51886 research outputs found
Sort by
When "loss-of-function" means proteostasis burden: Thinking again about coding DNA variants
No full textEach human genome has approximately 5 million DNA variants. Even for complete loss-of-function variants causing inherited, monogenic diseases, current understanding based on gene-specific molecular function does not adequately predict variability observed between people with identical mutations or fluctuating disease trajectories. We present a parallel paradigm for loss-of-function variants based on broader consequences to the cell when aberrant polypeptide chains of amino acids are translated from mutant RNA to generate mutated proteins. Missense variants that modify primary amino acid sequence, and nonsense/frameshift variants that generate premature termination codons (PTCs), are placed in context alongside emergent themes of chaperone binding, protein quality control capacity, and cellular adaptation to stress. Relatively stable proteostasis burdens are contrasted with rapid changes after induction of gene expression, or stress responses that suppress nonsense mediated decay (NMD) leading to higher PTC transcript levels where mutant proteins can augment cellular stress. For known disease-causal mutations, an adjunctive variant categorization system enhances clinical predictive power and precision therapeutic opportunities. Additionally, with typically more than 100 nonsense and frameshift variants, and ∼10,000 missense variants per human DNA, the paradigm focuses attention on all protein-coding DNA variants, and their potential contributions to multimorbid states beyond classically designated inherited diseases. Experimental testing in clinically relevant systems is encouraged to augment current atlases of protein expression at single-cell resolution, and high-throughput experimental data and deep-learning models that predict which amino acid substitutions generate enhanced degradative burdens. Incorporating additional dimensions such as pan-proteome competition for chaperones, and age-related loss of proteostasis capacity, should further accelerate health impacts
Variant Target Effects on Motor Learning With M1 Anodal tDCS
No full textPurpose: Learning a motor skill usually involves practicing the same task repetitively with the same end target or goal. Many overhand throwing studies have documented accelerated learning when the task is practiced with the addition of anodal transcranial direct current stimulation (a-tDCS) to the primary motor cortex (M1). However, these studies use the same target to throw at each time. The purpose of this study was to replicate previous work where a-tDCS applied to M1 improved performance of a dart-throwing task quicker than with SHAM stimulation, but to have subjects throw to different targets on the dartboard with each throw.
Method: Sixty-four healthy subjects practiced a dart-throwing task with their non-dominant arm. On the first visit, the subjects performed a pre- and post-test, as well as a 20-min practice in between, where they were randomized to receive 2 mA a-tDCS over the contralateral M1 to the throwing hand (n = 33) or very brief stimulation (SHAM, n = 31). The subjects repeated testing 1 and 24 h later to test for retention.
Finding: Both groups reduced their endpoint error and the variability in endpoint error (throwing consistency) over time. There were no significant differences between a-tDCS and SHAM conditions in either of these measures.
Conclusion: Unlike many previous studies, stimulation of M1 with a-tDCS did not accelerate learning of a dart-throwing task when the targets were constantly changed. It is hypothesized that this could have been due to the stimulation intensity being too high and possibly having a counter-regulatory effect on cortical activity, or it could have been due to some other learning mechanism that requires more time and practice to develop when the endpoint or target of the task changes. Alternatively, this task may have benefited from stimulation of the cerebellum, where it is known that motor adaptation can efficiently update and improve movements
Implementing early detection of cognitive impairment in primary care to improve care for older adults
No full textPrimary care is the ideal setting for early detection of mild cognitive impairment (MCI) and Alzheimer's disease and related dementias (ADRD), as it serves as the primary point of care for most older adults. With the growing aging population, reliance on specialists for detection and diagnosis is unsustainable, highlighting the need for primary care-led assessment. Recent research findings on successful brain health prevention strategies, AD diagnostic tools, and anti-amyloid treatments empower primary care to play a central role in early detection and intervention. Primary care-focused resources are being developed, including tools for cognitive assessments and materials designed to educate patients about brain health and initiate discussions on lifestyle modifications, thereby making early detection more feasible and efficient. Identifying risk factors early enables providers to implement interventions that can slow cognitive decline and improve outcomes for patients and caregivers. If left undetected and unmanaged, MCI and ADRD can lead to worse outcomes, including increased falls, hospitalizations, financial vulnerability, and caregiver stress. Early detection enables the identification of reversible causes of cognitive impairment, supports the management of comorbidities worsened by cognitive decline, mitigates safety risks, and can preserve quality of life. Importantly, primary care is essential for addressing ADRD-related health disparities that disproportionately affect racial minorities, rural populations, and those of lower socioeconomic status. With a focus on the United States healthcare system, this perspective addresses how implementing early detection practices into primary care can improve outcomes for patients and caregivers, reduce societal burdens, and promote health equity in ADRD care
Estrogens and breast cancer
No full textEstrogens have been associated with an increase in breast cancer risk. Yet emerging clinical and experimental evidence points to progestogens [endogenous progesterone or synthetic progesterone (progestin)] as the primary hormonal driver underlying seemingly estrogen-associated breast cancer risk. Estrogens may contribute to breast cancer risk indirectly by induction of the progesterone receptor and thus amplifying progesterone signaling. Large studies of hormonal contraceptives suggest that the small increase in breast cancer risk from hormonal contraceptives is mainly attributable to progestins, not estrogens. Estrogen-plus-progestin hormone replacement therapy (HRT) has consistently shown an increase in breast cancer risk among postmenopausal women, whereas estrogen-alone HRT has little impact on breast cancer risk in naturally or surgically menopausal women. In particular, the long-term follow-up of the Women's Health Initiative (WHI) randomized trials suggests a benefit of estrogen alone. Recent data further indicate that endogenously elevated estrogen during assisted reproductive technology (ART) exhibits little adverse effect on or potentially a reduction in breast cancer risk and recurrence. Also, accumulating evidence suggests that inhibition of progesterone signaling is a critical mechanism underlying the risk-reducing and therapeutic effects of antiestrogens. Estrogen HRT has shown an array of proven benefits, including ameliorating menopausal symptoms and improving bone health. Collective evidence thus suggests that estrogen HRT is likely to offer health benefits to perimenopausal or postmenopausal women, including breast cancer survivors, as well as young BRCA1/2 carriers with prophylactic oophorectomy for ovarian cancer prevention
Importance of Appropriate Coagulation Evaluation in a Peripartum Patient with a Complex Medical History
No full textBackground
Peripartum patients have physiologic changes affecting coagulation. Patients with complex disease states may have additional coagulopathy risks and have a higher risk of bleeding complications. It is important during the prenatal work-up to evaluate coagulation appropriately to prevent the risk of bleeding events such as postpartum hemorrhage.
Case Description
We present a 34-year-old G4P0121 patient at 37 weeks gestation, with a history of immune thrombocytopenia (ITP), hepatitis C, and repaired Tetralogy of Fallot. Her pregnancy was complicated by coagulopathy, necessitating medical optimization prior to delivery. On admission, the patient demonstrated thrombocytopenia, hypofibrinogenemia, increased von Willebrand activity with unremarkable multimer studies, and abnormal TEG results, prompting the initiation of Intravenous immunoglobulin (IVIG), prednisone, vitamin K, cryoprecipitate, and platelet transfusions in preparation of delivery. Despite medical management she suffered post-partum hemorrhage which was managed with uterotonic and antifibrinolytic agents. The remainder of the postpartum course was uncomplicated.
Clinical Significance
The patient’s complex medical background portends multiple effectors of her coagulation status. Pregnant patients have dilutional anemia, and increased prothrombotic factors, Factors V, VII, VIII, IX, XII, and fibrinogen, and positive D-dimer results. Patients with liver disease are affected by decreased and dysregulated coagulation factors and prothrombotic factors. Congenital heart disease can lead to high velocity gradients across abnormal heart valves leading to increased sheering stress. This leads to nonfunctional von Willibrand Factor (vWF) multimers that can’t function as effectively causing impaired platelet aggregation and adhesion.
Conclusions
A multifactorial approach with early, comprehensive coagulation workup and attention to less common differentials in high-risk PPH patients can provide targeted coagulation management before labor, thus significantly reducing the risk of bleeding complications
Non‐Carious Cervical Lesions in Wild Primates: Implications for Understanding Toothpick Grooves and Abfraction Lesions
No full textObjectives: In clinical settings, non-carious cervical lesions (NCCLs) are often linked to abrasion, erosion, abfraction, or a combination of these factors. In archaeological and paleontological remains, the most common NCCL is the "toothpick groove," yet little is known about the occurrence of these and other NCCLs in wild non-human primates.
Materials and methods: Here, we examine 531 individuals from 27 wild extant and extinct anthropoid primate taxa for NCCLs. Macroscopic examinations were followed by microwear and tissue-loss analyses using multiple imaging techniques, including stereoscopic microscopy, confocal laser, handheld digital microscopy, and 3D tissue loss analysis.
Results: NCCLs were identified in 21 individuals, indicating a prevalence of 4% within the sample. The distribution of NCCLs was uneven, with multiple cases concentrated in certain taxa and populations, but they are identified in all major groupings (e.g., Platyrrhini, Cercopithecidae, Hominoidea). Two distinct lesion types were identified: (1) localized U-shaped lesions with internal parallel striations, indicative of regular contact with abrasive materials (i.e., attrition or abrasion); and (2) smooth, shallow lesions characterized by tissue loss along the recessed gum line, indicative of a multifactorial process that may involve acid erosion.
Discussion: Several attrition/abrasion NCCLs resembled or have characteristic features of "toothpick grooves" known from hominin samples, suggesting the need for further comparative analyses between human and non-human primates. The absence of abfraction lesions supports the view that abfraction may be related to contemporary human behaviors. These findings emphasize the value of non-human primate data for interpreting NCCLs in both contemporary and ancient human populations
Validation of the Dermatologic Complexity Score for Dermatologic Triage
No full textBackground/Objectives: Demand for dermatologic services exceeds specialist capacity, with average wait times of 26-50 days in the United States. Current triage methods rely on subjective judgment or disease-specific indices that do not generalize across diagnoses or translate to operational decisions. We developed and validated the Dermatologic Complexity Score (DCS), a standardized instrument to guide case prioritization across dermatology care settings and evaluate DCS as a workload-reduction filter, enabling safe delegation of approximately half of routine teledermatology cases (DCS ≤ 40) away from specialist review. Methods: We conducted a prospective validation study of the DCS using 100 consecutive teledermatology cases spanning 30 common conditions. The DCS decomposes complexity into five domains (Diagnostic, Treatment, Risk, Patient Complexity, Monitoring) summed to a 0-100 total with prespecified bands: ≤40 (low) (41-70), (moderate) (71-89), (high), ≥90 (extreme). Five board-certified dermatologists and an automated module independently scored all cases. Two primary care physicians completed all ≤40 cases to assess feasibility. Primary outcomes were interrater reliability using ICC (2,1) and agreement with automation. Secondary outcomes included time-to-decision, referral rates, and primary care feasibility. Results: Mean patient age was 46.2 years; 47% of cases scored ≤40, 33% scored 41-70, 18% scored 71-89, and 2% scored ≥90. Interrater reliability was excellent (ICC (1,2)) = 0.979; 95% CI 0.974-0.983), with near-perfect agreement between automated and mean dermatologist scores (r = 0.998). Time-to-decision increased monotonically across DCS bands from 2.11 min (≤40) to 5 (90) min (≥90) (p = 1.36 × 10-14). Referral rates were 0% for ≤40, 3% for 41-70, 27.8% for 71-89, and 100% for ≥90 cases. DCS strongly predicted referral decisions (AUC = 0.919). Primary care physicians successfully managed all ≤40 cases but required 6-8 additional minutes per case compared to dermatologists. Conclusions: The DCS demonstrates excellent reliability and strong construct validity, mapping systematically to clinically relevant outcomes, including decision time and referral patterns. The instrument enables standardized, reproducible triage decisions that can optimize resource allocation across teledermatology, clinic, procedural, and inpatient settings. Implementation could improve access to dermatologic care by supporting appropriate delegation of low-complexity cases to primary care while ensuring timely specialist evaluation for high-complexity conditions
A descriptive analysis of substance use screening among youth involved in the legal system in eight counties
No full textBackground: Substance use disorders (SUDs) are more prevalent among youth involved in the legal system (YILS) compared to non-system-involved peers. Legal system involvement can serve as a gateway to health services, presenting an opportunity to identify YILS in need of SUD intervention. Here, aims included: (1) describe YILS patterns of substance use based on drug testing (e.g., urine) versus a self-report risk screener, (2) characterize how screening practices and results differ based on YILS demographic characteristics, and (3) compare how positive screening informs referrals to behavioral health treatment by screening type.
Methods: Administrative records were collected for all youth, ages 11–17, arrested in one of eight Indiana counties during 2019–2023 (N = 1,197 youth). Variables included youth demographics, most severe alleged charge at arrest, drug test results, self-report substance use screen results, and youth referrals to behavioral health services by probation officers. Prevalence of screening receipt by type, positive screens, and substance detected in drug tests are reported. Chi-square tests were conducted between demographic variables and drug test and self-report screener receipt, and positive screen per screening type. Logistic regression models were used to determine the association between positive screen and referral to services; models were compared using the c-statistic.
Results: Of sampled youth, 26.7% received a drug test, and 58.0% a self-report screener; of those, 54.4% and 42.0% screened positive, respectively. Cannabinoids (84.5%) and alcohol (28.2%) were detected most often. Youth whose most severe alleged charge was drug-related were more likely to receive a drug test, to receive a self-report screener, and screen positive. Positive drug test (OR = 8.48 95% CI = 6.06–11.87) and self-report screen (OR = 11.55, 95% CI = 8.33–16.01) were associated with behavioral health referral; the c-statistic was slightly higher for self-report screener (0.77) than for drug test (0.74).
Conclusions: Probation officers may be utilizing self-report screener results to make referral recommendations differently than drug test results. For less resourced counties that do not administer drug tests, self-report screeners may be particularly helpful in triaging youth to other services that routinely monitor substance use. Future research is needed to identify the optimal frequency of substance use screening to inform service referrals
Financial Barriers Are Associated With Self‐Managed Abortion in Indiana: Results From a Mixed‐Methods Study in 2021–2022
No full textObjectives: To measure knowledge of and experiences with self-managed abortion among abortion seekers in Indiana before the Supreme Court decision in Dobbs v. Jackson Women's Health Organization (Dobbs).
Study design: Between June 2021 and April 2022, we recruited a non-probability sample of Indiana residents of any age who were currently or recently pregnant and considering abortion via online advertisements, referrals from abortion funds, and flyers in abortion clinics. Participants completed two online surveys 1 month apart, and a subset completed in-depth interviews. We conducted descriptive and regression analyses of characteristics, methods, motivations, and knowledge of self-managed abortion.
Results: Among 434 total participants, 33 (7.6%, 95% CI: 5.5%-10.5%) reported a self-managed abortion attempt for their current/recent pregnancy; these participants were younger, less likely to be parents, more likely to be pregnant for the first time, and more likely to identify as a sexual and/or gender minority person than were participants who did not attempt to self-manage. Participants cited unaffordability of clinician-supported abortion care (n = 16/33, 49%) as the most common reason for attempting to self-manage. Those who reported challenges paying for abortion were three times more likely to attempt a self-managed abortion than those who did not (aRR: 3.0, 95% CI: 1.1, 8.2). Interviews (n = 40) highlighted low awareness of self-managed medication abortion.
Conclusions: Among people who faced financial barriers to clinician-supported abortion care in Indiana, financial distress motivated some residents to self-manage abortions. In the further restricted post-Dobbs period, financial support to obtain clinician-supported care and trusted, accessible information on safe and effective self-managed abortion options are imperative so that Indiana residents can access abortion care in accordance with their preferences