Comparing opioid utilization and costs for surgical management of single-level spondylolisthesis: A national claims database analysis.

Introduction: The rise in degenerative lumbar spondylolisthesis (DLS) cases has led to a significant increase in fusion surgeries, which incur substantial hospitalization costs and often necessitate chronic opioid use for pain management. Recent evidence suggests that single-level low-grade DLS outcomes are comparable whether a fusion procedure or decompression alone is performed, sparking debate over the cost-effectiveness of these procedures, particularly with the advent of minimally invasive techniques reducing the morbidity of fusion. This study aims to compare chronic opioid utilization and associated costs between decompression alone and decompression with instrumented fusion for single-level degenerative lumbar spondylolisthesis. Material and methods: Using data from the PearlDiver database, a retrospective database analysis was conducted. We analyzed records of Medicare and Medicaid patients undergoing lumbar fusion or decompression from 2010 to 2022. Patient cohorts were divided into decompression alone (DA) and decompression with instrumented fusion (DIF). Chronic opioid use, pain clinic visits, and total costs were compared between the two groups at 90 days, 1 year, and 2 years post-surgery. Theory: Does DIF offer a more cost-effective approach to managing DLS in terms of chronic opioid use in single-level DLS patients. Results: The study revealed comparable chronic opioid use and pain clinic visits between DA and DIF groups at 90 days and 1 year. However, total costs associated with opioid prescriptions as well as surgical aftercare were significantly higher in the DIF group at 90 days (p < 0.05), 1 year (p < 0.05), and 2 years (p < 0.05) post-surgery compared to the DA group. Conclusions: This study highlights the higher costs associated with DIF up to 2 years post-surgery despite comparable symptom improvement when compared to DA and DIF at the 1-year interval. DA emerges as a more financially favorable option, challenging the notion of fusion's cost-offsetting benefits. While further investigation is needed to understand underlying cost drivers and optimize outcomes, our findings emphasize the necessity of integrating clinical and economic factors in the management of single-level DLS.

A Comparison of Rosuvastatin Monotherapy and Rosuvastatin Plus Ezetimibe Combination Therapy in Patients With Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

Type 2 diabetes mellitus is a metabolic condition where vascular inflammation and oxidative stress contribute to disease progression and associated complications. Although statins are recommended for managing dyslipidemia in diabetes, additional therapies are often required to achieve target lipid levels. This meta-analysis aimed to evaluate the efficacy of rosuvastatin monotherapy versus combination therapy with ezetimibe in patients with type 2 diabetes. A systematic literature search was conducted across multiple databases until April 2024, identifying six randomized controlled trials meeting the inclusion criteria. The meta-analysis revealed that the rosuvastatin plus ezetimibe combination resulted in significantly greater reductions in total cholesterol (mean difference, or MD: 19.49; 95% CI: 13.99 to 24.99), triglycerides (MD: 13.44; 95% CI: 2.04 to 24.85), and low-density lipoprotein cholesterol (MD: -17.68; 95% CI: 12.85 to 22.51) compared to rosuvastatin monotherapy. Conversely, rosuvastatin monotherapy achieved a greater reduction in HbA1c levels (MD: -0.11; 95% CI: -0.17 to -0.04). Subgroup analysis demonstrated that using the same dose of rosuvastatin in both groups led to more significant improvements in lipid parameters with lower heterogeneity. The findings suggest that the rosuvastatin-ezetimibe combination may be a more effective lipid-lowering strategy for patients with type 2 diabetes, though larger studies are needed to assess long-term safety and optimal dosing. Additionally, while rosuvastatin monotherapy provided modest HbA1c reductions, the clinical relevance remains uncertain, and potential risks with high-dose statins should be considered.

Effect of Pulmonary Hypertension on Survival Outcomes in Patients With Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

The aim of this meta-analysis was to determine the effect of pulmonary hypertension (PH) on survival in patients undergoing transcatheter aortic valve replacement (TAVR). The present study was conducted according to the guidelines of Preferred Reporting of Systematic Review and Meta-Analysis (PRISMA). We conducted a comprehensive search of electronic databases including PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science from January 1, 2015, to March 10, 2024. Outcomes assessed in this meta-analysis included early and late all-cause mortality and cardiovascular mortality. Total 15 studies were integrated into the pooled analysis to assess the impact of PH on outcomes among patients undergoing TAVR, comprising a total sample size of 35,732 individuals. The pooled prevalence of PH stood at 52.57% (n=18,767). Predominantly, the studies were conducted in the United States (n=6), followed by Germany (n=3), with one study each from Japan, Italy, Switzerland, Brazil, Poland, and Australia. Pooled analysis showed that risk of short-term mortality was greater in patients with PH compared to patients without PH (risk ratio (RR): 1.46, 95% CI: 1.19 to 1.80). Risk of long-term mortality was greater in patients with PH (RR: 1.42, 95% CI: 1.29 to 1.55). Risk of cardiovascular mortality was also greater in patients with PH compared to patients without PH (RR: 1.66, 95% CI: 1.36 to 2.02). We advocate for further research to address gaps in understanding different types of PH and their impacts on mortality and cardiovascular outcomes.

Liposome-encapsulated cytochrome P450 and gibberellic acid biosynthesis in Priestia megaterium RP1.

This study explores the potential of liposome encapsulated silica immobilized cytochrome P450 monooxygenase (LSICY) for bioremediation of mercury (Hg2+). Current limitations in Hg2+ reduction, including sensitivity to factors like pH and cost, necessitate alternative methods. We propose LSICY as a solution, leveraging the enzymatic activities of cytochrome P450 monooxygenase (CYPM) for Hg2+ reduction through hydroxylation and oxygenation. Our investigation employs LSICY to assess its efficacy in mitigating Hg2+ toxicity in Oryza sativa (rice) plants. Gas chromatography confirmed gibberellic acid (GA) presence in the Hg2+ reducing bacteria Priestia megaterium RP1 (PMRP1), highlighting a potential link between CYP450 activity and plant health. This study demonstrates the promise of LSICY as a sustainable and effective approach for Hg2+ bioremediation, promoting a safer soil environment.

Design of Inhibitors That Target the Menin-Mixed-Lineage Leukemia Interaction.

The prognosis of mixed-lineage leukemia (MLL) has remained a significant health concern, especially for infants. The minimal treatments available for this aggressive type of leukemia has been an ongoing problem. Chromosomal translocations of the KMT2A gene are known as MLL, which expresses MLL fusion proteins. A protein called menin is an important oncogenic cofactor for these MLL fusion proteins, thus providing a new avenue for treatments against this subset of acute leukemias. In this study, we report results using the structure-based drug design (SBDD) approach to discover potential novel MLL-mediated leukemia inhibitors from natural products against menin. The three-dimensional (3D) protein model was derived from Protein Databank (Protein ID: 4GQ4), and EasyModeller 4.0 and I-TASSER were used to fix missing residues during rebuilding. Out of the ten protein models generated (five from EasyModeller and I-TASSER each), one model was selected. The selected model demonstrated the most reasonable quality and had 75.5% of residues in the most favored regions, 18.3% of residues in additionally allowed regions, 3.3% of residues in generously allowed regions, and 2.9% of residues in disallowed regions. A ligand library containing 25,131 ligands from a Chinese database was virtually screened using AutoDock Vina, in addition to three known menin inhibitors. The top 10 compounds including ZINC000103526876, ZINC000095913861, ZINC000095912705, ZINC000085530497, ZINC000095912718, ZINC000070451048, ZINC000085530488, ZINC000095912706, ZINC000103580868, and ZINC000103584057 had binding energies of -11.0, -10.7, -10.6, -10.2, -10.2, -9.9, -9.9, -9.9, -9.9, and -9.9 kcal/mol, respectively. To confirm the stability of the menin-ligand complexes and the binding mechanisms, molecular dynamics simulations including molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations were performed. The amino acid residues that were found to be potentially crucial in ligand binding included Phe243, Met283, Cys246, Tyr281, Ala247, Ser160, Asn287, Asp185, Ser183, Tyr328, Asn249, His186, Leu182, Ile248, and Pro250. MI-2-2 and PubChem CIDs 71777742 and 36294 were shown to possess anti-menin properties; thus, this justifies a need to experimentally determine the activity of the identified compounds. The compounds identified herein were found to have good pharmacological profiles and had negligible toxicity. Additionally, these compounds were predicted as antileukemic, antineoplastic, chemopreventive, and apoptotic agents. The 10 natural compounds can be further explored as potential novel agents for the effective treatment of MLL-mediated leukemia.

Anti-Ha Antisynthetase Syndrome: A Case Report.

Anti-synthetase syndrome (ASyS) is a rare systemic autoimmune myopathy characterized by the involvement of muscles, lungs, and joints, in addition to Raynaud's phenomenon, "mechanics' hand," and fever. Laboratory ASyS is defined by the positivity of anti-aminoacyl-tRNA synthetase autoantibodies, of which anti-Jo-1 is the most common. Herein, we reported an ASyS defined by an anti-Ha autoantibody, which has rarely been described in the literature. Moreover, to the best of our knowledge, we reported the first case of anti-Ha ASyS in Brazil.

An analysis of ChatGPT recommendations for the diagnosis and treatment of cervical radiculopathy.

OBJECTIVE: The objective of this study was to assess the safety and accuracy of ChatGPT recommendations in comparison to the evidence-based guidelines from the North American Spine Society (NASS) for the diagnosis and treatment of cervical radiculopathy. METHODS: ChatGPT was prompted with questions from the 2011 NASS clinical guidelines for cervical radiculopathy and evaluated for concordance. Selected key phrases within the NASS guidelines were identified. Completeness was measured as the number of overlapping key phrases between ChatGPT responses and NASS guidelines divided by the total number of key phrases. A senior spine surgeon evaluated the ChatGPT responses for safety and accuracy. ChatGPT responses were further evaluated on their readability, similarity, and consistency. Flesch Reading Ease scores and Flesch-Kincaid reading levels were measured to assess readability. The Jaccard Similarity Index was used to assess agreement between ChatGPT responses and NASS clinical guidelines. RESULTS: A total of 100 key phrases were identified across 14 NASS clinical guidelines. The mean completeness of ChatGPT-4 was 46%. ChatGPT-3.5 yielded a completeness of 34%. ChatGPT-4 outperformed ChatGPT-3.5 by a margin of 12%. ChatGPT-4.0 outputs had a mean Flesch reading score of 15.24, which is very difficult to read, requiring a college graduate education to understand. ChatGPT-3.5 outputs had a lower mean Flesch reading score of 8.73, indicating that they are even more difficult to read and require a professional education level to do so. However, both versions of ChatGPT were more accessible than NASS guidelines, which had a mean Flesch reading score of 4.58. Furthermore, with NASS guidelines as a reference, ChatGPT-3.5 registered a mean ± SD Jaccard Similarity Index score of 0.20 ± 0.078 while ChatGPT-4 had a mean of 0.18 ± 0.068. Based on physician evaluation, outputs from ChatGPT-3.5 and ChatGPT-4.0 were safe 100% of the time. Thirteen of 14 (92.8%) ChatGPT-3.5 responses and 14 of 14 (100%) ChatGPT-4.0 responses were in agreement with current best clinical practices for cervical radiculopathy according to a senior spine surgeon. CONCLUSIONS: ChatGPT models were able to provide safe and accurate but incomplete responses to NASS clinical guideline questions about cervical radiculopathy. Although the authors' results suggest that improvements are required before ChatGPT can be reliably deployed in a clinical setting, future versions of the LLM hold promise as an updated reference for guidelines on cervical radiculopathy. Future versions must prioritize accessibility and comprehensibility for a diverse audience.

Genome-wide association study for yield and quality of granulated cassava processed product.

The starchy storage roots of cassava are commonly processed into a variety of products, including cassava granulated processed products (gari). The commercial value of cassava roots depends on the yield and quality of processed products, directly influencing the acceptance of new varieties by farmers, processors, and consumers. This study aims to estimate genetic advance through phenotypic selection and identify genomic regions associated and candidate genes linked with gari yield and quality. Higher single nucleotide polymorphism (SNP)-based heritability estimates compared to broad-sense heritability estimates were observed for most traits highlighting the influence of genetic factors on observed variation. Using genome-wide association analysis of 188 clones, genotyped using 53,150 genome-wide SNPs, nine SNPs located on seven chromosomes were significantly associated with peel loss, gari yield, color parameters for gari and eba, bulk density, swelling index, and textural properties of eba. Future research will focus on validating and understanding the functions of identified genes and their influence on gari yield and quality traits.

Temporary Stabilization of Tibia Fractures: Does External Fixation or Temporary Plate Fixation Result in Better Outcomes?

Background: Provisional stabilization of high-energy tibia fractures using temporary plate fixation (TPF) or external fixation (ex-fix) prior to definitive medullary nailing (MN) is a strategy common in damage control orthopaedics. There is a lack of comprehensive data evaluating outcomes between these methods. This study compares outcomes of patients stabilized with either TPF or ex-fix, and with early definitive MN only, assessing complications including nonunion and deep infection. Methods: A retrospective review was performed on adult patients with tibia fractures treated with MN followed until fracture union (≥3 months) at a single level-1 trauma center from 2014 to 2022. Medical records were evaluated for nonunion and deep infection. Demographics, injury characteristics, and fixation methods were recorded. Significance between patients who underwent TPF and ex-fix was compared with a matched cohort of early MN using Pearson's exact tests, independent t-tests, and one-way ANOVA, depending on the appropriate variable. Results: 81 patients were included; 27 were temporized with TPF (n = 12) or ex-fix (n = 15). 54 early MN cases defined the matched cohort. All groups had similar patient and fracture characteristics. The difference in rates of nonunion between groups was significant, with TPF, ex-fix, and early MN groups at 17, 40, and 11% respectively (p = 0.027). Early MN had lower rates of nonunion (11% vs. 40%, p = 0.017) and deep infection (13% vs. 40%, p = 0.028) compared to ex-fix. Conclusion: Temporary ex-fix followed by staged MN was associated with higher rates of nonunion and deep infection. There was no difference in complication rates between TPF and early definitive MN. These data suggest that ex-fix followed by MN of tibia fractures should be avoided in favor of early definitive MN when possible. If temporization is needed, TPF may be a better option than ex-fix. Level of Evidence: IV.

Trends in Pediatric Attention-Deficit Hyperactive Disorder Diagnoses and Prescription Utilization: 2016 to 2019.

OBJECTIVE: Attention-deficit hyperactive disorder (ADHD) is one of the most common psychiatric disorders among children, with estimated prevalence of 7% to 15% worldwide. The aim of this analysis was to update and summarize trends in diagnosis, demographics, and drug utilization of pediatric patients with ADHD. METHODS: We used the Agency for Health care Research and Quality Medical Expenditure Panel Survey (MEPS), a survey of US individuals, families, their medical providers, and employers, using datasets from 2016 to 2019. The data sources from the MEPS database included the full-year consolidated files, medical conditions files, prescribed-medicines files, and condition-event link files for each year. We summarized trends in the proportion of children, ages 17 years and younger, with a diagnosis of ADHD, demographic information and a prescription for medication known to treat ADHD. In addition, we further stratified ADHD medication use by stimulant/nonstimulant categories. RESULTS: There was a 1.6% and 4.7% absolute increase in children with an ADHD diagnosis and those prescribed ADHD medications, respectively, from 2016 to 2019. Most of these children were male, non-Hispanic, and on public insurance. Of the children prescribed an ADHD medication and concomitant behavioral medications, stimulants-only use was the highest (60%-67%), followed by stimulants/nonstimulants (13%-15%), stimulant/antidepressants (6%-9%), and nonstimulants only (5%-9%). The proportion of patients with ADHD in the high-income and near-poor categories increased by 4% from 2016 to 2019. CONCLUSION: Diagnosis of ADHD among children is trending upward in the United States. Central nervous system stimulants, especially methylphenidate formulations, are the most prescribed ADHD medications for children 17 years and younger.

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Preventing Heart Failure in Patients Receiving Anthracycline-Based Cancer Therapy: A Systematic Review and Meta-Analysis.

Anthracyclines are effective chemotherapeutic agents widely used to treat various cancers, but their use is limited by the risk of cardiotoxicity and heart failure. While strategies like dose reduction have been explored, there are no well-established therapies to mitigate this risk. Emerging evidence suggests sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have cardioprotective effects, providing a rationale for investigating their potential utility in anthracycline-treated patients. We conducted a systematic review and meta-analysis to synthesize available evidence on the efficacy of SGLT2i in reducing heart failure incidence and mortality in patients undergoing anthracycline-based cancer therapy. Relevant studies were identified through comprehensive database searches and screened based on predefined criteria. Data extraction and quality assessment were performed independently by two reviewers. Four observational studies, encompassing 5,590 patients, were included. The pooled analysis showed a higher but non-significant risk of developing heart failure in the non-SGLT2i group compared to the SGLT2i group (RR = 0.67, 95% CI: 0.40-1.41). The risk of all-cause mortality was significantly lower in patients receiving SGLT2i (RR = 0.55, 95% CI: 0.39-0.77). This meta-analysis suggests SGLT2i are associated with a lower risk of mortality and heart failure incidence in anthracycline-treated patients, although larger studies are needed to confirm these findings. The mechanisms underlying these potential benefits require further elucidation. Despite limitations, this analysis highlights the promising role of SGLT2i as a cardioprotective strategy in this high-risk population.

The Effect of Intraoperative Overdistraction on Subsidence Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study was to evaluate the effect of overdistraction on interbody cage subsidence. BACKGROUND: Vertebral overdistraction due to the use of large intervertebral cage sizes may increase the risk of postoperative subsidence. METHODS: Patients who underwent anterior cervical discectomy and fusion between 2016 and 2021 were included. All measurements were performed using lateral cervical radiographs at 3 time points - preoperative, immediate postoperative, and final follow-up >6 months postoperatively. Anterior and posterior distraction were calculated by subtracting the preoperative disc height from the immediate postoperative disc height. Cage subsidence was calculated by subtracting the final follow-up postoperative disc height from the immediate postoperative disc height. Associations between anterior and posterior subsidence and distraction were determined using multivariable linear regression models. The analyses controlled for cage type, cervical level, sex, age, smoking status, and osteopenia. RESULTS: Sixty-eight patients and 125 fused levels were included in the study. Of the 68 fusions, 22 were single-level fusions, 35 were 2-level, and 11 were 3-level. The median final follow-up interval was 368 days (range: 181-1257 d). Anterior disc space subsidence was positively associated with anterior distraction (beta = 0.23; 95% CI: 0.08, 0.38; P = 0.004), and posterior disc space subsidence was positively associated with posterior distraction (beta = 0.29; 95% CI: 0.13, 0.45; P < 0.001). No significant associations between anterior distraction and posterior subsidence (beta = 0.07; 95% CI: -0.06, 0.20; P = 0.270) or posterior distraction and anterior subsidence (beta = 0.06; 95% CI: -0.14, 0.27; P = 0.541) were observed. CONCLUSIONS: We found that overdistraction of the disc space was associated with increased postoperative subsidence after anterior cervical discectomy and fusion. Surgeons should consider choosing a smaller cage size to avoid overdistraction and minimize postoperative subsidence.

Compound-specific stable isotope analyses of fatty acids indicate feeding zones of zooplankton across the water column of a subalpine lake.

Spatial and temporal zooplankton feeding dynamics across the water column of lakes are key for understanding site-specific acquisition of diet sources. During this 6-week lake study, we examined stable carbon (δ13C) and nitrogen (δ15N) isotopes and conducted compound-specific fatty acid (FA) stable isotope analysis (CSIA) of edible seston in the epi-, meta-, and hypolimnion, and zooplankton of Lake Lunz, Austria. We predicted that CSIA of essential FA can discern the foraging grounds of zooplankton more accurately than the commonly used bulk stable isotopes. The δ13C and δ15N values of seston from different lake strata were similar, whereas a dual CSIA approach using stable carbon and hydrogen isotopes of FA (δ13CFA and δ2HFA) provided sufficient isotopic difference in essential FA to discern different lake strata-specific diet sources throughout the study period. We present a CSIA model that suggests strata-specific foraging grounds for different zooplankton groups, indicating higher preference of cladocerans for feeding on epilimnetic diet sources, while calanoid copepods retained more hypolimnetic resources. The CSIA approach thus yields strata-specific information on foraging strategies of different zooplankton taxa and provides more details on the spatial and temporal trophodynamics of planktonic food webs than commonly used bulk stable isotopes.

Detecting co-selection through excess linkage disequilibrium in bacterial genomes.

Population genomics has revolutionized our ability to study bacterial evolution by enabling data-driven discovery of the genetic architecture of trait variation. Genome-wide association studies (GWAS) have more recently become accompanied by genome-wide epistasis and co-selection (GWES) analysis, which offers a phenotype-free approach to generating hypotheses about selective processes that simultaneously impact multiple loci across the genome. However, existing GWES methods only consider associations between distant pairs of loci within the genome due to the strong impact of linkage-disequilibrium (LD) over short distances. Based on the general functional organisation of genomes it is nevertheless expected that majority of co-selection and epistasis will act within relatively short genomic proximity, on co-variation occurring within genes and their promoter regions, and within operons. Here, we introduce LDWeaver, which enables an exhaustive GWES across both short- and long-range LD, to disentangle likely neutral co-variation from selection. We demonstrate the ability of LDWeaver to efficiently generate hypotheses about co-selection using large genomic surveys of multiple major human bacterial pathogen species and validate several findings using functional annotation and phenotypic measurements. Our approach will facilitate the study of bacterial evolution in the light of rapidly expanding population genomic data.

Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals.

In the European Medicines Agency (EMA) "Guideline for Environmental Risk Assessment of Medicinal Products for Human Use," a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation ('B') potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3 R s principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified.

Genomic tailoring of autogenous poultry vaccines to reduce Campylobacter from farm to fork.

Campylobacter is a leading cause of food-borne gastroenteritis worldwide, linked to the consumption of contaminated poultry meat. Targeting this pathogen at source, vaccines for poultry can provide short-term caecal reductions in Campylobacter numbers in the chicken intestine. However, this approach is unlikely to reduce Campylobacter in the food chain or human incidence. This is likely as vaccines typically target only a subset of the high genomic strain diversity circulating among chicken flocks, and rapid evolution diminishes vaccine efficacy over time. To address this, we used a genomic approach to develop a whole-cell autogenous vaccine targeting isolates harbouring genes linked to survival outside of the host. We hyper-immunised a whole major UK breeder farm to passively target offspring colonisation using maternally-derived antibody. Monitoring progeny, broiler flocks revealed a near-complete shift in the post-vaccination Campylobacter population with an ~50% reduction in isolates harbouring extra-intestinal survival genes and a significant reduction of Campylobacter cells surviving on the surface of meat. Based on these findings, we developed a logistic regression model that predicted that vaccine efficacy could be extended to target 65% of a population of clinically relevant strains. Immuno-manipulation of poultry microbiomes towards less harmful commensal isolates by competitive exclusion, has major potential for reducing pathogens in the food production chain.

Relevance of repeated analyses of albuminuria and glomerular filtration rate in African children with sickle cell anaemia.

Glomerular hyperfiltration and albuminuria are frequent kidney abnormalities in children with sickle cell anaemia (SCA). However, little is known about their persistence in African SCA children. This prospective study included 600 steady-state SCA children aged 2-18 years from the Democratic Republic of Congo. Participants were genotyped for apolipoprotein L1 (APOL1) risk variants (RVs) and haem oxygenase-1 (HMOX1) GT-dinucleotide repeats. Kidney abnormalities were defined as albuminuria, hyperfiltration or decreased estimated creatinine-based glomerular filtration rate (eGFRcr). At baseline, 247/600 (41.2%) participants presented with kidney abnormalities: 82/592 (13.8%) with albuminuria, 184/587 (31.3%) with hyperfiltration and 15/587 (2.6%) with decreased eGFRcr. After a median follow-up of 5 months, repeated testing was performed in 180/247 (72.9%) available participants. Persistent hyperfiltration and persistent albuminuria (PA) were present in 29.2% (38/130) and 39.7% (23/58) respectively. eGFR normalized in all participants with a baseline decreased eGFRcr. Haemoglobinuria (p = 0.017) and male gender (p = 0.047) were significantly associated with PA and persistent hyperfiltration respectively. APOL1 RVs (G1G1/G2G2/G1G2) were borderline associated with PA (p = 0.075), while HMOX1 long repeat was not associated with any persistent kidney abnormality. This study reveals that a single screening can overestimate the rate of kidney abnormalities in children with SCA and could lead to overtreatment.

The elucidation of species-specific receptor pharmacology: a case study using subtype selective para- and meta-carborane estrogen receptor agonists.

Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) ß is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERß without activating α is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERß-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine estrogen receptors. In vivo selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the in vivo pharmacokinetics of the analogs following single dose IV and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERß-12 for human ERß. However, like others in the meta-carborane series, its poor in vivo pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and in vitro human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK293 cells expressing murine estrogen receptors revealed species-specific differences in the ER-subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. Significance Statement This study investigates para- and meta-substituted carborane analogs targeting estrogen receptors, revealing the greater selectivity of carborane analogs for human ERß compared to the mouse homolog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.

Kigelia africana fruit fractions inhibit in vitro alpha-glucosidase activity: a potential natural alpha-glucosidase inhibitor.

BACKGROUND: Diabetes affects 75% of people in low-income countries, where conventional drugs like metformin are available, but newer drugs like alpha-glucosidase inhibitors are not accessible to most Southern African patients. AIM: To evaluate the α-glucosidase and α-amylase inhibitory activities of fractionated aqueous extracts of Kigelia africana fruit (KAFE) and their phytochemical fingerprints using gas chromatography-mass spectrometry (GC-MS). MATERIALS AND METHODS: We studied K. africana fruit fractions' inhibitory effects on alpha-glucosidase and alpha-amylase using bioassay-guided fractionation, and analyzed their phytochemical profiles with GC-MS. KEY FINDINGS: Both the aqueous extract and ethyl acetate fraction of the aqueous extract exhibited a low dose-dependent inhibition of alpha-amylase activity (p < 0.0001). At a concentration of 500 µg/mL, the aqueous extract caused an alpha-glucosidase inhibition of 64.10 ± 2.7%, with an estimated IC50 of 193.7 µg/mL, while the ethyl acetate fraction had an inhibition of 89.82 ± 0.8% and an estimated IC50 of 10.41 µg/mL. The subfraction G, which had the highest alpha-glucosidase inhibitory activity at 85.10 ± 0.7%, had significantly lower activity than the ethyl acetate fraction. The most bioactive fraction was found to contain 11"(2-cyclopenten-1-yl) undecanoic acid, ( +)- and cyclopentane undecanoic acid as well as the indole alkaloids Akuammilan-17-ol-10-methoxy, N-nitroso-2-methyl-oxazolidine and epoxide Oxirane2.2″ -(1.4-butanediyl) bis-. CONCLUSION: The K. africana fruit fraction demonstrated significant alpha-glucosidase inhibitory activity, while its alpha-amylase inhibitory activity was limited. This study suggests a potential natural alpha-glucosidase inhibitor and phytocompounds that could serve as leads for developing antidiabetic agents.

Strategies and outcomes of extracorporeal membrane oxygenation use in peripartum patients: a single institution experience.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) use in peripartum patients is rare, and there is a gap in the literature on the outcomes and guidance on using ECMO in peripartum patients. This study describes ECMO strategies our institution uses for peripartum patients and reports outcomes of ECMO use in peripartum patients with respiratory and/or cardiac failure. METHODS: A case series of all peripartum patients, defined as pregnant or up to 6 weeks after delivery of an infant >20 weeks gestation, from 2018 to 2023 from a single center requiring ECMO support. Patients were included if ECMO was initiated in the setting of cardiac, pulmonary, or combined failure. Patient demographics, operative details, ECMO data, and adverse outcomes for maternal, fetus, and neonates were all collected. RESULTS: Eighteen patients met the inclusion criteria. The cohort had a mean maternal age of 30.7 years old and was racially diverse. A majority of this cohort tested positive for COVID-19 (n = 10, 55%). ECMO was a bridge to recovery for all patients, of whom 14 (78%) were discharged out of the hospital alive. No patients received transplantation or a durable mechanical device. The most common complications were infection (25%) and postpartum hemorrhage (22%). CONCLUSIONS: ECMO use in peripartum patients in a single tertiary center was associated with a high survival rate. Furthermore, a strong multidisciplinary team, careful reevaluation of clinical trajectory, and consideration of complications and risks associated with using ECMO in peripartum patients are possible frameworks to use when challenged with critically ill peripartum patients.