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Our nation is engaged in deep debate over sexual consent. But to date the discussion has overlooked sexual consent’s implications for a key demographic: people with mental disabilities, for whom the reported incidence of sexual violence is three times that of the nondisabled population. Even as popular debate overlooks the question of sexual consent for those with disabilities, contemporary legal scholars critique governmental overregulation of this area, arguing that it diminishes the agency and dignity of people with disabilities. Yet in defending their position, these scholars rely on empirical data from over twenty years ago, when disability and sexual assault laws and social norms looked quite different than those of today. Current scholarly discussions about sexual consent and mental disability suffer from an outdated empirical baseline that masks critical information about the profile and experience of sexual violence. This Article creates a new empirical baseline for modern scholarship on sexual assault and disability. Based on an original survey of all fifty states and jurisprudence from the past twenty years of state sexual assault and rape appeals where the victim has a mental disability, this Article updates and critiques four major claims about sexual consent and disability in the current literature. First, through a review of statutes across the country, it complicates the traditional notion that statutes are unduly vague in their definition of disability, and as a result, either over- or under-emphasize disability. The author advances a new organizing taxonomy for sexual assault statutes addressing consent for people with mental disabilities. Second, this dataset upends the prevailing claim by legal scholars that courts overemphasize standardized evidence such as intelligence quotient (IQ) or mental age when judging a person’s functional capacity to consent to sex. Instead, this Article shows that courts frequently look at adaptive abilities to augment standardized evidence but, in doing so, overvalue certain kinds of adaptive evidence that have low probative value, to the detriment of persons with mental disabilities. Third, legislators and legal scholars focus on people in large institutional settings in their critiques of overregulation, but this new data shows that people in community-based settings are more often the complainants in rape and sexual assault cases. This raises important questions about the types of relationships the state regulates (formal versus informal care relationships), the location of these relationships (community versus institutional settings), and issues of class that intersect with disability and sexual regulation. By not addressing the right issues and contexts, current law leaves people with mental disabilities simultaneously more susceptible to sexual violence and less empowered to exercise sexual agency. Finally, the Article more deeply examines the traditional assumption that people with disabilities rarely have access to testify by considering a rarely-mentioned risk: whether testimony by people with disabilities skews capacity determinations because factfinders cannot see beyond the existence of the disability—a phenomenon which the author terms “the aesthetics of disability.” This Article calls upon scholars, courts, and policymakers to consider difficult questions of regulating sexual consent in ways that are consistent with the current profile and experience of sexual violence for people with mental disabilities reflected in this study.

Background Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting The study was set in primary and secondary care in England from 2010 to 2017. Participants Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval –£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval –£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration This trial is registered as ISRCTN76607611. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information. Plain language summary People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients’ attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks. Scientific summary Background Dual antiplatelet therapy (DAPT), a combination of aspirin and clopidogrel, prasugrel or ticagrelor, is recommended for up to 12 months for secondary prevention of ischaemic events (heart attack and stroke) among people undergoing coronary interventions [coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI)] and people with acute coronary syndrome (ACS) who are medically managed. Randomised controlled trials (RCTs) in these populations suggest that DAPT increases the risk of bleeding compared with aspirin monotherapy, and that more potent DAPT (with prasugrel and ticagrelor) increases the risk of bleeding compared with less potent DAPT (with clopidogrel). Adding an anticoagulant to DAPT (e.g. for the management of atrial fibrillation), known as triple therapy (TT), increases risk further. ‘Real-world’ bleeding among populations exposed to different DAPT and TT regimens has not been previously quantified. The economic impact of bleeding events is poorly characterised, in particular for minor bleeding, as is their impact on health-related quality of life (HRQoL). Objectives 1.Estimate rates of major and minor bleeding events with different DAPT (and TT) exposures among CABG, PCI and conservatively treated ACS patients. 2.Estimate hazard ratios (HRs) for bleeding for different antiplatelet regimens: for the PCI cohort, we compared aspirin and clopidogrel (AC) with aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); for the CABG and ACS no-procedure cohorts, we compared aspirin with AC. 3.Review the literature to estimate the deterioration in utility (quality-adjusted life-years) of patients who have minor or major bleeding events. 4.Revise/extend existing economic models of the cost-effectiveness of different DAPT regimens to include estimates of the incidence of minor and major bleeding events and associated impacts on utility in the general population. 5.Estimate the resources required and associated costs incurred of treating major and minor events of the alternative DAPT (TT) exposures in the three specified patient populations. 6.Understand patients’ perspectives of DAPT, and the factors that influence responses to nuisance bleeding focusing on adherence and information-seeking (this objective was identified through the patient and public involvement work after the start of the ADAPTT study). Methods Objectives 1 and 2 We conducted a study to identify confounders systematically by performing a systematic review of RCTs and cohort studies; conducting semistructured interviews with six cardiac surgeons, six cardiologists and five general practitioners (GPs); and conducting a survey of 79 cardiologists and 31 cardiac surgeons. We used linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations (CABG, PCI and conservatively managed ACS patients) eligible for three ‘target trials’. Inclusion criteria for the target trial were as follows: ≥ 18 years of age, ≥ 1 year of data in CPRD before the index event, no prescription for DAPT or anticoagulants in the preceding 3 months and a prescription for aspirin or DAPT within 2 months of discharge after the index event. The primary outcome was any bleeding event (CPRD or HES data) up to 12 months after the index event. We described rates of bleeding among patients prescribed different DAPT regimens and TT. We estimated adjusted HRs for time to first bleed comparing DAPT with AC (reference) versus aspirin monotherapy for CABG and conservatively managed ACS patient, and, in the emergency PCI population, DAPT with prasugrel versus DAPT with clopidogrel for ST-elevation myocardial infarction (STEMI) patients only and DAPT with ticagrelor versus DAPT with clopidogrel for all the emergency PCI population. We prespecified five sensitivity analyses and conducted three: sensitivity analysis 1 – multiple imputation for eligible patients for whom we had no data to assign an intervention; sensitivity analysis 3 – restricted to patients at low risk of bleeding; and sensitivity analysis 4 – repeating primary outcome analysis without censoring of any CPRD or HES bleed events at transfer-out or last collection date. The transfer-out or last collection date reflect the date that a patient leaves the general practice or the date that the last capture from CPRD was made. Objective 3 A systematic review was conducted of primary research and decision-analytic modelling studies reporting utility decrements for bleeds related to DAPT through a search of MEDLINE, PubMed and references of included studies. A health elicitation study was undertaken, comprising 21 participants (PCI, CABG and conservatively managed ACS) who completed an elicitation exercise involving vignettes describing minor and major bleeds and the EuroQol-5 Dimensions, three-level version (EQ-5D-3L), and the EuroQol-5 Dimensions, five-level version (EQ-5D-5L). Utility decrements were derived using linear regression, and were compared with existing estimates. Objective 4 No formal cost-effectiveness evaluation was undertaken. Objective 5 Data on health-care use were derived from the linked CPRD–HES data set. The total health-care costs associated with the different antiplatelet regimens in the three target trials were measured at 1, 2 and 3 years after the start of follow-up. We used inverse probability of treatment weighting to adjust for the same confounders identified for the main ADAPTT analysis. The total health-care costs at 1, 2 and 3 years of follow-up were estimated by fitting weighted generalised linear models with gamma distribution and log-link. Objective 6 Two focus groups were conducted with patients at the early stages of treatment (0–3 months, nine participants), and two with patients coming to the end of treatment (9–12 months, 12 participants), to explore their experiences with DAPT. Recordings were transcribed verbatim, anonymised and analysed using framework analysis. Research findings Objectives 1 and 2 Confounders study A total of 70 potential confounders were identified by systematic review, clinician interviews and surveys; of these, 34 (49%) were classified as true confounders (factors that influence both the assigned intervention and the outcome), of which 31 (91%) were identified by systematic review and three (9%) by clinician interview, and 31 (91%) were confirmed by the survey. The clinician interviews identified hard-to-measure factors not identified in the review (drug potency, resistance to antiplatelet medication and clinician concerns about adherence). Data that would enable the characterisation of risk, including presentation risk and procedural risk factors, were unavailable for 17 of the 34 confounders (50%). The ADAPTT study A proportion of eligible participants were excluded from each target trial because they could not be assigned an intervention at baseline (17%, 40% and 9% of the CABG, conservatively managed ACS and emergency PCI patients, respectively). The incidence of any bleeding was 5%, 10% and 9% in CABG patients, conservatively managed ACS patients and emergency PCI patients, respectively; the corresponding rates of minor bleeding were 4%, 7% and 7%, respectively. Compared with aspirin monotherapy, DAPT was associated with an increase in the hazards of any bleeding and of major adverse cardiovascular events (MACEs) among CABG [HR 1.72, 95% confidence interval (CI) 1.15 to 2.57, and HR 2.06, 95% CI 1.23 to 3.46, respectively] and conservatively managed ACS patients (HR 1.43, 95% CI 1.21 to 1.69, and HR 1.57, 95% CI 1.38 to 1.78, respectively). Among emergency PCI patients, compared with less potent DAPT (with clopidogrel), more potent DAPT with ticagrelor (ACS and STEMI patients only) or prasugrel (STEMI patients only) increased the hazard of bleeding (HR 1.47, 95% CI 1.19 to 1.82; HR 1.47, 95% CI 1.08 to 2.00; and HR 1.77, 95% CI 1.21 to 2.58, respectively), but there was no association with MACEs (HR 1.06, 95% CI 0.89 to 1.27; HR 1.21, 95% CI 0.94 to 1.56; and HR 1.10, 95% CI 0.80 to 1.51, respectively). Sensitivity analyses using multiple imputation to impute for the intervention assigned at baseline did not materially change these results. Non-adherence to the treatment assigned at baseline was generally higher in the CABG and conservatively-managed ACS target trials (affecting up to 46% and 44% of patients, respectively) than in the in emergency PCI (affecting up to 33% of patients). Triple therapy The median duration of TT was 3.5 months. The incidence of any bleeding among patients prescribed TT was 18%. There was no difference in the incidence of any bleeding, or of major bleeding or minor bleeding, between patients on TT with warfarin and patients on TT with a non-vitamin K oral anticoagulant (NOAC). However, mortality from bleeding was higher among patients on TT with a NOAC than among patients on TT with warfarin (2% vs. 0%), as was the incidence of stroke (4% vs. 0%). Objective 3 Twelve eligible studies were included for review. Reported utility decrements ranged from –0.002 to –0.03 for minor bleeds and –0.007 to –0.05 for major bleeds. Data sources used to estimate the decrements lacked relevance to our population group, and few studies adequately reported details of their measurement and valuation approaches. Our patient health elicitation study elicited utility decrements that overlapped existing estimates, ranging from –0.000848 to –0.00828 for minor bleeds and from –0.0187 to –0.0621 for major bleeds. However, the magnitude of difference depended on the instrument (EQ-5D-5L or EQ-5D-3L), estimation method and valuation approach applied. Objective 5 The mean total health-care cost in the year prior to the index event was much higher for CABG patients (£13,601) than for conservatively managed ACS (£3528) or emergency PCI patients (£3625). For CABG patients, mean costs were similar between different antiplatelet regimens (£13,623 for aspirin monotherapy and £13,537 for DAPT with clopidogrel). For conservatively managed ACS, patients on DAPT with clopidogrel had a lower mean total health-care cost in the year prior to the index date than patients on aspirin monotherapy (£3317 vs. £3857, respectively). Among emergency PCI patients, those initiated on DAPT with clopidogrel had a higher mean total health-care cost in the year prior to the index event (£4492) than those initiated on DAPT with prasugrel (STEMI patients only) (£1660) or ticagrelor (£2829). Among the CABG population, there was no difference in mean cumulative health-care costs between initiation of DAPT with clopidogrel and initiation of aspirin monotherapy; the mean difference at 1, 2 and 3 years was £94 (95% CI –£555 to £763), £236 (95% CI –£831 to £1223) and £113 (95% CI –£1318 to £1102), respectively. Among the conservatively managed ACS population, the mean cumulative health-care costs were estimated to be slightly higher if all patients were treated with DAPT with clopidogrel than if all were treated with aspirin monotherapy; the mean difference at 1, 2 and 3 years was £610 (95% CI –£626 to £1516), £1118 (95% CI –£226 to £2206) and £1225 (95% CI –£426 to £2423), respectively, although there was considerable overlap between CIs. For emergency PCI patients, the estimated cumulative health-care costs were comparable under the different antiplatelet regimens among patients not receiving concurrent proton pump inhibitor (PPI) prescriptions, but were higher for patients receiving DAPT with ticagrelor than for patients receiving DAPT with clopidogrel. At 1 year, for example, the predicted mean difference in health-care costs if all patients received DAPT with ticagrelor rather than DAPT with clopidogrel was £72 (95% CI –£532 to £762) among those not receiving concurrent PPI therapy and £1145 (95% CI £269 to £2195) among those receiving concurrent PPI therapy. Among STEMI patients receiving concurrent PPI therapy, DAPT with prasugrel was associated with higher costs than DAPT with clopidogrel or DAPT with ticagrelor. Objective 6 Participants would adhere to DAPT when they believed that DAPT was important to ACS outcomes. Those who had experienced nuisance bleeding reported symptoms to be mild and manageable and did not report the bleed to their GP. Adherence was influenced by participants’ and their families’ understanding of the risks and benefits of DAPT, and their ability to manage symptoms. Factors influencing knowledge about DAPT included access to medication counselling; processing of and engaging with information communicated during medication counselling; and access to timely, relevant and expert information and advice after discharge from hospital. Conclusions There is underascertainment of minor/nuisance bleeding in the CPRD, probably as a result of under-reporting of nuisance bleeding by patients to their GPs. In three retrospective population-based cohort studies emulating target trials, there was an increased risk of bleeding among patients receiving DAPT compared with those receiving aspirin monotherapy (CABG and conservatively managed ACS patients) and among patients receiving more potent DAPT than among those receiving less potent DAPT (emergency PCI patients), but not the expected decrease in MACEs. We identified several potential biases that may have influenced the results of the ADAPTT study as a result of imperfect emulation of the defined target trials: (1) selection bias – we excluded a subgroup of the eligible population because they could not be assigned an intervention; (2) confounding – we had no data for half of the confounders identified, including procedure-related characteristics and disease complexity, and evidence from clinician interviews and surveys that clinicians balance bleeding and ischaemic risk when prescribing DAPT to their patients; and (3) non-adherence to DAPT, which was substantial, and generally higher in the stronger antiplatelet treatment groups. Medication knowledge and understanding, and confidence in dealing with symptoms facilitate positive attitudes towards adherence to DAPT, but may be hindered by opportunities to access relevant, timely and appropriate medication counselling. Although we derived relevant utility decrements for the included population using a patient elicitation exercise, based on standardised definitions of minor and major bleeding events, using a validated HRQoL instrument and valued using general population tariffs, we could not conduct a formal cost-effectiveness analysis given the uncertainty around the estimates for bleeding. Nevertheless, the results using routinely collected data need to be carefully considered by clinicians and decision-makers, given that the increased risk of bleeding we observed with more potent DAPT was not offset by a reduced risk of cardiovascular events and that several recent large meta-analyses of RCTs have also failed to show a conclusive benefit of more potent antiplatelet therapy on cardiovascular events. Future work Future research should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Research is needed to develop guidance for identifying confounders and how confounders should be organised into confounding domains to facilitate consistent implementation of the Risk Of Bias In Non-randomized Studies – of Interventions (ROBINS-I) tool. The principle of designing an observational study to emulate a RCT by first defining a target trial appears to be a robust approach, highlighting where the emulation succeeds or fails. Nevertheless, further research is required to validate instances in which an emulation is considered to have been successful, ideally prospectively (i.e. using observational data to emulate ongoing RCTs before their data are analysed and the results are known).We recommend that our utility decrements are used in future cost-effectiveness analyses of DAPT in a UK setting, particularly for minor bleeding events for which existing evidence is limited. In addition, we recommend that future research focuses on quantifying the value of information from reducing the uncertainty of our estimated utility decrements. This research would demonstrate whether or not conducting a larger, more robust study to collect additional information on the HRQoL impact of minor and major bleeds for patients taking DAPT would be an efficient use of resources. The qualitative study with patients highlighted that medication knowledge and understanding, and confidence in dealing with symptoms, facilitate positive attitudes towards adherence to DAPT, but that, currently, there are limited opportunities for patients to access relevant, timely and appropriate DAPT medication counselling. Future qualitative research should focus on developing an intervention to support service users taking DAPT. Trial registration This trial is registered as ISRCTN76607611. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

Cor triatriatum sinister (CTS) is a rare congenital cardiac malformation. In CTS, a fibromuscular membrane subdivides the left atrium into 2 chambers. The communication between the 2 chambers is through 1 or more orifices in the dividing membrane. We present an interesting case of a 2-month-old infant with obstructed CTS membrane who first presented on account of poor feeding and failure to thrive. Echocardiography showed a persistent levoatrial cardinal vein (LACV) connecting the left atrium and the innominate vein. This allowed the proximal left atrial chamber to decompress its blood volume into the innominate vein and subsequently the superior vena cava. There was minimal prograde blood flow across the Cor triatriatum membrane, so the majority of pulmonary venous blood ultimately returned to the heart by way of the decompressing vertical vein into the systemic venous circulation. Surgical repair was performed with an uneventful postoperative course. The specific anatomical variant of Cor triatriatum found in our subject has rarely been reported.

Obesity has become a global problem. This problem is associated with a worldwide rising incidence of noncommunicable, chronic diseases. In countries with lower Gross National Products obesity tends to be a problem of the affluent. In those with high Gross National Products it tends to be a problem of those of lower socioeconomic status. The worldwide consequences of global obesity are devastating. This article addresses the scope, consequences, and etiology of the global obesity epidemic along with a comprehensive approach for combating this worldwide problem. In addition, ideas are given as to how dietitians, who have the training related to food and nutrition to be an asset in addressing global obesity, can become involved in combating this problem. [ABSTRACT FROM AUTHOR]

This study was an assessment of the knowledge, attitudes, and self-reported practices of Pennsylvania registered dietitians regarding functional foods and herbal medicine. Results showed a positive association between attitudes, knowledge, and personal use. Pennsylvania registered dietitians are knowledgeable and have positive attitudes toward functional foods and herbal medicine; however, they tend not to recommend them to patients. Oregon licensed dietitians compared with this sample were more knowledgeable and more likely to recommend these items to their clients. Generally, educational efforts to increase awareness and knowledge on functional foods and herbal medicine for the dietetics professional are needed. [ABSTRACT FROM AUTHOR]

OBJECTIVES: This research assessed the relationship between the deliveries of carcinogenic tobacco-specific nitrosamines (TSNAs) and the Federal Trade Commission (FTC) 'tar' ratings of US commercial cigarettes. METHODS: Analysis of covariance (ANCOVA) was used to assess the explanatory power of FTC tar, the particular manufacturer, and other cigarette characteristics to predict the yields of four TSNAs (N'-nitrosonornicotine [NNN], 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone [NNK], N'-nitrosoanatabine [NAT], and N'-nitrosoanabasine [NAB]) in 26 US commercial brands tested in the 1999 Massachusetts Benchmark Study. RESULTS: When FTC tar alone was used to predict TSNA yield, the squared correlation coefficient (R(2)) was only 38% for NNN, 76% for NNK, 46% for NAT, and 49% for NAB. Inclusion of manufacturer-specific variables significantly (p < 0.001) increased the estimated R(2) for three of the four species of nitrosamine to: 78% for NNN, 88% for NNK, and 81% for NAT. Inclusion of other cigarette characteristics (filter type, paper permeability, tobacco weight, tip dilution) did not reduce the significance of the manufacturer-specific effects. Federal Trade Commission nicotine and carbon monoxide (CO) yields were no better at predicting TSNA levels. CONCLUSIONS: FTC ratings for tar, nicotine, and carbon monoxide do not tell the entire story about the comparative yields of toxic agents in marketed cigarette brands. The significant manufacturer-specific effects suggest that proprietary blending and processing of tobacco matter as well. Public, brand-by-brand disclosure of the yields of TSNA and possibly other smoke constituents appears to be warranted. [ABSTRACT FROM AUTHOR]

Abstract Background Chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-seq) offers high resolution, genome-wide analysis of DNA-protein interactions. However, current standard methods require abundant starting material in the range of 1–20 million cells per immunoprecipitation, and remain a bottleneck to the acquisition of biologically relevant epigenetic data. Using a ChIP-seq protocol optimised for low cell numbers (down to 100,000 cells / IP), we examined the performance of the ChIP-seq technique on a series of decreasing cell numbers. Results We present an enhanced native ChIP-seq method tailored to low cell numbers that represents a 200-fold reduction in input requirements over existing protocols. The protocol was tested over a range of starting cell numbers covering three orders of magnitude, enabling determination of the lower limit of the technique. At low input cell numbers, increased levels of unmapped and duplicate reads reduce the number of unique reads generated, and can drive up sequencing costs and affect sensitivity if ChIP is attempted from too few cells. Conclusions The optimised method presented here considerably reduces the input requirements for performing native ChIP-seq. It extends the applicability of the technique to isolated primary cells and rare cell populations (e.g. biobank samples, stem cells), and in many cases will alleviate the need for cell culture and any associated alteration of epigenetic marks. However, this study highlights a challenge inherent to ChIP-seq from low cell numbers: as cell input numbers fall, levels of unmapped sequence reads and PCR-generated duplicate reads rise. We discuss a number of solutions to overcome the effects of reducing cell number that may aid further improvements to ChIP performance.

Abstract Background The scientific process around cancer research begins with scientific discovery, followed by development of interventions, and finally delivery of needed interventions to people with cancer. Numerous studies have identified substantial gaps between discovery and delivery in health research. Team science has been identified as a possible solution for closing the discovery to delivery gap; however, little is known about effective ways of collaborating within teams and across organizations. The purpose of this study was to determine benefits and drawbacks associated with organizational collaboration across the discovery-development-delivery research continuum. Methods Representatives of organizations working on cancer research across a state answered a survey about how they collaborated with other cancer research organizations in the state and what benefits and drawbacks they experienced while collaborating. We used exponential random graph modeling to determine the association between these benefits and drawbacks and the presence of a collaboration tie between any two network members. Results Different drawbacks and benefits were associated with discovery, development, and delivery collaborations. The only consistent association across all three was with the drawback of difficulty due to geographic differences, which was negatively associated with collaboration, indicating that those organizations that had collaborated were less likely to perceive a barrier related to geography. The benefit, enhanced access to other knowledge, was positive and significant in the development and delivery networks, indicating that collaborating organizations viewed improved knowledge exchange as a benefit of collaboration. ‘Acquisition of additional funding or other resources’ and ‘development of new tools and methods’ were negatively significantly related to collaboration in these networks. So, although improved knowledge access was an outcome of collaboration, more tangible outcomes were not being realized. In the development network, those who collaborated were less likely to see ‘enhanced influence on treatment and policy’ and ‘greater quality or frequency of publications’ as benefits of collaboration. Conclusion With the exception of the positive association between knowledge transfer and collaboration and the negative association between geography and collaboration, the significant relationships identified in this study all reflected challenges associated with inter-organizational collaboration. Understanding network structures and the perceived drawbacks and benefits associated with collaboration will allow researchers to build and funders to support successful collaborative teams and perhaps aid in closing the discovery to delivery gap.

Abstract Background The ability to share human biological samples, associated data and results across disease-specific and population-based human research biobanks is becoming increasingly important for research into disease development and translation. Although informed consent often does not anticipate such cross-domain sharing, it is important to examine its plausibility. The purpose of this study was to explore the feasibility of bridging consent between disease-specific and population-based research. Comparative analyses of 1) current ethical and legal frameworks governing consent and 2) informed consent models found in disease-specific and population-based research were conducted. Discussion Ethical and legal frameworks governing consent dissuade cross-domain data sharing. Paradoxically, analysis of consent models for disease-specific and population-based research reveals such a high degree of similarity that bridging consent could be possible if additional information regarding bridging was incorporated into consent forms. We submit that bridging of consent could be supported if current trends endorsing a new interpretation of consent are adopted. To illustrate this we sketch potential bridging consent scenarios. Summary A bridging consent, respectful of the spirit of initial consent, is feasible and would require only small changes to the content of consents currently being used. Under a bridging consent approach, the initial data and samples collection can serve an identified research project as well as contribute to the creation of a resource for a range of other projects.

Objective: We evaluated the impact of Seguro Popular (SP), a program introduced in 2001 in Mexico primarily to finance health care for the poor. We focused on the effect of household enrollment in SP on pregnant women's access to obstetrical services, an important outcome measure of both maternal and infant health.Data: We relied upon data from the cross-sectional 2006 National Health and Nutrition Survey (ENSANUT) in Mexico. We analyzed the responses of 3890 women who delivered babies during 2001-2006 and whose households lacked employer-based health care coverage.Methods: We formulated a multinomial probit model that distinguished between three mutually exclusive sites for delivering a baby: a health unit specifically accredited by SP; a non-SP-accredited clinic run by the Department of Health (Secretaría de Salud, or SSA); and private obstetrical care. Our model accounted for the endogeneity of the household's binary decision to enroll in the SP program.Results: Women in households that participated in the SP program had a much stronger preference for having a baby in a SP-sponsored unit rather than paying out of pocket for a private delivery. At the same time, participation in SP was associated with a stronger preference for delivering in the private sector rather than at a state-run SSA clinic. On balance, the Seguro Popular program reduced pregnant women's attendance at an SSA clinic much more than it reduced the probability of delivering a baby in the private sector. The quantitative impact of the SP program varied with the woman's education and health, as well as the assets and location (rural vs. urban) of the household.Conclusions: The SP program had a robust, significantly positive impact on access to obstetrical services. Our finding that women enrolled in SP switched from non-SP state-run facilities, rather than from out-of-pocket private services, is important for public policy and requires further exploration. [ABSTRACT FROM AUTHOR]

Background: Patients with continuous flow left ventricular assist devices (CF-LVADs) are at increased risk of gastrointestinal bleeding (GIB). Statins are commonly prescribed in LVAD patients for cardiovascular disease prevention. However, their impact on GIB events is controversial. Importantly, literature regarding statins impact on GIB in CF-LVAD patients is lacking., Methods: A single-center, retrospective review of adult patients who underwent CF-LVAD implantation between May 2016 and January 2020 was performed. Patients were categorized based on statin use throughout the study period. The primary outcome was the composite of arteriovenous malformation confirmed GIB and major GIB events for up to 1-year post-LVAD implantation., Results: Of 123 patients included in the final analysis, 66 (54%) received statin therapy during the study period. No difference was observed in the primary outcome between the statin and control groups (RR: 1.73; 95% CI: 0.75-3.98; p =0.20). Multivariable Cox regression revealed that older age and higher baseline creatinine were associated with an increased risk of GIB within 1-year of CF-LVAD implantation., Conclusion: Among patients with CF-LVADs, there was no significant difference in the incidence of major GIB events associated with the use of statin therapy. Further studies are needed to assess whether a true association exists., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We describe a novel approach for recovering the underlying parameters of the SIR dynamic epidemic model from observed data on case incidence. We formulate a discrete-time approximation of the original continuous-time model and search for the parameter vector that minimizes the standard least squares criterion function. We show that the gradient vector and matrix of second-order derivatives of the criterion function with respect to the parameters adhere to their own systems of difference equations and thus can be exactly calculated iteratively. Applying our new approach, we estimated a four-parameter SIR model from daily reported cases of COVID-19 during the SARS-CoV-2 Omicron/BA.1 surge of December 2021-March 2022 in New York City. The estimated SIR model showed a tight fit to the observed data, but less so when we excluded residual cases attributable to the Delta variant during the initial upswing of the wave in December. Our analyses of both the real-world COVID-19 data and simulated case incidence data revealed an important problem of weak parameter identification. While our methods permitted for the separate estimation of the infection transmission parameter and the infection persistence parameter, only a linear combination of these two key parameters could be estimated with precision. The SIR model appears to be an adequate reduced-form description of the Omicron surge, but it is not necessarily the correct structural model. Prior information above and beyond case incidence data may be required to sharply identify the parameters and thus distinguish between alternative epidemic models., Competing Interests: Declaration of conflicting interestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Allergic contact dermatitis (ACD) is a pruritic skin disease caused by environmental chemicals that induce cell-mediated skin inflammation within susceptible individuals. Irritant contact dermatitis (ICD) is caused by direct damage to the skin barrier by environmental insults. Diagnosis can be challenging because both types of contact dermatitis can appear similar by visual examination, and histopathological analysis does not reliably distinguish ACD from ICD. To discover specific biomarkers of ACD and ICD, we characterized the transcriptomic and proteomic changes that occur within the skin during each type of contact dermatitis. We induced ACD and ICD in healthy human volunteers and sampled skin using a nonscarring suction blister biopsy method that collects interstitial fluid and cellular infiltrate. Single-cell RNA sequencing analysis revealed that cell-specific transcriptome differences rather than cell-type proportions best distinguished ACD from ICD. Allergy-specific genes were associated with upregulation of IFNG, and cell signaling network analysis implicated several other genes such as IL4, despite their low expression levels. We validated transcriptomic differences with proteomic assays on blister fluid and trained a logistic regression model on skin interstitial fluid proteins that could distinguish ACD from ICD and healthy control skin with 93% sensitivity and 93% specificity., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To explore student and tutor perspectives on the learning efficacy of virtual, compared to in-person, problem-based tutorial (PBT) in occupational therapy, physiotherapy, and speech-language pathology health professional programs., Materials and Methods: This was a quality improvement study using a cross sectional survey at a single institution. Separate student and tutor surveys were disseminated online. Students received the survey at two timepoints, tutors received the survey at one timepoint. Descriptive statistics summarized quantitative survey questions. Chi-squared or Fischer's Exact analyses explored differences between in-person and virtual PBT. Exploratory analyses determined if associations amongst programs and/or between cohorts existed on variables of interest. Open-ended survey questions were analyzed using content analysis., Results: A total of 241 students and 85 tutors completed the survey. Results demonstrate most students and tutors were satisfied with the use of virtual tutorials (77%; 89% respectively) and felt that they were effective in exploring content within the PBT course. However, students in the most recent cohort rated virtual tutorials more highly ( p  = 0.01)., Conclusions: Virtual modes of PBT were successful in achieving course objectives and led to high satisfaction in users. Health professional programs can use this information when designing virtual problem-based tutorial courses in the post-pandemic era.

Background: Clinical quality registries (CQRs) are intended to enhance quality, safety, and cost reduction using real-world data for a self-improving health system. Starting in 2001, Kaiser Permanente established several medical device CQRs as a quality improvement initiative. This report examines the contributions of these CQRs on improvement in health outcomes, changes in clinical practice, and cost-effectiveness over the past 20 years., Methods: Eight implant registries were instituted with standardized collection from the electronic health record and other institutional data sources of patient characteristics, medical comorbidities, implant attributes, procedure details, surgical techniques, and outcomes (including complications, revisions, reoperations, hospital readmissions, and other utilization measures). A rigorous quality control system is in place to improve and maintain the quality of data. Data from the Implant Registries form the basis for multiple quality improvement and patient safety initiatives to minimize variation in care, promote clinical best practices, facilitate recalls, perform benchmarking, identify patients at risk, and construct reports about individual surgeons., Results: Following the inception of the Implant Registries, there was an observed (1) reduction in opioid utilization following orthopedic procedures, (2) reduction in use of bone morphogenic protein during lumbar fusion allowing for cost savings, (3) reduction in allograft for anterior cruciate ligament reconstruction and subsequent decrease in organizationwide revision rates, (4) cost savings through expansion of same-day discharge programs for joint arthroplasty, (5) increase in the use of cement fixation in the hemiarthroplasty treatment of hip fracture, and (6) organizationwide discontinuation of an endograft device associated with a higher risk for adverse outcomes following endovascular aortic aneurysm repair., Conclusion: The use of Implant Registries within our health system, along with clinical leadership and organizational commitment to a learning health system, was associated with improved quality and safety outcomes and reduced costs. The exact mechanisms by which such registries affect health outcomes and costs require further study., (Copyright © 2024 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Traditional skin sampling methods include punch or shave biopsies to produce a solid tissue sample for analysis. These biopsy procedures are painful, require anesthesia, and leave permanent scars. This unit describes a suction blister skin biopsy method that can be used in place of traditional biopsy methodologies as a minimally invasive, non-scarring skin sampling technique. The induction of suction blisters uses an instrument with a chamber that applies negative pressure and gentle heat to the skin. Blister formation occurs within 1 hr, producing up to five blisters, each 10 mm in diameter per biopsy site. Blister fluid can be extracted and centrifuged to retrieve cells from the epidermis and upper dermis for flow cytometry, single-cell RNA sequencing, cell culture, and more without the need for digestion protocols. In addition, the blister fluid can be used to measure soluble proteins and metabolites. This unit describes the preparation of supplies and subjects, the suction blister biopsy procedure and blister formation, fluid extraction, and post-blistering care. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Preparation of supplies and subject Basic Protocol 2: Suction blister biopsy procedure and formation Basic Protocol 3: Blister fluid extraction Basic Protocol 4: Post-blister care and clean up., (© 2024 Wiley Periodicals LLC.)

Background: Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo., Methods: This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6 mg (UPA6), upadacitinib 11 mg (UPA11), upadacitinib 22 mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975., Findings: Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n = 49), UPA11 (n = 47), UPA22 (n = 43), or PBO (n = 46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was -7.60 (95% CI -22.18 to 6.97; p = 0.3037) for UPA6, -21.27 (95% CI -36.02 to -6.52; p = 0.0051) for UPA11, and -19.60 (95% CI -35.04 to -4.16; p = 0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was -7.45 (95% CI -16.86 to 1.96; p = 0.1198) for UPA6, -10.84 (95% CI -20.37 to -1.32; p = 0.0259) for UPA11 and -14.27 (95% CI -24.24 to -4.30; p = 0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n = 1)] and non-fatal ischemic stroke [UPA11 (n = 1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed., Interpretation: Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15 mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial., Funding: AbbVie Inc., Competing Interests: TP is a consultant for AbbVie, Almirall, Amgen, Bristol Myers Squibb, Calypso, Galderma, Incyte Corporation, Janssen, Eli Lilly, Novartis, Pfizer, Roivant, UCB, and VYNE Therapeutics. He has received grants and/or honoraria from AbbVie, ACM Pharma, Almirall, Amgen, Astellas, Bristol Myers Squibb, Calypso, Celgene, Galderma, Genzyme/Sanofi, GlaxoSmithKline, Incyte Corporation, Janssen, LEO Pharma, Eli Lilly, Novartis, Pfizer, Roivant, Sun Pharmaceuticals, UCB, and VYNE Therapeutics. He is the cofounder of YUKIN Therapeutics; and has patents on WNT agonists or GSK3b antagonist for repigmentation of vitiligo and the use of CXCR3B blockers in vitiligo. KE is a consultant for AbbVie, Incyte Corporation, La Roche-Posay, Pfizer, Pierre Fabre, Sanofi, and Viela Bio. IH is a consultant for AbbVie, Almirall, Avita, Boehringer Ingelheim, Galderma, Incyte, Jansen, Novartis, Pfizer, Sonoma, UCB, and Union Therapeutics. He is an investigator for Avita, Incyte, Lenicura, L’Oréal/Laroche Posay, and Pfizer, and a board member and past president of the Hidradenitis Suppurativa Foundation and Global Vitiligo Foundation. NvG is a consultant and/or investigator for AbbVie, Pfizer, Incyte, MDS/Merck, and Sunpharma and has received grants from AbbVie, Incyte, Pfizer, and COURD-COUSIN Collaboration (C3). She is the chair of the Vitiligo International Task Force group. DR has served as a consultant, spoken for, or conducted trials for the following companies: AbbVie, Abcuro, AltruBio, Amgen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Galderma, Incyte, Janssen, Kyowa Kirin, Lilly, Merck, Nektar, Novartis, Pfizer, RAPT, Regeneron, Recludix, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, Viela Bio, and Zura Bio. JEH is a consultant for AbbVie, Aldena, Almiral, Avita, Biologics MD, Genzyme/Sanofi, Granular Therapeutics, Incyte, Klirna, LEO Pharma, Matchpoint Therapeutics, Merck, NIRA Biosciences, Pfizer, Sun Pharmaceuticals, Temprian Therapeutics, Vimela Therapeutics, and Vividion Therapeutics. He is an investigator for Genzyme/Sanofi, Incyte, LEO Pharma, Pfizer, and Sun Pharmaceuticals; and holds equity stock (founder) in Aldena, Klirna, NIRA Biosciences, and Vimela Therapeutics. AGP is a consultant for AbbVie, Arcutis, Avita, Immune Tolerance Network, Incyte, Pfizer, Thalocan, WCG/Trifecta, Twi Pharmaceuticals, Villaris, Vimela, and VYNE Therapeutics. He is an investigator for Incyte; and holds stock options in Tara Medical and Zerigo Health. BJS, XW, XH, AMS, and HSC are full-time employees of AbbVie and may own stock and/or options and patents., (© 2024 The Author(s).)

Competing Interests: None disclosed.

Objective: Biomechanical factors in lumbar fusions accelerate the development of adjacent-segment disease (ASD). Stiffness in the fused segment increases motion in the adjacent levels, resulting in ASD. The objective of this study was to determine if there are differences in the reoperation rates for symptomatic ASD (operative ASD) between anterior lumbar interbody fusion plus pedicle screws (ALIF+PS), posterior lumbar interbody fusion plus pedicle screws (PLIF+PS), transforaminal lumbar interbody fusion plus pedicle screws (TLIF+PS), and lateral lumbar interbody fusion plus pedicle screws (LLIF+PS)., Methods: A retrospective study using data from the Kaiser Permanente Spine Registry identified an adult cohort (≥ 18 years old) with degenerative disc disease who underwent primary lumbar interbody fusions with pedicle screws between L3 to S1. Demographic and operative data were obtained from the registry, and chart review was used to document operative ASD. Patients were followed until operative ASD, membership termination, the end of study (March 31, 2022), or death. Operative ASD was analyzed using Cox proportional hazards models., Results: The final study population included 5291 patients with a mean ± SD age of 60.1 ± 12.1 years and a follow-up of 6.3 ± 3.8 years. There was a total of 443 operative ASD cases, with an overall incidence rate of reoperation for ASD of 8.37% (95% CI 7.6-9.2). The crude incidence of operative ASD at 5 years was the lowest in the ALIF+PS cohort (7.7%, 95% CI 6.3-9.4). In the adjusted models, the authors failed to detect a statistical difference in operative ASD between ALIF+PS (reference) versus PLIF+PS (HR 1.06 [0.79-1.44], p = 0.69) versus TLIF+PS (HR 1.03 [0.81-1.31], p = 0.83) versus LLIF+PS (HR 1.38 [0.77-2.46], p = 0.28)., Conclusions: In a large cohort of over 5000 patients with an average follow-up of > 6 years, the authors found no differences in the reoperation rates for symptomatic ASD (operative ASD) between ALIF+PS and PLIF+PS, TLIF+PS, or LLIF+PS.

Background Context: Lumbar interbody instrumentation techniques are common and effective surgical options for a variety of lumbar degenerative pathologies. Anterior lumbar interbody fusion (ALIF) has become a versatile and powerful means of decompression, stabilization, and reconstruction. As an anterior only technique, the integrity of the posterior muscle and ligaments remain intact. Adding posterior instrumentation to ALIF is common and may confer benefits in terms of higher fusion rate but could contribute to adjacent segment degeneration due to additional rigidity. Large clinical studies comparing stand-alone ALIF with and without posterior supplementary fixation (ALIF+PSF) are lacking., Purpose: To compare rates of operative nonunion and adjacent segment disease (ASD) in ALIF with or without posterior instrumentation., Study Design: Retrospective cohort study., Patient Sample: Adult patients (≥18 years old) who underwent primary ALIF for lumbar degenerative pathology between levels L4 to S1 over a 12-year period. Exclusion criteria included trauma, cancer, infection, supplemental decompression, noncontiguous fusions, prior lumbar fusions, and other interbody devices., Outcome Measures: Reoperation for nonunion and ASD compared between ALIF only and ALIF+PSF., Methods: Reoperations were modeled as time-to-events where the follow-up time was defined as the difference between the primary ALIF procedure and the date of the outcome of interest. Crude cumulative reoperation probabilities were reported at 5-years follow-up. Multivariable Cox proportional hazard regression was used to evaluate risk of operative nonunion and for ASD adjusting for patient characteristics., Results: The study consisted of 1,377 cases; 307 ALIF only and 1070 ALIF+PSF. Mean follow-up time was 5.6 years. The 5-year crude nonunion incidence was 2.4% for ALIF only and 0.5% for ALIF+PSF; after adjustment for covariates, a lower operative nonunion risk was observed for ALIF+PSF (HR=0.22, 95% CI=0.06-0.76). Of the patients who are deemed potentially suitable for ALIF alone, one would need to add posterior instrumentation in 53 patients to prevent one case of operative nonunion at a 5-year follow-up (number needed to treat). Five-year operative ASD incidence was 4.3% for ALIF only and 6.2% for ALIF+PSF; with adjustments, no difference was observed between the cohorts (HR=0.96, 95% CI=0.54-1.71)., Conclusions: While the addition of posterior instrumentation in ALIFs is associated with lower risk of operative nonunion compared with ALIF alone, operative nonunion is rare in both techniques (<5%). Accordingly, surgeons should evaluate the added risks associated with the addition of posterior instrumentation and reserve the supplemental posterior fixation for patients that might be at higher risk for operative nonunion. Rates of operative ASD were not statistically higher with the addition of posterior instrumentation suggesting concern regarding future risk of ASD perhaps should not play a role in considering supplemental posterior instrumentation in ALIF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The Impella device historically required a heparin-based purge solution to reduce the risk of biomaterial deposition to maintain pump function. In April 2022, the Food and Drug Administration approved utilization of bicarbonate-based purge solutions (BBPS) as an alternative to heparin for patients who are intolerant to heparin or in whom heparin is contraindicated. The purpose of this case series is to report patient outcomes of Impella support with BBPS use at our institution., Summary: Eighteen patients who received BBPS via the Impella CP or Impella 5.5 device were included in our review. Patients were included if they had BBPS administration for greater than 24 hours. All patients were followed for 72 hours after cessation of BBPS. Indications for BBPS were coagulopathy (n = 5, 28%), suspected HIT (n = 2, 11%), confirmed HIT (n = 1, 6%), and major bleeding (n = 10, 56%). Three patients (17%) experienced an Impella complication while on BBPS. One patient required pump exchange, one required removal of the Impella device, and one received alteplase for suspected purge block. Of these, two patients experienced complications greater than 21 days into BBPS therapy., Conclusion: This case series adds to the literature describing clinical outcomes for patients on Impella support with BBPS. While BBPS offers a viable option for the management of patients on Impella devices who are unable to tolerate heparin-based purge solutions, further data is needed to determine the longevity of the Impella device with BBPS to minimize risk of Impella complications., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues., Competing Interests: A.K. is a founder of Atalanta Therapeutics and Comanche Biopharma; serves on the Scientific Advisory Board of Aldena Therapeutics, Prime Medicine, Alltrna, and Evox Therapeutics; and owns equities in RXi Pharmaceuticals and Advirna. J.E.H. owns equities in Rheos Medicines, and is a founder of Villaris Therapeutics, Aldena Therapeutics, NIRA Biosciences, Vimela Therapeutics, and Klirna Therapeutics. Q.T., H.H.F., K.Y.G., M.Z.U.I.A., K.R.M., J.E.H., A.K., and J.F.A. are listed as inventors of RNAi technology patents and patent applications. C.B., C.B.-P., and T.P. are executives of Aldena Therapeutics.