Citations

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

AbstractBackgroundBreast cancer patients experienced heightened anxiety during the pandemic. Also, modifications to clinical trial activities allowing for virtual platforms, local assessments, and greater flexibility were introduced to facilitate participation. We sought to evaluate the association between pandemic‐related anxiety and willingness to participate in trials and how pandemic‐era modifications to trial activities affect the decision to participate.MethodsWe conducted an online survey from August to September, 2021 of patients with breast cancer assessing pandemic‐related anxiety; clinical trials knowledge and attitudes; willingness to participate during and before the pandemic; and how each modification affects the decision to participate. Fisher's exact tests evaluated differences in proportions and two‐sample t‐tests evaluated differences in means. The association of pandemic‐related anxiety with a decline in willingness to participate during compared to prior to the pandemic was modeled using logistic regression.ResultsAmong 385 respondents who completed the survey, 81% reported moderate–severe pandemic‐related anxiety. Mean willingness to participate in a trial was lower during the pandemic than prior [2.97 (SD 1.17) vs. 3.10 (SD 1.09), (p < 0.001)]. Severe anxiety was associated with higher odds of diminished willingness to participate during the pandemic compared to prior (OR 5.07). Each of the modifications, with the exception of opting out of research‐only blood tests, were endorsed by >50% of respondents as strategies that would increase their likelihood of deciding to participate.ConclusionsWhile pandemic‐related anxiety was associated with diminished willingness to participate in trials, the leading reasons for reluctance to consider trial participation were unrelated to the pandemic but included worries about not getting the best treatment, side effects, and delaying care. Patients view trial modifications favorably, supporting continuation of these modifications, as endorsed by the National Cancer Institute and others.

Background: Multiple effective treatments exist for correction of skin photoaging. Topical L-ascorbic acid (vitamin C), a well-known antioxidant and topical human platelet extract (HPE), is a novel off-the-shelf cosmetic ingredient that has shown positive results in recent clinical studies. HPE is a leukocyte-depleted allogeneic product derived from United States–sourced, pooled, apheresed platelets produced with consistent batch quality, purity, and effect. The authors sought to characterize the effect of topical HPE (plated) intense serum (Rion Aesthetics) compared with vitamin C (C E Ferulic with 15% L-ascorbic acid; SkinCeuticals) in skin rejuvenation of dorsal hands after 12 to 26 weeks of twice-daily use. Methods: This prospective, longitudinal study sought to compare the effectiveness of 2 known treatments for skin rejuvenation. Evaluations at baseline and 6, 12, and 26 weeks included photographic documentation to assess common skin concerns related to aging. Results: For age-related skin appearance on the dorsal hands, topical HPE was noninferior to topical vitamin C for improvement in brown spot fractional area, wrinkle fractional area, and improvement in luminosity at 12 weeks after twice-daily topical use. Conclusions: HPE performed as well as vitamin C to rejuvenate the skin on the dorsal hands after 12 to 26 weeks of twice-daily topical use. Both topical serums may yield similar or superior results versus invasive procedures, such as intense pulsed light, in reducing brown spots on the dorsal hands. These topical products work equally well in both sexes. Skin improvements lasted through 6 months. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Since hemorrhage is a leading cause of preventable death in both civilian and military settings, the development of advanced decision support monitoring capabilities is necessary to promote improved clinical outcomes. The emergence of lower body negative pressure (LBNP) has provided a bioengineering technology for inducing progressive reductions in central blood volume shown to be accurate as a model for the study of the early compensatory stages of hemorrhage. In this context, the specific aim of this study was to provide for the first time a systematic technical evaluation to meet a commonly accepted engineering standard based on the FDA-recognized Standard for Assessing Credibility of Modeling through Verification and Validation (V&V) for Medical Devices (ASME standard V&V 40) specifically highlighting LBNP as a valuable resource for the safe study of hemorrhage physiology in humans. As an experimental tool, evidence is presented that LBNP is credible, repeatable, and validated as an analog for the study of human hemorrhage physiology compared to actual blood loss. The LBNP tool can promote the testing and development of advanced monitoring algorithms and evaluating wearable sensors with the goal of improving clinical outcomes during use in emergency medical settings.

Abstract Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus to understand ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglial-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.

Abstract Background Lambert-Eaton myasthenic syndrome (LEMS) is caused by IgG-mediated disruption of certain voltage-gated Ca2+-channel (VGCC) functions and diminished peripheral motor nerve-stimulated release of acetylcholine by presynaptic terminals at the neuromuscular junction and selected autonomic synapses. Both P/Q-type (Cav2.1) and N-type (Cav.2) channels are the targets of IgG-mediated autoimmunity in LEMS. Functional presynaptic VGCCs at the healthy mature mammalian neuromuscular junction are P/Q-type. About 60% of LEMS cases are paraneoplastic, of which a majority are associated with small-cell lung cancer (SCLC-LEMS). LEMS can also have a non-paraneoplastic etiology (idiopathic, non-tumor LEMS [NT-LEMS]). It is important to have reliable autoantibody biomarkers to aid the serological diagnosis of LEMS and to distinguish between SCLC-LEMS and NT-LEMS, because the treatment and prognosis differ. Previous studies have reported seropositivity for SOX1/AGNA-1-IgG in ∼ 64% of SCLC-LEMS cases, but in no NT-LEMS cases. When coexisting with P/Q-type VGCC IgG in LEMS patients, IgGs of both N-type VGCC and SOX1/AGNA-1 IgG specificities have been suggested as useful biomarkers for predicting SCLC. Here we compared the clinical utility of serological tests for P/Q-type and N-type VGCCs and SOX1/AGNA-1 IgGs as diagnostic aids for LEMS and for differentiating paraneoplastic from idiopathic LEMS. Methods This is a retrospective study of 102 patients with a clinical (electrophysiologically confirmed) diagnosis of LEMS who were tested for both P/Q-type and N-type VGCC IgGs by radioimmunoprecipitation assays performed at the Mayo Clinic Neuroimmunology Laboratory. 95 patients had comprehensive clinical screening for cancer; 66 had NT-LEMS, 21 had SCLC-LEMS and 8 had LEMS with non-SCLC cancers. Historical data were reviewed retrospectively. Of the NT-LEMS and SCLC-LEMS patients, 76 were tested for SOX1/AGNA-1 IgG. 122 healthy sex and age-matched controls were tested. Results Among the 102 LEMS patients, 92 (90%) were P/Q-VGCC IgG positive (P/Q+) and 26 (26%) were N-VGCC IgG positive (N+); 67 (66%) were P/Q+ only, 1 (0.9%) was N+ only, 25 (25%) were P/Q+N+, and 9 (9%) were seronegative for both. Three of the 122 healthy control subjects (2.5%) were N+ only, the rest were seronegative. The frequency of isolated N-type VGCC seropositivity did not differ significantly for LEMS patients and healthy controls (P = 0.69). All 21 SCLC-LEMS cases (100%) were P/Q-VGCC IgG positive, compared with 58 of the 66 NT-LEMS cases (88%). The rate of N-type VGCC IgG positivity in P/Q+ LEMS patients did not differ significantly for SCLC-LEMS (5 of 21) and NT-LEMS (13 of 58) diagnoses (24% vs 22%, P = 0.90). The frequency of SOX1/AGNA-1 IgG was 35% for the SCLC-LEMS cases (7 of 20), but none of the NT-LEMS cases (n = 56) was SOX1/AGNA-1 IgG positive. Conclusion N-type VGCC improved neither sensitivity for LEMS nor positive predictive value for cancer and has limited diagnostic utility in assessing patients with suspected LEMS. PQ-type VGCC IgG negativity does not exclude a diagnosis of LEMS. SOX1/AGNA-1 positivity has high specificity but low sensitivity for SCLC. Therefore, while antibody testing confirms a diagnosis of autoimmune LEMS, electrophysiology (to confirm neurological diagnosis) and body imaging (for cancer detection) remain important for the diagnostic evaluation.

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7–21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7–59.9, p < 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Objective In this case report, we discuss the rare manifestation of prolonged neuromuscular blockade in a patient with history of small cell lung cancer and undiagnosed Lambert-Eaton myasthenic syndrome (LEMS) who had previously received succinylcholine for general anesthesia without incident but subsequently exhibited prolonged neuromuscular blockade during a laparoscopic procedure. We aimed to emphasize the importance of reversal agent safety and precision as well as vigilant perioperative and postoperative care. Methods We used the patient's electronic medical record, direct patient care experiences, and comprehensive literature review for this case report. Results Sugammadex was administered with mild improvement. Suspecting undiagnosed LEMS, neostigmine was administered, yielding satisfactory muscle strength and successful extubation. In retrospect, the patient reported history of weakness when lifting weights that improved upon exertion. Conclusions Sugammadex is an efficient and effective agent for reversal of neuromuscular blockade. However, proper monitoring of the depth and recovery of blockade is imperative to when using sugammadex with optimal safety and precision in all patients. Perioperative care teams must remain vigilant with a high index of suspicion for neuromuscular junction pathology to properly plan perioperative care for patients at risk, especially those with small cell lung cancer who may have undiagnosed LEMS.

AbstractBackgroundFractional carbon dioxide (CO2) laser resurfacing is used successfully for facial rejuvenation. Post procedure skincare is a variable that influences downtime caused by pain/tenderness, erythema, crusting, and bruising.AimsThe primary objective of this pilot study was to demonstrate the benefits of human platelet extract (HPE) (plated)™ CALM Serum, a new topical cosmetic product, following fractionated CO2 ablative laser resurfacing treatment to the entire face versus standard of care.MethodsIn a single‐center, randomized, evaluator‐blinded pilot study, a total of 18 subjects were randomized into two groups, CO2 facial resurfacing followed by post‐procedural standard of care (Stratacel silicone gel) or CO2 facial resurfacing with the addition of HPE renewosomes in the CALM Serum.ResultsCALM Serum demonstrated statistically significant less crusting at Day 10 compared to the control group (p = 0.0193) with less downtime in the first 14 days (p = 0.03). Subjects treated with CALM Serum had statistically significant brighter appearing skin at 14 days (p = 0.007) and more youthful looking skin on Days 14 and 30 (p = 0.003 and 0.04, respectively).ConclusionsThis study demonstrates that Renewosome™ technology provides statistically significant post‐laser clinical recovery over silicone gel for reducing crusting, and downtime. Subjects reported less diary days of symptoms of pain/tenderness, redness, crusting/flaking, bruising, and itching in the first 14 days compared to the control group. CALM also demonstrated statistically significant improvements in brighter and more youthful appearing skin. CALM is safe and well tolerated.