Clinical outcomes of preimplantation genetic testing for hereditary cancer syndromes: A systematic review.

OBJECTIVE: To conduct a systematic review of the published literature on clinical outcomes following preimplantation genetic testing for monogenic disorders (PGT-M) for hereditary cancer syndromes (HCS). METHODS: Three electronic databases (PubMed, Cochrane, and EMBASE) were searched for publications related to PGT-M for HCS. When appropriate, weighted means were used to calculate clinical and live birth rates. RESULTS: We identified 22 publications that reported on clinical and/or psychosocial outcomes of PGT-M for HCS. The weighted mean clinical pregnancy rate (CPR) per embryo was 33.5% (11 studies, 95% CI: 29.1%, 38.2%), and the CPR per cycle with embryonic transfer was 40.1% (14 studies, 95% CI: 36.1%, 44.3%). The weighted mean live birth rate (LBR) per embryo was 28.9% (11 studies, 95% CI: 24.7%, 33.4%) and the LBR per cycle with embryonic transfer was 33.2% (13 studies, 95% CI: 29.2%, 37.4%). The limited literature regarding the psychosocial outcomes of PGT-M for HCS suggests reproductive decision-making is difficult and additional support may be desired. CONCLUSION: These findings suggest that CPR and LBR following PGT-M for HCS are comparable to other monogenic disorders. Heterogeneity across studies suggests the overall CPR and LBR found may not be applicable to all HCS indications and PGT-M methodologies.

The uptake and utility of genetic testing and genetic counseling for hypertrophic cardiomyopathy-A systematic review and meta-analysis.

Genetic testing and genetic counseling are routinely indicated for patients with hypertrophic cardiomyopathy (HCM); however, the uptake and utility of these services is not entirely understood. This systematic review and meta-analysis summarizes the uptake and utility of genetic counseling and genetic testing for patients with HCM and their at-risk family members, as well as the impact of genetic counseling/testing on patient-reported outcomes (PROs). A systematic search was performed through March 12, 2021. Meta-analyses were performed whenever possible; other findings were qualitatively summarized. Forty-eight studies met inclusion criteria (47 observational, 1 randomized). Uptake of genetic testing in probands was 57% (95% confidence interval [CI]: 40, 73). Uptake of cascade screening for at-risk relatives were as follows: 61% for cascade genetic testing (95% CI: 45, 75), 58% for cardiac screening (e.g. echocardiography) (95% CI: 40, 73), and 69% for either/both approaches (95% CI: 43, 87). In addition, relatives of probands with a positive genetic test result were significantly more likely to undergo cascade screening compared to relatives of probands with a negative result (odds ratio = 3.17, 95% CI: 2.12, 4.76). Overall, uptake of genetic counseling in both probands and relatives ranged from 37% to 84%. Multiple studies found little difference in PROs between individuals receiving positive versus negative genetic test results; however, other studies found that individuals with positive genetic test results experienced worse psychological outcomes. Genetic testing may also inform life choices, particularly decisions related to reproduction and insurance. Genetic counseling was associated with high satisfaction, increased perceived personal control and empowerment, and decreased anxiety. Approximately half to three-quarters of patients with HCM and their relatives undergo genetic testing or cascade screening. PROs after genetic testing varied and genetic counseling was associated with high satisfaction and improved PROs.

The characterization of hypodontia, hypohidrosis, and hypotrichosis associated with X-linked hypohidrotic ectodermal dysplasia: A systematic review.

The objective of this study was to review the published literature on X-linked hypohidrotic ectodermal dysplasia (XLHED) for the prevalence and characteristics of three features of XLHED: hypodontia, hypohidrosis, and hypotrichosis. A systematic search of English-language articles was conducted in May 2019 to identify publications with information on any of the three features of XLHED. We excluded studies with five or fewer participants, that did not specify X-linked inheritance or an EDA mutation, and discussed only management of features. The weighted means for total missing teeth, location of missing teeth, prevalence of reduced and absent sweating ability, and sparse or absent hair were analyzed across all studies. Additional findings for hypodontia, hypohidrosis, and hypotrichosis were summarized qualitatively. Twenty publications (18 studies) were accepted. Reported findings for males tended to be more informative than for carrier females. The weighted mean for missing teeth for affected males was 22.4 (range: 10-28) and carrier females was 3.4 (range: 0-22). The most common conserved teeth for males were the canines. The most common missing teeth for females were the maxillary lateral incisors. The weighted mean prevalence of reduced or absent sweating ability was 95.7% for males and 71.6% for females. The weighted mean prevalence for hypotrichosis was 88.1% for males and 61.6% for females. This systematic review provides insight into the prevalence, characteristics, and variability of the three classic features of XLHED. These findings provide detailed natural history information for families with XLHED as well as key characteristics that can aid in diagnosis.

Is there an association between elevated or low serum levels of phosphorus, parathyroid hormone, and calcium and mortality in patients with end stage renal disease? A meta-analysis.

BACKGROUND: Biochemical markers of altered mineral metabolism have been associated with increased mortality in end stage renal disease patients. Several studies have demonstrated non-linear (U-shaped or J-shaped) associations between these minerals and mortality, though many researchers have assumed linear relationships in their statistical modeling. This analysis synthesizes the non-linear relationships across studies. METHODS: We updated a prior systematic review through 2010. Studies included adults receiving dialysis and reported categorical data for calcium, phosphorus, and/or parathyroid hormone (PTH) together with all-cause mortality. We performed 2 separate meta-analyses to compare higher-than-referent levels vs referent and lower-than-referent levels vs referent levels. RESULTS: A literature review showed that when a linear relationship between the minerals and mortality was assumed, the estimated associations were more likely to be smaller or non-significant compared to non-linear models. In the meta-analyses, higher-than-referent levels of phosphorus (4 studies, RR = 1.20, 95% CI = 1.15-1.25), calcium (3 studies, RR = 1.10, 95% CI = 1.05-1.14), and PTH (5 studies, RR = 1.11, 95% CI = 1.07-1.16) were significantly associated with increased mortality. Although no significant associations between relatively low phosphorus or PTH and mortality were observed, a protective effect was observed for lower-than-referent calcium (RR = 0.86, 95% CI = 0.83-0.89). CONCLUSIONS: Higher-than-referent levels of PTH, calcium, and phosphorus in dialysis patients were associated with increased mortality risk in a selection of observational studies suitable for meta-analysis of non-linear relationships. Findings were less consistent for lower-than-referent values. Future analyses should incorporate the non-linear relationships between the minerals and mortality to obtain accurate effect estimates.

Comparison of adverse events and hospital length of stay associated with various amphotericin B formulations: sequential conventional amphotericin b/lipid versus lipid-only therapy for the treatment of invasive fungal infections in hospitalized patients.

PURPOSE: Patients with invasive fungal infections are often treated initially with conventional amphotericin B deoxycholate (CAB), followed by a switch to lipid-based formulations of amphotericin B (LF-AMB). Our study examined adverse events and hospital length of stay (LOS) among adults who received LF-AMB exclusively or CAB followed by LF-AMB (CAB/LF-AMB). METHODS: Data were extracted from the Cerner Health Facts database. The study included adults with evidence of infection by Aspergillus, Candida, or Cryptococcus in addition to either renal insufficiency, a clinical condition suggesting intolerance to CAB, or CAB exposure within 90 days of admission. Nephrotoxicity was defined as a serum creatinine (SCr) level exceeding a 100% increase from baseline and an absolute level above 1.2 mg/dL. We used a hierarchical mixed-effect logistic regression model with nephrotoxicity as the outcome for the multivariate analysis. RESULTS: The study included 327 LF-AMB and 81 CAB/LF-AMB patients with similar demographics and baseline SCr values. The mean pre-to-post percentage increase in SCr levels was greater for CAB/LF-AMB (122.9%) compared with LF-AMB (62.2%) (P < 0.001). The multivariate-adjusted odds ratio of nephrotoxicity was 5.93, for a 95% confidence interval of 2.92 to 12.05 (P < 0.001) for CAB/LF-AMB compared with LF-AMB. Hypokalemia, hypomagnesemia, and infusion-related reactions were more frequent with CAB/LF-AMB. Compared with the LF-AMB group, the CAB/LF-AMB patients had a longer post-amphotericin B LOS (24.1 days vs. 15.7 days, respectively; P < 0.001), with a marginal effect of 4.5 days longer for those receiving CAB/LF-AMB (P = 0.016). CONCLUSION: In this retrospective study, we noted a significantly longer post-amphotericin B LOS and a greater frequency of adverse events, including nephrotoxicity, for patients whose initial treatment was CAB and who were switched to LF-AMB, compared with patients who received LF-AMB only.

Prenatal diagnosis of Down syndrome: a systematic review of termination rates (1995-2011).

OBJECTIVE: The objective of this study was to review the published literature on pregnancy termination following a prenatal diagnosis of Down syndrome in the United States. METHOD: A systematic search of US English-language articles (1995-2011) was conducted to identify primary research studies that reported data for pregnancies with definitive prenatal diagnosis of Down syndrome with subsequent pregnancy termination. Studies that provided indirect estimates of pregnancy termination, such as mathematical models, were excluded. The weighted mean termination rate was calculated across studies. RESULTS: Twenty-four studies were accepted. The weighted mean termination rate was 67% (range: 61%-93%) among seven population-based studies, 85% (range: 60%-90%) among nine hospital-based studies, and 50% (range: 0%-100%) among eight anomaly-based studies. Evidence suggests that termination rates have decreased in recent years. Termination rates also varied with maternal age, gestational age, and maternal race/ethnicity. CONCLUSION: This systematic review presents the largest synthesis of United States data on termination rates following a prenatal diagnosis of Down syndrome. Evidence suggests that termination rates are lower than noted in a previous review that was based on less contemporary studies and had an international focus. Heterogeneity across studies suggests that a summary termination rate may not be applicable to the entire US population.

Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis.

OBJECTIVE: This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives. METHODS: A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool. RESULTS: A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003). CONCLUSIONS: This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study.

Clinical and subthreshold panic disorder.

BACKGROUND: Panic disorder (PD) is a highly prevalent and disabling condition, and subthreshold cases may be even more prevalent. This study examined psychiatric comorbidities, work functioning, and health-care utilization of individuals with subthreshold panic. The purpose of this study was to add to the accumulating evidence of significant comorbidity and disability associated with subthreshold PD. METHODS: Data are drawn from the Health Care for Communities study, a national household survey of the United States' adult, civilian, noninstitutionalized population (N=9585). Data assessing psychiatric disorders, employment and work productivity, and health-care utilization were collected. Seven categories of panic and subthreshold panic were created. RESULTS: The prevalence of clinical and subthreshold panic in the general population was 40%. Subthreshold panic was associated with increased odds of several comorbid disorders, including depression, dysthymia, psychosis, generalized anxiety disorder, bipolar disorder, and alcohol and drug use disorders. Subthreshold panic was also associated with greater likelihood of health-care service utilization but not with the intensity of mental health services. CONCLUSION: Psychiatric comorbidities and health-care utilization are common among patients with subthreshold panic. The relationship between varying degrees of panic symptomology and other mental health problems and indices of functioning impairment warrants further investigation. These results inform further research focusing on the course of subthreshold PD and its impact on quality of life.

Nephrotoxicity and other adverse events among inpatients receiving liposomal amphotericin B or amphotericin B lipid complex.

Nephrotoxicity evaluations between liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) have provided mixed results. This retrospective study used an electronic medical record database of hospitalized patients with invasive fungal infections treated with either L-AMB or ABLC. Patients had renal insufficiency, clinical condition suggesting intolerance to amphotericin B deoxycholate (CAB), or recent CAB exposure. Baseline SCr, exposure to other nephrotoxic agents, and total amphotericin B exposure were similar between the groups. In 105 patients administered L-AMB, 10.6% had nephrotoxicity versus 22.6% of 222 patients administered ABLC (P = 0.020). A logistic regression model found ABLC patients had 3.48 higher odds (95% CI 1.05-11.52) than L-AMB of developing nephrotoxicity. Infusion reactions were more prevalent with ABLC (23.9% versus 9.5%, P = 0.002) as was hypomagnesemia (44.3% versus 28.1%, P = 0.033). This study demonstrated that L-AMB is associated with less nephrotoxicity, infusion reactions and hypomagnesemia than ABLC in patients at increased risk of nephrotoxicity.

Systematic review of efficacy of dose-dense versus non-dose-dense chemotherapy in breast cancer, non-Hodgkin lymphoma, and non-small cell lung cancer.

Randomized controlled trials (RCTs) have suggested a potential advantage of dose-dense chemotherapy in improving disease-free and overall survival in patients with certain malignancies. This systematic review summarizes the literature on the efficacy of dose-dense chemotherapy across various cancers (breast cancer, non-Hodgkin lymphoma [NHL], and non-small cell lung cancer) and chemotherapy regimens. Among the 17 trials identified, few reported statistically significant differences between dose-dense and standard chemotherapy, and most were small with limited statistical power. Statistically significant differences in overall survival favoring dose-dense schedules were apparent among large RCTs in potentially curative settings such as early-stage breast cancer and NHL. Clinical and treatment heterogeneity demonstrated the flexibility of the dose-dense paradigm but also precluded quantitative meta-analysis of results. Further study of dose-dense schedules based on large RCTs is needed to demonstrate the consistency and generalizability of these findings.

Economic and clinical impact of inpatient diabetic hypoglycemia.

OBJECTIVE: To assess the clinical and economic impact of hypoglycemia that develops during hospitalization of patients with diabetes. METHODS: In this retrospective cohort study, data from 70 hospitals were used to identify the first inpatient encounter for adult patients with diabetes. Patients were included if all blood glucose measurements were 70 mg/dL or higher during the first 24 hours and their primary discharge diagnosis was for a condition other than hypoglycemia. Those who developed laboratory evidence of hypoglycemia (blood glucose <70 mg/dL after 24 hours) were compared with patients whose blood glucose values were all 70 mg/dL or higher. An alternative definition of hypoglycemia (blood glucose <50 mg/dL after 24 hours) was also evaluated. We adjusted for potential confounders with multivariate models. RESULTS: Hypoglycemia had an adverse effect on all outcomes among more than 100,000 diabetic patients. After adjustment, patients with diabetes who developed hypoglycemia had higher charges (38.9%), longer lengths of stay (3.0 days), higher mortality (odds ratio, 1.07; 95% confidence interval, 1.02-1.11), and higher odds of being discharged to a skilled nursing facility (odds ratio, 1.58; 95% confidence interval, 1.48-1.69) than diabetic patients without hypoglycemia (P<.01 for all). In all cases, using the lower threshold (<50 mg/dL) to define hypoglycemia resulted in similar findings with a larger magnitude of differences. CONCLUSIONS: Although a direct causal relationship cannot be inferred, these study findings suggest the importance of carefully maintaining euglycemia during hospitalizations. Whether the observed worse outcomes were due to hypoglycemia itself or whether they were a marker of worse outcomes due to other causes requires further research.

Review: use of electronic medical records for health outcomes research: a literature review.

This review assessed the use of electronic medical record (EMR) systems in outcomes research. We systematically searched PubMed to identify articles published from January 2000 to January 2007 involving EMR use for outpatient-based outcomes research in the United States. EMR-based outcomes research studies (n = 126) have increased sixfold since 2000. Although chronic conditions were most common, EMRs were also used to study less common diseases, highlighting the EMRs' flexibility to examine large cohorts as well as identify patients with rare diseases. Traditional multi-variate modeling techniques were the most commonly used technique to address confounding and potential selection bias. Data validation was a component in a quarter of studies, and many evaluated the EMR's ability to achieve similar results previously achieved using other data sources. Investigators using EMR data should aim for consistent terminology, focus on adequately describing their methods, and consider appropriate statistical methods to control for confounding and treatment-selection bias.