An optical tweezer array of ultracold polyatomic molecules.

Polyatomic molecules have rich structural features that make them uniquely suited to applications in quantum information science1-3, quantum simulation4-6, ultracold chemistry7 and searches for physics beyond the standard model8-10. However, a key challenge is fully controlling both the internal quantum state and the motional degrees of freedom of the molecules. Here we demonstrate the creation of an optical tweezer array of individual polyatomic molecules, CaOH, with quantum control of their internal quantum state. The complex quantum structure of CaOH results in a non-trivial dependence of the molecules' behaviour on the tweezer light wavelength. We control this interaction and directly and non-destructively image individual molecules in the tweezer array with a fidelity greater than 90%. The molecules are manipulated at the single internal quantum state level, thus demonstrating coherent state control in a tweezer array. The platform demonstrated here will enable a variety of experiments using individual polyatomic molecules with arbitrary spatial arrangement.

Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.

Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides. While the 11 PDE subfamilies share common features, key differences confer signaling specificity. The differences include substrate selectivity, enzymatic activity regulation, tissue expression, and subcellular localization. Selective inhibitors of each subfamily have elucidated the protean role of PDEs on normal cell function. PDEs are also linked to diseases, some of which affect the immune, cardiac, and vascular systems. Selective PDE inhibitors are clinically used to treat these specific disorders. Ongoing preclinical studies and clinical trials are likely to lead to the approval of additional PDE-targeting drugs for therapy in human disease. In this review, we discuss the structure and function of PDEs and examine current and evolving therapeutic uses of PDE inhibitors, highlighting their mechanisms and innovative applications that could further leverage this crucial family of enzymes in clinical settings.

High frequency of artemisinin partial resistance mutations in the Great Lakes region revealed through rapid pooled deep sequencing.

BACKGROUND: In Africa, the first Plasmodium falciparum artemisinin partial resistance mutation, was Kelch13 (K13) 561H - detected and validated at appreciable frequency in Rwanda in 2014. Surveillance to better define the extent of the emergence in Rwanda and neighboring countries is critical. METHODS: We used novel liquid blood drop preservation combined with pooled sequencing to provide cost-effective rapid assessment of resistance mutation frequencies at multiple collection sites across Rwanda and neighboring regions in Uganda, Tanzania, and the Democratic Republic of the Congo (DRC). Malaria-positive samples (n=5,465) from 39 health facilities collected between May 2022 and March 2023 were sequenced in 199 pools. RESULTS: In Rwanda, K13 561H and 675V were detected in 90% and 65% of sites with an average frequency of 19.0% (0-54.5%) and 5.0% (0-35.5%), respectively. In Tanzania, 561H had high frequency in multiple sites. 561H appeared at 1.6% in Uganda. 561H was absent from the DRC, although 675V was seen at low frequency. Concerningly candidate mutations were observed: 441L, 449A, and 469F co-occurred with validated mutations suggesting they are arising under the same pressures. Other markers for decreased susceptibility to artemether-lumefantrine are common: P. falciparum multidrug resistance protein 1 N86 at 98.0% (63.3-100%) and 184F at 47.0% (0-94.3%) and P. falciparum chloroquine resistance transporter 76T at 14.7% (0-58.6%). Additionally, sulfadoxine-pyrimethamine-associated mutations show high frequencies. CONCLUSION: K13 mutations are rapidly expanding in the region further endangering control efforts with the potential of engendering partner drug resistance.

Ocular adverse events associated with antibody-drug conjugates for cancer: evidence and management strategies.

Antibody-drug conjugates (ADCs) are a fast-growing class of cancer drugs designed to selectively deliver cytotoxic payloads through antibody binding to cancer cells with high expression of the target antigen, thus reducing systemic exposure and minimizing off-target effects. However, ADCs are associated with various ocular adverse events (AEs) that may impact treatment administration and patient outcomes. In this review, we provide a summary of ocular AEs associated with approved and investigational ADCs, recommendations for the mitigation and management of ocular AEs, current guidelines and expert opinions, and recommendations for clinical practice. A literature search was performed, using PubMed and Google Scholar, for English-language articles published between January 1985 and January 2023 to identify studies reporting ocular AEs associated with ADC use. Search terms included generic and investigational names of all identified ADCs, and further searches were performed to identify strategies for managing ADC-associated ocular AEs. ADC-associated ocular AEs include symptoms such as blurred vision and foreign-body sensation and signs such as corneal fluorescein staining, corneal pseudomicrocysts, and conjunctivitis. Reported management strategies include ADC dose modification (eg, dose delay or reduction), cool compresses, artificial tears, topical vasoconstrictors, and topical steroids. Although ADC dose modification appears to be beneficial, the preventive and/or therapeutic benefits of the remaining interventions are unclear. Although the exact mechanisms are not fully understood, most ADC-associated ocular AEs are reversible with dose delay or dose reduction. Management of ocular AEs requires a multidisciplinary approach to minimize treatment discontinuation and optimize clinical outcomes.

Sotorasib for Lung Cancers with KRAS p.G12C Mutation.

BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Intubation Decision Based on Illness Severity and Mortality in COVID-19: An International Study.

OBJECTIVES: To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices. DESIGN: Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022. SETTING: Ten academic institutions in the United States and Europe. PATIENTS: Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test. INTERVENTIONS: Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pa o2 /F io2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pa o2 /F io2 ratio less than or equal to 250. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group ( p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52-0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51-0.90; p = 0.006). CONCLUSIONS: In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.

Neurologic Manifestations of Long COVID Differ Based on Acute COVID-19 Severity.

OBJECTIVE: To characterize neurologic manifestations in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients. METHODS: Prospective study of the first 100 consecutive PNP and 500 NNP patients evaluated at a Neuro-COVID-19 clinic between 5/2020 and 8/2021. RESULTS: PNP were older than NNP patients (mean 53.9 vs 44.9 y; p < 0.0001) with a higher prevalence of pre-existing comorbidities. An average 6.8 months from onset, the main neurologic symptoms were "brain fog" (81.2%), headache (70.3%), and dizziness (49.5%) with only anosmia, dysgeusia and myalgias being more frequent in the NNP compared to the PNP group (59 vs 39%, 57.6 vs 39% and 50.4 vs 33%, all p < 0.003). Moreover, 85.8% of patients experienced fatigue. PNP more frequently had an abnormal neurologic exam than NNP patients (62.2 vs 37%, p < 0.0001). Both groups had impaired quality of life in cognitive, fatigue, sleep, anxiety, and depression domains. PNP patients performed worse on processing speed, attention, and working memory tasks than NNP patients (T-score 41.5 vs 55, 42.5 vs 47 and 45.5 vs 49, all p < 0.001) and a US normative population. NNP patients had lower results in attention task only. Subjective impression of cognitive ability correlated with cognitive test results in NNP but not in PNP patients. INTERPRETATION: PNP and NNP patients both experience persistent neurologic symptoms affecting their quality of life. However, they harbor significant differences in demographics, comorbidities, neurologic symptoms and findings, as well as pattern of cognitive dysfunction. Such differences suggest distinct etiologies of Neuro-PASC in these populations warranting targeted interventions. ANN NEUROL 2023;94:146-159.

Cardiac PDGFRα+ interstitial cells generate spontaneous inward currents that contribute to excitability in the heart.

The cell types and conductance that contribute to normal cardiac functions remain under investigation. We used mice that express an enhanced green fluorescent protein (eGFP)-histone 2B fusion protein driven off the cell-specific endogenous promoter for Pdgfra to investigate the distribution and functional role of PDGFRα+ cells in the heart. Cardiac PDGFRα+ cells were widely distributed within the endomysium of atria, ventricle, and sino-atrial node (SAN) tissues. PDGFRα+ cells formed a discrete network of cells, lying in close apposition to neighboring cardiac myocytes in mouse and Cynomolgus monkey (Macaca fascicularis) hearts. Expression of eGFP in nuclei allowed unequivocal identification of these cells following enzymatic dispersion of muscle tissues. FACS purification of PDGFRα+ cells from the SAN and analysis of gene transcripts by qPCR revealed that they were a distinct population of cells that expressed gap junction transcripts, Gja1 and Gjc1. Cardiac PDGFRα+ cells generated spontaneous transient inward currents (STICs) and spontaneous transient depolarizations (STDs) that reversed at 0 mV. Reversal potential was maintained when ECl = -40 mV. [Na+ ]o replacement and FTY720 abolished STICs, suggesting they were due to a non-selective cation conductance (NSCC) carried by TRPM7. PDGFRα+ cells also express ß2 -adrenoceptor gene transcripts, Adrb2. Zinterol, a selective ß2 -receptor agonist, increased the amplitude and frequency of STICs, suggesting these cells could contribute to adrenergic regulation of cardiac excitability. PDGFRα+ cells in cardiac muscles generate inward currents via an NSCC. STICs generated by these cells may contribute to the integrated membrane potentials of cardiac muscles, possibly affecting the frequency of pacemaker activity.

Intrinsic risk factors for alpha-gal syndrome in a case-control study, 2019 to 2020.

BACKGROUND: Alpha-gal syndrome (AGS) is an allergy to galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in most mammals. Evidence indicates that AGS develops after a tick bite, and in the United States, AGS is most associated with bites from Amblyomma americanum (lone star tick); however, not all persons bitten by ticks develop clinical AGS. OBJECTIVE: To investigate intrinsic risk factors associated with the development of AGS. METHODS: We performed a case-control study among adults presenting for diagnosis or management of AGS at an allergy clinic in North Carolina during 2019 to 2020 and compared them with controls enrolled from 2 nearby internal medicine clinics. A questionnaire gathered epidemiologic and tick exposure data, and blood was obtained for alpha-gal-specific IgE and other testing. RESULTS: The 82 enrolled case patients and 191 controls did not differ significantly by age or sex. Case patients were more likely than controls to have A or O blood types (non B-antigen), have experienced childhood allergies, and have a family history of AGS and other food allergies. Case patients were also more likely to report experiencing long healing times for insect bites or stings and a family history of allergy to stinging or biting insects. CONCLUSION: This study suggested that intrinsic factors contribute to risk of developing AGS. Some traits are genetic, but common behaviors among households and family units likely also contribute. Identification of these risk factors can inform personal risk, aid health care providers in understanding susceptible populations, and contribute to ongoing understanding of AGS epidemiology.

Body image dissatisfaction during the first year of pediatric inflammatory bowel disease diagnosis.

OBJECTIVES: Dissatisfaction with one's body can be distressing; youth with inflammatory bowel disease (IBD) may be at increased risk for body image dissatisfaction given disease symptoms and treatment side effects. Yet, no studies have examined body image dissatisfaction over time in youth with IBD and whether depressive symptoms are associated with change in dissatisfaction. METHODS: Fifty-seven pediatric participants (8-17 years old) newly diagnosed with IBD were enrolled. Youth completed questionnaires assessing body image dissatisfaction and depressive symptoms shortly after diagnosis (Time 1) and 12 months later (Time 2). Multilevel longitudinal modeling was used to test the extent to which body image dissatisfaction changed across the first year of diagnosis and to test change in body image dissatisfaction as a function of depressive symptoms. RESULTS: Findings indicated significant between- and within-person variance in body image dissatisfaction over the 12 months, yet the sample as a whole did not report significant changes in dissatisfaction from Time 1 to Time 2. Children reporting depressive symptoms greater than their individual average over time reported greater body image dissatisfaction. Between-person variation in depressive symptoms demonstrated a significant interaction with time. As an individual's depressive symptoms exceeded the group average, their body image dissatisfaction increased, although less drastically as time since diagnosis progressed. CONCLUSIONS: Findings suggest that body image dissatisfaction is a complex and dynamic construct across youth and that interventions for pediatric IBD patients need to be tailored to the needs of individuals. Methods for assessing body image dissatisfaction efficiently and repeatedly across multiple visits are provided.

Long-term benefit of sotorasib in patients with KRAS G12C-mutated non-small-cell lung cancer: plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).

Trilaciclib use in extensive-stage small cell lung cancer (ES-SCLC): are clinical benefits seen in the real-world setting?

BACKGROUND: Trilaciclib, in comparison to placebo plus carboplatin, etoposide, ± atezolizumab (PEA), has shown significant reductions in incidence of severe neutropenia (SN) among patients with extensive-stage small cell lung cancer (ES-SCLC). Despite these findings, real-world utility remains limited. METHODS: A single-center quasi-experimental study compared trilaciclib + PEA (PEAT) versus PEA in ES-SCLC patients. The study period ranged from April 1, 2021 to July 31, 2022, for the PEAT recipients and February 1, 2020, to February 28, 2021, for PEA recipients. The primary endpoint evaluated was incidence of SN after cycle 1 and during the treatment period. Secondary endpoints included measures related to myelopreservation and patient outcomes. RESULTS: Among 34 PEAT and 44 PEA patients, baseline characteristics were similar, except for a higher median age (69 vs 64 years) and more males (64.7% vs 38.6%) in the PEAT cohort. The PEAT cohort exhibited a lower SN rate (3%) versus the PEA cohort (18%), with statistical significance demonstrated on multivariate analysis (p = 0.015). Additionally, the PEAT cohort also demonstrated significant reductions in red blood cell transfusion requirements (3% vs 23%; p = 0.02), grade 3-4 anemia (6% vs 25%; p = 0.03), and grade 3-4 thrombocytopenia (0% vs 11%, p = 0.045). CONCLUSION: Trilaciclib, in combination with PEA, demonstrated an improvement in the safety profile without compromising survival outcomes in ES-SCLC patients. These findings underscore the potential benefits of incorporating trilaciclib in real-world clinical settings for enhanced patient care.

The Efficacy and Patient Experience of Virtual Reality in Labor: An Integrative Review of Pain and Anxiety Management.

BACKGROUND: Labor pain and anxiety are significant challenges in maternal healthcare, often managed through pharmacological interventions. Virtual Reality (VR), as a non- pharmacological method, has emerged as a potential tool for pain and anxiety relief in labor. This integrative review aims to synthesize evidence from randomized controlled trials (RCTs), qualitative studies, and mixed-methods research to evaluate the effectiveness of VR in labor pain and anxiety management and to understand patient experiences. METHODS: Adhering to the PRISMA guidelines, a structured literature search was conducted across databases, including PsycINFO, CINAHL, and PubMed, yielding 1,227 studies. Following a meticulous screening and selection process by authors, 13 studies (10 RCTs, 2 qualitative, and 1 mixed methods) met the inclusion criteria. Data extraction focused on study design, population characteristics, VR interventions, outcomes measured, and key findings, with a content analysis approach employed for thematic synthesis. RESULTS: The RCTs consistently showed VR's efficacy in reducing labor pain and, to some extent, anxiety. Qualitative studies highlighted VR's role in enhancing patient experiences, offering distraction, relaxation, and improved self-efficacy in pain management. The integration of findings from quantitative and qualitative studies provided a comprehensive understanding of VR's effectiveness and acceptability in labor. Notable themes included the importance of VR's immersive nature and its potential to reduce reliance on pharmacological interventions. CONCLUSION: VR emerges as a promising tool for managing labor pain and anxiety, offering a non-invasive and patient-friendly alternative to traditional pain relief methods. Its implementation in clinical practice could enhance patient satisfaction and overall birthing experiences. However, further research is needed to standardize VR interventions, assess long-term effects, and determine cost-effectiveness. The findings encourage the consideration of VR as part of holistic maternal care, emphasizing the need to integrate patient-centered healthcare technologies.

Integrating Nursing Practice and Policy in Opioid Overdose Prevention: Analysis of the Opioid-Overdose Reduction Continuum of Care Approach Practice Guide.

AIM: To present a comprehensive analysis of the Opioid-Overdose Reduction Continuum of Care Approach (ORCCA) Practice Guide 2023, evaluating its alignment with Russell and Fawcett's conceptual model of nursing and health policy and highlighting the implications for nursing practice and policy. DESIGN: This paper employs a policy analysis framework to evaluate the ORCCA Practice Guide, using Russell and Fawcett's conceptual model as a lens to assess the policy's structure and implementation. METHODS: The analysis is framed by Russell and Fawcett's conceptual model, focusing on the dimensions of efficacy, effectiveness, equity and justice. This framework assesses how well the ORCCA's strategies align with these dimensions in the context of nursing and health policy. RESULTS: Key findings indicate that the ORCCA's strategies are integral to nursing practice, particularly in frontline interventions such as education, naloxone distribution and Medication for Opioid Use Disorder (MOUD) delivery. The integration of these strategies demonstrates a significant impact on the opioid crisis, enhancing the roles nurses play in opioid overdose prevention. CONCLUSION: The ORCCA Practice Guide represents a multifaceted approach to addressing the opioid crisis, with strong alignment to the conceptual model used for analysis. It underscores the essential role of nurses in implementing and refining opioid overdose reduction strategies. IMPLICATIONS: The study highlights the critical need for nursing involvement in policy formation and practice implementation, suggesting that nurses are key to advancing comprehensive opioid overdose prevention measures. IMPACT: This study addresses the problem of opioid overdoses and the need for effective interventions. The main findings show the importance of nurse-driven strategies in opioid crisis management. The research impacts public health policy and practice, particularly influencing how nursing approaches are integrated into overall health strategies for overdose prevention. NO PATIENT OR PUBLIC CONTRIBUTION: No patients, caregivers, or members of the public were involved in conducting this analysis.

Complications of antibiotic cement spacers used for elbow infections.

BACKGROUND: Antibiotic cement spacers have been widely used in the treatment of joint infections. There are no commercially available antibiotic spacers for the elbow. Instead, they are typically fashioned by the surgeon at the time of surgery using cement alone or a combination of cement with sutures, Steinmann pins, external fixator components, or elbow arthroplasty components. There is no consensus regarding the ideal elbow antibiotic spacer and no previous studies have examined the complications associated with these handmade implants in relation to their unique structural design. METHODS: We retrospectively reviewed 55 patients who had 78 static antibiotic cement spacers implanted between January 1998 and February 2021 as part of a 2-stage treatment plan for infection of an elbow arthroplasty, other elbow surgery, or primary elbow infection. Several antibiotic spacer structures were used during the study period. For analysis purposes, the spacers were classified into linked and unlinked spacers based on whether there was a linking mechanism between the humerus and the ulna. Complications related to these spacers that occurred either during the implantation, between implantation and removal, or during removal were recorded and analyzed from chart review and follow-up x rays. Reoperations due to spacer-related complications were also recorded. RESULTS: Among the 55 patients (78 spacers), there were 23 complications, including 17 minor and 6 major complications. The most common complication of unlinked spacers (intramedullary [IM] dowels, beads and cap spacer) was spacer displacement. Other complications included IM dowel fracture and difficulty locating beads during spacer removal. The major complications of linked cement spacers included two periprosthetic humerus fractures after internal external fixator cement spacers and re-operation due to breakage and displacement of one bushing cement spacer. The major complications of unlinked cement spacers included two reoperations due to IM dowel displacement and one reoperation due to displacement of beads. Among patients who had removal of all components and those with native joints, there was no statistically significant difference between internal external fixator cement spacers and unlinked cement spacers in minor complication rates (30% vs. 16%, P = .16), major complication rates (7% vs. 8%, P = .85) and reoperation rates (0% vs. 8%, P = .12). CONCLUSIONS: Static handmade antibiotic elbow spacers have unique complications related to their structural designs. The most common complication of linked and nonlinked cement spacers were failure of the linking mechanism and displacement, respectively. Surgeons should keep in mind the possible complications of different structures of cement spacers when choosing 1 antibiotic spacer structure over another.

Psychosocial functioning in pediatric food allergies: A scoping review.

The psychosocial burden of food allergy (FA) can significantly affect the lives of pediatric patients and their families. A comprehensive understanding of the state of the literature on psychosocial functioning is imperative to identify gaps that may affect clinical care and future research. This review characterizes the current literature on psychosocial functioning in pediatric patients with FA and their caregivers, siblings, and families. A literature search of 5 databases (PubMed, Ovid MEDLINE, PsycINFO, Web of Science, and Embase) was conducted to identify original research articles and abstracts on psychosocial functioning of patients with FA who were aged 0 to 18 years and their caregivers, siblings, and families. A total of 257 studies met the inclusion criteria. The majority of studies examined child or caregiver psychosocial functioning, with child and caregiver quality of life examined most frequently. Most studies utilized quantitative and cross-sectional methods and inconsistently reported participant race and ethnicity. Existing research on psychosocial functioning in pediatric FA may not be generalizable to patients of color and families and siblings. Future research should diversify recruited samples regarding race, ethnicity, and country of origin; examine psychosocial functioning longitudinally; examine constructs beyond quality of life; and adopt a biopsychosocial approach by considering the interplay among psychosocial functioning, disease burden, and social contexts.

Xylazine in the Unregulated Drug Market: An Integrative Review of Its Prevalence, Health Impacts, and Detection and Intervention Challenges in the United States.

Xylazine, a veterinary sedative, has emerged as a concerning element in the landscape of substance use in the United States. This integrative review synthesizes evidence from a systematic examination of 14 selected studies conducted between 2008 and 2023. The primary objective is to comprehensively understand the epidemiology and prevalence of xylazine use, particularly its involvement in drug-related deaths, regional variations, national impact, co-occurrence with opioids, and challenges associated with detection and intervention. The results underscore stark regional disparities in xylazine prevalence. West Virginia and Miami-Dade County have experienced alarming surges in xylazine-involved drug-related deaths. Nationally, its influence extends beyond regional boundaries, predominantly affecting white males in the Northeast. The co-occurrence of xylazine with opioids, especially fentanyl and heroin, significantly amplifies the risks of fatal overdoses. Detecting xylazine presents formidable challenges due to its frequent presence alongside other substances, necessitating enhanced surveillance and more effective detection methods. User perspectives emerge as pivotal, emphasizing the importance of user-informed harm reduction strategies. In conclusion, this review has significant policy implications. Tailored, region-specific strategies are imperative to address the diverse prevalence of xylazine use. A nationwide response is indispensable, prioritizing harm reduction initiatives, enhanced detection methods, and active user engagement. The multifaceted nature of the xylazine issue requires comprehensive approaches to mitigate its profound risks effectively. Policymakers are urged to consider regional disparities and the co-occurrence of xylazine with opioids when crafting targeted interventions. Immediate, user-informed harm reduction is vital to address the evolving landscape of xylazine use in the United States.

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

ASC-dependent inflammasomes contribute to immunopathology and mortality in herpes simplex encephalitis.

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1ß and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.