing the actual cause of illness. We present a patient where the history and physical examination were essential in establishing the diagnosis. A 28-year-old female presented to the Emergency Department (ED) with an acute episode of epigastric pain radiating to the back associated with vomiting. Laboratory examinations revealed pancreatitis, imaging showed gallstones and the patient was admitted with the diagnosis of gallstone pancreatitis. A more detailed history and physical examination, however, was notable for a family history of "Mediterranean blood" and abdominal examination demonstrated splenomegaly and laboratory examination showed a microcytic anemia. The recognition of the family history, splenomegaly and microcytic anemia led to the diagnosis of thalassemia as the cause of the gallstone pancreatitis. Clearly, the history was essential in establishing the underlying cause of the problem.

Secondary Complement Deficiency Impairs Anti-Microbial Immunity to Klebsiella pneumoniae and Staphylococcus aureus During Severe Acute COVID-19.

A high incidence of secondary Klebsiella pneumoniae and Staphylococcus aureus infection were observed in patients with severe COVID-19. The cause of this predisposition to infection is unclear. Our data demonstrate consumption of complement in acute COVID-19 patients reflected by low levels of C3, C4, and loss of haemolytic activity. Given that the elimination of Gram-negative bacteria depends in part on complement-mediated lysis, we hypothesised that secondary hypocomplementaemia is rendering the antibody-dependent classical pathway activation inactive and compromises serum bactericidal activity (SBA). 217 patients with severe COVID-19 were studied. 142 patients suffered secondary bacterial infections. Klebsiella species were the most common Gram-negative organism, found in 58 patients, while S. aureus was the dominant Gram-positive organism found in 22 patients. Hypocomplementaemia was observed in patients with acute severe COVID-19 but not in convalescent survivors three months after discharge. Sera from patients with acute COVID-19 were unable to opsonise either K. pneumoniae or S. aureus and had impaired complement-mediated killing of Klebsiella. We conclude that hyperactivation of complement during acute COVID-19 leads to secondary hypocomplementaemia and predisposes to opportunistic infections.

YouTube as source of information on 2019 novel coronavirus outbreak: a cross sectional study of English and Mandarin content.

BACKGROUND: The current 2019 novel coronavirus outbreak is rapidly evolving. YouTube has been recognized as a popular source of information in previous disease outbreaks. We analyzed the content on YouTube about n-CoV in English and Mandarin languages. METHODS: YouTube was searched using the terms '2019 novel coronavirus', 'Wuhan virus' and '' (Mandarin for Wuhan virus) on 1st and 2nd February 2020. First 50 videos in each group were analyzed. Videos in other languages, duplicate videos, those without an audio and duration >15 min were excluded .72 videos in English and 42 in Mandarin were reviewed. 2 reviewers classified the videos as useful, misleading or news based on pre specified criterion. Inter-observer agreement was evaluated with kappa coefficient. Modified DISCERN index for reliability and medical information and content index (MICI) score were used for content analysis. RESULTS: These videos attracted cumulative 21,288,856 views. 67% of English and 50% Mandarin videos had useful information. The viewership of misleading Mandarin videos was higher than the useful ones. WHO accounted for only 4% of useful videos. Mean DISCERN score for reliability was 3.12/5 and 3.25/5 for English and Mandarin videos respectively. Mean cumulative MICI score of useful videos was low (6.71/25 for English and 6.28/25 for Mandarin). CONCLUSIONS: YouTube viewership during 2019 n-CoV outbreak is higher than previous outbreaks. The medical content of videos is suboptimal International health agencies are underrepresented. Given its popularity, YouTube should be considered as important platform for information dissemination.

Treatment to reduce vascular calcification in hemodialysis patients using vitamin K (Trevasc-HDK): A study protocol for a randomized controlled trial.

INTRODUCTION: End stage renal failure patients on hemodialysis have significant vascular calcification This is postulated to be related to sub-clinical vitamin K deficiency, which is prevalent in hemodialysis patients. Vitamin K deficiency result in the failure of the matrix GLA protein (MGP) to undergo carboxylation. MGP is a natural local inhibitor of vascular calcification and the lack of functional carboxylated MGP may contribute to increase vascular calcification. Vitamin K supplement should therefore correct this anomaly and decrease the rate or severity of vascular calcification in this population of patients on long-term maintenance hemodialysis. Our study seeks to evaluate the prevalence and the progression of vascular calcification in a cohort of maintenance hemodialysis patients. It will also evaluate the efficacy of vitamin K supplementation in reducing the progression of vascular calcification in this group of patients. METHODS: This will be a single-center randomized, prospective and open-label interventional clinical trial of end stage renal failure patients on hemodialysis. We aim to recruit 200 patients. Eligible patients will be randomized to either the standard care arm or active treatment arm. Active treatment arm patients will receive standard care plus supplementation with oral vitamin K2 isoform 360 mcg 3 times weekly for a total duration of 18 months. Primary outcome measured will be absolute difference in coronary artery calcification score at 18-month between control and intervention arms. Secondary outcomes will be to compare absolute difference in aortic valve calcification, percentage of patients with regression of coronary artery calcification of at least 10%, absolute difference in aortic and systemic arterial stiffness, mortality from any cause and major adverse cardiovascular over the same period. DISCUSSION: Evidence of successful regression or retardation of vascular calcification will support the conduct of larger and longer-term trials aimed at reducing cardiovascular disease mortality and major adverse cardiovascular events in this high-risk population using a safe and inexpensive strategy TRIAL REGISTRATION:: ClinicalTrials.gov NCT02870829. Registered on 17 August 2016 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02870829National University Hospital's Institutional Review Board (2015/01000).

Should antiviral monotherapy with nucleotide analogs be the primary treatment option for focal segmental glomerulosclerosis-related nephrotic syndrome in chronic hepatitis B infection?

Renal involvement is the most common extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. While membranous nephropathy is the most frequent, the association with focal segmental glomerulosclerosis (FSGS) is not as strong, and only a few cases have been described in the literature. In particular, the tip variant FSGS is extremely rare and to our knowledge has not previously been described in association with chronic HBV infection. The management of such cases can be challenging. Immunosuppression may lead to enhanced viral replication and flare-up of the hepatic disease. Antiviral treatment has been reported to induce remission in hepatitis B-associated glomerulonephritis in a few cases. However, their use is primarily restricted to the treatment of associated liver disease, and the current guidelines do not provide specific recommendations on HBV-mediated kidney disease in the absence of hepatic involvement. We describe a case of nephrotic syndrome due to secondary tip variant FSGS in a patient with chronic HBV infection who went into complete remission with antiviral therapy alone and present an argument for the use of oral antiviral agents as the primary treatment option for FSGS-related nephrotic syndrome in chronic HBV-infected patients without progressive liver disease.

Neoadjuvant chemotherapy in patients with locally advanced breast cancer: A pilot-observational study.

BACKGROUND: Locally advanced breast cancer (LABC) remains major clinical issue with regard to selection and duration of therapy since many years. Neoadjuvant chemotherapy (NACT) is multimodality program, established to treat LABC. Many research tasks are ongoing to develop specific neoadjuvant chemotherapy regimen with specific duration to improve long-term control of LABC. PATIENTS AND METHODS: Forty-seven patients diagnosed with LABC were Included and analyzed to compare the outcomes [pathological complete response (pCR), clinical response, overall response rate (ORR), disease control rate, overall survival and progression-free survival]. These patients treated with either combination of anthracycline and taxane-based chemotherapy or anthracycline-based chemotherapy. RESULTS: There was no any statistical significance with respect to demographic data treated of patients between two arms (P>0.05). Patients underwent TAC chemotherapy had pCR 20.8% whereas FAC/FEC chemotherapy patients had pCR 13% (P=0.48). Higher ORR was noted in TAC chemotherapy arm (75%) when compared with FAC/FEC chemotherapy arm (60.9%) (P=0.29). The study also shows better disease control rate in TAC chemotherapy arm (95.8%) as compared to FAC/FEC chemotherapy arm (82.6%). There was no statistical significance in overall survival (P=0.31) and progression-free survival (P=0.51) between two arms. CONCLUSION: Despite of the superiority of combination of anthracycline and taxane-based chemotherapy over the anthracycline-based chemotherapy in the present study, further pivotal studies should be conducted to confirm the combination of anthracycline and taxane-based chemotherapy as a better neoadjuvant regimen for treatment of LABC tumors.