Preventing Behavioral Human Immunodeficiency Virus Infections in Adolescents and Young Adults.

HIV prevention in adolescents and young adults (AYA) requires a multi-pronged strategy encompassing behavioral, biologic, and structural approaches. This article reviews the epidemiology of HIV infection in the United States and its pathogenesis and transmission. Prevention approaches are discussed in more detail, with an emphasis on how each approach is relevant to AYA populations. Information is summarized in a resource table with links to references and in-depth discussions of the topics reviewed in this article.

A 12.4-day periodicity in a close binary system after a supernova.

Neutron stars and stellar-mass black holes are the remnants of massive star explosions1. Most massive stars reside in close binary systems2, and the interplay between the companion star and the newly formed compact object has been theoretically explored3, but signatures for binarity or evidence for the formation of a compact object during a supernova explosion are still lacking. Here we report a stripped-envelope supernova, SN 2022jli, which shows 12.4-day periodic undulations during the declining light curve. Narrow Hα emission is detected in late-time spectra with concordant periodic velocity shifts, probably arising from hydrogen gas stripped from a companion and accreted onto the compact remnant. A new Fermi-LAT γ-ray source is temporally and positionally consistent with SN 2022jli. The observed properties of SN 2022jli, including periodic undulations in the optical light curve, coherent Hα emission shifting and evidence for association with a γ-ray source, point to the explosion of a massive star in a binary system leaving behind a bound compact remnant. Mass accretion from the companion star onto the compact object powers the light curve of the supernova and generates the γ-ray emission.

Sigma Receptor Ligands Prevent COVID Mortality In Vivo: Implications for Future Therapeutics.

The emergence of lethal coronaviruses follows a periodic pattern which suggests a recurring cycle of outbreaks. It remains uncertain as to when the next lethal coronavirus will emerge, though its eventual emergence appears to be inevitable. New mutations in evolving SARS-CoV-2 variants have provided resistance to current antiviral drugs, monoclonal antibodies, and vaccines, reducing their therapeutic efficacy. This underscores the urgent need to investigate alternative therapeutic approaches. Sigma receptors have been unexpectedly linked to the SARS-CoV-2 life cycle due to the direct antiviral effect of their ligands. Coronavirus-induced cell stress facilitates the formation of an ER-derived complex conducive to its replication. Sigma receptor ligands are believed to prevent the formation of this complex. Repurposing FDA-approved drugs for COVID-19 offers a timely and cost-efficient strategy to find treatments with established safety profiles. Notably, diphenhydramine, a sigma receptor ligand, is thought to counteract the virus by inhibiting the creation of ER-derived replication vesicles. Furthermore, lactoferrin, a well-characterized immunomodulatory protein, has shown antiviral efficacy against SARS-CoV-2 both in laboratory settings and in living organisms. In the present study, we aimed to explore the impact of sigma receptor ligands on SARS-CoV-2-induced mortality in ACE2-transgenic mice. We assessed the effects of an investigational antiviral drug combination comprising a sigma receptor ligand and an immunomodulatory protein. Mice treated with sigma-2 receptor ligands or diphenhydramine and lactoferrin exhibited improved survival rates and rapid rebound in mass following the SARS-CoV-2 challenge compared to mock-treated animals. Clinical translation of these findings may support the discovery of new treatment and research strategies for SARS-CoV-2.

A rotating white dwarf shows different compositions on its opposite faces.

White dwarfs, the extremely dense remnants left behind by most stars after their death, are characterized by a mass comparable to that of the Sun compressed into the size of an Earth-like planet. In the resulting strong gravity, heavy elements sink towards the centre and the upper layer of the atmosphere contains only the lightest element present, usually hydrogen or helium1,2. Several mechanisms compete with gravitational settling to change a white dwarf's surface composition as it cools3, and the fraction of white dwarfs with helium atmospheres is known to increase by a factor of about 2.5 below a temperature of about 30,000 kelvin4-8; therefore, some white dwarfs that appear to have hydrogen-dominated atmospheres above 30,000 kelvin are bound to transition to be helium-dominated as they cool below it. Here we report observations of ZTF J203349.8+322901.1, a transitioning white dwarf with two faces: one side of its atmosphere is dominated by hydrogen and the other one by helium. This peculiar nature is probably caused by the presence of a small magnetic field, which creates an inhomogeneity in temperature, pressure or mixing strength over the surface9-11. ZTF J203349.8+322901.1 might be the most extreme member of a class of magnetic, transitioning white dwarfs-together with GD 323 (ref. 12), a white dwarf that shows similar but much more subtle variations. This class of white dwarfs could help shed light on the physical mechanisms behind the spectral evolution of white dwarfs.

An infrared transient from a star engulfing a planet.

Planets with short orbital periods (roughly under 10 days) are common around stars like the Sun1,2. Stars expand as they evolve and thus we expect their close planetary companions to be engulfed, possibly powering luminous mass ejections from the host star3-5. However, this phase has never been directly observed. Here we report observations of ZTF SLRN-2020, a short-lived optical outburst in the Galactic disk accompanied by bright and long-lived infrared emission. The resulting light curve and spectra share striking similarities with those of red novae6,7-a class of eruptions now confirmed8 to arise from mergers of binary stars. Its exceptionally low optical luminosity (approximately 1035 erg s-1) and radiated energy (approximately 6.5 × 1041 erg) point to the engulfment of a planet of fewer than roughly ten Jupiter masses by its Sun-like host star. We estimate the Galactic rate of such subluminous red novae to be roughly between 0.1 and several per year. Future Galactic plane surveys should routinely identify these, showing the demographics of planetary engulfment and the ultimate fate of planets in the inner Solar System.

The feasibility and impact of implementing a computer-guided consultation to target health inequality in Asthma.

Greater Manchester has a greater prevalence and worse asthma outcomes than the national average. This study aims to evaluate a digital approach to primary care asthma management and in particular the initial impact of implementing Clinical Decision Support System software in the form of a computer-guided consultation (CGC) in the setting of primary care asthma reviews in deprived areas of Greater Manchester. The CGC (LungHealth Ltd) is an intelligent decision support system ensuring accurate guideline-based staging of asthma and assessment of asthma control with the software subsequently prompting guideline-standard management. Patients on asthma registers in Greater Manchester Primary Care Networks were identified and underwent remote review by nursing staff using the CGC linked directly to the GP clinical system. Three-hundred thirty-eight patients (mean age 59 (SD 17) years; 60% Female) were reviewed. The CGC reported the patient's asthma control to be "Good" in 22%, "Partial" in 6% and "Poor" in 72%. ACT scores were significantly higher in those patients exhibiting "Good" and "Partial" control when compared to those with "Poor" control. The number of steroid courses and hospital admissions in the previous 12 months was significantly lower in those patients exhibiting "Good" and "Partial" control when compared to those with "Poor" control. Nineteen percent were found not to have a personalised asthma management plan during CGC review, which was alerted by the CGC and subsequently, all but 3 patients had this created on review completion (McNemar's test; p < 0.001). 5% were found not to have been prescribed regular inhaled steroid therapy resulting in the operator being alerted by the CGC in all cases. Overall, 44% underwent alteration in asthma therapy following the CGC review with 82% of these representing treatment escalation. An end-to-end digital service solution is feasible for Asthma within primary care and the utilisation of a CGC when conducting primary care asthma reviews increases implementation of guideline-level management thus addressing healthcare inequality while enabling identification of "high risk" asthma patients and guiding appropriate therapy escalation and de-escalation.

Latitudes and attitudes: A multinational study of laparoscopic pyeloplasty in children.

PURPOSE: The Anderson-Hynes technique has been the treatment of choice for primary ureteropelvic junction obstruction in children. Laparoscopic approach has shown similar outcomes to open, with advantages of shorter hospital stay and less pain. We reviewed the experience of 11 geographically diverse, tertiary pediatric urology institutions focusing on the outcomes and complications of laparoscopic pyeloplasty. MATERIALS AND METHODS: A descriptive, retrospective study was conducted evaluating patients undergoing Anderson-Hynes dismembered laparoscopic pyeloplasty. Centers from four different continents participated. Demographic data, perioperative management, results, and complications are described. RESULTS: Over a 9-year period, 744 laparoscopic pyeloplasties were performed in 743 patients. Mean follow-up was 31 months (6-120m). Mean age at surgery was 82 months (1 w-19 y). Median operative time was 177 min. An internal stent was placed in 648 patients (87%). A catheter was placed for bladder drainage in 702 patients (94%). Conversion to open pyeloplasty was necessary in seven patients. Average length of hospital stay was 2.8 days. Mean time of analgesic requirement was 3.2 days. Complications, according to Clavien-Dindo classification, were observed in 56 patients (7.5%); 10 (1%) were Clavien-Dindo IIIb. Treatment failure occurred in 35 cases with 30 requiring redo pyeloplasty (4%) and 5 cases requiring nephrectomy (0.6%). CONCLUSION: We have described the laparoscopic pyeloplasty experience of institutions with diverse cultural and economic backgrounds. They had very similar outcomes, in agreement with previously published data. Based on these findings, we conclude that laparoscopic pyeloplasty is safe and successful in diverse geographics areas of the world.

The Elusive Coreceptors for the SARS-CoV-2 Spike Protein.

Evidence suggests that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein interacts with host coreceptors that participate in viral entry. Resolving the identity of coreceptors has important clinical implications as it may provide the basis for the development of antiviral drugs and vaccine candidates. The majority of characteristic mutations in variants of concern (VOCs) have occurred in the NTD and receptor binding domain (RBD). Unlike the RBD, mutations in the NTD have clustered in the most flexible parts of the spike protein. Many possible coreceptors have been proposed, including various sugars such as gangliosides, sialosides, and heparan sulfate. Protein coreceptors, including neuropilin-1 and leucine-rich repeat containing 15 (LRRC15), are also proposed coreceptors that engage the NTD.

Revision Anterior Cruciate Ligament, Lateral Collateral Ligament Reconstruction, and Osteochondral Allograft Transplantation for Complex Knee Instability.

Anterior cruciate ligament (ACL) injuries rarely occur as an isolated event and often include associated meniscal, subchondral bone, and collateral ligament injuries. Concomitant pathology frequently complicates primary and revision ACL reconstruction and must be addressed to ensure comprehensive diagnosis and treatment. In this Technical Note, we describe our method for treatment of complex knee instability following multiple failed ACL reconstruction using a multiligament reconstruction technique with an osteochondral allograft transplantation to the lateral femoral condyle. This comprehensive repair technique restores the anatomic load bearing forces of the cruciate and collateral ligaments and promotes biological repair through incorporation of cartilage resurfacing to ultimately achieve optimal kinematics of the knee joint.

Covert capture and attenuation of a hippocampus-dependent fear memory.

Reconsolidation may be a viable therapeutic target to inhibit pathological fear memories. In the clinic, incidental or imaginal reminders are used for safe retrieval of traumatic memories of experiences that occurred elsewhere. However, it is unknown whether indirectly retrieved traumatic memories are sensitive to disruption. Here we used a backward (BW) conditioning procedure to indirectly retrieve and manipulate a hippocampus (HPC)-dependent contextual fear engram in male rats. We show that conditioned freezing to a BW conditioned stimulus (CS) is mediated by fear to the conditioning context, activates HPC ensembles that can be covertly captured and chemogenetically activated to drive fear, and is impaired by post-retrieval protein synthesis inhibition. These results reveal that indirectly retrieved contextual fear memories reactivate HPC ensembles and undergo protein synthesis-dependent reconsolidation. Clinical interventions that rely on indirect retrieval of traumatic memories, such as imaginal exposure, may open a window for editing or erasure of neural representations that drive pathological fear.

Behavioral and brain mechanisms mediating conditioned flight behavior in rats.

Environmental contexts can inform animals of potential threats, though it is currently unknown how context biases the selection of defensive behavior. Here we investigated context-dependent flight responses with a Pavlovian serial-compound stimulus (SCS) paradigm that evokes freeze-to-flight transitions. Similar to previous work in mice, we show that male and female rats display context-dependent flight-like behavior in the SCS paradigm. Flight behavior was dependent on contextual fear insofar as it was only evoked in a shock-associated context and was reduced in the conditioning context after context extinction. Flight behavior was only expressed to white noise regardless of temporal order within the compound. Nonetheless, rats that received unpaired SCS trials did not show flight-like behavior to the SCS, indicating it is associative. Finally, we show that pharmacological inactivation of two brain regions critical to the expression of contextual fear, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), attenuates both contextual fear and flight responses. All of these effects were similar in male and female rats. This work demonstrates that contextual fear can summate with cued and innate fear to drive a high fear state and transition from post-encounter to circa-strike defensive modes.

NMDA receptors in the CeA and BNST differentially regulate fear conditioning to predictable and unpredictable threats.

Considerable work demonstrates that Pavlovian fear conditioning depends on N-methyl-D-aspartate (NMDA) receptor-dependent plasticity within the amygdala. In addition, the bed nucleus of the stria terminalis (BNST) has also been implicated in fear conditioning, particularly in the expression of fear to poor predictors of threat. We recently found that the expression of backward (BW) fear conditioning, in which an auditory conditioned stimulus (CS) follows a footshock unconditioned stimulus (US), requires the BNST; the expression of forward (FW) fear conditioning was not disrupted by BNST inactivation. However, whether NMDA receptors within the BNST contribute to the acquisition of fear conditioning is unknown. Moreover, the central nucleus of the amygdala (CeA), which has extensive connections with the BNST, is critically involved in FW conditioning, however whether it participates in BW conditioning has not been explored. Here we test the specific hypothesis that the CeA and the BNST mediate the acquisition of FW and BW fear conditioning, respectively. Adult female and male rats were randomly assigned to receive bilateral infusions of the NMDA receptor antagonist, D,L-2-amino-5-phosphonovalerate (APV), into the CeA or BNST prior to FW or BW fear conditioning. We found that intra-CeA APV impaired the acquisition of both FW and BW conditioning, whereas intra-BNST APV produced selective deficits in BW conditioning. Moreover, APV in the BNST significantly reduced contextual freezing, whereas CeA NMDA receptor antagonism impeded early but not long-lasting contextual fear. Collectively, these data reveal that CeA and BNST NMDA receptors have unique roles in fear conditioning.

Locus coeruleus toggles reciprocal prefrontal firing to reinstate fear.

The medial prefrontal cortex (mPFC) plays an essential role in regulating emotion, including inhibiting fear when danger has passed. The extinction of fear, however, is labile and a number of factors, including stress, cause extinguished fear to relapse. Here we show that fear relapse in rats limits single-unit activity among infralimbic (IL) neurons, which are critical for inhibiting fear responses, and facilitates activity in prelimbic (PL) neurons involved in fear expression. Pharmacogenetic activation of noradrenergic neurons in the locus coeruleus mimics this shift in reciprocal IL-PL spike firing, increases the expression of conditioned freezing behavior, and causes relapse of extinguished fear. Noradrenergic modulation of mPFC firing represents a mechanism for relapse and a potential target for therapeutic interventions to reduce pathological fear.

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals.

The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.

Synaptic encoding of fear memories in the amygdala.

Over the years Pavlovian fear conditioning has proved to be a powerful model to investigate the neural underpinnings of aversive associative memory formation. Although it is well appreciated that plasticity occurring at excitatory synapses within the basolateral complex of the amygdala (BLA) plays a critical role in associative memory formation, recent evidence suggests that plasticity within the amygdala is more distributed than previously appreciated. In particular, studies demonstrate that plasticity in the central nucleus (CeA) is critical for the acquisition of conditioned fear. In addition, a variety of interneuron populations within the amygdala, defined by unique neurochemical markers, contribute to distinct aspects of stimulus processing and memory formation during fear conditioning. Here, we will review and summarize recent advances in our understanding of amygdala networks and how unique players within this network contribute to synaptic plasticity associated with the acquisition of conditioned fear.

Nucleus Reuniens Is Required for Encoding and Retrieving Precise, Hippocampal-Dependent Contextual Fear Memories in Rats.

The nucleus reuniens (RE) is a ventral midline thalamic nucleus that interconnects the medial prefrontal cortex (mPFC) and hippocampus (HPC). Considerable data indicate that HPC-mPFC circuits are involved in contextual and spatial memory; however, it is not clear whether the RE mediates the acquisition or retrieval of these memories. To examine this question, we inactivated the RE with muscimol before either the acquisition or retrieval of pavlovian fear conditioning in rats; freezing served as the index of fear. We found that RE inactivation before conditioning impaired the acquisition of contextual freezing, whereas inactivation of the RE before retrieval testing increased the generalization of freezing to a novel context; inactivation of the RE did not affect either the acquisition or expression of auditory fear conditioning. Interestingly, contextual conditioning impairments were absent when retrieval testing was also conducted after RE inactivation. Contextual memories acquired under RE inactivation were hippocampal independent, insofar as contextual freezing in rats conditioned under RE inactivation was insensitive to intrahippocampal infusions of the NMDA receptor antagonist aminophosphonovalerate. Together, these data reveal that the RE supports hippocampal-dependent encoding of precise contextual memories that allow discrimination of dangerous contexts from safe contexts. When the RE is inactive, however, alternate neural systems acquire an impoverished contextual memory that is expressed only when the RE is off-line.SIGNIFICANCE STATEMENT The midline thalamic nucleus reuniens (RE) coordinates communication between the hippocampus and medial prefrontal cortex, brain areas that are critical for contextual and spatial memory. Here we show that temporary pharmacological inactivation of RE impairs the acquisition and precision of contextual fear memories after pavlovian fear conditioning in rats. However, inactivating the RE before retrieval testing restored contextual memory in rats conditioned after RE inactivation. Critically, we show that imprecise contextual memories acquired under RE inactivation are learned independently of the hippocampus. These data reveal that the RE is required for hippocampal-dependent encoding of precise contextual memories to support the discrimination of safe and dangerous contexts.

Electrochemical Azidooxygenation of Alkenes Mediated by a TEMPO-N3 Charge-Transfer Complex.

We report a mild and efficient electrochemical protocol to access a variety of vicinally C-O and C-N difunctionalized compounds from simple alkenes. Detailed mechanistic studies revealed a distinct reaction pathway from those previously reported for TEMPO-mediated reactions. In this mechanism, electrochemically generated oxoammonium ion facilitates the formation of azidyl radical via a charge-transfer complex with azide, TEMPO-N3. DFT calculations together with spectroscopic characterization provided a tentative structural assignment of this charge-transfer complex. Kinetic and kinetic isotopic effect studies revealed that reversible dissociation of TEMPO-N3 into TEMPO• and azidyl precedes the addition of these radicals across the alkene in the rate-determining step. The resulting azidooxygenated product could then be easily manipulated for further synthetic elaborations. The discovery of this new reaction pathway mediated by the TEMPO+/TEMPO• redox couple may expand the scope of aminoxyl radical chemistry in synthetic contexts.

Enhancing and impairing extinction of habit memory through modulation of NMDA receptors in the dorsolateral striatum.

The present experiments investigated the involvement of N-methyl-d-aspartate (NMDA) receptors of the dorsolateral striatum (DLS) in consolidation of extinction in a habit memory task. Adult male Long-Evans rats were initially trained in a food-reinforced response learning version of a plus-maze task and were subsequently given extinction training in which the food was removed from the maze. In experiment 1, immediately after the first day of extinction training, rats received bilateral intra-DLS injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 2µg/side) or physiological saline. In experiment 2, immediately following the first day of extinction training, animals were given intra-DLS injections of NMDA receptor partial agonist d-cycloserine (DCS; 10 or 20µg/side) or saline. In both experiments, the number of perseverative trials (a trial in which a rat made the same previously reinforced body-turn response) and latency to reach the previously correct food well were used as measures of extinction behavior. Results indicated that post-training intra-DLS injections of AP5 impaired extinction. In contrast, post-training intra-DLS infusions of DCS (20µg) enhanced extinction. Intra-DLS administration of AP5 or DCS given two hours after extinction training did not influence extinction of response learning, indicating that immediate post-training administration of AP5 and DCS specifically influenced consolidation of the extinction memory. The present results indicate a critical role for DLS NMDA receptors in modulating extinction of habit memory and may be relevant to developing therapeutic approaches to combat the maladaptive habits observed in human psychopathologies in which DLS-dependent memory has been implicated (e.g. drug addiction and relapse and obsessive compulsive disorder).

Effects of naltrexone are influenced by childhood adversity during negative emotional processing in addiction recovery.

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone (n=18, alcohol) and in combination with cocaine and/or opioid dependence (n=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence (n=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.

Patient Throughput in a Sports Medicine Clinic With the Implementation of an Athletic Trainer: A Retrospective Analysis.

BACKGROUND: Orthopaedic clinics have acquired a multitude of health professionals to improve clinic efficiency. More recently, athletic trainers (ATs) have been utilized to improve clinical efficiency and patient care because of their extensive background in musculoskeletal injuries and anatomy. Improved clinical efficiency allows for increased patient visits, potentially enhancing patient access and downstream revenue via relative value units (RVUs). HYPOTHESIS: The addition of an AT into a sports medicine physician's clinic will increase total patient throughput and overall RVU production. STUDY DESIGN: Retrospective analysis. LEVEL OF EVIDENCE: Level 4. METHODS: Patients seen by each of the 2 primary care sports medicine physicians at St Luke's Sports Medicine for a 2-year period were retrospectively evaluated. The initial clinic model included the physician and a medical assistant; during the second year of analysis an AT was added to the clinic staffing model. Two-tailed t tests were used to determine significant differences in patient volume between the 2 periods of data collection. RESULTS: Through the implementation of an AT, patient throughput increased by 0.7 patients per hour over 2 half-day clinics, a 25% increase ( P < 0.01). Physician B patient visits increased by 21%, or 3.8 patients per 6.5-hour clinic day ( P < 0.01). Additionally, RVU production increased by 3.23 per half-day and 4.3 per full day for physicians A and B, respectively. CONCLUSION: Clinical efficiency was improved with the addition of an AT. Total physician RVUs improved, thereby raising the potential revenue of both the physician and health care institution. Employing ATs in a sports medicine clinic may improve clinical productivity and financial stability, thereby validating the incorporation of ATs into the established clinical model. CLINICAL RELEVANCE: Limited research exists measuring patient throughput with an AT in a sports medicine clinic. This study investigates patient throughput and the subsequent increase in work-based RVUs.