Propofol sedation does not improve measures of colonoscopy quality but increase cost - findings from a large population-based cohort study.

Background: Propofol is often used for sedation during colonoscopy. We assessed the impact of propofol sedation on colonoscopy related quality metrics and cost in a population-based cohort study. Methods: All colonoscopies performed at 21 hospitals in the province of Ontario, Canada, during an 18-month period, from April 1, 2017 to October 31, 2018, using either propofol or conscious sedation were evaluated. The primary outcome was adenoma detection rate (ADR) and secondary outcomes were sessile serrated polyp detection rate (ssPDR), polyp detection rate (PDR), cecal intubation rate (CIR), and perforation rate. Binary outcomes were assessed using a modified Poisson regression model adjusted for clustering and potential confounders based on patient, procedure, and physician characteristics. Findings: A total of 46,634 colonoscopies were performed, of which 16,408 (35.2%) received propofol and 30,226 (64.8%) received conscious sedation. Compared to conscious sedation, the use of propofol was associated with a lower ADR (24.6% vs. 27.0%, p < 0.0001) but not ssPDR (5.0% vs. 4.7%, p = 0.26), PDR (40.5% vs 40.4%, p = 0.79), CIR (97.1% vs. 96.8%, p = 0.15) or perforation rate (0.04% vs. 0.06%, p = 0.45). On multi-variable analysis, propofol sedation was not associated with any differences in ADR (RR = 0.90, 95% CI 0.74-1.10, p = 0.30), ssPDR (RR = 1.20, 95% CI 0.90-1.60, p = 0.22), PDR (RR = 1.00, 95% CI 0.90-1.11, p = 0.99), or CIR (RR = 1.00, 95% CI 0.80-1.26, p = 0.99). The additional cost associated with propofol sedation was $12,730,496 for every 100,000 cases. Interpretation: The use of propofol sedation was not associated with improved colonoscopy related quality metrics but increased costs. The routine use of propofol for colonoscopy should be reevaluated. Funding: None.

Long-term outcomes after new onset seizure in children living with HIV: A cohort study.

OBJECTIVE: To determine the long-term outcomes, including mortality and recurrent seizures, among children living with HIV (CLWH) who present with new onset seizure. METHODS: Zambian CLWH and new onset seizure were enrolled prospectively to determine the risk of and risk factors for recurrent seizures. Demographic data, clinical profiles, index seizure etiology, and 30-day mortality outcomes were previously reported. After discharge, children were followed quarterly to identify recurrent seizures and death. Given the high risk of early death, risk factors for recurrent seizure were evaluated using a model that adjusted for mortality. RESULTS: Among 73 children enrolled, 28 died (38%), 22 within 30-days of the index seizure. Median follow-up was 533 days (IQR 18-957) with 5% (4/73) lost to follow-up. Seizure recurrence was 19% among the entire cohort. Among children surviving at least 30-days after the index seizure, 27% had a recurrent seizure. Median time from index seizure to recurrent seizure was 161 days (IQR 86-269). Central nervous system opportunistic infection (CNS OI), as the cause for the index seizure was protective against recurrent seizures and higher functional status was a risk factor for seizure recurrence. SIGNIFICANCE: Among CLWH presenting with new onset seizure, mortality risks remain elevated beyond the acute illness period. Recurrent seizures are common and are more likely in children with higher level of functioning even after adjusting for the outcome of death. Newer antiseizure medications appropriate for co-usage with antiretroviral therapies are needed for the care of these children. CNS OI may represent a potentially reversible provocation for the index seizure, while seizures in high functioning CLWH without a CNS OI may be the result of a prior brain injury or susceptibility to seizures unrelated to HIV and thus represent an ongoing predisposition to seizures. PLAIN LANGUAGE SUMMARY: This study followed CLWH who experienced a new onset seizure to find out how many go on to have more seizures and identify any patient characteristics associated with having more seizures. The study found that mortality rates continue to be high beyond the acute clinical presentation with new onset seizure. Children with a CNS OI causing the new onset seizure had a lower risk of later seizures, possibly because the trigger for the seizure can be treated. In contrast, high functioning children without a CNS OI were at higher risk of future seizures.

Early Initiation of Antiretroviral Therapy is Protective Against Seizures in Children With HIV in Zambia: A Prospective Case-Control Study.

BACKGROUND: Seizures are relatively common among children with HIV in low- and middle-income countries and are associated with significant morbidity and mortality. Early treatment with antiretroviral therapy (ART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. METHODS: We conducted a prospective, unmatched case-control study. We enrolled children with new-onset seizure from University Teaching Hospital in Lusaka, Zambia and 2 regional hospitals in rural Zambia. Controls were children with HIV and no history of seizures. Recruitment took place from 2016 to 2019. Early treatment was defined as initiation of ART before 12 months of age, at a CD4 percentage >15% in children aged 12-60 months or a CD4 count >350 cells/mm 3 for children aged 60 months or older. Logistic regression models were used to evaluate the association between potential risk factors and seizures. RESULTS: We identified 73 children with new-onset seizure and compared them with 254 control children with HIV but no seizures. Early treatment with ART was associated with a significant reduction in the odds of seizures [odds ratio (OR) 0.04, 95% confidence interval: 0.02 to 0.09; P < 0.001]. Having an undetectable viral load at the time of enrollment was strongly protective against seizures (OR 0.03, P < 0.001), whereas history of World Health Organization Stage 4 disease (OR 2.2, P = 0.05) or CD4 count <200 cells/mm 3 (OR 3.6, P < 0.001) increased risk of seizures. CONCLUSIONS: Early initiation of ART and successful viral suppression would likely reduce much of the excess seizure burden in children with HIV.

Characterizing Epstein-Barr virus infection of the central nervous system in Zambian adults living with HIV.

The significance of Epstein-Barr virus (EBV) detection in the cerebrospinal spinal fluid (CSF) in people living with HIV (PLWH) is not entirely understood. The detection of EBV DNA may represent active central nervous system (CNS) infection, reactivation in the setting of another CNS pathogen or due to impaired immunity, or detection of quiescent virus. We screened 470 adult PLWH in Zambia with neurological symptoms for the presence of EBV DNA in the CSF. We performed quantitative EBV PCR on the CSF and blood. We then performed quantitative EBV DNA PCR on the blood of controls with documented HIV viral suppression without CNS symptoms. The prevalence of EBV DNA in the CSF of patients with CNS symptoms was 28.9% (136/470). EBV DNA positivity was associated with younger age, shorter duration of HIV diagnosis, lower CSF glucose levels, higher CSF protein and white blood cell levels, and a positive CSF Mycobacterium tuberculosis result. The median EBV DNA load was 8000 cps/mL in both the CSF and blood with a range of 2000-2,753,000 cps/mL in the CSF and 1000 to 1,871,000 cps/mL in the blood. Molecular screening of CSF for other possible causes of infection identified Mycobacterium tuberculosis in 30.1% and cytomegalovirus (CMV) in 10.5% of samples. EBV DNA load in the blood and CSF was not associated with mortality. Our results suggest that even though EBV DNA was commonly detected in the CSF of our population, it appears to have limited clinical significance regardless of EBV DNA load.

Hemodynamic testing to guide vasodilator therapy in cardiac amyloidosis.

Cardiac amyloidosis is a restrictive cardiomyopathy for which diuretics are frequently used, but vasodilators have classically been relatively contraindicated due to side effects of hypotension. In the setting of decompensated heart failure, this may not be the case. We report a man with advanced cardiac amyloidosis who presented to the hospital with decompensated heart failure, in part, due to elevated systemic vascular resistance. Through the use of invasive hemodynamic testing, we were able to demonstrate an increase in cardiac output in response to a nitroprusside challenge. In turn, the patient had an improvement in his symptoms and was sent home on afterload reducing medications. This discerns a subpopulation of cardiac amyloidosis patients in decompensated heart failure who benefit from medications that reduce systemic vascular resistance, and can benefit from hemodynamic testing, especially when diuretics fail to control symptoms. Learning objective: Medications that cause peripheral vasodilation are standard therapy for patients with reduced ejection fraction, however, they are seldom used for patients with cardiac amyloidosis due to adverse effects. In some cases, there may be value in using hemodynamic measurements in patients with advanced cardiac amyloidosis to guide management as some patients may have hemodynamics that resemble those of systolic heart failure. This may offer a novel approach to symptomatic treatment of advanced cardiac amyloidosis.

Predictors of treatment response and survival outcomes in patients with advanced cardiac AL amyloidosis.

Patients with advanced cardiac immunoglobulin light chain (AL) amyloidosis have a poor prognosis. Early hematologic and cardiac responses can prolong survival, but predictors of these outcomes have yet to be clarified. We report on 142 patients with newly diagnosed stage IIIb AL amyloidosis. After a median follow-up of 60 months, the median overall survival (OS) was 9 months. Independent baseline factors associated with shorter OS were symptom onset to diagnosis >6 months (hazard ratio [HR], 1.94; P = .003); bone marrow plasmacytosis ≥ 10% (HR, 1.98; P = .01); troponin I > 0.635 ng/mL (HR, 1.62; P = .04); New York Heart Association class III or IV (HR, 1.67; P = .04); and 6-minute walk test distance < 200 m (HR, 1.85; P = .01). Early hematologic (within 1 month) and cardiac (within 3 months) responses were significantly associated with longer survival. In a 1-month landmark analysis, patients with a hematologic very good partial response, partial response, and no response had a median OS of 47, 25, and 5 months, respectively (P < .0001). Patients with cardiac response at 3 months had significantly longer OS (47 vs 11 months; P < .0001). On multivariable modeling, bortezomib use was associated with early hematologic and cardiac responses and longer OS. Symptom onset to diagnosis duration of >6 months and difference between the involved and uninvolved free light chain > 350 mg/L were independently associated with lower odds of an early cardiac response. This study identified factors predictive of treatment outcomes and survival in advanced cardiac AL amyloidosis.

Efficacy and safety of MAS825 (anti-IL-1ß/IL-18) in COVID-19 patients with pneumonia and impaired respiratory function.

MAS825, a bispecific IL-1ß/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 ± 1.87 and 13.5 ± 1.8 in the MAS825 and placebo groups, respectively (P = 0.33). MAS825 + SoC led to 33% relative reduction in intensive care unit (ICU) admissions, ~1 day reduction in ICU stay, reduction in mean duration of oxygen support (13.5 versus 14.3 days), and earlier clearance of virus on Day 15 versus placebo + SoC group. On Day 15, compared with placebo group, patients treated with MAS825 + SoC showed a 51% decrease in CRP levels, 42% lower IL-6 levels, 19% decrease in neutrophil levels, and 16% lower interferon-γ levels, indicative of IL-1ß and IL-18 pathway engagement. MAS825 + SoC did not improve APACHE II score in hospitalized patients with severe COVID-19 pneumonia; however, it inhibited relevant clinical and inflammatory pathway biomarkers and resulted in faster virus clearance versus placebo + SoC. MAS825 used in conjunction with SoC was well tolerated. None of the adverse events (AEs) or serious AEs were treatment-related.

Consensus Competencies for Postgraduate Fellowship Training in Global Neurology.

BACKGROUND AND OBJECTIVES: Use a modified Delphi approach to develop competencies for neurologists completing ≥1 year of advanced global neurology training. METHODS: An expert panel of 19 United States-based neurologists involved in global health was recruited from the American Academy of Neurology Global Health Section and the American Neurological Association International Outreach Committee. An extensive list of global health competencies was generated from review of global health curricula and adapted for global neurology training. Using a modified Delphi method, United States-based neurologists participated in 3 rounds of voting on a survey with potential competencies rated on a 4-point Likert scale. A final group discussion was held to reach consensus. Proposed competencies were then subjected to a formal review from a group of 7 neurologists from low- and middle-income countries (LMICs) with experience working with neurology trainees from high-income countries (HICs) who commented on potential gaps, feasibility, and local implementation challenges of the proposed competencies. This feedback was used to modify and finalize competencies. RESULTS: Three rounds of surveys, a conference call with United States-based experts, and a semistructured questionnaire and focus group discussion with LMIC experts were used to discuss and reach consensus on the final competencies. This resulted in a competency framework consisting of 47 competencies across 8 domains: (1) cultural context, social determinants of health and access to care; (2) clinical and teaching skills and neurologic medical knowledge; (3) team-based practice; (4) developing global neurology partnerships; (5) ethics; (6) approach to clinical care; (7) community neurologic health; (8) health care systems and multinational health care organizations. DISCUSSION: These proposed competencies can serve as a foundation on which future global neurology training programs can be built and trainees evaluated. It may also serve as a model for global health training programs in other medical specialties as well as a framework to expand the number of neurologists from HICs trained in global neurology.

Patient, Provider, and Health Systems Factors Leading to Lumbar Puncture Nonperformance in Zambia: A Qualitative Investigation of the "Tap Gap".

Lumbar puncture (LP) and cerebrospinal fluid (CSF) diagnostics are critical for evaluating central nervous system infections but are often not conducted, resulting in the "Tap Gap." To investigate patient, provider, and health systems factors contributing to the Tap Gap in Zambia, we conducted focus group discussions with adult caregivers of hospitalized inpatients and in-depth interviews with nurses, clinicians, pharmacy workers, and laboratory staff. Transcripts were independently thematically categorized by two investigators using inductive coding. We identified seven patient-related factors: 1) alternative understandings of CSF; 2) alternative information about LPs, including misinformation; 3) mistrust of doctors; 4) consent delays; 5) fear of blame; 6) peer pressure against consent; and 7) association between LP and stigmatized conditions. Four clinician-related factors were identified: 1) limited LP knowledge and expertise, 2) time constraints, 3) delays in LP requests by clinicians, and 4) fear of blame for bad outcomes. Finally, five health systems-related factors were identified: 1) supply shortages, 2) constrained access to neuroimaging, 3) laboratory factors, 4) availability of antimicrobial medications, and 5) cost barriers. Efforts to improve LP uptake must incorporate interventions to increase patient/proxy willingness to consent and improve clinician LP competencies while addressing both upstream and downstream health system factors. Key upstream factors include inconsistently available consumables for performing LPs and lack of neuroimaging. Critical downstream factors include laboratory services that offer poor availability, reliability, and/or timeliness of CSF diagnostics and the reality that medications needed to treat diagnosed infections are often unavailable unless the family has resources to purchase privately.

Consensus Clinical Guidance for Diagnosis and Management of Adult COVID-19 Encephalopathy Patients.

Encephalopathy, a common condition among patients hospitalized with COVID-19, can be a challenge to manage and negatively affect prognosis. While encephalopathy may present clinically as delirium, subsyndromal delirium, or coma and may be a result of systemic causes such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma (with or without cerebrovascular involvement), demyelination, or seizures, which may be disproportionate to COVID-19 severity and require specific management. Given the large number of patients hospitalized with severe acute respiratory syndrome coronavirus-2 infection, even these relatively unlikely complications are increasingly recognized and are particularly important because they require specific management. Therefore, the aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through consensus agreement of the Global COVID-19 Neuro Research Coalition. A systematic literature search of MEDLINE, medRxiv, and bioRxiv was conducted between January 1, 2020, and June 21, 2021, with additional review of references cited within the identified bibliographies. A modified Delphi approach was then undertaken to develop recommendations, along with a parallel approach to score the strength of both the recommendations and the supporting evidence. This review presents analysis of contemporaneous evidence for the definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and both acute and long-term management.

Cardiovascular Morbidity in Monoclonal Gammopathy of Undetermined Significance: A Danish Nationwide Study.

Background: Monoclonal gammopathy of undetermined significance (MGUS) is associated with renal dysfunction, inflammation, and increased cardiovascular mortality, but the cardiovascular risks are not fully understood. Objectives: The authors explored the association of MGUS with a spectrum of cardiovascular diseases using the Danish nationwide databases. Methods: Between 1995 and 2018, patients 18 years and older with MGUS were age- and sex-matched (1:10) with control patients and followed prospectively until December 31, 2018, for the occurrence of cardiovascular diseases. Patients diagnosed with multiple myeloma, lymphoma, or amyloidosis were excluded. Multivariable adjusted hazard ratios (HRs) for cardiovascular outcomes were estimated using Cox proportional hazard regression. Results: Patients with MGUS (n = 8,189; mean age 69.8 ± 11.7 years; 51.2% male) had higher prevalence of cardiovascular risk factors at baseline, including hypertension (48.0% vs 38.5%) and type 2 diabetes (13.0% vs 9.3%), compared with control patients. Outcomes included an increased risk of heart failure (HR: 1.55; 95% CI: 1.41-1.69), acute myocardial infarction (HR: 1.22; 95% CI: 1.06-1.40), ischemic stroke (HR: 1.16; 95% CI: 1.03-1.30), atrial fibrillation (HR: 1.32; 95% CI: 1.23-1.42), aortic aneurysm (HR: 1.55; 95% CI: 1.28-1.89), aortic stenosis (HR: 1.60; 95% CI: 1.41-1.82), aortic regurgitation (HR: 1.67; 95% CI: 1.34-2.07), heart block (HR: 1.32; 95% CI: 1.08-1.61), peripheral artery disease (HR: 1.69; 95% CI: 1.47-1.95), cor pulmonale (HR: 2.06; 95% CI: 1.55-2.73), and venous thromboembolism (HR: 1.43; 95% CI: 1.24-1.65). A sensitivity analysis including only patients without certain comorbidities (type 2 diabetes, hypertension, acute myocardial infarction, and chronic kidney disease) yielded similar results. Conclusions: MGUS is associated with a broad spectrum of cardiovascular diseases, with greater relative risks observed for diseases previously associated with infiltrative and inflammatory disorders. Further studies are warranted to explore the underlying mechanisms.

Epstein-Barr Virus Detection in the Central Nervous System of HIV-Infected Patients.

Simply detecting Epstein-Barr virus deoxyribonucleic acid (EBV-DNA) is insufficient to diagnose EBV-associated diseases. The current literature around EBV-DNA detection from cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV)-positive non-lymphoma patients was systematically reviewed and a meta-analysis reporting the estimated pooled prevalence in this population when PCR methods are employed, targeting different sequence segments within the EBV genome, was conducted. Using a combination of three key concepts-Epstein-Barr virus detection, central nervous system disease, and human cerebrospinal fluid-and their MeSH terms, the PubMed database was searched. A total of 273 papers reporting the detection of EBV in CNS were screened, of which 13 met the inclusion criteria. The meta-analysis revealed a pooled prevalence of EBV-DNA in CSF of 20% (CI: 12-31%). The highest pooled prevalence was from studies conducted on the African population at 39% (CI: 27-51%). The investigation of the presence of EBV-DNA in the CSF was also very varied, with several gene targets used. While most patients from the articles included in this review and meta-analysis were symptomatic of CNS disorders, the pathogenicity of EBV in non-lymphoma HIV patients when detected in CSF has still not been determined. The presence of EBV-DNA in the CNS remains a concern, and further research is warranted to understand its significance in causing CNS disorders.

Clinical presentation and outcomes of syphilitic meningitis among hospitalized adults in lusaka, Zambia.

BACKGROUND: Few studies exist to describe the characteristics of symptomatic syphilitic meningitis, particularly in sub-Saharan Africa, despite a global resurgence. METHODS: We conducted a retrospective analysis of a cohort of adults with meningitis presenting to Zambia's largest referral hospital between April 2014 and December 2017. Individuals with pyogenic bacterial and cryptococcal meningitis were excluded from this cohort. We calculated the prevalence of syphilitic meningitis in the cohort and described the demographic, clinical and laboratory characteristics and outcomes. RESULTS: Of 512 participants, 273 were male, mean age was 37 ± 11 years and 84% were people living with HIV. The prevalence of syphilitic meningitis was 5% with in-hospital and 1-year mortality of 17% and 53%, respectively. Participants with syphilitic meningitis had lower Glasgow Coma Scores than those with other forms of meningitis. Among people living with HIV, those with syphilitic meningitis were less likely to have meningismus and had higher CSF white cell counts. CONCLUSIONS: Syphilitic meningitis was found in 5% of Zambian adults presenting with non-pyogenic bacterial meningitis and non-cryptococcal meningitis, and one-year mortality was high. A high degree of clinical suspicion for syphilitic meningitis in all individuals with meningitis in Zambia is recommended, especially in people living with HIV.

Association of Trainee Participation in Colonoscopy Procedures With Quality Metrics.

Importance: Trainees routinely participate in colonoscopy procedures, yet whether their involvement is positively or negatively associated with procedural quality is unknown because prior studies involved small number of trainees and/or supervisors, lacked generalizability, and/or failed to adjust for potential confounders. Objective: To assess the association between trainee participation and colonoscopy quality metrics. Design, Setting, and Participants: This multicenter population-based cohort study was conducted at 21 academic and community hospitals between April 1, 2017, and October 31, 2018, among consecutive adult patients undergoing colonoscopy. Procedures performed by endoscopists who did not supervise trainees were excluded. Statistical analysis was performed from April 3, 2017, to October 31, 2018. Exposure: Participation by a trainee, defined as a resident or fellow enrolled in a gastroenterology or general surgery training program. Main Outcomes and Measures: The primary outcome was the adenoma detection rate (ADR), and secondary outcomes were sessile serrated polyp detection rate (ssPDR), polyp detection rate (PDR), cecal intubation rate (CIR), and perforation rate. Results: A total of 35 499 colonoscopies (18 989 women [53.5%]; mean [SD] patient age, 60.0 [14.1] years) were performed by 71 physicians (mean [SD] time in practice, 14.0 [9.3] years); 5941 colonoscopies (16.7%) involved trainees. There were no significant differences in the ADR (26.4% vs 27.3%; P = .19), CIR (96.7% vs 97.2%; P = .07), and perforation rate (0.05% vs 0.06%; P = .82) when trainees participated vs when they did not participate, whereas the the ssPDR (4.4% vs 5.2%; P = .009) and PDR (39.2% vs 42.0%; P < .001) were significantly lower when trainees participated vs when they did not. After adjustment for potential confounders, the ADR (risk ratio [RR], 0.97; 95% CI, 0.91-1.03; P = .30), PDR (RR, 0.98; 95% CI, 0.93-1.04; P = .47), and CIR (RR, 0.93; 95% CI, 0.78-1.10; P = .38) were not associated with trainee participation, although the ssPDR remained significantly lower (RR, 0.79; 95% CI, 0.64-0.98; P = .03). Conclusions and Relevance: This study suggests that trainee involvement during colonoscopy was associated with reduced ssPDR but not other colonoscopy outcome measures. Extra care should be exercised when examining the right colon when trainees are involved.

Light Chain Testing Abnormalities Among Patients With Transthyretin Amyloid Cardiomyopathy Referred for Technetium-99m Pyrophosphate Imaging.

Clinical algorithms stipulate that transthyretin amyloid cardiomyopathy (ATTR-CM) can be diagnosed noninvasively by technetium-99m pyrophosphate (PYP) imaging when light chain (AL) amyloidosis has been excluded. We sought to define the distribution of light chain abnormalities and final diagnosis of ATTR-CM among patients referred for PYP imaging. We conducted a retrospective cohort study of 378 sequential patients with suspected ATTR-CM, referred for PYP imaging from October 2014 to January 2019. PYP scans were adjudicated as per guidelines. We found that 97 patients (26%) had abnormal plasma cell dyscrasia (PCD) markers, including serum free light chain (FLC) and/or urine/serum immunofixation electrophoresis (IFE). After exclusions for incomplete data or known AL amyloidosis, the final study population with abnormal PCD testing was n = 82. Final adjudication of amyloidosis was determined by multidisciplinary clinical assessment and/or tissue biopsy. The median age of cohort was 75 (68 to 81) years, 88% were men, and 33% were Black. Of the 82 patients, 62 had positive PYP scans (76%) and 20 had negative PYP scans (24%). A total of 64 patients had adjudicated ATTR-CM, confirmed by tissue biopsy in 41 (64%). Of those with confirmed ATTR-CM, 44 (69%) had abnormal FLC ratio between 1.65 and 3.1 and normal IFE. In conclusion, among patients referred for technetium-99m-PYP imaging for suspected ATTR-CM, 26% exhibited abnormalities of PCD markers. An FLC ratio 1.65 to 3.1, with normal IFE was noted in 69% of those with ATTR-CM, suggesting that ATTR-CM can be diagnosed noninvasively without cardiac biopsy in patients with positive PYP scan and similar plasma cell testing results.

Predictors of hematologic response and survival with stem cell transplantation in AL amyloidosis: A 25-year longitudinal study.

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.

A novel substitution of proline (P32L) destabilises ß2-microglobulin inducing hereditary systemic amyloidosis.

BACKGROUND: ß2-microglobulin amyloidosis was first described in the 1980s as a protein deposition disease associated with long-term haemodialysis. More recently, two inherited forms resulting from separate point mutations in the ß2-microglobulin gene have been identified. In this report, we detail a novel ß2M variant, P32L, caused by a unique dinucleotide mutation that is linked to systemic hereditary ß2-microglobulin amyloidosis. METHODS: Three family members from a Portuguese kinship featured cardiomyopathy, requiring organ transplantation in one case, along with soft tissue involvement; other involvements included gastrointestinal, neuropathic and sicca syndrome. In vitro studies with recombinant P32L, P32G, D76N and wild-type ß2-microglobulin were undertaken to compare the biophysical properties of the proteins. RESULTS: The P32L variant was caused by the unique heterozygous dinucleotide mutation c.154_155delinsTT. Amyloid disease featured lowered serum ß2-microglobulin levels with near equal amounts of circulating P32L and wild-type proteins; amyloid deposits were composed exclusively of P32L variant protein. In vitro studies of P32L demonstrated thermodynamic and chemical instability and enhanced susceptibility to proteolysis with rapid formation of pre-fibrillar oligomeric structures by N- and C-terminally truncated species under physiological conditions. CONCLUSIONS: This work provides both clinical and experimental evidence supporting the critical role of P32 residue replacement in ß2M amyloid fibrillogenesis.

Clinical characteristics and outcomes after new-onset seizure among Zambian children with HIV during the antiretroviral therapy era.

OBJECTIVE: This study describes clinical profiles including human immunodeficiency virus (HIV) disease history and seizure etiology among children living with HIV presenting with new-onset seizure during the era of antiretroviral therapy (ART) in Zambia. 30-day mortality and cause of death are also reported. METHODS: Children living with HIV (CLWHIV) with new-onset seizures were prospectively evaluated at one large urban teaching hospital and two non-urban healthcare facilities. Interviews with family members, review of medical records, and where needed, verbal autopsies were undertaken. Two clinicians who were not responsible for the patients' care independently reviewed all records and assigned seizure etiology and cause of death with adjudication as needed. RESULTS: From April 2016 to June 2019, 73 children (49 urban, 24 rural) were identified. Median age was 6 years (IQR 2.2-10.0) and 39 (53%) were male children. Seizures were focal in 36 (49%) and were often severe, with 37% presenting with multiple recurrent seizures in the 24 hours before admission or in status epilepticus. Although 36 (49%) were on ART at enrollment, only 7 of 36 (19%) were virally suppressed. Seizure etiologies were infectious in over half (54%), with HIV encephalitis, bacterial meningitis, and tuberculous meningitis being the most common. Metabolic causes (19%) included renal failure and hypoglycemia. Structural lesions identified on imaging accounted for 10% of etiologies and included stroke and non-accidental trauma. No etiology could be identified in 12 (16%) children, most of whom died before the completion of clinical investigations. Twenty-two (30%) children died within 30 days of the index seizure. SIGNIFICANCE: Despite widespread ART roll out in Zambia, new-onset seizure in CLWHIV occurs in the setting of advanced, active HIV disease. Seizure severity/burden is high as is early mortality. Enhanced programs to assure early ART initiation, improve adherence, and address ART failure are needed to reduce the burden of neurological injury and premature death in CLWHIV.