A Systematic Review on the Efficacy and Safety of Alginate-based Liquid Formulations in Reducing Gastroesophageal Reflux in Neonates and Infants.

Background: Neonates and infants experience gastroesophageal reflux as manifested through vomiting, reflux, and coughing. The complaint from many caregivers begins around the 2nd or 3rd month of life and subside around the 6th month of infancy. The standard of care has not been established and treatment options are limited owing to the pharmacological interventions that are deemed safe and effective. Alginate-based formulations, a widely used product in adults such as Gaviscon™, have been explored as another option to treat gastroesophageal reflux. Objectives: To determine the safety and efficacy of alginate-based formulations in reducing symptoms of gastroesophageal reflux in neonates and infants. Methods: An electronic search was conducted for randomized control trials in MEDLINE via PubMed, Herdin Plus, Cochrane Central Register of Controlled Trials, SCOPUS, and Clinical Trials Registry. The search terms were "gastroesophageal reflux," "acid reflux," "neonates," "newborn," "infants," "baby," "babies,", and "alginate." Two review authors independently assessed the available full text articles and a third author intervened to settle the discussion. Results: Two studies were identified and included in this study. Due to the difference in the period of measurement of the trials, a meta-analysis was not pursued. However, a systematic review was still conducted. The two studies suggest a significant improvement of symptoms with alginate-based liquid formulations as intervention. No significant adverse events have been noted making this treatment option generally safe for use in infants. Conclusion: There is insufficient evidence to conclude that alginate-based formulations ultimately help decrease gastroesophageal reflux in neonates and infants, but initial trials show promising results. There is also insufficient data to conclude the safety profile of this treatment option given the small sample.

Dissecting the sequential evolution of a selfish mitochondrial genome in Caenorhabditis elegans.

Mitochondrial genomes exist in a nested hierarchy of populations where mitochondrial variants are subject to genetic drift and selection at each level of organization, sometimes engendering conflict between different levels of selection, and between the nuclear and mitochondrial genomes. Deletion mutants in the Caenorhabditis elegans mitochondrial genome can reach high intracellular frequencies despite strongly detrimental effects on fitness. During a mutation accumulation (MA) experiment in C. elegans, a 499 bp deletion in ctb-1 rose to 90% frequency within cells while significantly reducing fitness. During the experiment, the deletion-bearing mtDNA acquired three additional mutations in nd5, namely two single insertion frameshift mutations in a homopolymeric run, and a base substitution. Despite an additional fitness cost of these secondary mutations, all deletion-bearing molecules contained the nd5 mutations at the termination of the MA experiment. The presence of mutant mtDNA was associated with increased mtDNA copy-number. Variation in mtDNA copy-number was greater in the MA lines than in a wildtype nuclear background, including a severe reduction in copy-number at one generational timepoint. Evolutionary replay experiments using different generations of the MA experiment as starting points suggests that two of the secondary mutations contribute to the proliferation of the original ctb-1 deletion by unknown mechanisms.

PET/CT-Based Absorbed Dose Maps in 90Y Selective Internal Radiation Therapy Correlate with Spatial Changes in Liver Function Derived from Dynamic MRI.

Functional liver parenchyma can be damaged from treatment of liver malignancies with 90Y selective internal radiation therapy (SIRT). Evaluating functional parenchymal changes and developing an absorbed dose (AD)-toxicity model can assist the clinical management of patients receiving SIRT. We aimed to determine whether there is a correlation between 90Y PET AD voxel maps and spatial changes in the nontumoral liver (NTL) function derived from dynamic gadoxetic acid-enhanced MRI before and after SIRT. Methods: Dynamic gadoxetic acid-enhanced MRI scans were acquired before and after treatment for 11 patients undergoing 90Y SIRT. Gadoxetic acid uptake rate (k1) maps that directly quantify spatial liver parenchymal function were generated from MRI data. Voxel-based AD maps, derived from the 90Y PET/CT scans, were binned according to AD. Pre- and post-SIRT k1 maps were coregistered to the AD map. Absolute and percentage k1 loss in each bin was calculated as a measure of loss of liver function, and Spearman correlation coefficients between k1 loss and AD were evaluated for each patient. Average k1 loss over the patients was fit to a 3-parameter logistic function based on AD. Patients were further stratified into subgroups based on lesion type, baseline albumin-bilirubin scores and alanine transaminase levels, dose-volume effect, and number of SIRT treatments. Results: Significant positive correlations (ρ = 0.53-0.99, P < 0.001) between both absolute and percentage k1 loss and AD were observed in most patients (8/11). The average k1 loss over 9 patients also exhibited a significant strong correlation with AD (ρ ≥ 0.92, P < 0.001). The average percentage k1 loss of patients across AD bins was 28%, with a logistic function model demonstrating about a 25% k1 loss at about 100 Gy. Analysis between patient subgroups demonstrated that k1 loss was greater among patients with hepatocellular carcinoma, higher alanine transaminase levels, larger fractional volumes of NTL receiving an AD of 70 Gy or more, and sequential SIRT treatments. Conclusion: Novel application of multimodality imaging demonstrated a correlation between 90Y SIRT AD and spatial functional liver parenchymal degradation, indicating that a higher AD is associated with a larger loss of local hepatocyte function. With the developed response models, PET-derived AD maps can potentially be used prospectively to identify localized damage in liver and to enhance treatment strategies.

Coumarin-Derived Caging Groups in the Spotlight: Tailoring Physiochemical and Photophysical Properties.

The development of light-responsive molecular tools enables spatiotemporal control of biochemical processes with superior precision. Amongst these molecular tools, photolabile caging groups are employed to prevent critical binding interactions between a bioactive molecule and its corresponding target. Only upon irradiation with light, the bioactive is released in its 'active' form and is now readily available to bind to its target. Coumarin-derived caging groups constitute one of the most popular classes of photolabile protecting groups, due to their facile synthetic accessibility, ease of tuning photophysical properties via structural modification and rapid photolysis reactions. Herein, we highlight the recent progress made on the development of coumarin-derived caging groups, in which the red-shifting of absorption spectra, improving aqueous solubility and tailoring sub-cellular localisation has been of particular interest.

X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction.

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

Cluster Formation of Self-Assembled Triarylbismuthanes and Charge Transport Characterizations of Gold-Triarylbismuthane-Gold Junctions.

Organometallic molecules are promising for molecular electronic devices due to their potential to improve electrical conductance through access to complex orbital covalency that is not available to light-element organic molecules. However, studies of the formation of organometallic monolayers and their charge transport properties are scarce. Here, we report the cluster formation and charge transport properties of gold-triarylbismuthane-gold molecular junctions. We found that triarylbismuthane molecules with -CN anchoring groups form clusters during the creation of self-assembled submonolayers. This clustering is attributed to strong interactions between the bismuth (Bi) center and the nitrogen atom in the -CN group of adjacent molecules. Examination of the influence of -NH2 and -CN anchoring groups on junction conductance revealed that, despite a stronger binding energy between the -NH2 group and gold, the conductance per molecular unit (i.e., molecule for the -NH2 group and cluster for the -CN group) is higher with the -CN anchoring group. Further analysis showed that an increase in the number of -CN groups from one to three within the junctions leads to a decrease in conductance while increasing the size of the cluster. This demonstrates the significant effects of different anchoring groups and the impact of varying the number of -CN groups on both the charge transport and cluster formation. This study highlights the importance of selecting the appropriate anchoring group in the design of molecular junctions. Additionally, controlling the size and formation of clusters can be a strategic approach to engineering charge transport in molecular junctions.

Thresholds For Diminishing Returns In Postoperative Range Of Motion After Total Shoulder Arthroplasty.

BACKGROUND: Satisfaction following shoulder arthroplasty (TSA), which is commonly reported using patient-reported outcome measures (PROMs), is partially dependent upon restoring shoulder range of motion (ROM). We hypothesized there exists a minimum amount of ROM necessary to perform functional tasks queried in PROM questionnaires, beyond which further ROM may provide no further improvement in PROMs. METHODS: A retrospective review of a multicenter international shoulder arthroplasty database was performed between 2004-2020 for patients undergoing anatomic or reverse TSA (aTSA, rTSA) with minimum 2-year follow-up. Our primary outcome was to determine the threshold in postoperative active ROM (abduction, forward elevation [FE], external rotation [ER], and internal rotation [IR] score) whereby additional improvement was not associated with additional improvement in PROMs (Simple Shoulder Test [SST], American Shoulder and Elbow Surgeons [ASES] score, and the Shoulder Pain and Disability Index [SPADI]). For comparison, we also evaluated the Shoulder Arthroplasty Smart (SAS) score, which is not subject to the ceiling effect. RESULTS: We included 4,459 TSAs (1,802 aTSAs, 2,657 rTSAs) with minimum 2-year follow-up (mean, 56±32 months). The threshold in postoperative ROM that were associated with no further improvement were: active abduction, 107-113° for PROMs versus 163° for the SAS score; active FE, 149-162° for PROMs versus 176° for the SAS score; active ER, 50-52° for PROMs versus 72° for the SAS score; IR score, 4-5 points for all PROMs versus 6 points for the SAS score. Out of 3,508 TSAs with complete postoperative ROM data, 8.5% achieved or exceeded all ROM thresholds (14.5% aTSAs, 4.8% rTSAs). CONCLUSIONS: Our findings demonstrate that postoperative ROM exceeding 113° of abduction, 162° of FE, 52° of ER, and IR to L1 is associated with minimal additional improvement in PROMs. While individual patient needs vary, the thresholds may provide helpful targets for patients undergoing postoperative rehabilitation.

The impact of hematology electronic consultations on the management of iron deficiency.

OBJECTIVES: Delays in the evaluation and treatment of iron deficiency can lead to increased disease-related morbidity and mortality. Electronic consultation (e-consult) is a referral modality that allows providers quicker access to recommendations from a specialist based on electronic chart review. While the use of e-consult is expanding in classical hematology, gaps exist in the understanding of patient outcomes related to its use for iron deficiency. METHODS: We randomly selected 200 e-consults and 200 traditional referrals from 3,336 hematology referrals for iron deficiency at a single center. The primary outcomes of the retrospective analysis were: time to completion of the referral, and time to treatment with intravenous iron. Secondary outcomes included recurrence of iron deficiency, need for repeat e-consult, conversion to in-person evaluation, and assessment of whether the etiology of iron deficiency was addressed. RESULTS: E-consults significantly reduced the time from referral to intravenous iron repletion (e-consult, 33 days; traditional referral, 68 days; p < .05). Assessment of the underlying etiology occurred in 70.7% of the e-consult encounters compared to 92.5% of traditional referrals (p < .05). CONCLUSIONS: These findings highlight advantages of e-consults in improving care delivery in iron deficiency, and identifying gaps that can be improved through practice standardization to ensure equitable, high-value care.

Anatomic Versus Reverse Total Shoulder Arthroplasty for Primary Osteoarthritis With an Intact Rotator Cuff: A Midterm Comparison of Early Top Performers.

BACKGROUND: Several surgeons state that their best anatomic total shoulder arthroplasty (aTSA) outperforms their best reverse total shoulder arthroplasty (rTSA) when performed for rotator cuff-intact glenohumeral osteoarthritis. We identified the top-performing aTSAs and rTSAs at short-term follow-up and compared their clinical performance at midterm follow-up to validate this common claim. METHODS: A retrospective review of a multicenter shoulder arthroplasty database was conducted. All shoulders undergoing primary aTSA or rTSA for rotator cuff-intact glenohumeral osteoarthritis between 2007 and 2020 were reviewed. Shoulders with a follow-up clinical visit between 2 and 3 years and a clinical follow-up of minimum 5 years were included. Two separate cohorts were identified: patients with a top 20% (1) American Shoulder and Elbow Surgeons (ASES) score and (2) Shoulder Arthroplasty Smart (SAS) score at 2 to 3 years of follow-up. Clinical outcomes including range of motion, outcome scores, and rates of complications and revision surgeries were compared at minimum 5-year follow-up. RESULTS: The ASES score cohort comprised 185 aTSAs (mean age 67 years, 42% female) and 49 rTSAs (mean age 72 years, 45% female). The SAS score cohort comprised 145 aTSAs (mean age 67 years, 59% female) and 42 rTSAs (mean age 71 years, 57% female). Active external rotation (ER) was greater after aTSA at midterm follow-up in both ASES and SAS score cohorts; however, preoperative to postoperative improvement was equivalent. Postoperative ER and SAS scores were greater after aTSA in both cohorts (P < 0.05); however, no other significant differences in any preoperative or postoperative clinical outcomes were present (P > 0.05), and patients achieved the minimal clinically important difference and substantial clinical benefit at similar rates for all outcomes. No difference was found in the incidence of complications and revision surgeries between top-performing aTSAs and rTSAs. CONCLUSION: Among top-performing shoulder arthroplasties at early follow-up, aTSA does not appear to outperform rTSA, except superior ER at midterm follow-up. LEVEL OF EVIDENCE: Retrospective comparative cohort study, Level Ⅲ.

Neuropsychological and neuroanatomical underpinnings of the face pareidolia errors on the noise pareidolia test in patients with mild cognitive impairment and dementia due to Lewy bodies.

OBJECTIVE: Prior research on the Noise Pareidolia Test (NPT) has demonstrated its clinical utility in detecting patients with mild cognitive impairment and dementia due to Lewy Body Disease (LBD). However, few studies to date have investigated the neuropsychological factors underlying pareidolia errors on the NPT across the clinical spectrum of LBD. Furthermore, to our knowledge, no research has examined the relationship between cortical thickness using MRI data and NPT subscores. As such, this study sought to explore the neuropsychological and neuroanatomical factors influencing performance on the NPT utilizing the National Alzheimer's Coordinating Center Lewy Body Dementia Module. METHODS: Our sample included participants with normal cognition (NC; n = 56), LBD with mild cognitive impairment (LBD-MCI; n = 97), and LBD with dementia (LBD-Dementia; n = 94). Archival data from NACC were retrospectively analyzed for group differences in neuropsychological test scores and cognitive and psychiatric predictors of NPT scores. Clinicoradiological correlates between NPT subscores and a small subsample of the above LBD participants were also examined. RESULTS: Analyses revealed significant differences in NPT scores among groups. Regression analysis demonstrated that dementia severity, attention, and visuospatial processing contributed approximately 24% of NPT performance in LBD groups. Clinicoradiological analysis suggests a potential contribution of the right fusiform gyrus, but not the inferior occipital gyrus, to NPT pareidolia error scores. CONCLUSIONS: Our findings highlight the interplay of attention and visuoperceptual functions in complex pareidolia in LBD. Further investigation is needed to refine the utility of NPT scores in clinical settings, including identifying patients at risk for visual illusions and hallucinations.

Assessment of diagnostic delay, morbidity, and mortality outcomes in 302 calciphylaxis patients over a 17-year period: A retrospective cohort study.

BACKGROUND: Calciphylaxis patients historically have experienced diagnostic challenges and high morbidity, however limited data is available examining these characteristics over time. OBJECTIVE: The primary goals were to a) investigate factors associated with diagnostic delay of calciphylaxis and b) assess morbidity outcomes. The secondary goal was to provide updated mortality rates. METHODS: A retrospective review of 302 adult patients diagnosed with calciphylaxis between January 1, 2006 and December 31, 2022 was conducted. Univariate and multivariate statistical analyses were performed. RESULTS: Non-nephrogenic calciphylaxis (p=0.0004) and involvement of the fingers (p=0.0001) were significantly associated with an increased diagnostic delay, whereas involvement of the arms (p=0.01) and genitalia (p=0.022) resulted in fewer days to diagnosis. Almost all patients with genitalia, finger, or toe involvement had nephrogenic disease. The number of complications per patient decreased with time, especially for wound infections (p=0.028), increase in lesion number (p=0.012), and recurrent hospitalizations (p=0.020). Updated 1-year mortality rates were 36.70% and 30.77% for nephrogenic and non-nephrogenic calciphylaxis, respectively. LIMITATIONS: Limitations include the retrospective nature and data from a single institution. CONCLUSION: Diagnostic delay, particularly in non-nephrogenic calciphylaxis, and complications per patient decreased with time, highlighting the importance of continued awareness to expedite diagnosis. Mortality rates have continued to improve in recent years.

Relationship between Jo-1 B Cell Epitope Profile and Clinical Features of Anti-Synthetase Syndrome.

OBJECTIVE: Anti-histidyl-transfer RNA synthetase (Jo-1) antibodies are associated with myositis as well as different extramuscular organ complications comprising the anti-synthetase syndrome. This study aimed to clarify the relationship between anti-Jo-1 epitope recognition patterns and specific clinical features of this syndrome. METHODS: B cell epitope mapping was performed via enzyme-linked immunosorbent assay in 180 patients who were anti-Jo-1 antibody-positive using overlapping peptides/protein fragments spanning the amino-terminal 151 amino acids of Jo-1 as substrate antigens. Statistical associations with clinical features were assessed through rank-sum, correlation, and cluster analyses. RESULTS: The level of reactivity against subfragments spanning amino acids 1-151 of Jo-1 paralleled that of full-length Jo-1, confirming the immunodominance of this amino-terminal region. The corresponding frequencies of reactivity to peptides 1 (amino acids [aa] 1-21), 3 (aa 27-47), 4 (aa 40-60), 10 (aa 118-138), and 11 (aa 131-151) were 6.1%, 42.5%, 6.8%, 6.7%, and 20.3%. While anti-full-length Jo-1 antibodies were significantly associated with Raynaud phenomenon, anti-fragment A2 (aa 1-60) and A3 (aa 1-90) antibodies were associated with proximal muscle weakness, Raynaud phenomenon, arthritis, and sicca syndrome. Anti-fragment A4 (aa 1-120) and A5 (aa 1-151) antibodies were also associated with sicca syndrome. Peptide 1 (aa 1-21) antibodies were associated with Raynaud phenomenon and dysphagia. Whereas anti-peptide 3 (aa 27-47) antibodies were also linked to Raynaud phenomenon, anti-peptide 9 (aa 105-125) antibodies were associated with mechanic's hands. CONCLUSION: Autoantibodies targeting different amino-terminal subfragments and/or peptides of Jo-1 were associated with specific clinical features of the anti-synthetase syndrome, demonstrating the biomarker potential of B cell epitope profiling in this disorder.

Trends in reported outcomes and patient reported outcome measures (PROMs) in humeral shaft fracture literature: a systematic review.

PURPOSE: With a lack of standardization among outcome measures in fracture literature, cross-study comparisons remain limited. This systematic review aimed to identify trends in outcome measures reported by studies of the treatment of humeral shaft fractures. METHODS: A systematic review was performed of studies reporting clinical outcomes of humeral shaft fractures indexed in PubMed. Extracted data included demographics, fracture characteristics, treatment modalities, outcomes, patient reported outcome measures (PROMs), and journal characteristics. Cochran-Armitage tests and linear regressions were used to identify data trends. Pearson chi-square and Kruskal-Wallis tests were used for comparisons between studies. RESULTS: This review included 197 studies with outcomes of 15,445 humeral shaft fractures. 126 studies reported PROMs and 37 different PROMs were used. The Constant Score was most commonly reported (34% of studies), followed by ASES Score (21%), MEPS (21%), and DASH Score (20%). There was a significant increase in PROM usage over time (p = 0.016) and in articles using three or more PROMs (p = 0.005). The number of PROMs were significantly greater in prospective cohort studies and RCTs (p = 0.012) compared to retrospective cohort studies and case series (p = 0.044 for both). Post-treatment shoulder motion was reported in 43% of studies and 34% reported elbow motion. 86% of studies reported complications as an outcome parameter. Time to union and nonunion rate were published in 69% and 88% of studies, respectively. CONCLUSION: This study identified increasing PROM usage over time and disparities in the reporting of outcomes in humeral shaft fracture literature requiring further validation and standardization of available outcome measures.

Financial Incentives for Smoking Cessation Among Socioeconomically Disadvantaged Adults: A Randomized Clinical Trial.

Importance: Socioeconomically disadvantaged individuals (ie, those with low socioeconomic status [SES]) have difficulty quitting smoking and may benefit from incentive-based cessation interventions. Objectives: To evaluate the impact of incentivizing smoking abstinence on smoking cessation among adults with low SES. Design, Setting, and Participants: This study used a 2-group randomized clinical trial design. Data collection occurred between January 30, 2017, and February 7, 2022. Participants included adults with low SES who were willing to undergo smoking cessation treatment. Data were analyzed from April 18, 2023, to April 19, 2024. Interventions: Participants were randomized to usual care (UC) for smoking cessation (counseling plus pharmacotherapy) or UC plus abstinence-contingent financial incentives (UC plus FI). Main Outcomes and Measures: The primary outcome was biochemically verified 7-day point prevalence smoking abstinence (PPA) at 26 weeks after the quit date. Secondary outcomes included biochemically verified 7-day PPA at earlier follow-ups, 30-day PPA at 12 and 26 weeks, repeated 7-day PPA, and continuous abstinence. Multiple approaches were employed to handle missing outcomes at follow-up, including categorizing missing data as smoking (primary), complete case analysis, and multiple imputation. Results: The 320 participants had a mean (SD) age of 48.9 (11.6) and were predominantly female (202 [63.1%]); 82 (25.6%) were Black, 15 (4.7%) were Hispanic, and 200 (62.5%) were White; and 146 (45.6%) participated during the COVID-19 pandemic. Overall, 161 were randomized to UC and 159 were randomized to UC plus FI. After covariate adjustment with missing data treated as smoking, assignment to UC plus FI was associated with a greater likelihood of 7-day PPA at the 4-week (adjusted odds ratio [AOR], 3.11 [95% CI, 1.81-5.34]), 8-week (AOR, 2.93 [95% CI, 1.62-5.31]), and 12-week (AOR, 3.18 [95% CI, 1.70-5.95]) follow-ups, but not at the 26-week follow-up (22 [13.8%] vs 14 [8.7%] abstinent; AOR, 1.79 [95% CI, 0.85-3.80]). However, the association of group assignment with smoking cessation reached statistical significance at all follow-ups, including 26 weeks, with multiple imputation (37.37 [23.5%] in the UC plus FI group vs 19.48 [12.1%] in the UC group were abstinent; AOR, 2.29 [95% CI, 1.14-4.63]). Repeated-measures analyses indicated that participants in the UC plus FI group were significantly more likely to achieve PPA across assessments through 26 weeks with all missing data estimation methods. Other secondary cessation outcomes also showed comparable patterns across estimation methods. Participants earned a mean (SD) of $72 ($90) (of $250 possible) in abstinence-contingent incentives. Participation during the COVID-19 pandemic reduced the likelihood of cessation across assessments. Conclusions and Relevance: In this randomized clinical trial, incentivizing smoking cessation did not increase cessation at 26 weeks when missing data were treated as smoking; however, the UC plus FI group had greater odds of quitting at follow-ups through 12 weeks. Cessation rates were higher for the UC plus FI group at all follow-ups through 26 weeks when multiple imputation was used to estimate missing outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02737566.

Developing, characterizing and modeling CRISPR-based point-of-use pathogen diagnostics.

Recent years have seen intense interest in the development of point-of-care nucleic acid diagnostic technologies to address the scaling limitations of laboratory-based approaches. Chief among these are combinations of isothermal amplification approaches with CRISPR-based detection and readouts of target products. Here, we contribute to the growing body of rapid, programmable point-of-care pathogen tests by developing and optimizing a one-pot NASBA-Cas13a nucleic acid detection assay. This test uses the isothermal amplification technique NASBA to amplify target viral nucleic acids, followed by Cas13a-based detection of amplified sequences. We first demonstrate an in-house formulation of NASBA that enables optimization of individual NASBA components. We then present design rules for NASBA primer sets and LbuCas13a guide RNAs for fast and sensitive detection of SARS-CoV-2 viral RNA fragments, resulting in 20 - 200 aM sensitivity without any specialized equipment. Finally, we explore the combination of high-throughput assay condition screening with mechanistic ordinary differential equation modeling of the reaction scheme to gain a deeper understanding of the NASBA-Cas13a system. This work presents a framework for developing a mechanistic understanding of reaction performance and optimization that uses both experiments and modeling, which we anticipate will be useful in developing future nucleic acid detection technologies.

Team Approach: Neuromuscular Training for Primary and Secondary Prevention of Anterior Cruciate Ligament Injury.

Neuromuscular training is a method of performance optimization-typically combining plyometrics, balancing training, agility, and dynamic stabilization-predicated on improving the efficiency of fundamental movement patterns. Neuromuscular training has consistently been shown to reduce the risk of anterior cruciate ligament injury, particularly for athletes engaged in activities associated with noncontact knee injuries (i.e., women's soccer). Successful implementation of neuromuscular training programs requires input from coaches, physical therapists, athletic trainers, and physicians to generate efficacious programs with high rates of adherence.

Physiology of malate dehydrogenase and how dysregulation leads to disease.

Malate dehydrogenase (MDH) is pivotal in mammalian tissue metabolism, participating in various pathways beyond its classical roles and highlighting its adaptability to cellular demands. This enzyme is involved in maintaining redox balance, lipid synthesis, and glutamine metabolism and supports rapidly proliferating cells' energetic and biosynthetic needs. The involvement of MDH in glutamine metabolism underlines its significance in cell physiology. In contrast, its contribution to lipid metabolism highlights its role in essential biosynthetic processes necessary for cell maintenance and proliferation. The enzyme's regulatory mechanisms, such as post-translational modifications, underscore its complexity and importance in metabolic regulation, positioning MDH as a potential target in metabolic dysregulation. Furthermore, the association of MDH with various pathologies, including cancer and neurological disorders, suggests its involvement in disease progression. The overexpression of MDH isoforms MDH1 and MDH2 in cancers like breast, prostate, and pancreatic ductal adenocarcinoma, alongside structural modifications, implies their critical role in the metabolic adaptation of tumor cells. Additionally, mutations in MDH2 linked to pheochromocytomas, paragangliomas, and other metabolic diseases emphasize MDH's role in metabolic homeostasis. This review spotlights MDH's potential as a biomarker and therapeutic target, advocating for further research into its multifunctional roles and regulatory mechanisms in health and disease.

The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.