A Nationwide, Population-Based, Study In Italy

[Posted 22/May/2023]

AUDIENCE: Family Medicine

KEY FINDINGS: The findings suggest that primary care databases may be used to enhance the early identification of SMA. Additional efforts are needed to exploit the electronic health records of general practitioners to allow early recognition of SMA.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic disease with a broad spectrum of severity. Although an early diagnosis of SMA is crucial to allow proper management of patients, the diagnostic delay is still an issue. Therefore, this study aimed to investigate the clinical correlates of SMA among primary care patients.

DETAILS: The Health Search Database (HSD) was adopted. To estimate the prevalence and incidence rate of SMA, a cohort study was conducted on the population (aged >=6 years) being registered in HSD from 1 January 2000 up to 31 December 2019. To investigate the clinical correlates of SMA, a nested case-control study was performed. SMA cases have been classified according to a clinically based iterative process as "certain", "probable" or "possible". To test the association between clinical correlates and SMA cases a multivariate conditional logistic regression model was estimated. The SMA prevalence combining "certain", "probable" and "possible" cases was 5.1 per 100,000 in 2019 (i.e. 1.12 per 100,000 when limited to "certain" cases), while the yearly incidence rate ranged from 0.12 to 0.56 cases per 100,000. Comparing "certain" cases with matched controls, the presence of neurology visits (OR = 6.5; 95% CI: 1.6-25.6) and prescription of electromyography (OR = 4.6; 95% CI: 1.1-18.7) were associated with higher odds of SMA diagnosis.

Copyright © The Authors. Oxford University Press. All rights reserved.

Source: Maggi, L., Vita, G., Marconi, E., et al. (2023). Opportunities For An Early Recognition Of Spinal Muscular Atrophy In Primary Care: A Nationwide, Population-Based, Study In Italy. Family Practice. 2023; 40(2): 308-313. Published: April, 2023. DOI: 10.1093/fampra/cmac091.

[Posted 31/May/2023]

AUDIENCE: Hematology, Infectious Disease

DETAILS: The U.S. Food and Drug Administration finalized recommendations for assessing blood donor eligibility using a set of individual risk-based questions to reduce the risk of transfusion-transmitted HIV. These questions will be the same for every donor, regardless of sexual orientation, sex or gender. Blood establishments may now implement these recommendations by revising their donor history questionnaires and procedures.

This updated policy is based on the best available scientific evidence and is in line with policies in place in countries like the United Kingdom and Canada. It will potentially expand the number of people eligible to donate blood, while also maintaining the appropriate safeguards to protect the safety of the blood supply.

These final recommendations are consistent with the policy initially proposed in January. The FDA worked diligently to review and consider all comments submitted to the agency to finalize these recommendations as quickly as possible. "The FDA has worked diligently to evaluate our policies and ensure we had the scientific evidence to support individual risk assessment for donor eligibility while maintaining appropriate safeguards to protect recipients of blood products. The implementation of these recommendations will represent a significant milestone for the agency and the LGBTQI+ community," said Peter Marks, M.D., PhD., director of the FDA’s Center for Biologics Evaluation and Research. "The FDA is committed to working closely with the blood collection industry to help ensure timely implementation of the new recommendations and we will continue to monitor the safety of the blood supply once this individual risk-based approach is in place."

This policy eliminates time-based deferrals and screening questions specific to men who have sex with men (MSM) and women who have sex with MSM. Under the final guidance issued today, all prospective blood donors will answer a series of individual, risk-based questions to determine eligibility. All prospective donors who report having a new sexual partner, or more than one sexual partner in the past three months, and anal sex in the past three months, would be deferred to reduce the likelihood of donations by individuals with new or recent HIV infection who may be in the window period for detection of HIV by nucleic acid testing.

Additionally, under these final recommendations, those taking medications to treat or prevent HIV infection (e.g., antiretroviral therapy (ART), pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP)), will also be deferred. Though these antiretroviral drugs are safe, effective, and an important public health tool, the available data demonstrate that their use may delay detection of HIV by currently licensed screening tests for blood donations, which may potentially give false negative results. Although HIV is not transmitted sexually by individuals with undetectable viral levels, this does not apply to transfusion transmission of HIV because a blood transfusion is administered intravenously, and a transfusion involves a large volume of blood compared to exposure with sexual contact. As stated in the guidance, individuals should not stop taking their prescribed medications, including PrEP, or PEP, in order to donate blood. The FDA remains committed to evaluating additional data and new technological developments as they become available to inform our donor eligibility recommendations.

The FDA has been evaluating alternatives to time-based deferrals for MSM and helping to facilitate the generation of scientific evidence that would support an individual risk based- assessment blood donor questionnaire. This scientific information has given the agency a solid foundation to support this new policy. The FDA strongly believes the implementation of an individual risk-based approach will not adversely affect the safety or availability of the U.S. blood supply.

The FDA carefully reviewed numerous data sources, including data from countries with similar HIV epidemiology that have implemented an individual risk-based approach for assessing donor eligibility, surveillance information obtained from the Transfusion Transmissible Infections Monitoring System, performance characteristics of nucleic acid testing for HIV and the FDA-funded Assessing Donor Variability And New Concepts in Eligibility study. The ADVANCE study examined the rates of HIV risk factors, such as anal sex and rates of HIV infection, as well as the usage of medications to treat or prevent HIV infection, among MSM study participants.

Copyright © FDA. All rights reserved.

Source: FDA Finalizes Move to Recommend Individual Risk Assessment to Determine Eligibility for Blood Donations. FDA. Published: May 11, 2023.

[Posted 26/May/2023]

AUDIENCE: Dermatology, Oncology

KEY FINDINGS: Patients with second primary melanomas demonstrated a significant survival advantage and thinner lesions compared with those with single primary melanomas. The reported tumor distributions support the role of full body skin examinations, with attention to the region of initial diagnosis.

BACKGROUND: Patients with single primary melanomas have an increased risk of developing subsequent melanomas. Secondary tumors diagnosed within and after 3 months are termed "synchronous" and "asynchronous," respectively. Purpose of the study is to compare tumor distributions and survival characteristics between patients with second primary melanomas and those with single primary melanomas.

DETAILS: Retrospective cohort study. Data were collected from an institutional database from 14,029 patients with a diagnosis of a primary melanoma seen between 1970 and 2004. The synchronous and asynchronous cohorts demonstrated significantly improved survival probabilities compared with the single primary cohort (P = .04 and .002, respectively). Single primary lesions (2.2 ± 2.3 mm) were significantly thicker than the first-identified synchronous (2.0 ± 1.7 mm) and asynchronous (1.7 ± 1.3 mm) lesions. Synchronous lesions were more likely to be anatomically concordant compared with asynchronous lesions (55.7% vs 38.2%, P < .001).

Copyright © Elsevier Ltd. All rights reserved.

Source: Sarver, M. M., Rames, J. D., Beasley, G. M., et al. (2023). Survival and Tumor Characteristics Of Patients Presenting With Single Primary Versus Second Primary Melanoma Lesions. Journal of the American Academy of Dermatology. 2023; 88(5): 1033-1039. Published: May, 2023. DOI: 10.1016/j.jaad.2022.04.046.

[Posted 26/May/2023]

AUDIENCE: Psychiatry, Family Medicine

KEY FINDINGS: This study found that memantine treatment resulted in statistically significant reductions in hair pulling and skin-picking symptoms compared with placebo, with relatively high efficacy (based on number needed to treat), and was well tolerated. The glutamate system may prove to be a beneficial target in the treatment of compulsive behaviors.

BACKGROUND: Trichotillomania and skin-picking disorder are underrecognized and often disabling conditions in which individuals repeatedly pull at their hair or pick at their skin, leading to noticeable hair loss or tissue damage. To date there is a severe paucity of evidence-based treatments for these conditions. In this study, the authors sought to determine whether memantine, a glutamate modulator, is more effective than placebo in reducing hair-pulling and skin-picking behavior.

DETAILS: One hundred adults with trichotillomania or skin-picking disorder (86 women; mean age, 31.4 years [SD=10.2]) were enrolled in a double-blind trial of memantine (dosing range, 10-20 mg/day) or placebo for 8 weeks. Participants were assessed with measures of pulling and picking severity. Outcomes were examined using a linear mixed-effects model. The prespecified primary outcome measure was treatment-related change on the NIMH Trichotillomania Symptom Severity Scale, modified to include skin picking. Compared with placebo, memantine treatment was associated with significant improvements in scores on the NIMH scale, Sheehan Disability Scale, and Clinical Global Impressions severity scale in terms of treatment-by-time interactions. At study endpoint, 60.5% of participants in the memantine group were "much or very much improved," compared with 8.3% in the placebo group (number needed to treat=1.9). Adverse events did not differ significantly between the treatment arms.

Copyright © American Psychiatric Association. All rights reserved.

Source: Grant, J. E., Chesivoir, E., Valle, S., et al. (2023). Double-Blind Placebo-Controlled Study of Memantine in Trichotillomania and Skin-Picking Disorder. Am J Psychiatry. 2023; 180(5): 348-356. Published: May, 2023. DOI: 10.1176/appi.ajp.20220737.

[Posted 25/May/2023]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: The results show that combining scRNA-seq and WGS data can successfully detect putative somatic mutations. The putative somatic mutations detected from ROSMAP data set have provided new insights into the association of AD and aging with brain somatic mutagenesis.

BACKGROUND: With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the etiology of AD.

DETAILS: Authors designed a somatic mutation detection workflow by contrasting genotypes derived from whole-genome sequencing (WGS) data with genotypes derived from scRNA-seq data and applied this workflow to 76 participants from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP) cohort. We focused only on excitatory neurons, the dominant cell type in the scRNA-seq data. 196 sites were identified that harbored at least 1 individual with an excitatory neuron–specific somatic mutation (ENSM), and these 196 sites were mapped to 127 genes. The single base substitution (SBS) pattern of the putative ENSMs was best explained by signature SBS5 from the Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, a clock-like pattern correlating with the age of the individual. The count of ENSMs per individual also showed an increasing trend with age. Among the mutated sites, we found 2 sites tend to have more mutations in older individuals (16:6899517 [RBFOX1], p = 0.04; 4:21788463 [KCNIP4], p < lt; 0.05). In addition, 2 sites were found to have a higher odds ratio to detect a somatic mutation in AD samples (6:73374221 [KCNQ5], p = 0.01 and 13:36667102 [DCLK1], p = 0.02). Thirty-two genes that harbor somatic mutations unique to AD and the KCNQ5 and DCLK1 genes were used for gene ontology (GO)–term enrichment analysis. We found the AD-specific ENSMs enriched in the GO-term "vocalization behavior" and "intraspecies interaction between organisms." Of interest we observed both age-specific and AD-specific ENSMs enriched in the K+ channel–associated genes.

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Zhang, M., Bouland, G. A., Holstege, H., et al. (2023). Identifying Aging and Alzheimer Disease-Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex. Neuro Genetics. 2023; 9(3): e200066. Published: June, 2023. DOI: 10.1212/NXG.0000000000200066.

A Population-Based Cohort Study

[Posted 24/May/2023]

AUDIENCE: Endocrinology, Ob/Gyn

KEY FINDINGS: Gestational glucose intolerance, including conditions not meeting gestational diabetes criteria of the two-step strategy, confers a high risk of type 2 diabetes in young adulthood. These conditions should be recognised as risk factors for type 2 diabetes, especially among women with abnormal fasting glucose concentrations during pregnancy.

BACKGROUND: The risk of type 2 diabetes among women with glucose intolerance during pregnancy that does not meet gestational diabetes criteria requires further investigation. We aimed to explore the associations between various degrees of gestational glucose intolerance and the risk of type 2 diabetes in young adulthood.

DETAILS: For this population-based cohort study, the national Israeli conscription database was linked to Maccabi Healthcare Services (MHS), the second-largest state-mandated health provider in Israel. Researcghers included 177,241 women who underwent a pre-recruitment evaluation at adolescence (age 16-20 years), 1 year before mandatory military service, and later underwent, from Jan 1, 2001, to Dec 31, 2019, two-step gestational diabetes screening with a 50 g glucose challenge test (GCT) based on a threshold of 140 mg/dL (7.8 mmol/L), followed as needed by a 100 g oral glucose tolerance test (OGTT). Abnormal OGTT values were defined according to the Carpenter-Coustan thresholds: 95 mg/dL (5.3 mmol/L) or higher in the fasting state; 180 mg/dL (10.0 mmol/L) or higher at 1 h; 155 mg/dL (8.6 mmol/L) or higher at 2 h; and 140 mg/dL (7.8 mmol/L) or higher at 3 h. The primary outcome was incident type 2 diabetes in the MHS diabetes registry. Cox proportional hazards models were applied to estimate adjusted hazard ratios (HRs) with 95% CIs for incident type 2 diabetes. During a cumulative follow-up of 1,882,647 person-years, and with a median follow-up of 10.8 (IQR 5.2-16.4) years, 1262 women were diagnosed with type 2 diabetes. Crude incidence rates of type 2 diabetes were 2.6 (95% CI 2.4-2.9) per 10,000 person-years in women with gestational normoglycaemia, 8.9 (7.4-10.6) per 10,000 person-years in women with an abnormal GCT and normal OGTT, 26.1 (22.4-30.1) per 10,000 person-years in women with one abnormal OGTT value (in the fasting state or 1 h, 2 h, or 3 h post-challenge), and 71.9 (66.0-78.3) per 10,000 person-years in women with gestational diabetes. After adjustment for sociodemographic characteristics, adolescent BMI, and age at gestational screening, the risk of type 2 diabetes was higher, compared to the gestational normoglycaemia group, in women with an abnormal GCT and normal OGTT (adjusted hazard ratio [HR] 3.39 [95% CI 2.77-4.16]; p<0.0001), in women with one abnormal OGTT value (9.11 [7.64-10.86]; p<0.0001), and in women with gestational diabetes (24.84 [21.78-28.34]; p<0.0001). The risk of type 2 diabetes was modestly increased in women with isolated elevated fasting glucose (adjusted HR 11.81 [95% CI 8.58-16.25]; p<0.0001), and in women with gestational diabetes and an abnormal fasting glucose (38.02 [32.41-44.61]; p<0.0001).

Copyright © Elsevier Ltd. All rights reserved.

Source: Bardugo, A., Bendor, C. D., Rotem, R. S., et al. (2023). Glucose Intolerance In Pregnancy and Risk Of Early-Onset Type 2 Diabetes: A Population-Based Cohort Study. The Lancet. 2023; 11(5): 333-344. Published: May, 2023. DOI: 10.1016/S2213-8587(23)00062-1.