Epidemiology of clinically significant forms of alpha- and beta-thalassemia: A global map of evidence and gaps.

This systematic literature review assessed the global prevalence and birth prevalence of clinically significant forms of alpha- and beta-thalassemia. Embase, MEDLINE, and the Cochrane Library were searched for observational studies published January 1, 2000, to September 21, 2021. Of 2093 unique records identified, 69 studies reported across 70 publications met eligibility criteria, including 6 records identified from bibliography searches. Thalassemia prevalence estimates varied across countries and even within countries. Across 23 population-based studies reporting clinically significant alpha-thalassemia (e.g., hemoglobin H disease and hemoglobin Bart's hydrops fetalis) and/or beta-thalassemia (beta-thalassemia intermedia, major, and/or hemoglobin E/beta-thalassemia), prevalence estimates per 100 000 people ranged from 0.2 in Spain (over 2014-2017) to 27.2 in Greece (2010-2015) for combined beta- plus alpha-thalassemia; from 0.03 in Spain (2014-2017) to 4.5 in Malaysia (2007-2018) for alpha-thalassemia; and from 0.2 in Spain (2014-2017) to 35.7 to 49.6 in Iraq (2003-2018) for beta-thalassemia. Overall, the estimated prevalence of thalassemia followed the predicted pattern of being higher in the Middle East, Asia, and Mediterranean than in Europe or North America. However, population-based prevalence estimates were not found for many countries, and there was heterogeneity in case definitions, diagnostic methodology, type of thalassemia reported, and details on transfusion requirements. Limited population-based birth prevalence data were found. Twenty-seven studies reported thalassemia prevalence from non-population-based samples. Results from such studies likely do not have countrywide generalizability as they tended to be from highly specific groups. To fully understand the global prevalence of thalassemia, up-to-date, population-based epidemiological data are needed for many countries.

Burden of neutropenia and leukopenia among adult kidney transplant recipients: A systematic literature review of observational studies.

BACKGROUND: Leukopenia and neutropenia (L/N) may affect treatment decisions, potentially resulting in poor clinical and economic outcomes among kidney transplant recipients (KTRs). The burden of L/N is poorly quantified systematically. This systematic literature review aimed to summarize the incidence of, risk factors for, and clinical and economic outcomes associated with L/N post-KT. METHODS: We systematically searched MEDLINE, Embase, and the Cochrane Library (from database inception-June 14, 2021) and conferences (past 3 years) to identify observational studies examining epidemiology, risk factors, or outcomes associated with L/N among adult KTRs. RESULTS: Of 2081 records, 82 studies met inclusion criteria. Seventy-three studies reported the epidemiology of L/N post-KT. Pooled incidence of neutropenia, defined as absolute neutrophil counts (ANC) <1000/µl, ranged from 13% to 48% within 1-year post-transplant; ANC <500/µl ranged from 15% to 20%. Leukopenia, defined as white blood cell counts <3500/µl, was 19% to 83%. Eleven studies reported independent risk factors associated with L/N post-KT. D+/R- cytomegalovirus status, mycophenolic acid (MPA), and tacrolimus use were the most consistent risk factors across studies. Fourteen studies reported L/N-associated clinical outcomes. We noted a trend toward a positive association between neutropenia and acute rejection/opportunistic infections. Mixed findings were noted on the association between L/N and graft failure or mortality. Dosage modifications of valganciclovir, MPA, cotrimoxazole, and anti-thymoglobulin and the need for granulocyte colony-stimulating factor (G-CSF) use were common with L/N. CONCLUSION: Findings suggest post-transplant L/N were common and associated with frequent modifications of immunosuppressive agents, requiring G-CSF use, and rejection or opportunistic infections. Findings highlight the need for interventions to reduce risk of L/N post-KT.

Systematic Literature Review of Real-World Effectiveness Results Data for First-Line Ibrutinib in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma.

BACKGROUND AND OBJECTIVE: Ibrutinib, an oral Bruton's tyrosine kinase inhibitor, has demonstrated efficacy as a first-line treatment for chronic lymphocytic leukemia in multiple, phase III, randomized clinical trials. This systematic literature review assessed the clinical effectiveness of ibrutinib in the first-line treatment of chronic lymphocytic leukemia in real-world clinical settings. METHODS: MEDLINE, EMBASE, and relevant conference websites were searched for articles published in the USA from 1 January, 2014 to 30 June, 2020. Overall survival, progression-free survival, overall response rate, and time to next treatment were summarized. RESULTS: This analysis included a total of 12 publications representing data from 112 to 2033 patients from community and academic centers, and the multicenter informCLL registry. Patients were predominantly male (60-99%) with a median age range from 62 to 77 years, and included those with high-risk genomic features (del[17p]: 21-33%; del[11q]: 33%; and unmutated immunoglobulin heavy chain variable gene: 59%). Real-world effectiveness with ibrutinib complemented the efficacy demonstrated in randomized clinical trials. Across various studies, the 12-month overall survival rates ranged from 95% to 96%; 18-month overall survival rates were similarly high (91%). Twelve-month progression-free survival rates ranged from 89% to 93%, and the overall response rate ranged from 71% to 90% across four studies. In the studies that reported time to next treatment, 91% and 87% of patients treated with first-line ibrutinib did not initiate new treatment at 12 months and 24 months, respectively. CONCLUSIONS: This systematic literature review confirms the benefit of ibrutinib as a first-line treatment in patients with chronic lymphocytic leukemia in real-world clinical settings and is consistent with results from randomized clinical trials, including in patients with high-risk genomic features.

Global incidence of intraventricular hemorrhage among extremely preterm infants: a systematic literature review.

OBJECTIVES: To conduct a systematic literature review to evaluate the global incidence of intraventricular hemorrhage grade 2-4 among extremely preterm infants. METHODS: We performed searches in MEDLINE and Embase for intraventricular hemorrhage and prematurity cited in English language observational studies published from May 2006 to October 2017. Included studies analyzed data from infants born at ≤28 weeks' gestational age and reported on intraventricular hemorrhage epidemiology. RESULTS: Ninety-eight eligible studies encompassed 39 articles from Europe, 31 from North America, 25 from Asia, five from Oceania, and none from Africa or South America; both Europe and North America were included in two publications. The reported global incidence range of intraventricular hemorrhage grade 3-4 was 5-52% (Europe: 5-52%; North America: 8-22%; Asia: 5-36%; Oceania: 8-13%). When only population-based studies were included, the incidence range of intraventricular hemorrhage grade 3-4 was 6-22%. The incidence range of intraventricular hemorrhage grade 2 was infrequently documented and ranged from 5-19% (including population-based studies). The incidence of intraventricular hemorrhage was generally inversely related to gestational age. CONCLUSIONS: Intraventricular hemorrhage is a frequent complication of extremely preterm birth. Intraventricular hemorrhage incidence range varies by region, and the global incidence of intraventricular hemorrhage grade 2 is not well documented.

Global incidence of bronchopulmonary dysplasia among extremely preterm infants: a systematic literature review.

BACKGROUND: Infants born extremely preterm (<28 weeks gestational age (GA)) face a high risk of neonatal mortality. Bronchopulmonary dysplasia (BPD) is the most common morbidity of prematurity. OBJECTIVE: To evaluate the global incidence of BPD among infants born extremely preterm. DESIGN: A systematic review of the literature was conducted in Embase and MEDLINE (via PubMed) using a prespecified search strategy for BPD and prematurity. Observational studies published in English between 16 May 2006 and 16 October 2017 reporting on the occurrence of BPD in infants born <28 weeks GA were included. RESULTS: Literature searches yielded 103 eligible studies encompassing 37 publications from Europe, 38 publications from North America, two publications from Europe and North America, 19 publications from Asia, one publication from Asia and North America, six publications from Oceania, and zero publications from Africa or South America. The reported global incidence range of BPD was 10-89% (10-73% in Europe, 18-89% in North America, 18-82% in Asia, and 30-62% in Oceania). When only population-based observational studies that defined BPD as requiring supplemental oxygen at 36 weeks postmenstrual age were included, the global incidence range of BPD was 17-75%. The wide range of incidences reflected interstudy differences in GA (which was inversely related to BPD incidence), birthweight, and survival rates across populations and institutions. CONCLUSIONS: BPD is a common health morbidity occurring with extremely preterm birth. Further study of factors that impact incidence, aside from low GA, may help to elucidate modifiable risks.

Epidemiology, risk factors, and outcomes associated with cytomegalovirus in adult kidney transplant recipients: A systematic literature review of real-world evidence.

Kidney transplant recipients (KTRs) have increased risk for cytomegalovirus (CMV) infection/disease given the necessity of drug-induced immunosuppression. A comprehensive review of published literature reporting real-world data on prevention strategies utilized and associated CMV burden outcomes is limited. Such data could help inform future clinical practice and identify unmet needs in CMV management. We conducted a systematic review of observational studies published in Medline or EMBASE from January 2008 to November 2018 to identify current real-world CMV management approaches, CMV infection/disease risk factors, and outcomes associated with CMV infection. Descriptive statistics and pooled quantitative analyses were conducted. From 1608 records screened, 86 citations, including 69 803 adult KTR, were included. Prophylaxis and preemptive therapy (PET) were predominant approaches among D+/R- and R + CMV serostatus transplants, respectively. Valganciclovir and ganciclovir were frequently utilized across CMV risk strata. Despite prevention approaches, approximately one-fourth of KTR developed CMV infection. Age and D+/R- CMV serostatus were consistent risk factors for CMV infection/disease. CMV infection/disease was associated with increased mortality and graft loss. CMV was similarly associated with acute rejection (AR) risk, but with high heterogeneity among studies. Limited data were available on CMV and opportunistic infections (OIs) risk. CMV remains a significant issue. New strategies may be needed to optimize CMV management.

Systematic literature review of clinical trials evaluating pharmacotherapy for overactive bladder in elderly patients: An assessment of trial quality.

AIMS: Overactive bladder (OAB) disproportionately affects older-aged adults, yet most randomized controlled trials (RCTs) underrepresent patients ≥65. This systematic literature review (SLR) identified RCTs evaluating ß-3 adrenergic agonists or muscarinic antagonists in elderly patients with OAB, and compared study quality across trials. METHODS: MEDLINE® , Embase® , and Cochrane Collaboration Central Register of Clinical Trials databases were searched from inception through April 28, 2015 to identify published, peer-reviewed RCT reports evaluating ß-3 adrenergic agonists or muscarinic antagonists in elderly OAB patients (either ≥65 years or study-described as "elderly"). To assess study quality of RCT reports, we focused on internal/external validity, assessed via two scales: the validated Effective Public Health Practice Project [EPHPP]): Quality Assessment Tool for Quantitative Studies, and a tool commissioned by the Agency for Healthcare Research and Quality (AHRQ). RESULTS: Database searches yielded 1380 records that were then screened according to predefined inclusion/exclusion criteria. We included eight papers meeting study criteria. Despite scientific community efforts to improve RCT reporting standards, published reports still include incomplete and inconsistent reporting-of subject attrition, baseline patient characteristics, inclusion/exclusion criteria, and other important details. Only three of the eight OAB RCTs in this review received quality ratings of Strong (EPHPP) or Fair (AHRQ) and were multicenter with large samples. CONCLUSIONS: Despite the prevalence of OAB among older age individuals, relatively few RCTs evaluate OAB treatments explicitly among elderly subjects. The findings from this quality assessment suggest some areas for improvement in both conduct and reporting of future RCTs assessing OAB treatment in elderly.

Incidence and Risk of Cardiac Events in Patients With Previously Treated Multiple Myeloma Versus Matched Patients Without Multiple Myeloma: An Observational, Retrospective, Cohort Study.

BACKGROUND: Multiple myeloma (MM) patients have age-, disease-, and treatment-related risk factors for cardiac events. MATERIALS AND METHODS: We analyzed the 2006 to 2011 MarketScan database to determine whether the risk of cardiac events is greater in MM patients than in non-MM patients. Included were 1723 MM patients treated with corticosteroids and ≥ 3 drugs (bortezomib, immunomodulatory derivatives, and alkylating agents or anthracyclines). The index date (ID) was the date on which the 3-drug exposure criterion was met. Also included were 8615 age- and gender-matched non-MM patients (5:1). The distribution of non-MM patients' IDs matched that of the MM patients' IDs. Baseline was 6 months before the ID. The follow-up duration was from the ID to study end (ie, 2011 or end of enrollment or prescription drug coverage). Hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for baseline variables when the univariate analyses showed a 10% difference. RESULTS: The median duration of observation was 9 months (range, 0-60 months) for MM patients and 19 months (range, 0-66 months) for non-MM patients. The risk of any cardiac event (HR, 2.2; 95% CI, 1.9-2.5), dysrhythmia (HR, 4.1; 95% CI, 3.5-4.8), congestive heart failure (HR, 2.9; 95% CI, 2.2-3.7), cardiomyopathy (HR, 2.6; 95% CI, 1.8-3.8), and conduction disorders (HR, 1.7; 95% CI, 1.2-2.5) was significantly greater for MM than for non-MM patients. The incidence of hypertensive or arterial events and ischemic heart disease was similar between the 2 groups. CONCLUSION: The present study provides the first known comparison of cardiac event risk in patients with MM versus age- and gender-matched patients without MM. The cardiac event risk was greater in MM patients with ≥ 3 previous drugs for any cardiac event, dysrhythmias, congestive heart failure, cardiomyopathy, and conduction disorders compared with patients without MM.

Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a distinct form of interstitial pneumonia with unknown origin and poor prognosis. Current pharmacologic treatments are limited and lung transplantation is a viable option for appropriate patients. The aim of this review was to summarize lung transplantation survival in IPF patients overall, between single (SLT) vs. bilateral lung transplantation (BLT), pre- and post Lung Allocation Score (LAS), and summarize wait-list survival. METHODS: A systematic review of English-language studies published in Medline or Embase between 1990 and 2013 was performed. Eligible studies were those of observational design reporting survival post-lung transplantation or while on the wait list among IPF patients. RESULTS: Median survival post-transplantation among IPF patients is estimated at 4.5 years. From ISHLT and OPTN data, one year survival ranged from 75% - 81%; 3-year: 59% - 64%; and 5-year: 47% - 53%. Post-transplant survival is lower for IPF vs. other underlying pre-transplant diagnoses. The proportion of IPF patients receiving BLT has steadily increased over the last decade and a half. Unadjusted analyses suggest improved long-term survival for BLT vs. SLT; after adjustment for patient characteristics, the differences tend to disappear. IPF patients account for the largest proportion of patients on the wait list and while wait list time has decreased, the number of transplants for IPF patients has increased over time. OPTN data show that wait list mortality is higher for IPF patients vs. other diagnoses. The proportion of IPF patients who died while awaiting transplantation ranged from 14% to 67%. While later transplant year was associated with increased survival, no significant differences were noted pre vs. post LAS implementation; however a high LAS vs low LAS was associated with decreased one-year survival. CONCLUSIONS: IPF accounts for the largest proportion of patients awaiting lung transplants, and IPF is associated with higher wait-list and post-transplant mortality vs. other diagnoses. Improved BLT vs. SLT survival may be the result of selection bias. Survival pre- vs. post LAS appears to be similar except for IPF patients with high LAS, who have lower survival compared to pre-LAS. Data on post-transplant morbidity outcomes are sparse.

Thromboprophylaxis, bleeding and post-operative prosthetic joint infection in total hip and knee arthroplasty: a comprehensive literature review.

INTRODUCTION: Concerns regarding risk versus benefit, that is, the possible impact of surgical-site bleeding on post-operative joint infections, have contributed to a continuing debate over recommendations for venous thromboembolism (VTE) prophylaxis in post-surgical orthopedic patients undergoing total hip and knee arthroplasty (THA/TKA). AREAS COVERED: A comprehensive literature search using MEDLINE covering the period 2004-2009 was conducted, and published studies that focused on THA and TKA and contained data applicable to thromboprophylaxis, post-surgical wound infection and bleeding are reviewed in this paper. The search strategy included various combinations of terms related to lower limb joint arthroplasty, anticoagulant drugs, post-operative bleeding and prosthetic joint infection (wound infection). Methodological constraints included failure in some studies to define an infection, variations among the studies in the definitions of bleeding and differences in the follow-up time for capturing infection and bleeding events. Despite this, this comprehensive review identified observational, 'real-world' data that can contribute in important ways to the existing evidence base. EXPERT OPINION: There are insufficient data to either confirm or refute the hypothesis that post-operative bleeding is a mediating pathophysiologic factor linking pharmacologic VTE prophylaxis to an increased risk for wound infection. Studies specifically designed to examine the interrelationship between thromboprophylaxis, bleeding and wound infections following THA/TKA are warranted.

The impact of CMV prevention on long-term recipient and graft survival in heart transplant recipients: analysis of the Scientific Registry of Transplant Recipients (SRTR) database.

The association between cytomegalovirus immunoglobulin (CMVIG) and long-term clinical outcomes in heart transplantation has not been evaluated using data from large national databases. We examined the association between CMVIG, with and without antivirals, or antivirals alone, and long-term recipient and graft survival in heart transplantation using data from the Scientific Registry of Transplant Recipients. Recipients transplanted between January 1995 and October 2008, ≤80 yr old, of primary, single-organ heart transplants, recorded as receiving CMVIG with or without antivirals (n = 2112), antivirals without CMVIG (n = 12 089), or no prophylaxis (n = 14 661), at hospital discharge, were included. Kaplan-Meier analysis was used to examine death and graft loss at seven yr post-transplantation; Cox proportional hazards regression was used to estimate the adjusted risk of graft loss and death for prophylaxis vs. no prophylaxis. CMVIG use (± other antivirals) was associated with increased recipient (69% vs. 64%, p < 0.001) and graft (67% vs. 63%, p < 0.001) survival. Antivirals alone also demonstrated increased recipient (68% vs. 64%, p < 0.001) and graft survival (66% vs. 63%, p < 0.001). Cox models demonstrated that CMVIG (± other antivirals) was independently associated with decreased risk for death (hazard ratio, HR 0.79, p < 0.001) and graft loss (HR 0.78, p < 0.001) as were antivirals alone (mortality HR: 0.79, p < 0.001; graft loss: HR 0.78, p < 0.001).

Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease.

OBJECTIVES: Factors that determine disease severity in nonalcoholic fatty liver disease (NAFLD) are unclear, but exercise is a recommended treatment. We evaluated the association between physical activity intensity and histological severity of NAFLD. METHODS: We conducted a retrospective analysis of adults with biopsy-proven NAFLD enrolled in the NASH CRN (Nonalcoholic Steatohepatitis Clinical Research Network). Using self-reported time spent in physical activity, we classified participants as inactive or as meeting the US guidelines for either moderate or vigorous exercise. Histology was reviewed by a central pathology committee. Frequency and odds of steatohepatitis (NASH) and advanced fibrosis were compared between subjects who either met or did not meet exercise recommendations, and by the total amount of exercise per week. RESULTS: A total of 813 adults (males=302, females=511) with NAFLD were included, with a mean age of 48 years. Neither moderate-intensity exercise nor total exercise per week was associated with NASH or stage of fibrosis. Meeting vigorous recommendations was associated with a decreased adjusted odds of having NASH (odds ratio (OR): 0.65 (0.43-0.98)). Doubling the recommended time spent in vigorous exercise, as is suggested for achieving additional health benefits, was associated with a decreased adjusted odds of advanced fibrosis (OR: 0.53 (0.29-0.97)). CONCLUSIONS: These data support an association of vigorous but not moderate or total exercise with the severity of NAFLD. Optimal doses of exercise by duration and intensity for the prevention or treatment of NASH have not been established; however, intensity may be more important than duration or total volume.

Cytomegalovirus prevention and long-term recipient and graft survival in pediatric heart transplant recipients.

INTRODUCTION: The association between cytomegalovirus (CMV) immune globulin (CMVIG) and clinical outcomes in pediatric heart transplantation has not been evaluated. Long-term recipient and graft survival were compared between pediatric heart recipients who received CMV prophylaxis with CMVIG (with or without antivirals), antivirals without CMVIG, and no prophylaxis. CMVIG (with or without antivirals) versus no prophylaxis was also assessed in the CMV-positive donor/CMV-negative recipient cohort. METHODS: Data from the Scientific Registry of Transplant Recipients included patients with a transplant date between January 1995 and October 2008; follow-up data were through March 2009. All pediatric (younger than 18 years) recipients of primary, single-organ heart transplants were included. Kaplan-Meier analysis was used to examine rates of recipient death and graft loss at 7 years posttransplantation. Cox proportional hazards regression was used to estimate adjusted risk for graft loss and death. RESULTS: CMVIG (with or without antivirals) and antivirals without CMVIG were both associated with significantly (P≤0.05) lower rates of graft loss and death versus no prophylaxis. After adjustment, CMVIG was associated with a significantly decreased adjusted risk for graft loss and a borderline (P=0.09) decreased adjusted mortality risk; antiviral prophylaxis was associated with decreased adjusted risk for graft loss and mortality. In the CMV-positive donor/CMV-negative recipient cohort, CMVIG (with or without antivirals) was associated with decreased adjusted risk for graft loss and death. CONCLUSIONS: CMV prophylaxis with CMVIG or antivirals seems to offer long-term clinical outcome benefits. Determination of optimal regimen, dosage, and duration remains to be examined.