Assessing the therapeutic and toxicological profile of novel GLP-1 receptor agonists for type 2 diabetes.

INTRODUCTION: GLP-1 receptor agonists provide multiple benefits for patients with type 2 diabetes. Nonetheless, there are also several significant adverse effects associated with these agents. A thorough understanding of both therapeutic and toxicological profiles of GLP-1 receptor agonists is crucial for appropriate utilization of this medication class. A literature search of PubMed and ClinicalTrials.gov was carried out to inform discussion on the topic. AREAS COVERED: This review article discusses the key advantages and disadvantages derived from the use of GLP-1 receptor agonists in the treatment of type 2 diabetes. Landmark trials which helped characterize the cardiovascular and renal benefits of GLP-1 receptor agonists are highlighted. We also discuss key studies still in progress and new formulations under investigation. EXPERT OPINION: GLP-1 receptor agonists provide glycemic and complication-risk reduction benefits for individuals with type 2 diabetes. Current data suggests there is a lot of potential for further applications, even outside of type 2 diabetes management. It would be of particular interest to see the range of benefits conferred from GLP-1 receptor agonists in individuals without type 2 diabetes. Broader application of these medications could be expected given the ongoing development of new oral formulations and combination agents.

Give It a Rest: The Impact of Rest Days on Musculoskeletal Injuries Among Starting Pitchers in Major League Baseball.

OBJECTIVE: Examine the impact of rest days on musculoskeletal (MSK) injury incidence in Major League Baseball (MLB) starting pitchers. DESIGN: Descriptive epidemiological study. SETTING: MLB pitching and injury reports. PARTICIPANTS: MLB starting pitchers. METHODS: Data (2022-2023) were obtained from Baseball-Reference.com and fangraphs.com. Teams were grouped by average rest days between starts (Group A <5 rest days, Group B >5 rest days). Poisson regression was used to compare main outcome measure incidence rate ratios (IRRs). INDEPENDENT VARIABLES: Number of rest days between starts. MAIN OUTCOME MEASURES: Pitches per start, MSK injury incidence, injured list (IL) days for MSK injury. RESULTS: From 2022 to 2023, the average MLB rest days between starts was 4.80. Group A had 54 teams. Group B had 6 teams. The range of average rest days per start by team was 4.56 to 5.73 with a mean of 4.80. Group B pitchers spent 10.7 days on IL for MSK injuries per 1000 pitches, while Group A spent 13.6 days on IL (IRR = 0.78 [95% CI, 0.72-0.85]; P < 0.0001). Group B averaged 0.93 more pitches per start than Group A (P = 0.0164). Group B had a lower number of IL assignments for MSK injuries per 1000 pitches (0.245 vs 0.351, IRR = 0.70 [95% CI, 0.38-1.18]; P = 0.1715). CONCLUSIONS: Starting pitchers on MLB teams averaging > 5 rest days between starts spent less time on the IL for MSK injuries than MLB teams averaging < 5 rest days from 2022 to 2023. There was no clinically significant difference in pitch count and no significant difference in the number of IL assignments for MSK injuries.

Nitric Oxide as an Efficient Antimicrobial Treatment for Second-Degree Burn Wounds.

INTRODUCTION: Nitric oxide (NO) is a lipophilic gas with potent antimicrobial activity. Several in vitro and in vivo studies have demonstrated the broad-spectrum antimicrobial activity of NO-releasing compounds against bacteria, viruses, and parasites. The objective of this study was to assess the efficacy of topical NO formations with sustained release on microbial reduction in wounds. MATERIALS AND METHODS: Swine was used as the preclinical animal model because of the similarities of porcine skin to human skin. Second-degree burn wounds were created in 3 pigs and then inoculated with Methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, or Candida albicans and covered with polyurethane film dressings to create biofilms. After 48 hours, wounds were then treated daily and then recovered for the bacterial burden assessments. Statistical analysis was performed using IBM SPSS statistics 27 using one-way ANOVA. RESULTS: All treatments significantly reduced (P ≤ .05) the bacterial counts between assessment days 4 and 7. Wounds treated with the NVN4000 (1.8%) exhibited greater than 99.7% bacterial reduction on days 4 and 7. Significant differences (P ≤ .05) were observed in wounds treated with NVN4000 (1.8%) compared to silver sulfadiazine. CONCLUSIONS: These studies demonstrate that topical NO-releasing formulations effectively reduce the microbial burden of several microorganisms and exhibit superior antimicrobial efficacy compared to silver sulfadiazine in the porcine wound model.

Characterization and individual-level prediction of cognitive state in the first year after 'mild' stroke.

BACKGROUND: Mild stroke affects more than half the stroke population, yet there is limited evidence characterizing cognition over time in this population, especially with predictive approaches applicable at the individual-level. We aimed to identify patterns of recovery and the best combination of demographic, clinical, and lifestyle factors predicting individual-level cognitive state at 3- and 12-months after mild stroke. METHODS: In this prospective cohort study, the Montreal Cognitive Assessment (MoCA) was administered at 3-7 days, 3- and 12-months post-stroke. Raw changes in MoCA and impairment rates (defined as MoCA<24 points) were compared between assessment time-points. Trajectory clusters were identified using variations of ≥1 point in MoCA scores. To further compare clusters, additional assessments administered at 3- and 12-months were included. Gamma and Quantile mixed-effects regression were used to predict individual MoCA scores over time, using baseline clinical and demographic variables. Model predictions were fitted for each stroke survivor and evaluated using model cross-validation to identify the overall best predictors of cognitive recovery. RESULTS: Participants' (n = 119) MoCA scores improved from baseline to 3-months (p<0.001); and decreased from 3- to 12-months post-stroke (p = 0.010). Cognitive impairment rates decreased significantly from baseline to 3-months (p<0.001), but not between 3- and 12-months (p = 0.168). Nine distinct trajectory clusters were identified. Clinical characteristics between clusters at each time-point varied in cognitive outcomes but not in clinical and/or activity participation outcomes. Cognitive performance at 3- and 12-months was best predicted by younger age, higher physical activity levels, and left-hemisphere lesion side. CONCLUSION: More than half of mild-stroke survivors are at risk of cognitive decline one year after stroke, even when preceded by a significantly improving pattern in the first 3-months of recovery. Physical activity was the only modifiable factor independently associated with cognitive recovery. Individual-level prediction methods may inform the timing and personalized application of future interventions to maximize cognitive recovery post-stroke.

Technical note: Determination of C Q $C_{Q}$ for a miniature x-ray source using a soft x-ray ionization chamber calibrated in NIST reference beam qualities.

BACKGROUND: The C Q $C_Q$ formalism proposed by Watson et al. allows users of the INTRABEAM (Carl Zeiss Medical AG, Jena, Germany) electronic brachytherapy system to accurately determine the absorbed dose to water, in the absence of a primary dosimetry standard. However, all published C Q $C_Q$ values are for PTW 34013 ionization chambers calibrated in a TW30 reference beam, traceable to PTB (Germany). For North American users, it would be advantageous to have C Q $C_Q$ data for chambers calibrated in a kV reference beam maintained by the National Institute of Standards and Technology (NIST). PURPOSE: In this work, we determine C Q $C_Q$ for a PTW 34013 chamber calibrated in three NIST-traceable reference beams: M30, L40, and L50. METHODS: Using available photon spectra data for M30, L40, and L50 reference beam qualities, Monte Carlo simulations using EGSnrc were performed to calculate the ratio of the absorbed dose to the PTW 34013 chamber air cavity to air-kerma ( D gas / K a $D_{\textrm {gas}}/K_a$ ) for these beams. From this ratio, C Q $C_Q$ as a function of depth in water was determined. The effect of the use of a buildup foil was also investigated. An uncertainty analysis considering both the Type A and Type B uncertainties in the calculation of C Q $C_Q$ was performed. RESULTS: The largest difference in C Q $C_Q$ was found between L50 and TW30, with a relative decrease of 1.4% (no buildup) to 1.6% (buildup). For M30 and L40, the differences were minimal compared with measurement uncertainties. CONCLUSIONS: We report C Q $C_Q$ values for three NIST-traceable kV reference beams. This study reinforces the feasibility of adapting the Watson et al. methodology using different kV reference beams, facilitating the use of INTRABEAM in North America and ensuring the continuity and accuracy of dosimetry standards in intraoperative radiation therapy.

Implementation of an optimised tele-medicine platform for stroke in South Australia improves patient care.

Background: Patients with a large vessel occlusion require a transfer from a primary stroke centre to access thrombectomy, often over significant distances in regional areas. We sought to optimise stroke care access in the regional South Australian Tele-Strokeservice (SATS) to improve patient access to thrombectomy. Methods: We undertook a 24-month interventional historically controlled cohort study comparing acute stroke care metrics in the SATS. This consisted of a 12-month control period and a 12-month intervention monitoring period. The study intervention considered of an education package provided to the regional hospitals, a stroke neurologist roster to receive consultations and the intervention of a centralised tele-stroke system to provide treatment advice and organise patient transfers where needed. The SATS services 61 rural hospitals in South Australia, and Alice Springs in the Northern Territory. Suspected acute stroke patients presenting to the participating regional hospitals in SATS network where a telehealth consultation took place. Results: Over the study period, there were 919 patient referrals, with 449 consultations in the pre-intervention phase and 470 in the post-intervention phase. Demographic features in both epochs were similar. The post-intervention phase was associated with shorter door-to-scan time (35 min, IQR: 18,70; vs. 49 min, IQR:25,102, p < 0.0001), faster door-to-thrombolysis time (58 min, IQR: 39,91, vs.83 min, IQR: 55,100, p = 0.0324) and a higher portion of patients treated with thrombectomy (54, 11.5% vs. 26, 5.8%, p = 0.002). Conclusion: An optimised implementation of a streamlined telehealth platform with ongoing education and feedback to referring sites was associated with improved stroke workflow metrics and higher thrombectomy rates.

AAPM WGTG51 Report 385: Addendum to the AAPM's TG-51 protocol for clinical reference dosimetry of high-energy electron beams.

An Addendum to the AAPM's TG-51 protocol for the determination of absorbed dose to water is presented for electron beams with energies between 4 MeV and 22 MeV ( 1.70 cm ≤ R 50 ≤ 8.70 cm $1.70\nobreakspace {\rm cm} \le R_{\text{50}} \le 8.70\nobreakspace {\rm cm}$ ). This updated formalism allows simplified calibration procedures, including the use of calibrated cylindrical ionization chambers in all electron beams without the use of a gradient correction. New k Q $k_{Q}$ data are provided for electron beams based on Monte Carlo simulations. Implementation guidance is provided. Components of the uncertainty budget in determining absorbed dose to water at the reference depth are discussed. Specifications for a reference-class chamber in electron beams include chamber stability, settling, ion recombination behavior, and polarity dependence. Progress in electron beam reference dosimetry is reviewed. Although this report introduces some major changes (e.g., gradient corrections are implicitly included in the electron beam quality conversion factors), they serve to simplify the calibration procedure. Results for absorbed dose per linac monitor unit are expected to be up to approximately 2 % higher using this Addendum compared to using the original TG-51 protocol.

Coblation Versus Surgical Debridement Against MRSA Infection in Wounds With Shrapnel: A Preliminary Study.

INTRODUCTION: Debridement plays a critical role in wound management. In addition to removing necrotic tissue, debridement can eliminate bacteria frequently harbored within the tissue. This study evaluated a novel debridement method that uses plasma-based radiofrequency technology to remove tissue and bacteria. Coblation is a technology that uses radiofrequency energy to excite the electrolytes in a conductive medium, such as saline, to create a precisely focused plasma. This plasma field contains highly energized particles that possess sufficient energy to break tissue molecular bonds, causing the tissue to dissolve at relatively low temperatures (typically 40 °C to 70 °C). MATERIALS AND METHODS: Eighteen deep dermal wounds measuring 22 mm × 22 mm × 3 mm deep were created on pigs. Wounds were inoculated with methicillin-resistant Staphylococcus aureus USA300 (MRSA USA300) in combination with shrapnel and then covered with a polyurethane dressing for 24 hours. Wounds were then randomly assigned to one of the 3 treatment groups: (1) Coblation, (2) surgical debridement, and (3) no debridement. Wounds were biopsied on days 0, 5, 9, and 12, and specimens were processed for MRSA counts using selective media. Statistical analysis was performed using IBM SPSS statistics 27 using one-way ANOVA. RESULTS: Comparison between coblation and surgical debridement showed a decrease in bacterial count in all assessment times. The lowest bacterial count in all assessment times was observed in wounds debrided with coblation showing a statistically significant (P ≤ .05) decrease in more than 2 Log CFU/g on days 0, 5, and 9 compared to no debridement. On day 12, coblation-debrided wounds exhibited 6.10 ± 0.22 Log CFU/g, and this value represents 99.99% of reduction compared with non-debrided wounds (P ≤ .05). More than 96% of reduction (P ≤ .05) resulted in wounds treated with coblation compared with surgically debrided. CONCLUSIONS: Reducing MRSA bacterial infection counts, especially of biofilm-associated organisms, in combination with shrapnel may have important clinical implications, especially for the military personnel. Further research into the use of this technology in wound management is warranted.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Are Cellular Bone Matrix Allografts a Viable Option for Mandibular Tissue Engineering and Reconstruction?

BACKGROUND: Traditional mandibular reconstruction has relied on the use of vascularized and non-vascularized autografts. The use of allografts and tissue engineering modalities has risen as an alternative. PURPOSE: The purpose of this study was to determine the success of a cellular bone matrix (CBM) allograft composed of lineage committed bone forming cells for mandibular tissue engineering and reconstruction. STUDY DESIGN, SETTING, SAMPLE: A retrospective cohort study was implemented using data from subjects treated with a CBM at the University of Louisville from 2019 to 2023. Subjects were excluded if they were not treated with a CBM, data were not complete, or postoperative follow-up time was less than 3 months. PREDICTOR VARIABLES: The predictor variables were composed of heterogenous variables grouped into the following categories: demographics (age, sex), medical history (history of penicillin [PCN] allergy, history of diabetes mellitus [DM] and tobacco use), etiology (benign tumor, ballistic trauma, nonballistic trauma, odontogenic cyst, osteomyelitis/ medication-related osteonecrosis of the jaw), mandibular resection length (cm) and type (marginal, segmental), delayed versus immediate reconstruction, and whether an autograft (proximal tibia) with platelet-rich fibrin was used in combination with the CBM. MAIN OUTCOME VARIABLE: The primary outcome variable was graft success (yes or no). Success was defined as bony union and defect fill (demonstrated on panoramic radiograph) and mandibular stability (based on postoperative clinical examination at 3 months). COVARIATES: Not applicable. ANALYSES: Descriptive statistics were calculated for each variable. To measure the associations between the risk factors and graft success, Fisher's exact test for categorical variables and the Wilcoxon rank sum test for numeric data were used. A P value of <.05 was considered significant. RESULTS: The sample included 38 subjects. The median age of all subjects was 46 (interquartile range 32.6) years. Overall, 28 (73.7%) cases were successful. Subjects with a reported PCN allergy or a history of DM had significantly lower success (2, 7.1% with PCN allergy or DM) compared to those who did not (P = .008, PCN allergy; P = .03, DM). CONCLUSIONS AND RELEVANCE: This is the largest case series of CBM based mandibular reconstruction relative to the available maxillofacial surgery literature. The clinician should consider confirmation of PCN allergy so PCN-type antibiotics can be used. CBMs may be an alternative to autografts.

In vitro analysis of interactions between Pseudomonas aeruginosa and Candida albicans treated with silver sulfadiazine in wound infections.

Background: Microorganisms tend to rely on close relationships with other species to survive. Consequently, biofilms formed by interactions of different species have been shown to delay the wound healing process. Studies suggest these mixed-population infections contribute to the development of drug resistance and inhibition of host immune response. Silver sulfadiazine (SSD) has been shown to effectively decrease the risk of infection in an open wound. Typically, these are bacterial wound infections; however, the role of fungal species needs further attention. Objectives: The purpose of this in vitro study was to determine the effect of SSD on interactions between Pseudomonas aeruginosa 09-009 (PA1) or P. aeruginosa 09-010 (PA2) and Candida albicans ATTC 64550 (CA). Methods: A mixture of 4 mL of tryptic soy broth (TSB) and 100 µL of CA and/or PA1 or PA2 (∼106 log cfu/mL) inoculums were deposited into either wells or vials. The wells or vials were then sonicated (50 W for 10 s) to separate microorganisms attached to the walls. After incubation, cell counts were performed at 24 and 48 h for each microorganism using specific media. Results: Our results show that without SSD treatment, P. aeruginosa exhibits an inhibitory effect on C. albicans. Treatment with SSD demonstrated significant reduction of P. aeruginosa; however, C. albicans persisted. This experiment demonstrates that SSD was effective in reducing the bioburden of both P. aeruginosa strains after 24 and 48 h; however, it was not as effective in reducing C. albicans. Conclusions: The data suggest that for polymicrobial mixed infections containing Pseudomonas spp. and C. albicans, treatment with SSD may be beneficial but does not provide adequate microorganism eradication. As such, added treatments that provide coverage for Candida infection are necessary. Additional in vivo studies are needed to obtain a better understanding of the complex interactions between these organisms.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

Pre-COVID Trends in Substance Use Disorders and Treatment Utilization during Pregnancy in West Virginia 2016-2019.

Introduction: Access to prenatal care offers the opportunity for providers to assess for substance use disorders (SUDs) and to offer important treatment options, but utilization of treatment during pregnancy has been difficult to measure. This study presents pre-COVID trends of a subset of SUD diagnosis at the time of delivery and related trends in treatment utilization during pregnancy. Materials and Methods: A retrospective cohort design was used for the analysis of West Virginia Medicaid claims data from 2016 to 2019. Diagnosis of SUDs at the time of delivery and treatment utilization for opioid use disorder (OUD) and non-OUD diagnosis during pregnancy across time were the principal outcomes of interest. This study examined data from n = 49,398 pregnant individuals. Results: Over the 4-year period, a total of 2,830 (5.7%) individuals had a SUD diagnosis at the time of delivery. The frequency of opioid-related diagnoses decreased by 29.3%; however, non-opioid SUD diagnoses increased by 55.8%, with the largest increase in the diagnosis of stimulant use disorder (30.9%). Treatment for OUD increased by 13%, but treatment for non-opioid SUD diagnoses during pregnancy declined by 41.1% during the same period. Conclusions: Interventions enacted within West Virginia have improved access and utilization of treatment for OUD in pregnancy. However, consistent with national trends in the general population, non-opioid SUD diagnoses, especially for stimulants, have rapidly increased, while treatment for this group decreased. Early identification and referral to treatment by OB-GYN providers are paramount to reducing pregnancy and postpartum complications for the mother and neonate.

Baseline perihematomal edema, C-reactive protein, and 30-day mortality are not associated in intracerebral hemorrhage.

Background: The relationship between baseline perihematomal edema (PHE) and inflammation, and their impact on survival after intracerebral hemorrhage (ICH) are not well understood. Objective: Assess the association between baseline PHE, baseline C-reactive protein (CRP), and early death after ICH. Methods: Analysis of pooled data from multicenter ICH registries. We included patients presenting within 24 h of symptom onset, using multifactorial linear regression model to assess the association between CRP and edema extension distance (EED), and a multifactorial Cox regression model to assess the association between CRP, PHE volume and 30-day mortality. Results: We included 1,034 patients. Median age was 69 (interquartile range [IQR] 59-79), median baseline ICH volume 11.5 (IQR 4.3-28.9) mL, and median baseline CRP 2.5 (IQR 1.5-7.0) mg/L. In the multifactorial analysis [adjusting for cohort, age, sex, log-ICH volume, ICH location, intraventricular hemorrhage (IVH), statin use, glucose, and systolic blood pressure], baseline log-CRP was not associated with baseline EED: for a 50% increase in CRP the difference in expected mean EED was 0.004 cm (95%CI 0.000-0.008, p = 0.055). In a further multifactorial analysis, after adjusting for key predictors of mortality, neither a 50% increase in PHE volume nor CRP were associated with higher 30-day mortality (HR 0.97; 95%CI 0.90-1.05, p = 0.51 and HR 0.98; 95%CI 0.93-1.03, p = 0.41, respectively). Conclusion: Higher baseline CRP is not associated with higher baseline edema, which is also not associated with mortality. Edema at baseline might be driven by different pathophysiological processes with different effects on outcome.

A common regulatory haplotype doubles lactoferrin concentration in milk.

BACKGROUND: Bovine lactoferrin (Lf) is an iron absorbing whey protein with antibacterial, antiviral, and antifungal activity. Lactoferrin is economically valuable and has an extremely variable concentration in milk, partly driven by environmental influences such as milking frequency, involution, or mastitis. A significant genetic influence has also been previously observed to regulate lactoferrin content in milk. Here, we conducted genetic mapping of lactoferrin protein concentration in conjunction with RNA-seq, ChIP-seq, and ATAC-seq data to pinpoint candidate causative variants that regulate lactoferrin concentrations in milk. RESULTS: We identified a highly-significant lactoferrin protein quantitative trait locus (pQTL), as well as a cis lactotransferrin (LTF) expression QTL (cis-eQTL) mapping to the LTF locus. Using ChIP-seq and ATAC-seq datasets representing lactating mammary tissue samples, we also report a number of regions where the openness of chromatin is under genetic influence. Several of these also show highly significant QTL with genetic signatures similar to those highlighted through pQTL and eQTL analysis. By performing correlation analysis between these QTL, we revealed an ATAC-seq peak in the putative promotor region of LTF, that highlights a set of 115 high-frequency variants that are potentially responsible for these effects. One of the 115 variants (rs110000337), which maps within the ATAC-seq peak, was predicted to alter binding sites of transcription factors known to be involved in lactation-related pathways. CONCLUSIONS: Here, we report a regulatory haplotype of 115 variants with conspicuously large impacts on milk lactoferrin concentration. These findings could enable the selection of animals for high-producing specialist herds.

Large vessel occlusive stroke with milder baseline severity shows better collaterals and reduced harm from thrombectomy transfer delays.

BACKGROUND: Patients with large vessel occlusion (LVO) stroke presenting with milder baseline clinical severity are common and require endovascular thrombectomy. However, such patients are difficult to recognize using pre-hospital severity-based triage tools and therefore are likely to require a secondary inter-hospital transfer if transported to a non-thrombectomy center. Given the potential for milder severity to represent better underlying cerebrovascular collateral circulation, it is unknown whether transfer delays are still associated with poorer post-stroke outcomes in this patient group. AIMS: We primarily aimed to examine whether the harmful effect of inter-hospital transfer delay for thrombectomy was different for LVO patients with mild or severe deficits. Secondarily, we also investigated whether imaging markers of collateral circulation were different between severity groups. METHODS: Registry data from two large Australian thrombectomy centers were used to identify all directly presenting and secondarily transferred LVO patients undergoing thrombectomy, divided into those with lower (NIHSS < 10) and higher (NIHSS ⩾ 10) baseline deficits. The primary outcome was the functional independence or return to baseline defined as modified Rankin Scale 0-2 or baseline at 90 days. Patients with complete baseline CT-perfusion data were analyzed for imaging markers of collateral circulation by baseline severity group. RESULTS: A total of 1210 LVO patients undergoing thrombectomy were included, of which 273 (22.6%) had lower baseline severity. Despite similar thrombolysis and recanalization rates, transferred patients had lower odds of achieving the primary outcome compared to the primary presentation to a thrombectomy center, where baseline severity was higher (adjusted odds ratio (aOR) 0.759 (95% CI 0.576-0.999)), but not when severity was lower (aOR 1.357 (95% CI 0.764-2.409), p-interaction = 0.122). In the imaging analysis of 436 patients, those with milder severity showed smaller median ischemic core volumes (12.6 (IQR 0.0-17.9) vs 27.5 (IQR 6.5-37.1) mL, p < 0.001)), higher median perfusion mismatch ratio (10.8 (IQR 4.8-54.5) vs 6.6 (IQR 3.5-16.5), p < 0.001), and lower median hypoperfusion intensity ratio (0.25 (IQR 0.18-0.38) vs 0.40 (IQR 0.22-0.57), p < 0.001). DISCUSSION: Patients receiving secondary inter-hospital transfer for thrombectomy had poorer outcomes compared to those presenting directly to a thrombectomy center if baseline deficits were severe, but this difference was not observed when baseline deficits were milder. This result may potentially be due to our secondary findings of significantly improved collateral circulation markers in lower-severity LVO patients. As such, failure of pre-hospital screening tools to detect lower-severity LVO patients for pre-hospital bypass to a thrombectomy center may not necessarily deleteriously affect outcome. DATA ACCESS STATEMENT: Anonymized data not published within this article will be made available on request from any qualified investigator.

Thrombolysis for Wake-Up Stroke Versus Non-Wake-Up Unwitnessed Stroke: EOS Individual Patient Data Meta-Analysis.

BACKGROUND: Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. METHODS: Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. RESULTS: Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. CONCLUSIONS: There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.