A quantum enhanced search for dark matter axions.

The manipulation of quantum states of light1 holds the potential to enhance searches for fundamental physics. Only recently has the maturation of quantum squeezing technology coincided with the emergence of fundamental physics searches that are limited by quantum uncertainty2,3. In particular, the quantum chromodynamics axion provides a possible solution to two of the greatest outstanding problems in fundamental physics: the strong-CP (charge-parity) problem of quantum chromodynamics4 and the unknown nature of dark matter5-7. In dark matter axion searches, quantum uncertainty manifests as a fundamental noise source, limiting the measurement of the quadrature observables used for detection. Few dark matter searches have approached this limit3,8, and until now none has exceeded it. Here we use vacuum squeezing to circumvent the quantum limit in a search for dark matter. By preparing a microwave-frequency electromagnetic field in a squeezed state and near-noiselessly reading out only the squeezed quadrature9, we double the search rate for axions over a mass range favoured by some recent theoretical projections10,11. We find no evidence of dark matter within the axion rest energy windows of 16.96-17.12 and 17.14-17.28 microelectronvolts. Breaking through the quantum limit invites an era of fundamental physics searches in which noise reduction techniques yield unbounded benefit compared with the diminishing returns of approaching the quantum limit.

National Institute on Drug Abuse Clinical Trials Network Meeting Report: Managing Patients Exposed to Xylazine-Adulterated Opioids in Emergency, Hospital and Addiction Care Settings.

Used as a veterinary sedative and not approved for human use, xylazine has been increasingly linked with opioid overdose deaths in the United States. A growing number of people have been exposed to xylazine in the illicit opioid supply (especially fentanyl) or in other drugs, particularly in some areas of the Northeast. Xylazine is an α-2 adrenergic agonist that decreases sympathetic nervous system activity. When combined with fentanyl or heroin, it is purported to extend the duration of the opioid's sedative effect and to cause dependence and an associated withdrawal syndrome; however, data to support these concerns are limited. Despite the escalating frequency of detection of xylazine in people with nonfatal and fatal opioid overdose, direct links to these outcomes have not been identified. Because the strongest causal link is to fentanyl coexposure, ventilatory support and naloxone remain the cornerstones of overdose management. Xylazine is also associated with severe tissue injury, including skin ulcers and tissue loss, but little is known about the underlying mechanisms. Nonetheless, strategies for prevention and treatment are emerging. The significance and clinical effects of xylazine as an adulterant is focused on 4 domains that merit further evaluation: fentanyl-xylazine overdose, xylazine dependence and withdrawal, xylazine-associated dermal manifestations, and xylazine surveillance and detection in clinical and nonclinical settings. This report reflects the Proceedings of the National Institute on Drug Abuse Center for the Clinical Trials Network convening of clinical and scientific experts, federal staff, and other stakeholders to describe emerging best practices for treating people exposed to xylazine-adulterated opioids. Participants identified scientific gaps and opportunities for research to inform clinical practice in emergency departments, hospitals, and addiction medicine settings.

Function and biochemistry of the dorsolateral prefrontal cortex during placebo analgesia: how the certainty of prior experiences shapes endogenous pain relief.

Prior experiences, conditioning cues, and expectations of improvement are essential for placebo analgesia expression. The dorsolateral prefrontal cortex is considered a key region for converting these factors into placebo responses. Since dorsolateral prefrontal cortex neuromodulation can attenuate or amplify placebo, we sought to investigate dorsolateral prefrontal cortex biochemistry and function in 38 healthy individuals during placebo analgesia. After conditioning participants to expect pain relief from a placebo "lidocaine" cream, we collected baseline magnetic resonance spectroscopy (1H-MRS) at 7 Tesla over the right dorsolateral prefrontal cortex. Following this, functional magnetic resonance imaging scans were collected during which identical noxious heat stimuli were delivered to the control and placebo-treated forearm sites. There was no significant difference in the concentration of gamma-aminobutyric acid, glutamate, Myo-inositol, or N-acetylaspartate at the level of the right dorsolateral prefrontal cortex between placebo responders and nonresponders. However, we identified a significant inverse relationship between the excitatory neurotransmitter glutamate and pain rating variability during conditioning. Moreover, we found placebo-related activation within the right dorsolateral prefrontal cortex and altered functional magnetic resonance imaging coupling between the dorsolateral prefrontal cortex and the midbrain periaqueductal gray, which also correlated with dorsolateral prefrontal cortex glutamate. These data suggest that the dorsolateral prefrontal cortex formulates stimulus-response relationships during conditioning, which are then translated to altered cortico-brainstem functional relationships and placebo analgesia expression.

Opioid and Benzodiazepine Co-Prescribing Trends from the Emergency Department from 2012 to 2019: A National Analysis.

BACKGROUND: In 2016, the U.S. Food and Drug Administration (FDA) issued its strongest safety warning ("Black Box Warning") for concomitant use of prescription opioids and benzodiazepines due to overdose deaths. OBJECTIVE: Our objective was to look at trends of opioid and benzodiazepine co-prescribing in the emergency department (ED) using national data, because recent data are sparse. METHODS: This is a retrospective review of data collected by the National Hospital Ambulatory Medical Care Survey between 2012 and 2019. Our primary outcome was to determine whether there was a trend in ED visits when opioids and benzodiazepines were co-prescribed at discharge. We also compared the rate of visits when co-prescribing occurred before (2012-2015) and after (2017-2019) the 2016 FDA warning. We identified commonly co-prescribed benzodiazepines and opioids, and the rate of naloxone co-prescribing. We used descriptive statistics and bivariate tests to describe data. RESULTS: Between 2012 and 2019, there were 4,489,613 ED visits (0.41% of ED visits) when benzodiazepines and opioids were co-prescribed. There was no trend in the rate of co-prescribing overall, but a decrease in visits after the 2016 FDA Black Box Warning (2012-2015: mean 0.49%; 2017-2019: mean 0.29%; p < 0.0001). There were 7980 ED visits (0.18%) when naloxone was co-prescribed for these visits within this time frame and an increase over time (p < 0.001). CONCLUSIONS: Our study found that between 2012 and 2019, there was no overall reduction in co-prescribing of opioids and benzodiazepines across EDs nationwide, but a decrease after the 2016 Black Box Warning.

Surgical and Radiology Trainees' Proficiency in Reading Mammograms: the Importance of Education for Cancer Localisation.

Medical imaging with mammography plays a very important role in screening and diagnosis of breast cancer, Australia's most common female cancer. The visualisation of cancers on mammograms often forms a diagnosis and guidance for radiologists and breast surgeons, and education platforms that provide real cases in a simulated testing environment have been shown to improve observer performance for radiologists. This study reports on the performance of surgical and radiology trainees in locating breast cancers. An enriched test set of 20 mammography cases (6 cancer and 14 cancer free) was created, and 18 surgical trainees and 32 radiology trainees reviewed the cases via the Breast Screen Reader Assessment Strategy (BREAST) platform and marked any lesions identifiable. Further analysis of performance with high- and low-density cases was undertaken, and standard metrics including sensitivity and specificity. Radiology trainees performed significantly better than surgical trainees in terms of specificity (0.72 vs. 0.35; P < 0.01). No significant differences were observed between the surgical and radiology trainees in sensitivity or lesion sensitivity. Mixed results were obtained with participants regarding breast density, with higher density cases generally having lower performance. The higher specificity of the radiology trainees compared to the surgical trainees likely represents less exposure to negative mammography cases. The use of high-fidelity simulated self-test environments like BREAST is able to benchmark, understand and build strategies for improving cancer education in a safe environment, including identifying challenging scenarios like breast density for enhanced training.

Detailed organisation of the human midbrain periaqueductal grey revealed using ultra-high field magnetic resonance imaging.

The midbrain periaqueductal grey (PAG) is a critical region for the mediation of pain-related behavioural responses. Neuronal tract tracing techniques in experimental animal studies have demonstrated that the lateral column of the PAG (lPAG) displays a crude somatotopy, which is thought to be critical for the selection of contextually appropriate behavioural responses, without the need for higher brain input. In addition to the different behavioural responses to cutaneous and muscle pain - active withdrawal versus passive coping - there is evidence that cutaneous pain is processed in the region of the lPAG and muscle pain in the adjacent ventrolateral PAG (vlPAG). Given the fundamental nature of these behavioural responses to cutaneous and muscle pain, these PAG circuits are assumed to have been preserved, though yet to be definitively documented in humans. Using ultra-high field (7-Tesla) functional magnetic resonance imaging we determined the locations of signal intensity changes in the PAG during noxious cutaneous heat stimuli and muscle pain in healthy control participants. Images were processed and blood oxygen level dependant (BOLD) signal changes within the PAG determined. It was observed that noxious cutaneous stimulation of the lip, cheek, and ear evoked maximal increases in BOLD activation in the rostral contralateral PAG, whereas noxious cutaneous stimulation of the thumb and toe evoked increases in the caudal contralateral PAG. Analysis of individual participants demonstrated that these activations were located in the lPAG. Furthermore, we found that deep muscular pain evoked the greatest increases in signal intensity in the vlPAG. These data suggest that the crude somatotopic organization of the PAG may be phyletically preserved between experimental animals and humans, with a body-face delineation capable of producing an appropriate behavioural response based on the location and tissue origin of a noxious stimulus.

Diagnosis, treatment, and outcome of patients with oesophagogastric cancer during the COVID-19 pandemic: national study.

BACKGROUND: The national response to COVID-19 has had a significant impact on cancer services. This study investigated the effect of national lockdown on diagnosis, management, and outcomes of patients with oesophagogastric cancers in Scotland. METHODS: This retrospective cohort study included consecutive new patients presenting to regional oesophagogastric cancer multidisciplinary teams in National Health Service Scotland between October 2019 and September 2020. The study interval was divided into before and after lockdown, based on the first UK national lockdown. Electronic health records were reviewed and results compared. RESULTS: Some 958 patients with biopsy-proven oesophagogastric cancer in 3 cancer networks were included: 506 (52.8 per cent) before and 452 (47.2 per cent) after lockdown. Median age was 72 (range 25-95) years and 630 patients (65.7 per cent) were men. There were 693 oesophageal (72.3 per cent) and 265 gastric (27.7 per cent) cancers. Median time to gastroscopy was 15 (range 0-337) days before versus 19 (0-261) days after lockdown (P < 0.001). Patients were more likely to present as an emergency after lockdown (8.5 per cent before versus 12.4 per cent after lockdown; P = 0.005), had poorer Eastern Cooperative Oncology group performance status, were more symptomatic, and presented with a higher stage of disease (stage IV: 49.8 per cent before versus 58.8 per cent after lockdown; P = 0.04). There was a shift to treatment with non-curative intent (64.6 per cent before versus 77.4 per cent after lockdown; P < 0.001). Median overall survival was 9.9 (95 per cent c.i. 8.7 to 11.4) months before and 6.9 (5.9 to 8.3) months after lockdown (HR 1.26, 95 per cent c.i. 1.09 to 1.46; P = 0.002). CONCLUSION: This national study has highlighted the adverse impact of COVID-19 on oesophagogastric cancer outcomes in Scotland. Patients presented with more advanced disease and a shift towards treatment with non-curative intent was observed, with a subsequent negative impact on overall survival.

Workplace Mistreatment, Career Choice Regret, and Burnout in Emergency Medicine Residency Training in the United States.

STUDY OBJECTIVE: The influence of workplace mistreatment on the well-being and career satisfaction of emergency medicine residents is unknown. This study examined the relationships between burnout, career choice regret, and workplace mistreatment in a national sample of emergency medicine residents. METHODS: This was a secondary analysis of a survey study on the prevalence of workplace mistreatment among emergency residents. Residents who reported emotional exhaustion or depersonalization at least once per week were considered to have burnout. Residents who reported dissatisfaction with their decision to become an emergency physician were considered to have career choice regret. Respondents also reported the type (discrimination, abuse, sexual harassment) and frequency of mistreatment over the academic year. Multivariable logistic regression, adjusting for program characteristics, was used to examine resident characteristics associated with burnout and career choice regret, with the frequency of mistreatment as a covariate. RESULTS: Of the 8,162 eligible residents, 7,680 (94.1 %) participated. About a third of respondents reported burnout (2,188 of 6,902, 31.7%), whereas a minority (224 of 6,923, 3.2%) reported career choice regret. Of the 7,087 responses on mistreatment frequency, 2,117 (29.9%) reported "a few times per year," and 1,296 (18.3%) reported "a few times per month or more." Compared with residents who never experienced mistreatment, residents who reported increasing frequencies of mistreatment were associated with having burnout-from mistreatment a few times per year (OR [odds ratio],1.6; 99% CI [confidence interval], 1.3 to 1.9) to a few times per month or more (OR, 3.3; 99% CI, 2.7 to 4.1). Compared with residents without burnout, residents who reported burnout were associated with having career choice regret (OR, 11.3; 99% CI, 7.0 to 18.1). After adjusting for burnout, there were no significant relationships between the frequency of mistreatment and career choice regret. CONCLUSIONS: Workplace mistreatment is associated with burnout, but not career choice regret, among emergency medicine residents. Efforts to address workplace mistreatment may improve emergency medicine residents' professional well-being.

Integrating Navajo Pottery Techniques To Improve Silver Nanoparticle-Enabled Ceramic Water Filters for Disinfection.

Point-of-use treatment technologies can increase access to safe drinking water in rural areas. Sustained use of these technologies is uncommon due to oversight of community needs, user-perceived risks, long-term maintenance, and conflict with traditional practices. Nanosilver-enabled ceramic water filters are unique due to the use of locally sourced materials available at or near the target community; however, technical limitations persist (e.g., nanosilver's uncontrolled release and passivation from sulfide or chloride). This work aims to overcome these limitations by impregnating nanosilver onto ceramics with a Navajo pottery rosin, collected from pinyon trees with a third-generation artisan. Here, we investigate this sustainable and novel material for drinking water treatment; the study ranges from a proof of concept to testing under realistic conditions. Results show that when embedded in a thin film, the biopolymer controlled ionic silver dissolution and prevented silver passivation from sulfide and chloride. When applied to ceramic filters, the biopolymer effectively immobilized nanosilver in a range of waters. Over a 25 day study to emulate household-use conditions, this coating method sustained disinfection of a coculture of Gram-positive and Gram-negative bacteria while controlling biofouling. Overall, the use of this Navajo pottery material can facilitate adoption while providing the needed technological advancement to these widely used treatment devices.

Impact of the COVID-19 pandemic on emergency department alcohol intoxication presentations and positive screens for problem drinking.

Our aim was to assess the changes in patients presenting with acute alcohol intoxications or positive screens for problem drinking during the COVID-19 pandemic compared to before the pandemic in a seven-hospital health system. A retrospective chart review of emergency department (ED) visits from seven hospitals in the Washington, DC/Baltimore, and MD area from January 2019 to June 2021 is provided. The health system utilizes a validated system for Screening, Brief Intervention, and Referral to Treatment (SBIRT) for ED patients. We evaluated trends in patients who had a positive SBIRT screen for problem drinking (AUDIT-C score ≥ 3 in women, 4 in men), alcohol misuse (≥5), and those presenting with acute alcohol intoxication before March 2020 and during the early COVID pandemic period. There were 510 648 patients who were screened, ranging from ages of 16 to 95 years during the study period. There was an overall increase in patients who screened positive for problem drinking, alcohol misuse, and acute intoxications. While there was an overall decrease in the total number of ED visits during the start of the pandemic, which later increased near prepandemic levels, alcohol-related presentations as a percentage of total visits increased during the early pandemic period. There was an overall decrease in ED visits during the COVID-19 pandemic study period; problem drinking and acute intoxication presentation held steady, leading to an overall increase in proportion compared to pre-COVID-19 levels. Future research should focus on lessons learned during this time and should navigate the postpandemic care of patients with AUD. There was an increase in the proportion of ED visits for alcohol intoxications and positive screens for problem drinking during the COVID-19 pandemic in our seven-hospital system.

A national analysis of ED presentations for early pregnancy and complications: Implications for post-Roe America.

BACKGROUND: Most obstetric emergencies are initially managed in the emergency department (ED). The Supreme Court decision of Dobbs v. Jackson Women's Health Organization, overturning Roe v. Wade, in June 2022, eliminated constitutional protection of abortion rights, allowing states to swiftly enact laws that can greatly change reproductive medicine. In this post-Roe landscape, the ambiguity and uncertainty being imposed on clinicians regarding the legality of certain interventions may have catastrophic effects. To understand and plan for the changes that will come and attempt to mitigate adverse outcomes, the authors first assessed the current state of pregnancy-related complication care in the ED setting. This study utilized data obtained from the National Hospital Ambulatory Medical Care Survey (NHAMCS) to evaluate trends in pregnancy-related ED visits from 2016 to 2020 that could be impacted by restricted abortion access and trigger laws. The authors subsequently analyzed the legislative changes and translated the pertinent ones to dispel misunderstandings and provide a framework for appropriate medical practice. METHODS: The retrospective study utilized data from the NHAMCS database from 2016 to 2020, encompassing an estimated total of 4,556,778 pregnancy-related ED visits. NHAMCS is a multi-stage probabilistic sample collected by the National Center for Health Statistics (NCHS) at the Centers for Disease Control and Prevention (CDC) using an annual survey of EDs in the United States. All data were summarized using descriptive statistics such as proportions and 95% confidence intervals Furthermore, the supreme court decision was analyzed in addition to multiple state laws and legal texts. The findings were summarized and discussed. RESULTS: The majority (79.4%) of all studied visits were for patients between the ages of 18-34 years, capturing those in peak reproductive years. This age group also comprised of the bulk (76.4%) of visits for pathologic pregnancies, including ectopic and molar pregnancies, and 79.8% of visits for a spontaneous miscarriage or threatened miscarriage in early pregnancy. Black patients accounted for 25.7%, white patients 70.1%. Regarding ethnicity, patients were separated into Hispanic and non-Hispanic, with Hispanic patients comprising 27% of all ED visits for included diagnoses between 2016 and 2020. Most visits for complications following an induced abortion occurred in the south (70.8%) and were nearly twice as likely to occur in non-metropolitan areas. Approximately 18% patients presenting with a pathologic pregnancy required admission to the hospital and approximately 50% of those visits for pathologic pregnancies and visits for bleeding in pregnancy had a procedure in the ED (49.8% and 49.5%). There were 111,264 estimated visits in which methotrexate was administered, amounting to approximately 1 in 7 visits for ectopic or molar pregnancy. In this data set, approximately 14,000 miscarriage and early bleeding patients received misoprostol. CONCLUSION: Pregnancy-related ED visits comprise of a significant proportion of emergency care. As it relates to many of the trends previously elucidated on, the true extent of the burden cannot be predicted. It must be emphasized that contrary to popular belief, Dobbs v. Jackson does not prohibit termination of pregnancy in the setting of life-threatening conditions to the mother, including ectopic pregnancy, preeclampsia, and others, but the resultant uncertainty and ambiguity surrounding the constitutional change is leading to an over-compliance of the law, necessarily obstructing reproductive health care. The authors recommend that physicians be mindful of the rapidly-evolving laws in their particular state, and to also practice in accordance with Emergency Medical Treatment and Active Labor Act (EMTALA). Patient safety must be prioritized.

Systematic Review of Naloxone Dosing and Adverse Events in the Emergency Department.

BACKGROUND: Experts recommend using the lowest effective dose of naloxone to balance the reversal of opioid-induced respiratory depression and avoid precipitated opioid withdrawal, however, there is no established dosing standards within the emergency department (ED). OBJECTIVES: The aim of this review was to determine current naloxone dosing practice in the ED and their association with adverse events. METHODS: We conducted a systematic review by searching PubMed, Cochrane, Embase, and EBSCO from 2000-2021. Articles containing patient-level data for initial ED dose and patient outcome had data abstracted by two independent reviewers. Patients were divided into subgroups depending on the initial dose of i.v. naloxone: low dose ([LD], < 0.4 mg), standard dose ([SD], 0.4-2 mg), or high dose ([HD], > 2 mg). Our outcomes were the dose range administered and adverse events per dose. We compared groups using chi-squared difference of proportions or Fisher's exact test. RESULTS: The review included 13 articles with 209 patients in the results analysis: 111 patients in LD (0.04-0.1 mg), 95 in SD (0.4-2 mg), and 3 in HD (4-12 mg). At least one adverse event was reported in 37 SD patients (38.9%), compared with 14 in LD (12.6%, p < 0.0001) and 2 in HD (100.0%, p = 0.16). At least one additional dose was administered to 53 SD patients (55.8%), compared with 55 in LD (49.5%, p < 0.0001), and 3 in HD (100.0%, p = 0.48). CONCLUSIONS: Lower doses of naloxone in the ED may help reduce related adverse events without increasing the need for additional doses. Future studies should evaluate the effectiveness of lower doses of naloxone to reverse opioid-induced respiratory depression without causing precipitated opioid withdrawal.

Brainstem Mechanisms of Pain Modulation: A within-Subjects 7T fMRI Study of Placebo Analgesic and Nocebo Hyperalgesic Responses.

Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study used ultra-high-field 7 tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants (N = 25, 12 male). Over 2 successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled lidocaine (placebo) and capsaicin (nocebo) were acting to modulate their pain relative to a third Vaseline (control) cream. In a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG-RVM pathway, which in concert with other brainstem sites likely influences the experience of pain by modulating activity at the level of the dorsal horn.SIGNIFICANCE STATEMENT Understanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation; however, because of the small size and complex organization of the nuclei, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of antinociceptive and pro-nociceptive effects. We used ultra-high-field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation.

Regional hypothalamic, amygdala, and midbrain periaqueductal gray matter recruitment during acute pain in awake humans: A 7-Tesla functional magnetic resonance imaging study.

Over the past two decades, magnetic resonance imaging (MRI) studies have explored brain activation patterns during acute noxious stimuli. Whilst these human investigations have detailed changes in primarily cortical regions, they have generally not explored discrete changes within small brain areas that are critical in driving behavioural, autonomic, and endocrine responses to pain, such as within subregions of the hypothalamus, amygdala, and midbrain periaqueductal gray matter (PAG). Ultra-high field (7-Tesla) MRI provides enough signal-to-noise at high spatial resolutions to investigate activation patterns within these small brain regions during acute noxious stimulation in awake humans. In this study we used 7T functional MRI to concentrate on hypothalamic, amygdala, and PAG signal changes during acute noxious orofacial stimuli. Noxious heat stimuli were applied in three separate fMRI scans to three adjacent sites on the face in 16 healthy control participants (7 females). Images were processed using SPM12 and custom software, and blood oxygen level dependent signal changes within the hypothalamus, amygdala, and PAG assessed. We identified altered activity within eight unique subregions of the hypothalamus, four unique subregions of the amygdala, and a single region in the lateral PAG. Specifically, within the hypothalamus and amygdala, signal intensity largely decreased during noxious stimulation, and increased in the lateral PAG. Furthermore, we found sex-related differences in discrete regions of the hypothalamus and amygdala. This study reveals that the activity of discrete nuclei during acute noxious thermal stimulation in awake humans.

The metabolic health of young men conceived using intracytoplasmic sperm injection.

STUDY QUESTION: Is the metabolic health of men conceived using ICSI different to that of IVF and spontaneously conceived (SC) men? SUMMARY ANSWER: ICSI-conceived men aged 18-24 years, compared with SC controls, showed differences in some metabolic parameters including higher resting diastolic blood pressure (BP) and homeostasis model assessment for insulin resistance (HOMA-IR) scores, although the metabolic parameters of ICSI- and IVF-conceived singleton men were more comparable. WHAT IS KNOWN ALREADY: Some studies suggest that IVF-conceived offspring may have poorer cardiovascular and metabolic profiles than SC children. Few studies have examined the metabolic health of ICSI-conceived offspring. STUDY DESIGN, SIZE, DURATION: This cohort study compared the metabolic health of ICSI-conceived men to IVF-conceived and SC controls who were derived from prior cohorts. Participants included 121 ICSI-conceived men (including 100 singletons), 74 IVF-conceived controls (all singletons) and 688 SC controls (including 662 singletons). PARTICIPANTS/MATERIALS, SETTING, METHODS: Resting systolic and diastolic BP (measured using an automated sphygmomanometer), height, weight, BMI, body surface area and fasting serum metabolic markers including fasting insulin, glucose, total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, triglycerides, highly sensitive C-reactive protein (hsCRP) and HOMA-IR were compared between groups. Data were analysed using multivariable linear regression adjusted for various covariates including age and education level. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusting for covariates, compared to 688 SC controls, 121 ICSI-conceived men had higher diastolic BP (ß 4.9, 95% CI 1.1-8.7), lower fasting glucose (ß -0.7, 95% CI -0.9 to -0.5), higher fasting insulin (ratio 2.2, 95% CI 1.6-3.0), higher HOMA-IR (ratio 1.9, 95% CI 1.4-2.6), higher HDLC (ß 0.2, 95% CI 0.07-0.3) and lower hsCRP (ratio 0.4, 95% CI 0.2-0.7) levels. Compared to 74 IVF-conceived singletons, only glucose differed in the ICSI-conceived singleton men (ß -0.4, 95% CI -0.7 to -0.1). No differences were seen in the paternal infertility subgroups. LIMITATIONS, REASONS FOR CAUTION: The recruitment rate of ICSI-conceived men in this study was low and potential for recruitment bias exists. The ICSI-conceived men, the IVF-conceived men and SC controls were from different cohorts with different birth years and different geographical locations. Assessment of study groups and controls was not contemporaneous, and the measurements differed for some outcomes (BP, insulin, glucose, lipids and hsCRP). WIDER IMPLICATIONS OF THE FINDINGS: These observations require confirmation in a larger study with a focus on potential mechanisms. Further efforts to identify whether health differences are due to parental characteristics and/or factors related to the ICSI procedure are also necessary. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by an Australian National Health and Medical Research Council Partnership Grant (NHMRC APP1140706) and was partially funded by the Monash IVF Research and Education Foundation. S.R.C. was supported through an Australian Government Research Training Program Scholarship. R.J.H. is supported by an NHMRC project grant (634457), and J.H. and R.I.M. have been supported by the NHMRC as Senior and Principal Research Fellows respectively (J.H. fellowship number: 1021252; R.I.M. fellowship number: 1022327). L.R. is a minority shareholder and the Group Medical Director for Monash IVF Group, and reports personal fees from Monash IVF Group and Ferring Australia, honoraria from Ferring Australia and travel fees from Merck Serono and MSD and Guerbet; R.J.H. is the Medical Director of Fertility Specialists of Western Australia and has equity in Western IVF; R.I.M. is a consultant for and shareholder of Monash IVF Group and S.R.C. reports personal fees from Besins Healthcare and nonfinancial support from Merck outside of the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

A Neuropharmacological Model to Explain Buprenorphine Induction Challenges.

Buprenorphine induction for treating opioid use disorder is being implemented in emergency care. During this era of high-potency synthetic opioid use, novel and divergent algorithms for buprenorphine induction are emerging to optimize induction experience, facilitating continued treatment. Specifically, in patients with chronic fentanyl or other drug exposures, some clinicians are using alternative buprenorphine induction strategies, such as quickly maximizing buprenorphine agonist effects (eg, macrodosing) or, conversely, giving smaller initial doses and slowing the rate of buprenorphine dosing to avoid antagonist/withdrawal effects (eg, microdosing). However, there is a lack of foundational theory and empirical data to guide clinicians in evaluating such novel induction strategies. We present data from clinical studies of buprenorphine induction and propose a neuropharmacologic working model, which posits that acute clinical success of buprenorphine induction (achieving a positive agonist-to-withdrawal balance) is a nonlinear outcome of the opioid balance at the time of initial buprenorphine dose and mu-opioid-receptor affinity, lipophilicity, and mu-opioid-receptor intrinsic efficacy (the "ALE value") of the prior opioid. We discuss the rationale for administering smaller or larger doses of buprenorphine to optimize the patient induction experience during common clinical situations.

American Board of Emergency Medicine Report on Residency and Fellowship Training Information (2021-2022).

The American Board of Emergency Medicine gathers extensive background information on the Accreditation Council of Graduate Medical Education-accredited emergency medicine residency and fellowship programs, as well as the residents and fellows training in those programs. We present the 2022 annual report on the status of physicians training in Accreditation Council of Graduate Medical Education-accredited emergency medicine training programs in the United States.

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.

Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and sensorineural hearing loss.

BACKGROUND: Pathogenic variants in KITLG, a crucial protein involved in pigmentation and neural crest cell migration, cause non-syndromic hearing loss, Waardenburg syndrome type 2, familial progressive hyperpigmentation and familial progressive hyper- and hypopigmentation, all of which are inherited in an autosomal dominant manner. OBJECTIVES: To describe the genotypic and clinical spectrum of biallelic KITLG-variants. METHODS: We used a genotype-first approach through the GeneMatcher data sharing platform to collect individuals with biallelic KITLG variants and reviewed the literature for overlapping reports. RESULTS: We describe the first case series with biallelic KITLG variants; we expand the known hypomelanosis spectrum to include a 'sock-and-glove-like', symmetric distribution, progressive repigmentation and generalized hypomelanosis. We speculate that KITLG biallelic loss-of-function variants cause generalized hypomelanosis, whilst variants with residual function lead to a variable auditory-pigmentary disorder mostly reminiscent of Waardenburg syndrome type 2 or piebaldism. CONCLUSIONS: We provide consolidating evidence that biallelic KITLG variants cause a distinct auditory-pigmentary disorder. We evidence a significant clinical variability, similar to the one previously observed in KIT-related piebaldism.

Tramadol Use in United States Emergency Departments 2007-2018.

BACKGROUND: Amidst the opioid epidemic, there has been an increasing focus on opioid utilization in U.S. emergency departments (EDs). Compared with other opioids, little is known about the use of tramadol over the past decade. Tramadol has uncertain efficacy and a concerning adverse effect profile compared with traditional opioids. OBJECTIVE: Our aim was to describe trends in tramadol use in U.S. EDs between 2007 and 2018. METHODS: We analyzed the National Hospital Ambulatory Medical Care Survey from 2007 to 2018 to examine ED visits by patients 18 years or older in which tramadol was administered or prescribed. We examined trends in demographics and resource utilization and compared these trends with those of traditional opioids. Survey-weighted analyses were conducted to provide national-level estimates. RESULTS: Between 2007 and 2018, ED visits in which tramadol was used increased 70.6%, from 1.7% of all ED visits in 2007 to 2.9% in 2018. The largest increases were noted among patients aged 55 through 64 years and 65 years and older. Diagnostic resource utilization increased across the study period. Overall opioid utilization during the study period decreased from 28.4% in 2007 to 17.9% in 2018 (p < 0.001). The use of other specific opioids declined or remained stable between 2007 and 2018. CONCLUSIONS: Although the use of traditional opioids decreased from 2007 to 2018, the use of tramadol increased. Increases were largest among older patients, who may be more susceptible to the adverse effects associated with this medication. Further research in the appropriate use of tramadol in the ED setting is warranted.