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Introduction: Family-centred rounds benefit families and clinicians and improve outcomes in general paediatrics, but are understudied in subspecialty settings. We sought to improve family presence and participation in rounds in a paediatric acute care cardiology unit. Methods: We created operational definitions for family presence, our process measure, and participation, our outcome measure, and gathered baseline data over 4 months of 2021. Our SMART aim was to increase mean family presence from 43 to 75% and mean family participation from 81 to 90% by 30 May, 2022. We tested interventions with iterative plan-do-study-act cycles between 6 January, 2022 and 20 May, 2022, including provider education, calling families not at bedside, and adjustment to rounding presentations. We visualised change over time relative to interventions with statistical control charts. We conducted a high census days subanalysis. Length of stay and time of transfer from the ICU served as balancing measures. Results: Mean presence increased from 43 to 83%, demonstrating special cause variation twice. Mean participation increased from 81 to 96%, demonstrating special cause variation once. Mean presence and participation were lower during high census (61 and 93% at project end) but improved with special cause variation. Length of stay and time of transfer remained stable. Conclusions: Through our interventions, family presence and participation in rounds improved without apparent unintended consequences. Family presence and participation may improve family and staff experience and outcomes; future research is warranted to evaluate this. Development of high level of reliability interventions may further improve family presence and participation, particularly on high census days.

Dysregulation of the input from the prefrontal cortex (PFC) to the nucleus accumbens (NAc) contributes to cue-induced opioid seeking but the heterogeneity in, and regulation of, prelimbic (PL)-PFC to NAc (PL->NAc) neurons that are altered has not been comprehensively explored. Recently, baseline and opiate withdrawal-induced differences in intrinsic excitability of Drd1+(D1+) versus Drd2+(D2+) PFC neurons have been demonstrated. Thus, here we investigated physiological adaptations of PL->NAc D1+versus D2+neurons after heroin abstinence and cue-induced relapse. Drd1-Cre+and Drd2-Cre+transgenic male Long–Evans rats with virally labeled PL->NAc neurons were trained to self-administer heroin followed by 1 week of forced abstinence. Heroin abstinence significantly increased intrinsic excitability in D1+and D2+PL->NAc neurons and increased postsynaptic strength selectively in D1+neurons. These changes were normalized by cue-induced relapse to heroin seeking. Based on protein kinase A (PKA)-dependent changes in the phosphorylation of plasticity-related proteins in the PL cortex during abstinence and cue-induced relapse to cocaine seeking, we assessed whether the electrophysiological changes in D1+and D2+PL->NAc neurons during heroin abstinence were regulated by PKA. In heroin-abstinent PL slices, application of the PKA antagonist (R)-adenosine, cyclic 3′,5′-(hydrogenphosphorothioate) triethylammonium (RP-cAMPs) reversed intrinsic excitability in both D1+and D2+neurons and postsynaptic strength in only D1+neurons. Additionally,in vivobilateral intra-PL infusion of RP-cAMPs after abstinence from heroin inhibited cue-induced relapse to heroin seeking. These data reveal that PKA activity in D1+and D2+PL->NAc neurons is not only required for abstinence-induced physiological adaptations but is also required for cue-induced relapse to heroin seeking.SIGNIFICANCE STATEMENTNeuronal plasticity in the medial prefrontal cortex is thought to underlie relapse to drug seeking, yet the subpopulation of neurons that express this plasticity to functionally guide relapse is unclear. Here we show cell type-specific adaptations in Drd1-expressing versus Drd2-expressing prelimbic pyramidal neurons with efferent projections to nucleus accumbens. These adaptations are bidirectionally regulated during abstinence versus relapse and involve protein kinase A (PKA) activation. Furthermore, we show that disruption of the abstinence-associated adaptations via site-specific PKA inhibition abolishes relapse. These data reveal the promising therapeutic potential of PKA inhibition for preventing relapse to heroin seeking and suggest that cell type-specific pharmacologies that target subpopulations of prefrontal neurons would be ideal for future therapeutic developments.

Non-B DNA structures formed by repetitive sequence motifs are known instigators of mutagenesis in experimental systems. Analyzing this phenomenon computationally in the human genome requires careful disentangling of intrinsic confounding factors, including overlapping and interrupted motifs and recurrent sequencing errors. Here, we show that accounting for these factors eliminates all signals of repeat-induced mutagenesis that extend beyond the motif boundary, and eliminates or dramatically shrinks the magnitude of mutagenesis within some motifs, contradicting previous reports. Mutagenesis not attributable to artifacts revealed several biological mechanisms. Polymerase slippage generates frequent indels within every variety of short tandem repeat motif, implicating slipped-strand structures. Interruption-correcting single nucleotide variants within short tandem repeats may originate from error-prone polymerases. Secondary-structure formation promotes single nucleotide variants within palindromic repeats and duplications within direct repeats. G-quadruplex motifs cause recurrent sequencing errors, whereas mutagenesis at Z-DNAs is conspicuously absent.

In response to increased prenatal drug use since the 2000s, states have adopted treatment-oriented laws giving pregnant and postpartum people priority access to public drug treatment programs as well as multiple punitive policy responses. No prior studies have systematically characterized these state statutes or examined implementation of state priority access laws in the context of co-existing punitive laws.We conducted legal mapping to examine state priority access laws and their overlap with state laws deeming prenatal drug use to be child maltreatment, mandating reporting of prenatal drug use to child protective services, or criminalizing prenatal drug use. We also conducted interviews with 51 state leaders with expertise on their states' prenatal drug use laws to understand how priority access laws were implemented.Thirty-three states and the District of Columbia have a priority access law, and more than 80% of these jurisdictions also have one of the punitive prenatal drug use laws described. Leaders reported major barriers to implementing state priority access laws, including the lack of drug treatment programs, stigma, and conflicts with punitive prenatal drug use laws.Our results suggest that state laws granting pregnant and postpartum people priority access to drug treatment programs are likely insufficient to significantly increase access to evidence-based drug treatment. Punitive state prenatal drug use laws may counteract priority access laws by impeding treatment seeking. Findings highlight the need to allocate additional resources to drug treatment for pregnant and postpartum people.

Purpose of Review This systematic review aims to evaluate physical performance outcome tools that are used most frequently to assess rehabilitation interventions. The scope of this paper focused on outcomes used with established lower limb amputees when assessing interventions such as exercise programs or changes in prescription published in the last 5 years. Recent Findings The most recorded outcome measures used across all the papers were timed walk tests and the Activity Balance Confidence Scale. Many outcomes did not produce statistically significant results with established amputee cohorts. Understanding the minimal important clinical difference is key. Summary The use of outcome measures is essential. Training and education are likely to increase the use of outcome measures. Quality of life measures are important in conjunction with physical outcomes. Simple timed walk tests are commonly used. These are in general easy to administer requiring a small space, limited equipment, and a short time frame.

Policy Points Over the past several decades, states have adopted policies intended to address prenatal drug use. Many of these policies have utilized existing child welfare mechanisms despite potential adverse effects. Recent federal policy changes were intended to facilitate care for substance-exposed infants and their families, but state uptake has been incomplete. Using legal mapping and qualitative interviews, we examine the development of state child welfare laws related to substance use in pregnancy from 1974 to 2019, with a particular focus on laws adopted between 2009 and 2019. Our findings reveal policies that may disincentivize treatment-seeking and widespread implementation challenges, suggesting a need for new treatment-oriented policies and refined state and federal guidance.Amid increasing drug use among pregnant individuals, legislators have pursued policies intended to reduce substance use during pregnancy. Many states have utilized child welfare mechanisms despite evidence that these policies might disincentivize treatment-seeking. Recent federal changes were intended to facilitate care for substance-exposed infants and their families, but implementation of these changes at the state level has been slowed and complicated by existing state policies. We seek to provide a timeline of state child welfare laws related to prenatal drug use and describe stakeholder perceptions of implementation.We catalogued child welfare laws related to prenatal drug use, including laws that defined child abuse and neglect and established child welfare reporting standards, for all 50 states and the District of Columbia (DC), from 1974 to 2019. In the 19 states that changed relevant laws between 2009 and 2019, qualitative interviews were conducted with stakeholders to capture state-level perspectives on policy implementation.Twenty-four states and DC have passed laws classifying prenatal drug use as child abuse or neglect. Thirty-seven states and DC mandate reporting of suspected prenatal drug use to the state. Qualitative findings suggested variation in implementation within and across states between 2009 and 2019 and revealed that implementation of changes to federal law during that decade, intended to encourage states to provide comprehensive social services and linkages to evidence-based care to drug-exposed infants and their families, has been complicated by existing policies and a lack of guidance for practitioners.Many states have enacted laws that may disincentivize treatment-seeking among pregnant people who use drugs and lead to family separation. To craft effective state laws and support their implementation, state policymakers and practitioners could benefit from a treatment-oriented approach to prenatal substance use and additional state and federal guidance.

Background Interest in complementary and integrative health (CIH) approaches, such as meditation, yoga, and acupuncture, continues to grow. The evidence of effectiveness for some CIH approaches has increased in the last decade, especially for pain, with many being recommended in varying degrees in national guidelines. To offer nonpharmacological health management options and meet patient demand, the nation’s largest integrated healthcare system, the Veterans Health Administration (VA), greatly expanded their provision of CIH approaches recently. Objective This paper addressed the questions of how many VA patients might use CIH approaches and chiropractic care if they were available at modest to no fee, and would patients with some health conditions or characteristics be more likely than others to use these therapies. Design Using electronic medical records, we conducted a national, three-year, retrospective analysis of VA patients’ use of eleven VA-covered therapies: chiropractic care, acupuncture, Battlefield Acupuncture, biofeedback, clinical hypnosis, guided imagery, massage therapy, meditation, Tai Chi/Qigong, and yoga. Participants We created a national cohort of veterans using VA healthcare from October 2016–September 2019. Key Results Veterans’ use of these approaches increased 70% in three years. By 2019, use was 5.7% among all VA patients, but highest among patients with chronic musculoskeletal pain (13.9%), post-traumatic stress disorder (PTSD; 10.6%), depression (10.4%), anxiety (10.2%), or obesity (7.8%). The approach used varied by age and race/ethnicity, with women being uniformly more likely than men to use each approach. Patients having chronic musculoskeletal pain, obesity, anxiety, depression, or PTSD were more likely than others to use each of the approaches. Conclusions Veterans’ use of some approaches rapidly grew recently and was robust, especially among patients most in need. This information might help shape federal/state health policy on the provision of evidence-based CIH approaches and guide other healthcare institutions considering providing them.

People often value the sensual, celebratory, and health aspects of food, but behind this experience exists many other value-laden agricultural production, distribution, manufacturing, and physiological processes that support or undermine a healthy population and a sustainable future. The complexity of such processes is evident in both every-day food preparation of recipes and in industrial food manufacturing, packaging and storage, each of which depends critically on human or machine agents, chemical or organismal ingredient references, and the explicit instructions and implicit procedures held in formulations or recipes. An integrated ontology landscape does not yet exist to cover all the entities at work in this farm to fork journey. It seems necessary to construct such a vision by reusing expert-curated fit-to-purpose ontology subdomains and their relationship, material, and more abstract organization and role entities. The challenge is to make this merger be, by analogy, one language, rather than nouns and verbs from a dozen or more dialects which cannot be used directly in statements about some aspect of the farm to fork journey without expensive translation or substantial dialect education in order to understand a particular text or domain of knowledge. This work focuses on the ontology components – object and data properties and annotations – needed to model food processes or more general process modelling within the context of the Open Biological and Biomedical Ontology Foundry and congruent ontologies. Ideally these components can be brought together in a general process ontology that can be specialized not only for the food domain but for carrying out other protocols as well. Many operations involved in food identification, preparation, transportation and storage – shaking, boiling, mixing, freezing, labeling, shipping – are actually common to activities from manufacturing and laboratory work to local or home food preparation.

This article describes a series of more than 20 new compounds formed by the combination of 2,4,6-trihydroxybenzoic acid (H4thba) with metal ions in the presence of a base, with structures that include discrete molecular units, chains, and two- and three-dimensional networks. As a result of the presence of two ortho-hydroxy groups, H4thba is a relatively strong acid (pK a1 = 1.68). The carboxylate group in H3thba− is therefore considerably less basic than most carboxylates with intramolecular hydrogen bonds, conferring a rigid planar geometry upon the anion. These characteristics of H3thba− significantly impact upon the way it interacts with metal ions. In s-block metal compounds, where the interaction of the metal centres with the carboxylate O atoms is essentially ionic, the anion bonds to up to three metal centres via a variety of binding modes. In cases where the metal ion is able to form directional coordinate bonds, however, the carboxylate group tends to bond in a monodentate mode, interacting with just one metal centre in the syn mode. A dominant influence on the structures of the complexes seems to be the face-to-face stacking of the aromatic rings, which creates networks containing layers of metal–oxygen polyhedra that participate in hydrogen bonding. This investigation was undertaken, in part, by a group of secondary school students as an educational exercise designed to introduce school students to the technique of single-crystal X-ray diffraction and enhance their understanding of primary and secondary bonding.

Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. Results: The median age was 68 years, 23% of participants were women, 51% had ST-segment–elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71–1.35]). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian 20 and 50 mg versus placebo: hazard ratio, 1.05 [90% CI, 0.69–1.61]). Conclusions: In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients who experienced acute MI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search ; Unique identifier: 2019-003244-79.

Aims: To determine weed efficacy when using adjuvants such as Grounded or Spectrum in combination with pendimethalin or S-metolachlor. Study Design: Randomized complete-block with 3 replications. Place and Duration of Study: Field studies were conducted during the 2021 growing season near Yoakum (29.2765o N, 97.1238o W) in south-central Texas and near Corpus Christi (27.7817o N, 97.5737o W) along the upper Texas Gulf Coast. Methodology: Herbicides were applied preemergence either alone or in combination with Grounded at 2.3 L ha-1 or Spectrum at 0.6 L ha-1 after corn (Zea mays L.) or peanut (Arachis hypogaea L.) were planted at Yoakum and under a non-crop situation at Corpus Christi. Results: In corn when evaluated 7 weeks after treatment (WAT), the addition of Grounded to pendimethalin at 1.06 kg ha-1 reduced Palmer amaranth control when compared with pendimethalin alone at the same rate or with the addition of Spectrum. Smellmelon control with pendimethalin at 0.53 kg ha-1 improved with the addition of Grounded over pendimethalin alone. When evaluated 15 WAT, only Texas millet was present in consistent enough populations to evaluate and no differences in control were noted with/without an adjuvant with either pendimethalin or S-metolachlor. In peanut when evaluated 26 and 54 days after treatment (DAT), Texas millet or smellmelon control was not influenced with the use of either Grounded or Spectrum. In the non-cropland study, when evaluated 14 DAT, both Texas millet and Palmer amaranth control was > 97% with all combinations of pendimethalin or S-metolachlor with/without an adjuvant. At the 42 DAT evaluation, again no differences in weed control were noted between the herbicides without an adjuvant and with the addition of Grounded or Spectrum. Conclusion: In none of the trials did the addition of either Grounded or Spectrum to either pendimethalin or S-metolachlor consistently improve weed efficacy. Also the length of herbicide persistence was not increased with these adjuvants.

In 2019, the first cases of SARS-CoV-2 were detected in Wuhan, China, and by early 2020 the first cases were identified in the United States. SARS-CoV-2 infections increased in the US causing many states to implement stay-at-home orders and additional safety precautions to mitigate potential outbreaks. As policies changed throughout the pandemic and restrictions lifted, there was an increase in demand for COVID-19 testing which was costly, difficult to obtain, or had long turn-around times. Some academic institutions, including Boston University (BU), created an on-campus COVID-19 screening protocol as part of a plan for the safe return of students, faculty, and staff to campus with the option for in-person classes. At BU, we put together an automated high-throughput clinical testing laboratory with the capacity to run 45,000 individual tests weekly by Fall of 2020, with a purpose-built clinical testing laboratory, a multiplexed reverse transcription PCR (RT-qPCR) test, robotic instrumentation, and trained staff. There were many challenges including supply chain issues for personal protective equipment and testing materials in addition to equipment that were in high demand. The BU Clinical Testing Laboratory (CTL) was operational at the start of Fall 2020 and performed over 1 million SARS-CoV-2 PCR tests during the 2020-2021 academic year.

Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astrocyte glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observe functional adaptations in the PrL cortical astrocyte following heroin self-administration (SA) and extinction as measured by the electrophysiologically evoked plasmalemmal glutamate transporter 1 (GLT-1)-dependent current. We likewise observed the increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astrocytic plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astrocytic complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased the apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague–Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased the co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, the accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Finally, we show that the NAC treatment and elimination of thrombospondin 2 (TSP-2) block cue-induced heroin relapse. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at the synapses. Additionally, these data demonstrate that NAC reverses PrL cortical heroin SA-and-extinction-induced adaptations in both astrocytes and corticostriatal neurons.

Eukaryotic gene compaction takes place at multiple levels to package DNA to chromatin and chromosomes. Two of the most fundamental levels of DNA packaging are at the nucleosome and dinucleosome stacks. The nucleosome is the basic gene-packing unit and is composed of DNA wrapped around a histone core. Nucleosomes stack with one another for further compaction of DNA. The first stacking step leads to dinucleosome formation, which is driven by internucleosomal interactions between various parts of two nucleosomes. Histone proteins are rich targets for post-translational modifications, some of which affect the structure of the nucleosome and the interactions between nucleosomes. These effects are often implicated in the regulation of various genomic transactions. In particular, histone H2B ubiquitylation has been associated with facilitated transcription and hexasome formation. Here, we employed semi-synthetically ubiquitylated histone H2B and single-molecule FRET to investigate the effects of H2B ubiquitylations at lysine 34 (H2BK34) and lysine 120 (H2BK120) on the structure of the nucleosome and the interactions between two nucleosomes. Our results suggest that H2BK34 ubiquitylation widens the DNA gyre gap in the nucleosome and stabilizes long- and short-range internucleosomal interactions while H2BK120 ubiquitylation does not affect the nucleosome structure or internucleosomal interactions. These results suggest potential roles for H2B ubiquitylations in facilitated transcription and hexasome formation while maintaining the structural integrity of chromatin.

Context: The Mental Health Parity and Addiction Equity Act (MHPAEA) requires coverage for mental health and substance use disorder (MH/SUD) benefits to be no more restrictive than for medical/surgical benefits in commercial health plans. State insurance departments oversee enforcement for certain plans. Insufficient enforcement is one potential source of continued MH/SUD treatment gaps among commercial insurance enrollees. This study explored state-level factors that may drive enforcement variation. Methods: The authors conducted a four-state multiple-case study to explore factors influencing state insurance offices' enforcement of MHPAEA. They interviewed 21 individuals who represented state government offices, advocacy organizations, professional organizations, and a national insurer. Their analysis included a within-case content analysis and a cross-case framework analysis. Findings: Common themes included insurance office relationships with other stakeholders, policy complexity, and political priority. Relationships between insurance offices and other stakeholders varied between states. MHPAEA complexity posed challenges for interpretation and application. Policy champions influenced enforcement via priorities of insurance commissioners, governors, and legislatures. Where enforcement of MHPAEA was not prioritized by any actors, there was minimal state enforcement. Conclusions: Within a state, enforcement of MHPAEA is influenced by insurance office relationships, legal interpretation, and political priorities. These unique state factors present significant challenges to uniform enforcement.

The COVID-19 pandemic has taken many lives in the last two years. Handling high volumes of decedents within and beyond a hospital’s environment has put healthcare- and deathcare-workers at an increased health risk throughout this pandemic. However, systematic research about manual handling of the dead either at the hospital, morgue, funeral home, or in situations of mass fatalities is still in infancy. This session aims to educate ergonomics and safety professionals on the importance of understanding the risk factors associated with handling the decedents, design issues of body bags, effects of PPE, routine versus mass fatality handling of the decedents, and participatory ergonomics. This session will also examine the feasibility of translating the past and current research on the handling of live patients to the handling of patients postmortem. Finally, psychosocial risks due to handling the deceased within the pandemic environment that might influence these workers’ risk of musculoskeletal injuries will be deliberated.

Background: The prevalence of unreported concussions is high, and undiagnosed concussions can lead to worse postconcussion outcomes. It is not clear how those with a history of undiagnosed concussion perform on subsequent standard concussion baseline assessments. Purpose: To determine if previous concussion diagnosis status was associated with outcomes on the standard baseline concussion assessment battery. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Concussion Assessment, Research, and Education (CARE) Consortium participants (N = 29,934) self-reported concussion history with diagnosis status and completed standard baseline concussion assessments, including assessments for symptoms, mental status, balance, and neurocognition. Multiple linear regression models were used to estimate mean differences and 95% CIs among concussion history groups (no concussion history [n = 23,037; 77.0%], all previous concussions diagnosed [n = 5315; 17.8%], ≥1 previous concussions undiagnosed [n = 1582; 5.3%]) at baseline for all outcomes except symptom severity and Brief Symptom Inventory–18 (BSI-18) score, in which negative binomial models were used to calculate incidence rate ratios (IRRs). All models were adjusted for sex, race, ethnicity, sport contact level, and concussion count. Mean differences with 95% CIs excluding 0.00 and at least a small effect size (≥0.20), and those IRRs with 95% CIs excluding 1.00 and at least a small association (IRR, ≥1.10) were considered significant. Results: The ≥1 previous concussions undiagnosed group reported significantly greater symptom severity scores (IRR, ≥1.38) and BSI-18 (IRR, ≥1.31) scores relative to the no concussion history and all previous concussions diagnosed groups. The ≥1 previous concussions undiagnosed group performed significantly worse on 6 neurocognitive assessments while performing better on only 2 compared with the no concussion history and all previous concussions diagnosed groups. There were no between-group differences on mental status or balance assessments. Conclusion: An undiagnosed concussion history was associated with worse clinical indicators at future baseline assessments. Individuals reporting ≥1 previous undiagnosed concussions exhibited worse baseline clinical indicators. This may suggest that concussion-related harm may be exacerbated when injuries are not diagnosed.

To evaluate the effects of state opioid prescribing cap laws on opioid prescribing after surgery.OptumLabs Data Warehouse administrative claims data covering all 50 states from July 2012 through June 2019.We included individuals from 20 states that had implemented prescribing cap laws without exemptions for postsurgical pain by June 2019 and individuals from 16 control states plus the District of Columbia. We used a difference-in-differences approach accounting for differential timing in law implementation across states to estimate the effects of state prescribing cap laws on postsurgical prescribing of opioids. Outcome measures included filling an opioid prescription within 30 days after surgery; filling opioid prescriptions of specific doses or durations; and the number, days' supply, daily dose, and pill quantity of opioid prescriptions. To assess the validity of the parallel counterfactual trends assumption, we examined differences in outcome trends between law-implementing and control states in the years preceding law implementation using an equivalence testing framework.We included the first surgery in the study period for opioid-naïve individuals undergoing one of eight common surgical procedures.State prescribing cap laws were associated with 0.109 lower days' supply of postsurgical opioids on the log scale (95% Confidence Interval [CI]: -0.139, -0.080) but were not associated with the number (Average treatment effect on the treated [ATT]: -0.011; 95% CI: -0.043, 0.021) or daily dose of postsurgical opioid prescriptions (ATT: -0.013; 95% CI: -0.030, 0.005). The negative association observed between prescribing cap laws and the probability of filling a postsurgical opioid prescription (ATT: -0.041; 95% CI: -0.054, -0.028) was likely spurious, given differences between law-implementing and control states in the pre-law period.Prescribing cap laws appear to have minimal effects on postsurgical opioid prescribing.

Constraint-induced movement therapy (CIMT) and bimanual therapy (BT) are among the most effective hand therapies for children with unilateral cerebral palsy (uCP). Since they train different aspects of hand use, they likely have synergistic effects. The aim of this study was to examine the efficacy of different combinations of mCIMT and BT in an intensive occupational therapy program for children with uCP. Children (n = 35) participated in intensive modified CIMT (mCIMT) and BT, 6 weeks, 5 days/week, 6 h/day. During the first 2 weeks, children wore a mitt over the less-affected hand and engaged in functional and play activities with the affected hand. Starting in week 3, bimanual play and functional activities were added progressively, 1 hour/week. This intervention was compared to two different schedules of block interventions: (1) 3 weeks of mCIMT followed by 3 weeks of BT, and (2) 3 weeks of BT followed by 3 weeks of mCIMT. Hand function was tested before, after, and two months after therapy with the Assisting Hand Assessment (AHA), Pediatric Evaluation of Disability Inventory (PEDI), and Canadian Occupational Performance Measure (COPM). All three groups of children improved in functional independence (PEDI; p < 0.031), goal performance (COPM Performance; p < 0.0001) and satisfaction (COPM Satisfaction; p < 0.0001), which persisted two months post-intervention. All groups showed similar amounts of improvement, indicating that the delivery schedule for mCIMT and BT does not significantly impact the outcomes.

BACKGROUND: Local heating of the skin elicits a biphasic vasodilatory response. The initial peak of this response is largely mediated by sensory nerve mechanisms. Receptors for estradiol (E2), the primary form of estrogen, have been found on peripheral sensory neurons indicating E2 impacts the nociceptive response. In animal models, E2 may decrease pain tolerance or act as an analgesic but it is currently unclear how E2 affects sensory nerve-mediated responses in women, particularly in E2-deficient postmenopausal women. PURPOSE: We tested the hypothesis that E2 augments sensory nerve-mediated vasodilation during local heating in E2-deficient postmenopausal women. METHODS: We measured cutaneous vasodilation to local heating (42°C) via laser Doppler flowmetry during microdialysis perfusions of lactated Ringer’s (control) and in a subset (n=4), L-NAME (non-selective nitric oxide synthase inhibition; 15mM) in 10 healthy postmenopausal women (55±2 yrs) at baseline (BL) and after 7 days E2 administration using a transdermal patch (E2; 0.1 mg/day, Vivelle-Dot). Cutaneous vascular conductance (CVC) was calculated as SkBF/MAP normalized to maximal vasodilation achieved by perfusion of sodium nitroprusside (28mM) and heating to 43°C. RESULTS: All women were less than 10 years post menopause (average 5±3 years), normotensive (SBP: 123±12 mmHg; DBP 77±5 mmHg) and not obese (BMI: 24±3 kg/m2). Sensory nerve-mediated dilation was unaffected by E2 administration (E2: 56±8 vs BL: 55±13 %CVCmax; p=0.72). Inhibition of eNOS with L-NAME did not blunt sensory nerve-mediated dilation and was not impacted by E2 (E2: 71±18 vs BL: 56±33 %CVCmax; p=0.55). In a subset (n=5) serum E2 concentration increased after E2 administration (E2: 80.42±11.90 vs BL: 25.74±4.42; p=0.0005) CONCLUSIONS: These preliminary findings suggest E2 administration does not impact sensory nerve-mediated dilation in postmenopausal women. Furthermore, sensory nerve-mediated dilation does not appear to be mediated by nitric oxide. Additional research is needed to further understand the impact of sex hormones and aging on sensory nerve-mediated dilation in women. Research supported by AHA award 16SDG30700015 and NIH Grant P20 GM113125 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Zooplankton play a crucial role in marine ecosystems as the link between the primary producers and higher trophic levels, and as such they are key components of global biogeochemical and ecosystem models. While phytoplankton spatial-temporal dynamics can be tracked using satellite remote sensing, no analogous data product is available to validate zooplankton model output. We develop a procedure for linking irregular and sparse observations of mesozooplankton biomass with model output to assess regional seasonality of mesozooplankton. We use output from a global biogeochemical/ecosystem model to partition the ocean according to seasonal patterns of modeled mesozooplankton biomass. We compare the magnitude and temporal dynamics of the model biomass with in situ observations averaged within each partition. Our analysis shows strong correlations and little bias between model and data in temperate, strongly seasonally variable regions. Substantial discrepancies exist between model and observations within the tropical partitions. Correlations between model and data in the tropical partitions were not significant and in some cases negative. Seasonal changes in tropical mesozooplankton biomass were weak, driven primarily by local perturbations in the velocity and extent of currents. Microzooplankton composed a larger fraction of total zooplankton biomass in these regionsWe also examined the ability of the model to represent several dominant taxonomic groups. We identified several Calanus species in the North Atlantic partitions and Euphausiacea in the Southern Ocean partitions that were well represented by the model. This partition-scale comparison captures biogeochemically important matches and mismatches between data and models, suggesting that elaborating models by adding trait differences in larger zooplankton and mixotrophy may improve model-data comparisons. We propose that where model and data compare well, sparse observations can be averaged within partitions defined from model output to quantify zooplankton spatio-temporal dynamics.

Background. The messages used to communicate about harm reduction are critical in garnering public support for adoption of harm reduction interventions. Despite the demonstrated effectiveness of harm reduction interventions at reducing overdose deaths and disease transmission, the United States has been slow to adopt harm reduction to scale. Implementation of evidence-based interventions has been hindered by a historical framing of drug use as a moral failure and related stigmatizing attitudes among the public towards people who use drugs. Understanding how professional harm reduction advocates communicate to audiences about the benefits of harm reduction is a critical step to designing persuasive messaging strategies.Methods. We conducted qualitative interviews with a purposively recruited sample of U.S. professional harm reduction advocates (N = 15) to examine their perspectives on which types of messages are effective in persuading U.S. audiences on the value of harm reduction. Participants were professionals working in harm reduction advocacy at national- or state-level organizations promoting and/or implementing harm reduction. Semi-structured interviews were audio-recorded, transcribed, and analyzed using a hybrid inductive/deductive approach.Results. Interviewees agreed that messages about the scientific evidence demonstrating the effectiveness of harm reduction approaches are important but insufficient, on their own, to persuade audiences. Interviewees identified two overarching messaging strategies they perceived as persuasive: using messages about harm reduction that align with audience-specific values, for example centering the value of life or individual redemption; and positioning harm reduction as part of the comprehensive solution to current issues audiences are facing related to drug use and overdose in their community. Interviewees discussed tailoring messages strategies to four key audiences: policymakers; law enforcement; religious groups; and the family and friends of people who use, or have used, drugs. For example, advocates discussed framing messages to law enforcement from the perspective of public safety.Conclusions. Interviewees viewed messages as most persuasive when they align with audience values and audience-specific concerns related to drug use and overdose death. Future research should test effectiveness of tailored messaging strategies to audiences using experimental approaches.

Field studies were conducted in 2016, 2017, and 2020 in south-central and the Coastal Bend regions of Texas to determine the effects of various biostimulants and soil additives on corn growth and yield. In south-central Texas, the use of pop-up fertilizer (9-30-0 + Zn) either alone or in combination with either 2% N, bifenthrin, or bifenthrin + pyraclostrobin resulted in the greatest corn vigor but a yield response was only noted with pop-up fertilizer alone at 28062 or 46771 ml ha-1 in one year. In the Coastal Bend region, leaf tissue analysis showed that only Fe was affected with the use of any soil additive. Bacillus licheniformis + bacillus megaterium + bacillus pumilus increased Fe leaf tissue content by 20% over the untreated check. Radicoat seed coating at 438 ml ha-1 reduced corn plant stand by 10% and Pseudomonas brassicaceanum reduced corn height when compared with the untreated check; however, no differences in test weight or yield from the untreated check were noted with any soil additive. Little if any impacts of the use of biostimulants or soil amendments were seen in these studies.

Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, before breast tumor initiation, enhances early dissemination of hormone receptor–positive (HR+) mammary tumor cells. Here, we sought to determine whether cellular changes occurring in normal mammary tissues, before tumor initiation and in response to dysbiosis, enhanced dissemination of HR+ tumors. Commensal dysbiosis increased both the frequency and profibrogenicity of mast cells in normal, non–tumor-bearing mammary tissues, a phenotypic change that persisted after tumor implantation. Pharmacological and adoptive transfer approaches demonstrated that profibrogenic mammary tissue mast cells from dysbiotic animals were sufficient to enhance dissemination of HR+ tumor cells. Using archival HR+ patient samples, we determined that enhanced collagen levels in tumor-adjacent mammary tissue positively correlated with mast cell abundance and HR+ breast cancer recurrence. Together, these data demonstrate that mast cells programmed by commensal dysbiosis activate mammary tissue fibroblasts and orchestrate early dissemination of HR+ breast tumors.

Supplementary Figure from Reciprocal Interactions Between the Gut Microbiome and Mammary Tissue Mast Cells Promote Metastatic Dissemination of HR+ Breast Tumors

Low wages are associated with an increased risk of occupational injuries. Increasing the minimum wage is one way to increase workers' wages; however, a previous study found that higher state minimum wage was associated with an increase in nonfatal occupational injuries and illnesses. This study aims to examine the association between state minimum-wage laws and fatal occupational injuries.Fatal occupational injury data (2003-2017) for the 50 U.S. states were obtained from the Census of Fatal Occupational Injuries. State minimum-wage law information was obtained from Temple's LawAtlas website. Linear and Poisson regression models were used to analyze the association between state minimum-wage laws and the rates of fatal occupational injury per 100,000 workers. All data were analyzed in 2020.Having a state minimum wage higher than the federal minimum had no statistically significant association with fatal occupational injury rate, (-4.0%, 95% CI= -9.1, 1.5). State minimum wage amount was also not associated with fatal occupational injuries (-4.0%, 95% CI= -9.1, 1.5).Although previous research suggested that state minimum-wage laws were associated with increased rates of nonfatal occupational injuries, these findings indicate that these laws are not associated with an increased risk of fatal occupational injuries. Concerns that raising the minimum wage will lead to worse workplace safety may be unfounded.

A key role of chromatin kinases is to phosphorylate histone tails during mitosis to spatiotemporally regulate cell division. Vaccinia-related kinase 1 (VRK1) is a serine–threonine kinase that phosphorylates histone H3 threonine 3 (H3T3) along with other chromatin-based targets. While structural studies have defined how several classes of histone-modifying enzymes bind to and function on nucleosomes, the mechanism of chromatin engagement by kinases is largely unclear. Here, we paired cryo-electron microscopy with biochemical and cellular assays to demonstrate that VRK1 interacts with both linker DNA and the nucleosome acidic patch to phosphorylate H3T3. Acidic patch binding by VRK1 is mediated by an arginine-rich flexible C-terminal tail. Homozygous missense and nonsense mutations of this acidic patch recognition motif in VRK1 are causative in rare adult-onset distal spinal muscular atrophy. We show that these VRK1 mutations interfere with nucleosome acidic patch binding, leading to mislocalization of VRK1 during mitosis, thus providing a potential new molecular mechanism for pathogenesis.

BACKGROUND Attenuated familial adenomatous polyposis is characterised by low number (≤ 100) and delayed development of colorectal adenomas. Various definitions have been used, and genotype-phenotype correlations suggested. OBJECTIVE We aim to evaluate phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and assess familial variability. DESIGN This is a retrospective study. SETTINGS This study was conducted at a tertiary polyposis registry. PATIENTS Individuals with attenuated familial adenomatous polyposis were identified. Phenotypic group was defined as ≤ 100 adenomas at age 25 years and genotypic group was defined as a variant in the Adenomatous polyposis coli region associated with attenuated familial adenomatous polyposis. Pathology polyp count was used for patients who had undergone surgery and endoscopic polyp count for those with intact colon. MAIN OUTCOME MEASURES We evaluated phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and familial variability. RESULTS A total of 69 patients were identified in the phenotypic group of which 54 (78%) had a pathogenic variant in the attenuated regions of the adenomatous polyposis coli gene. Forty-eight (70%) had intact colon (median age at last colonoscopy 43 [25-73] years; median endoscopic polyp count 20 [0-100]) and 21 (30%) had undergone colectomy (median age at surgery 45 [25-54] years; median pathology polyp count 43 [3-100]). Eighty-three patients were identified in the genotypic group of which 54 (65%) had attenuated phenotype. Inter- and intra- familial variability were observed. LIMITATIONS This study was limited by its retrospective nature and single-center experience. CONCLUSION Phenotype in familial adenomatous polyposis lies on a spectrum - being determined in part by genotype and age at adenoma count. Diagnosis of attenuated familial adenomatous polyposis should be based on phenotype; genotype is not a reliable indicator. Management should be personalized according to the phenotype of each individual. See Video Abstract at http://links.lww.com/DCR/B775.

OBJECTIVE: The goal was to evaluate the likelihood of hospital admission, mechanical ventilation, in-hospital mortality, and overall mortality within 30 days after a COVID-19 diagnosis in persons with versus without serious mental illness. METHODS: Adults with and without serious mental illness diagnosed with COVID-19 in the first year of the pandemic were identified in the TriNetX database, a network of electronic health records from 49 U.S. healthcare systems and representing 63.5 million individuals. Propensity score-matched cohorts (N=85,257) were used to compare outcomes. RESULTS: Compared with persons without serious mental illness, persons with serious mental illness were more likely to be hospitalized or to die after COVID-19 diagnosis. No difference in use of mechanical ventilation or death was observed in groups admitted to the hospital with COVID-19. CONCLUSIONS: Disparities in overall mortality after COVID-19 for persons with serious mental illness likely are driven by factors outside of acute care settings.

There is substantial evidence that adequate access to healthcare among low-income adults through the Affordable Care Act Medicaid expansion mitigates risk factors associated with childhood maltreatment, including parental financial insecurity, substance use, and poor mental health. Indeed, studies identified reduced reports of child neglect in states that expanded Medicaid, relative to those that did not. However, it is unknown whether Medicaid expansion is associated with reported child sexual abuse (CSA). We present findings from a study evaluating the association of Medicaid expansion with incidents of CSA reported to child protective services. Using a difference-in-differences approach, we analyzed data from the National Child Abuse and Neglect Data System to examine the effects of state-level adoption of the Medicaid expansion on CSA reports per 100,000 children across 2008–2018. Results indicated no statistically significant association between Medicaid expansion and CSA incidents. We discuss potential reasons for differential association of macro-level policies on types of child maltreatment.

Background The National Institutes of Health (NIH) announced a revised, expanded definition of ‘clinical trial’ in 2014 to improve trial identification and administrative compliance. Some stakeholders voiced concerns that the policy added administrative burden potentially slowing research progress. Methods This quasi-experimental study examined the difference-in-differences impact of the new NIH clinical trial definition policy on participant recruitment progress in grants funded by the National Institute of Mental Health (NIMH). Results One hundred thirty-two funded clinical trial grants were identified. While more grants were identified as clinical trials under the revised definition, the difference-in-differences in recruitment progress before and after the policy change was not statistically significant. Conclusions The revised NIH clinical trial definition had no clear effect on recruitment progress in newly identified NIMH-funded clinical trials as compared to traditionally identified clinical trials. Concerns that administrative delays and burden could impact study progress may be alleviated by these initial results.

A uniform carbon tax and Citizen Carbon Fund are proposed as a zero-sum system of transfers that can increase equilibrium participation and result in a positive carbon check for each citizen covered by the agreement. The carbon tax results in efficient abatement, generates tax revenue and finances transfers that increase equilibrium participation in a climate agreement. A single carbon price is easier to negotiate than many different abatement requirements, but mirrors the results of a cap-and-trade agreement. An example using the four largest carbon emitters illustrates the set of stable agreements, the transfers required for stability and the resulting carbon checks.

Drug-filled implants (DFIs) have emerged as an innovative approach to control the delivery of drugs. These devices contain the drug within the structure of the implant itself and avoid the need to include additional drug carrier materials such as a polymers, which are often associated with inflammation and delayed healing/tissue regeneration at the implant site. One common feature of in vitro experiments to generate drug release profiles is stirring or agitation of the release medium. However, the influence of the resulting fluid flow on the rate of drug release from DFIs has yet to be quantified. In this paper we consider two DFIs, which although similar in shape and size, employ different strategies to control the release of drug: a porous pin with pores on the order of μm and a pin drilled with orifices of the order of mm. We develop a multiphysics mathematical model of drug release from these DFIs, subject to fluid flow induced through stirring and show that fluid flow greatly influences the drug release profile for the orifice pin, but that the porous pin drug release profile is relatively insensitive to flow. We demonstrate that drug release from the porous pin may adequately be described through a simplified radial 1D dissolution-diffusion model, while a 3D dissolution-advection-diffusion model is required to describe drug release from the orifice pin. A sensitivity analysis reveals that that the balance of reaction-advection-diffusion in terms of key nondimensional numbers governs the overall drug release. Our findings potentially have important implications in terms of devising the most relevant experimental protocol for quantifying drug release from DFIs.