Application of Near-Infrared Spectroscopy for Screening of Chlorothiazide Sodium Vials.

Chlorothiazide sodium for injection, USP, is a diuretic and antihypertensive medication in the form of a white or practically white, sterile, lyophilized powder. Each vial contains 500 mg of chlorothiazide sodium, equivalent to 500 mg of chlorothiazide, and 250 mg of mannitol as an inactive ingredient. The pH is adjusted with sodium hydroxide. Chlorothiazide sodium has a molecular weight of 317.71 amu. Since 2020 there have been multiple national shortages of chlorothiazide. Recent studies target chlorothiazide's low bioavailability, aiming to enhance it through nanoparticle production via a supercritical method. The drug's solubility in supercritical carbon dioxide (scCO2) is vital, with measurements ranging from 0.417×10-5 to 1.012×10-5 mole fraction under specific conditions. Adding co-solvents, like ethanol, DMSO, and acetone, to scCO2 boosts solubility, with ethanol proving most effective, enhancing solubility by 2.02-11.75 times. Intra-lot variability was discovered in a sample of a lot of chlorothiazide sodium by the University of Kentucky Drug Quality Task Force. Two vials of six screened in one lot were displaced from the center of the lot by 4.0 and 4.2 SDs, respectively. Inter-lot variability was confirmed in the near-IR spectra of 204 vials obtained from 28 different lots of chlorothiazide sodium. Using full spectrum BEST analysis 13 vials (6.4%) were outliers.

Tendon Transfers in Reverse Total Shoulder Arthroplasty: A Systematic Review and Descriptive Synthesis of Biomechanical Studies.

BACKGROUND: The role of tendon transfer and ideal insertion sites to improve axial rotation in reverse total shoulder arthroplasty (RTSA) is debated. We systematically reviewed the available biomechanical evidence to elucidate the ideal tendon transfer and insertion site for restoration of external and internal rotation in the setting of RTSA and the influence of implant lateralization. PATIENTS AND METHODS: We queried the PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases to identify biomechanical studies examining the application of tendon transfer to augment shoulder external or internal rotation range of motion in the setting of concomitant RTSA. A descriptive synthesis of six included articles was conducted to elucidate trends in the literature. RESULTS: Biomechanics literature demonstrates that increasing humeral-sided lateralization optimized tendon transfers performed for both ER and IR. The optimal latissimus dorsi (LD) transfer site for ER is posterior to the greater tuberosity (adjacent to the teres minor insertion); however, LD transfer to this site results in greater tendon excursion compared to posterodistal insertion site. In a small series with nearly 7-year mean follow-up, the LD transfer demonstrated longevity with all 10 shoulders having >50% ER strength compared to the contralateral native shoulder and a negative Hornblower's at latest follow-up; however, reduced electromyography activity of the transferred LD compared to the native contralateral side was noted. One study found that transfer of the pectoralis major has the greatest potential to restore IR in the setting of lateralized humerus RTSA. CONCLUSION: To restore ER, LD transfer posterior on the greater tuberosity provides optimal biomechanics with functional longevity. The pectoralis major has the greatest potential to restore IR. Future clinical investigation applying the biomechanical principles summarized herein is needed to substantiate the role of tendon transfer in the modern era of lateralized RTSA. LEVEL OF EVIDENCE: IV; systematic review.

Seven-years of alcohol consumption in Australia by wastewater analysis: Exploring patterns by remoteness and socioeconomic factors.

BACKGROUND: Wastewater analysis provides a complementary measure of alcohol use in whole communities. We assessed absolute differences and temporal trends in alcohol consumption by degree of remoteness and socioeconomics indicators in Australia from 2016 to 2023. METHODS: Alcohol consumption estimates from 50 wastewater treatment plants (WWTP) in the Australian National Wastewater Drug Monitoring Program were used. Trends were analysed based on 1) site remoteness: Major Cities, Inner Regional and a combined remoteness category of Outer Regional and Remote, and 2) using two socioeconomic indexes from the Australian Bureau of Statistics (ABS) relating to advantage and disadvantage for Income, education, occupation, and housing. RESULTS: Consumption estimates were similar for Major Cities and Inner Regional areas (14.3 and 14.4L/day/1000 people), but significantly higher in Outer Regional and Remote sites (18.6L/day/1000 people). Consumption was decreasing in Major cities by 4.5% annually, Inner Regional by 2.4%, and 3.5% in the combined Outer Regional and Remote category. Consumption estimates were higher in socioeconomically advantaged quartiles than those of lower advantage (0%-25% mean = 13.0, 75%-100% mean = 17.4). Consumption in all quartiles decreased significantly over the 7 year period with annual rates of decrease of 0.9%, 3.7%, 3.6%, and 3.0% for the lowest to highest quartile, respectively. CONCLUSIONS: Declines in Australian alcohol consumption have been steeper in large urban areas than regional and remote areas. There were smaller annual decreases in the most socioeconomically disadvantaged areas. If continued, these trends may increase Australian health inequalities. Policy and prevention work should be appropriately targeted to produce more equitable long-term outcomes.

Influence of previous plane of nutrition on molecular mechanisms regulating the expression of urea and water metabolism related genes in the rumen and kidney of finishing crossbred Angus steers.

This study aimed to understand how molecular mechanisms controlling water and urea metabolism at the finishing phase can be affected by previous plane of nutrition of crossbred Angus beef steers. Twenty-four (n = 24) animals were randomly distributed into either a moderate (MP) or high plane of nutrition during the background phase for 85 d. Animals were then blocked by their previous plane and were moved onto a 105-d finishing phase in a 2 × 2 factorial arrangement. The forage-finished group received only high-quality alfalfa hay, whereas the grain-fed group received a high grain diet (80% whole corn and 20% alfalfa hay). By the end of the finishing phase, animals were harvested and tissue samples from the rumen and kidney were collected. Changes in gene expression of aquaporins (AQP)-2, -3, -4, -7, ATP1A1, ATP1B1, SGK1, CLIC1 (kidney and rumen), UT-A1 (kidney only) and UT-B (rumen only), were assayed via real-time qPCR; 18S rRNA was used as an endogenous control. One-way ANOVA followed by Tukey's post hoc analysis was conducted. When animals were from MP, forage-finishing increased the relative abundance of AQP3 (P ≤ 0.05), AQP7 (P ≤ 0.05), ATP1B1 (P ≤ 0.05), and SGK1 (P ≤ 0.05) in the kidney when compared to grain-fed animals. In the rumen, for the MP group, AQP7 was differentially expressed in both treatments at the finishing phase (P ≤ 0.01), with forage-finished steers having the highest expression of AQP7. For the MP group, UT-B had a tendency of presenting a higher expression on grain-fed animals (P = 0.075). Overall, these results suggest that previous plane can impact expression of genes associated with water and urea metabolism during the finishing phase, namely AQP3, AQP7, ATP1B1, and SGK1 in the kidney, and AQP7 and UT-B in the rumen. The greatest impact observed on gene expression changes of investigated genes at the finishing phase was reflective of animals backgrounded on the moderate previous plane.

Periods of low renal perfusion pressure are associated with acute kidney injury following paediatric cardiac surgery.

INTRODUCTION: Acute kidney injury is associated with worse outcomes after cardiac surgery. The haemodynamic goals to ameliorate kidney injury are not clear. Low post-operative renal perfusion pressure has been associated with acute kidney injury in adults. Inadequate oxygen delivery may also cause kidney injury. This study evaluates pressure and oximetric haemodynamics after paediatric cardiac surgery and their association with acute kidney injury. MATERIALS AND METHODS: Retrospective case-control study at a children's hospital. Patients were < 6 months of age who underwent a Society of Thoracic Surgery-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery categories ≥ 3. Low renal perfusion pressure was time and depth below several tested thresholds. The primary outcome was serum creatine-defined acute kidney injury in the first 7 days. RESULTS: Sixty-six patients (median age 8 days) were included. Acute kidney injury occurred in 36%. The time and depth of renal perfusion pressure < 42 mmHg in the first 24 hours was greater in acute kidney injury patients (94 versus 35 mmHg*minutes of low renal perfusion pressure/hour, p = 0.008). In the multivariable model, renal perfusion pressure < 42 mmHg was associated with acute kidney injury (aOR: 2.07, 95%CI: 1.25-3.82, p = 0.009). Mean arterial pressure, central venous pressure, and measures of inadequate oxygen delivery were not associated with acute kidney injury. CONCLUSION: Periods of low renal perfusion pressure (<42 mmHg) in the first 24 post-operative hours are associated with acute kidney injury. Renal perfusion pressure is a potential modifiable target that may mitigate the impact of acute kidney injury after paediatric cardiac surgery.

Chronic use of Antihypertensive Medications and Peak Exercise Blood Pressure in Adult Men and Women from the BALL ST Cohort.

PURPOSE: To determine if individuals chronically (>1 year) prescribed antihypertensive medications have a normal BP response to peak exercise compared to unmedicated individuals. METHODS: Participants included 2,555 adults from the Ball State Adult Fitness Longitudinal Lifestyle STudy cohort who performed a peak treadmill exercise test. Participants were divided into groups by sex and antihypertensive medication status. Individuals prescribed antihypertensive medications for >1 year were included. Exaggerated and blunted SBP within each group was categorized using the Fitness Registry and the Importance of Exercise: A National Database (FRIEND) and absolute criteria as noted by the Amercian Heart Association. RESULTS: The unmedicated group had a greater prevalence (p < 0.05) of blunted SBP responses, whereas the medicated group had a higher prevalence (p < 0.05) of exaggerated SBP responses using both the FRIEND and absolute criteria. Peak SBP was higher (p < 0.01) in medicated compared to unmedicated participants in the overall cohort when controlling for age and sex, but not after controlling for resting SBP (p = 0.613), risk factors (p = 0.104), or cardiorespiratory fitness (p = 0.191). When men and women were assessed independently, peak SBP remained higher in the medicated women after controlling for age and resting SBP (p = 0.039), but not for men (p = 0.311). Individuals on beta-blockers had a higher peak SBP even after controlling for age, sex, risk factors and cardiorespiratory fitness (p = 0.022). CONCLUSIONS: Individuals on antihypertensive medications have a higher peak SBP response to exercise. Given the prognostic value of exaggerated peak SBP, control of exercise BP should be considered in routine BP assessment and in the treatment of hypertension.

A Systematic Review of Patient Selection Criteria for Outpatient Total Shoulder Arthroplasty.

The utilization of total shoulder arthroplasty (TSA) is increasing, driving associated annual health care costs higher. Opting for outpatient over inpatient TSA may provide a solution by reducing costs. However, there is no single set of accepted patient selection criteria for outpatient TSA. Here, the authors identify and systematically review 14 articles to propose evidence-based criteria that merit postoperative admission. Together, the studies suggest that patients with limited ability to abmluate independently or a history of congestive heart failure may benefit from postoperative at least one night of hospital based monitoring and treatment.

Telehealth Visits have Lower Non-attendance than Traditional Orthopaedic Clinic Visits.

The use of telemedicine has rapidly expanded in the wake of the COVID pandemic, but its effect on patient attendance remains unknown for different clinicians. This study compared traditional in-clinic visits with telehealth visits by retrospectively reviewing all scheduled orthopaedic clinic visits. Results demonstrated lower rates of cancellations in patients scheduled for telehealth visits as compared to in-clinic visits, during the initial COVID pandemic. In general, physicians can expect a lower cancellation rate than non-physician practitioners.

A randomized trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations (PExs) in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 second (ppFEV1) in CF PExs not responding to antibiotic therapy. METHODS: This was a randomized, double-blind, placebo-controlled trial in pwCF treated with intravenous (IV) antibiotics for a PEx. At Day 7, those who had not returned to >90% baseline ppFEV1 were randomized to adjuvant prednisone 1 mg·kg-1 twice daily (max 60 mg/day) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline ppFEV1 at Day 14 of IV antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomized. 50% of subjects in the prednisone group recovered baseline FEV1 on Day 14 compared to 39% of subjects in the placebo group for a difference of 11% (95% CI -11, 34%, p=0.34). The mean (sd) change in ppFEV1 from Day 7 to Day 14 was 6.8% predicted (8.8) in the prednisone group and 4.6% (6.9) in the placebo group (mean difference 2.2% predicted 95% CI -1.5, 5.9%, p=0.24). Time to subsequent exacerbation was not prolonged in prednisone treated subjects (HR 0.83, 95% CI 0.45, 1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in ppFEV1 recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of IV antibiotic therapy for PExs.

Rehabilitation Protocols in Elbow Medial Ulnar Collateral Ligament Injuries: A Systematic Review of Articles Published in the Last 20 Years.

CONTEXT: Elbow medial ulnar collateral ligament (UCL) injuries have become increasingly common in athletes. Despite this, rehabilitation protocols appear to vary drastically, which may explain the clinical equipoise regarding optimal management. OBJECTIVE: This systematic review reports rehabilitation characteristics reported after UCL injuries and compares reported outcomes based on early versus delayed rehabilitation. DATA SOURCES: Our search utilized PubMed/MEDLINE, Embase, Web of Science, and Cochrane to identify all articles on UCL rehabilitation published between January 1, 2002 and October 1, 2022. STUDY SELECTION: Studies in English with ≥5 patients that reported rehabilitation protocols for UCL injuries were evaluated. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: Data included sample characteristics, time to achieve physical therapy milestones, outcome scores, and return-to-play (RTP) rate and timing. RESULTS: Our review included 105 articles with a total of 15,928 elbows (98% male; weighted mean age, 23 years; follow-up, 47 months), with 15,077 treated operatively and 851 treated nonoperatively. The weighted mean time patients spent adhering to nonweightbearing status was 42 days. The mean time until patients were given clearance for active range of motion (ROM) 15 days, full ROM 40 days, and elbow strengthening exercises 32 days. The mean time until all restrictions were lifted was 309 days. The mean time to begin a throwing program was 120 days. Across all rehabilitation characteristics, protocols for patients undergoing nonoperative management started patients on rehabilitation earlier. After UCL reconstruction, earlier active ROM (≤14 days), elbow strengthening (≤30 days), no restrictions (≤180 days), and throwing (≤120 days) postoperatively led to earlier RTP without a negative effect on functional outcome scores. CONCLUSION: Current literature provides a spectrum of protocols for elbow UCL rehabilitation, regardless of management. Nonoperative patients began ROM activities, strengthening, and throwing programs sooner than operative patients, and earlier milestones led to earlier RTP.

On the Use of Minimum Penalties in Statistical Learning.

Modern multivariate machine learning and statistical methodologies estimate parameters of interest while leveraging prior knowledge of the association between outcome variables. The methods that do allow for estimation of relationships do so typically through an error covariance matrix in multivariate regression which does not generalize to other types of models. In this article we proposed the MinPen framework to simultaneously estimate regression coefficients associated with the multivariate regression model and the relationships between outcome variables using common assumptions. The MinPen framework utilizes a novel penalty based on the minimum function to simultaneously detect and exploit relationships between responses. An iterative algorithm is proposed as a solution to the non-convex optimization. Theoretical results such as high dimensional convergence rates, model selection consistency, and a framework for post selection inference are provided. We extend the proposed MinPen framework to other exponential family loss functions, with a specific focus on multiple binomial responses. Tuning parameter selection is also addressed. Finally, simulations and two data examples are presented to show the finite sample properties of this framework. Supplemental material providing proofs, additional simulations, code, and data sets are available online.

Long-term outcomes after recurrent acute thoracic aortic dissection: Insights from the International Registry of Aortic Dissection.

OBJECTIVE: With an aging population and advancements in imaging, recurrence of thoracic aortic dissection is becoming more common. METHODS: All patients enrolled in the International Registry of Aortic Dissection from 1996 to 2023 with type A and type B acute aortic dissection were identified. Among them, initial dissection and recurrent dissection were discerned. The study period was categorized into 3 eras: historic era, 1996 to 2005; middle era, 2006 to 2015; most recent era, 2016 to 2023. Propensity score matching was applied between initial dissection and recurrent dissection. Outcome of interests included long-term survival and cumulative incidence of major aortic events defined by the composite of reintervention, aortic rupture, and new dissection. RESULTS: The proportion of recurrent dissection increased from 5.9% in the historic era to 8.0% in the most recent era in the entire dissection cohort. In patients with type A dissection, propensity score matching between initial dissection and recurrent dissection yielded 326 matched pairs. Kaplan-Meier curves showed similar long-term survival between the 2 groups. However, the cumulative incidence of major aortic events was significantly higher in the recurrent dissection group (40.3% ± 6.2% vs 17.8% ± 5.1% at 4 years in the initial dissection group, P = .02). For type B dissection, 316 matched pairs were observed after propensity score matching. Long-term survival and the incidence of major aortic events were equivalent between the 2 groups. CONCLUSIONS: The case volume of recurrent dissection or the ability to detect recurrent dissection has increased over time. Acute type A recurrent dissection was associated with a higher risk of major aortic events than initial dissection. Further judicious follow-up may be crucial after type A recurrent dissection.

Alignment in Total Knee Arthroplasty: Avoid Crossing Over From Varus to Valgus.

BACKGROUND: Ideal target limb alignment remains a debated topic in total knee arthroplasty (TKA). We aimed to determine the effect of limb alignment correction on patient-reported outcomes and knee range of motion (ROM) following TKA. METHODS: In this retrospective analysis, patients (N = 409) undergoing primary TKA at a single institution were studied. Using full leg-length radiographs, limb alignment was measured preoperatively and postoperatively. Patients were categorized by preoperative (Preop) alignment (varus > 0°; valgus < 0°). Preop varus patients were then divided as follows based on postoperative alignment: neutral (VAR-NEUT, 0°± 2), remaining in varus (VAR-rVAR, ≥3°), and cross-over to valgus (VAR-CO, ≤-3°). Similarly, Preop valgus patients were divided as follows for postoperative alignment: neutral (VAL-NEUT, 0°± 2), remaining in valgus (VAL-rVAL, ≤-3°), and cross-over to varus (VAL-CO, ≥3°). The Knee Injury and Osteoarthritis Outcome Score for Joint Replacement survey scores were collected at preoperatively as well as at 6 weeks, 3, 6, and 12 months postoperatively. Knee ROM was collected at 2 weeks, 6 to 12 weeks, and >6 months postoperatively. An analysis of variance repeated on time followed by a Bonferroni post hoc test was used to compare outcomes for the postoperative alignment subgroups. RESULTS: Preop Varus patients: Those in the VAR-CO group (overcorrected to -4.03° ± 1.95valgus) were observed to have lower Knee Injury and Osteoarthritis Outcome Score for Joint Replacement scores at 3, 6, and 12 months postoperatively compared to those in the NEUT group (P < .05). This finding was paired with reduced ROM at 6 to 12 weeks postoperatively in the VAR-CO group compared to VAR-NEUT and VAR-rVAR (P < .05). Preop Valgus patients: Those in the VAL-rVal group (left in -4.39° ± 1.39valgus) were observed to have reduced knee flexion at 6 to 12 weeks postoperatively compared to VAL-NEUT and VAL-CO. CONCLUSIONS: These findings indicate that postoperative valgus alignment via either crossing over to valgus (VAR-CO) or remaining in valgus (VAL-rVAL) alignment may result in less preferable outcomes than correction to neutral or slightly varus alignment.

Pediatric growth hormone deficiency: Understanding the patient and caregiver perspectives.

Childhood growth hormone deficiency (GHD) is a rare disorder associated with significant burden on both patients and caregivers. Although previous reports have detailed aspects of the burden experienced by patients and their caregivers, there is a paucity of first-hand information on the patient and caregiver journeys from their respective voices. To address this need, an advisory board meeting was conducted on September 30, 2022, with 4 pediatric patients with GHD and their caregivers to discuss their experiences prior to GHD diagnosis, during the diagnostic process, and during ongoing treatment with recombinant growth hormone. Feedback from patients and caregivers was reviewed by pediatric endocrinologists, who provided their own perspectives on the patient and caregiver journeys based on the information reported. Despite the small sample size, important insights were obtained: patients and caregivers reported remarkable growth benefits achieved with treatment, which provided strong motivation to remain adherent to daily injection regimens. Patient and caregiver accounts reflected wide variability between families in time from suspicion to diagnosis and in treatment challenges faced, ranging from practical issues such as handling and administration of medication to broader concerns about treatment access and continuity, as well as key knowledge gaps among patients, caregivers, and clinicians. Recommendations are provided to enhance the patient and caregiver journeys, including increasing development and availability of educational materials, providing opportunities for patient advocacy by clinicians and health care providers, and encouraging institutional improvements to ensure that patients continue to receive uninterrupted treatment during their critical period of growth.

Impact of Deltoid Computer Tomography Image Data on the Accuracy of Machine Learning Predictions of Clinical Outcomes after Anatomic and Reverse Total Shoulder Arthroplasty.

Background: Despite the importance of the deltoid to shoulder biomechanics, very few studies have quantified the three-dimensional shape, size, or quality of the deltoid muscle, and no studies have correlated these measurements to clinical outcomes after anatomic (aTSA) and/or reverse (rTSA) total shoulder arthroplasty in any statistically/scientifically relevant manner. Methods: Preoperative computer tomography (CT) images from 1057 patients (585 female, 469 male; 799 primary rTSA and 258 primary aTSA) of a single platform shoulder arthroplasty prosthesis (Equinoxe; Exactech, Inc., Gainesville, FL) were analyzed in this study. A machine learning (ML) framework was used to segment the deltoid muscle for 1057 patients and quantify 15 different muscle characteristics, including volumetric (size, shape, etc.) and intensity-based Hounsfield (HU) measurements. These deltoid measurements were correlated to postoperative clinical outcomes and utilized as inputs to train/test ML algorithms used to predict postoperative outcomes at multiple postoperative timepoints (1 year, 2-3 years, and 3-5 years) for aTSA and rTSA. Results: Numerous deltoid muscle measurements were demonstrated to significantly vary with age, gender, prosthesis type, and CT image kernel; notably, normalized deltoid volume and deltoid fatty infiltration were demonstrated to be relevant to preoperative and postoperative clinical outcomes after aTSA and rTSA. Incorporating deltoid image data into the ML models improved clinical outcome prediction accuracy relative to ML algorithms without image data, particularly for the prediction of abduction and forward elevation after aTSA and rTSA. Analyzing ML feature importance facilitated rank-ordering of the deltoid image measurements relevant to aTSA and rTSA clinical outcomes. Specifically, we identified that deltoid shape flatness, normalized deltoid volume, deltoid voxel skewness, and deltoid shape sphericity were the most predictive image-based features used to predict clinical outcomes after aTSA and rTSA. Many of these deltoid measurements were found to be more predictive of aTSA and rTSA postoperative outcomes than patient demographic data, comorbidity data, and diagnosis data. Conclusions: While future work is required to further refine the ML models, which include additional shoulder muscles, like the rotator cuff, our results show promise that the developed ML framework can be used to evolve traditional CT-based preoperative planning software into an evidence-based ML clinical decision support tool.

Mapping early brain-body interactions: associations of fetal heart rate variation with newborn brainstem, hypothalamic, and dorsal anterior cingulate cortex functional connectivity.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal autonomic nervous system development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with post-birth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40-46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower and higher order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants.Significance statement Fetal heart rate indices are quantifiable, developmental markers of the fetal autonomic nervous system. Variations in their trajectories can signal compromised neurodevelopmental outcomes. We assessed associations between fetal heart rate indices and early infant brain development to identify unique or common associations corresponding to autonomic nervous system maturation patterns. We found associations between fetal heart rate indices and infant brainstem, hypothalamic, and dACC connectivity-areas that support autonomic and behavioral regulatory functions. The study demonstrates that these associations between ANS and brain regions involved in autonomic regulation exist early in life. These findings are a first step to understanding how these brain connections form the basis of future regulatory development.

Exploring Mechanisms of Lipid Nanoparticle-Mucus Interactions in Healthy and Cystic Fibrosis Conditions.

Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR-based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerge as versatile non-viral gene delivery systems that can help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein-loaded LNP-mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics (BD) simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery.

Reported Outcome Measures in Complex Fracture Elbow Dislocations: A Systematic Review.

BACKGROUND: Complex elbow fracture dislocations, dislocation with fracture of one or several surrounding bony stabilizers, are difficult to manage and associated with poor outcomes. While many studies have explored treatment strategies but a lack of standardization of patient-reported outcome measures (PROMs) makes cross-study comparison difficult. In this systematic review, we aim to describe what injury patterns, measured outcomes, and associated complications are reported in the complex elbow fracture dislocation literature to provide outcome reporting recommendations that will facilitate improved future cross-study comparison. METHODS: A systematic review was performed per PRISMA guidelines. We queried PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases to identify articles published between 2010 and 2022 reporting on adult patients who had a complex elbow fracture dislocation. Pathologic fractures were excluded. A bias assessment using the methodological index for non-randomized studies criteria was conducted. For each article, patient demographics, injury pattern, outcome measures, and complications were recorded. RESULTS: Ninety-one studies reporting on 3664 elbows (3654 patients) with an elbow fracture and dislocation (weighted mean age 44 years, follow-up of 30 months, 41% female) were evaluated. Of these, the injury pattern was described in 3378 elbows and included 2951 (87%) terrible triad injuries and 72 (2%) transolecranon fracture-dislocations. The three most commonly reported classification systems were: Mason classification for radial head fractures, Regan and Morrey coronoid classification for coronoid fractures, and O'Driscoll classification for coronoid fractures. Range of motion was reported in 87 (96%) studies with most reporting flexion (n=70), extension (n=62), pronation (n=68), or supination (n=67). Strength was reported in 11 (12%) studies. PROMs were reported in 83 (91%) studies with an average of 2.6 outcomes per study. There were 14 outcome scores including the Mayo Elbow Performance Score (MEPS) (n=69 [83%]), the Disabilities of Arm, Shoulder and Hand (DASH) score (n=28 [34%]), the visual analog scale for pain (VAS) (n=27 [33%]), QuickDASH score (n=13 [15.7%]), and Oxford Elbow score (n=5 [6.0%]). No significance was found between the number of PROMs used per article and the year of publication (P=.313), study type (P=.689), complex fracture pattern (P=.211), or number of elbows included (P=.152). CONCLUSION: There is great heterogeneity in reported PROMs in the complex elbow fracture dislocation literature. Although there is no gold standard PROM for assessing complex elbow fracture dislocations, we recommend the use of at least the MEPS and DASH outcomes measures as well as VAS pain rating scale in future studies to facilitate cross-study comparisons.

Update on the diagnosis and management of cystic fibrosis pulmonary exacerbations.

Pulmonary exacerbations in people with cystic fibrosis are associated with significant morbidity and reduced quality of life. Pulmonary exacerbation treatment guidelines, published by an expert panel assembled by the Cystic Fibrosis Foundation nearly 15 years ago, were primarily consensus-based as there were several gaps in the evidence base. In particular, limited evidence existed regarding optimal pulmonary exacerbation treatment strategies, including duration of antibiotic therapy, treatment location, antibiotic selection, and the role of systemic corticosteroids. Over the last decade, results from observational studies and large multi-center randomized controlled trials have begun to answer important questions related to pulmonary exacerbation treatment. This review focuses on the diagnosis, etiology, and changing epidemiology of pulmonary exacerbations, and also summarizes the most recent and up-to-date studies describing pulmonary exacerbation treatment. Finally, this review provides consideration for future pulmonary exacerbation research priorities, particularly in the current highly effective modulator therapy era.

Pre-pregnancy maternal obesity and infant neurodevelopmental outcomes in Latino infants.

OBJECTIVE: This study explores the impact of maternal pre-pregnancy BMI on infant neurodevelopment at 24 months in low-income Latino families. It also investigates whether infant diet mediates this relationship. METHODS: Latino mother-infant pairs (n = 163) were enrolled at 1 month post partum and were followed for 2 years, with assessments at 6-month intervals. Maternal pre-pregnancy anthropometrics were self-reported at baseline, and child neurodevelopment was assessed at 24 months using the Bayley Scales of Infant Development. Diet quality of infants was measured using the Healthy Eating Index (HEI)-2015 and HEI-Toddlers-2020 scores at multiple time points. Mediation and regression models that adjust for maternal factors were used to examine the associations. RESULTS: Pre-pregnancy BMI showed significant negative associations with child cognitive scores (ß = -0.1, 95% CI: -0.2 to -0.06, p < 0.001) and language scores (ß = -0.1, 95% CI: -0.2 to -0.03, p = 0.01) at 24 months. Infant HEI-2015 scores at 24 months partly mediated these associations, explaining 23% and 30% of the total effect on cognitive and language subscales, respectively. No specific dietary components in infants mediated the relationship, except for the total HEI-2015 score. CONCLUSIONS: Managing maternal obesity pre-pregnancy is crucial for improving infant neurodevelopmental outcomes, especially in low-income Latino families. Promoting healthy weight and enhancing infant diet quality can enhance neurodevelopment in these populations.