Discovery medicine - the HVTN's iterative approach to developing an HIV-1 broadly neutralizing vaccine.

PURPOSE OF REVIEW: In the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine. RECENT FINDINGS: With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes. SUMMARY: The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.

Besieged in the Bronx: Lessons from an in-hospital mass casualty.

BACKGROUND: An active shooter in a hospital is an emergency extraordinaire. We report a single institution's response to the largest active shooter mass casualty event in American History. METHODS: Review of notification, flow of prioritized patients, and key elements of the day's dynamic after a hospital attack by a lone gunman were commenced. The review includes outcomes on seven victims and assailants. RESULTS: "Code Silver" announced: open display of a weapon. Concise, known, and published chain of command implemented. All house staff to the Emergency Department (ED) via text blast. Operating room (OR) notified. Injured to ED, then triaged to OR. Armed NYPD stationed throughout OR. Senior surgeons controlled key triage during attack with flow controlled from the ED and OR control desk. One fatality plus shooter. CONCLUSION: Success favors the prepared. The response to attack, readiness of medical personnel, mitigation, and recovery have brought the following recommendations: (1) single entrance access; (2) armed, professional guards at all entrances; (3) camouflage metal detectors; (4) mandatory, recurrent hospital-wide active shooter training, mock, and table top; (5) published physician chain of command; (6) intercom code system known to all hospital personnel indicating a weapon is openly displayed; (7) a "no fly" list of former employees who are prohibited on premises; (8) stop the bleed training with kits on every floor; (9) one voice, one face to disseminate information. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level I.

A Horizon Scan to Support Chemical Pollution-Related Policymaking for Sustainable and Climate-Resilient Economies.

While chemicals are vital to modern society through materials, agriculture, textiles, new technology, medicines, and consumer goods, their use is not without risks. Unfortunately, our resources seem inadequate to address the breadth of chemical challenges to the environment and human health. Therefore, it is important we use our intelligence and knowledge wisely to prepare for what lies ahead. The present study used a Delphi-style approach to horizon-scan future chemical threats that need to be considered in the setting of chemicals and environmental policy, which involved a multidisciplinary, multisectoral, and multinational panel of 25 scientists and practitioners (mainly from the United Kingdom, Europe, and other industrialized nations) in a three-stage process. Fifteen issues were shortlisted (from a nominated list of 48), considered by the panel to hold global relevance. The issues span from the need for new chemical manufacturing (including transitioning to non-fossil-fuel feedstocks); challenges from novel materials, food imports, landfills, and tire wear; and opportunities from artificial intelligence, greater data transparency, and the weight-of-evidence approach. The 15 issues can be divided into three classes: new perspectives on historic but insufficiently appreciated chemicals/issues, new or relatively new products and their associated industries, and thinking through approaches we can use to meet these challenges. Chemicals are one threat among many that influence the environment and human health, and interlinkages with wider issues such as climate change and how we mitigate these were clear in this exercise. The horizon scan highlights the value of thinking broadly and consulting widely, considering systems approaches to ensure that interventions appreciate synergies and avoid harmful trade-offs in other areas. We recommend further collaboration between researchers, industry, regulators, and policymakers to perform horizon scanning to inform policymaking, to develop our ability to meet these challenges, and especially to extend the approach to consider also concerns from countries with developing economies. Environ Toxicol Chem 2023;42:1212-1228. © 2023 Crown copyright and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.

Cardiac Imaging for Diagnosis and Management of Infective Endocarditis.

Imaging is central to the care of patients with infective endocarditis. Although transthoracic and transesophageal echocardiography are the principal imaging techniques, additional modalities including positron emission tomography and cardiac computed tomography, and to a lesser extent intracardiac echocardiography, play an increasing role. This review discusses the role of cardiac imaging in establishing the diagnosis of endocarditis, in predicting its embolic risk, and in making decisions regarding the need for and timing of surgery.

Evidence that loneliness can be reduced by a whole-of-community intervention to increase neighbourhood identification.

RATIONALE: Social identification with the people in one's neighbourhood has a wide variety of benefits for individual and community health and wellbeing. In particular, previous research shows that residents' social identification with their neighbourhood is protective of mental health. However, researchers are only just beginning to design and evaluate interventions that directly target social identification on health grounds. OBJECTIVE: This longitudinal study evaluated a whole-of-community intervention at scale (Neighbour Day, 2019), in which Australian residents were encouraged to build social connections in their local community. Neighbour Day is a campaign that seeks to raise public awareness of the importance of connecting with neighbours and had a reach of approximately 300,000 people in 2019. METHODS: Participants were 437 hosts of neighbourhood events held across 276 diverse suburbs across Australia. Participants were surveyed at three-time points; before and after Neighbour Day, as well as at six-month follow up. RESULTS: Hosting a Neighbour Day event led to a significant increase in neighbourhood social identification, which was sustained six months later. This increase in social identification predicted increased social cohesion, reduced loneliness and improved wellbeing. CONCLUSIONS: This study provides evidence that neighbourhood identification is an effective target mechanism to curb loneliness and social fragmentation in the community. Implications are discussed with a focus on how social identity-building interventions can be effectively implemented in community settings to benefit public health.

Outcomes of Transradial Versus Transfemoral Access of Percutaneous Coronary Intervention in STEMI: Systematic Review and Updated Meta-analysis.

BACKGROUND: Transradial (TR) percutaneous coronary intervention (PCI) is a preferable PCI route. The complication difference between TR and TF approaches is controversial. METHODS: PubMed, Embase, and the Cochrane databases were queried for PCI outcomes of TR TF in STEMI for major cardiac and cerebrovascular events (MACCE), major bleeding, and mortality. The odds ratio (OR) was calculated using the random-effect model. RESULTS: We included 56 studies comprising of 68,733 patients (TR, n = 26,179; TF, n = 42,537). TR-PCI was associated with statistically significant lower odds of MACCE (OR = 0.66, 95% CI: 0.49-0.88, p-value = 0.005), major bleeding (OR = 0.47, 95% CI 0.32-0.68, p-value<0.001), mortality (OR = 0.59, 95% CI 0.43-0.80, p-value<0.001) at in hospital follow-up. TR-PCI was associated with statistically significant lower MACCE (OR = 0.59, 95% CI 0.43-0.80, p-value<0.001), major bleeding (OR = 0.58, 95% CI 0.49-0.68, p-value<0.001), and mortality (OR = 0.61, 95% CI 0.44-0.86, p-value = 0.005) at 30-day follow-up. The same difference was seen at 1-year. CONCLUSION: TR-PCI was associated with lower odds of MACCE, major bleeding, and mortality during short- and long-term follow-up.

Innovation in a crisis: rethinking conferences and scholarship in a pandemic and climate emergency.

It is a cliché of self-help advice that there are no problems, only opportunities. The rationale and actions of the BSHS in creating its Global Digital History of Science Festival may be a rare genuine confirmation of this mantra. The global COVID-19 pandemic of 2020 meant that the society's usual annual conference - like everyone else's - had to be cancelled. Once the society decided to go digital, we had a hundred days to organize and deliver our first online festival. In the hope that this will help, inspire and warn colleagues around the world who are also trying to move online, we here detail the considerations, conversations and thinking behind the organizing team's decisions.

Characterization of Myocardial Injury in Patients With COVID-19.

BACKGROUND: Myocardial injury is frequent among patients hospitalized with coronavirus disease-2019 (COVID-19) and is associated with a poor prognosis. However, the mechanisms of myocardial injury remain unclear and prior studies have not reported cardiovascular imaging data. OBJECTIVES: This study sought to characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in patients with COVID-19. METHODS: We conducted an international, multicenter cohort study including 7 hospitals in New York City and Milan of hospitalized patients with laboratory-confirmed COVID-19 who had undergone transthoracic echocardiographic (TTE) and electrocardiographic evaluation during their index hospitalization. Myocardial injury was defined as any elevation in cardiac troponin at the time of clinical presentation or during the hospitalization. RESULTS: A total of 305 patients were included. Mean age was 63 years and 205 patients (67.2%) were male. Overall, myocardial injury was observed in 190 patients (62.3%). Compared with patients without myocardial injury, those with myocardial injury had more electrocardiographic abnormalities, higher inflammatory biomarkers and an increased prevalence of major echocardiographic abnormalities that included left ventricular wall motion abnormalities, global left ventricular dysfunction, left ventricular diastolic dysfunction grade II or III, right ventricular dysfunction and pericardial effusions. Rates of in-hospital mortality were 5.2%, 18.6%, and 31.7% in patients without myocardial injury, with myocardial injury without TTE abnormalities, and with myocardial injury and TTE abnormalities. Following multivariable adjustment, myocardial injury with TTE abnormalities was associated with higher risk of death but not myocardial injury without TTE abnormalities. CONCLUSIONS: Among patients with COVID-19 who underwent TTE, cardiac structural abnormalities were present in nearly two-thirds of patients with myocardial injury. Myocardial injury was associated with increased in-hospital mortality particularly if echocardiographic abnormalities were present.

Australian general practitioners' attitudes and knowledge of sentinel lymph node biopsy in melanoma management.

BACKGROUND AND OBJECTIVES: In Australia, the uptake of the sentinel lymph node biopsy (SLNB) appears low despite clinical practice guideline recommendations. The aim of this study was to describe the knowledge and attitudes of general practitioners (GPs) to SLNB. METHOD: GPs were recruited at an annual conference and a skin cancer skills workshop, and using GP professional communications. A mixed methods approach comprised a cross-sectional questionnaire and, for a subset of participants, semi-structured interviews. RESULTS: Overall, 231 GPs completed the questionnaire, of whom 23 were interviewed. One-third (32%) described themselves as quite or very familiar with the guidelines, and two-thirds (68%) thought that SLNB had an important role in the management of patients with melanoma. Of GPs who would discuss SLNB with eligible patients, <40% correctly identified that SLNB is recommended for patients with an invasive melanoma >1 mm thick. DISCUSSION: GPs were generally supportive of SLNB. Familiarity with the guidelines was low, particularly regarding which patients should be considered for SLNB.

Submucosal lingualplasty for adult obstructive sleep apnea.

OBJECTIVE: To measure quality-of-life outcomes, polysomnographic outcomes, and adverse effects for a new technique of tongue reduction in obstructive sleep apnea. STUDY DESIGN: Case series. SETTING: Tertiary hospital. SUBJECTS AND METHODS: Consecutively treated adult patients (N = 27) with obstructive sleep apnea having submucosal lingualplasty in 2007 were studied. All had concurrent or previous uvulopalatoplasty ± palatal advancement. Full polysomnography preoperatively and 3.7 ± 0.4 months postoperatively, scored using the American Academy of Sleep Medicine 2007 criteria, was recorded. Snoring severity score, Epworth Sleepiness Scale, and complication data were collected at a 2.61 ± 0.08-year follow-up via questionnaire. RESULTS: Mean snoring severity score fell from 7.1 ± 0.4 to 2.3 ± 0.6 (P < .05). Epworth Sleepiness Scale score fell from 8.3 ± 1.1 to 5.8 ± 1.0 (P < .05). The apnea-hypopnea index (AHI) fell from 44.0 ± 4.3 to 12.5 ± 2.3 (P < .05). Success, defined as achieving an AHI <15 postoperatively, was observed in 74% (20/27), with each of these patients achieving a reduction in AHI >50%. Lowest oxygen saturation improved from 84 ± 1 to 88 ± 1 (P < .05). Pain was mild to moderate. Short-term postoperative complications included bleeding (3.7%) and infection (14.8%). Some minor long-term (6 months) alteration in tongue function was reported with regard to speech (47%), swallow (33%), and taste (33%). CONCLUSION: Submucosal lingualplasty with concurrent palatal surgery is a promising treatment option in adult patients with obstructive sleep apnea with macroglossia.

What is "success" following surgery for obstructive sleep apnea? The effect of different polysomnographic scoring systems.

OBJECTIVES/HYPOTHESIS: To illustrate that the diagnosis of obstructive sleep apnea (OSA) is dependent on the polysomnographic scoring criteria used, and the success rates of treatments for OSA are dependent on the defined outcome measures. STUDY DESIGN: Retrospective case series with prospective reanalysis of polysomnographic data. METHODS: Consecutively treated adult patients (N = 40) with moderate to severe OSA having multilevel pharyngeal surgery in 2007 were studied. All patients underwent submucosal lingualplasty and concurrent or previous uvulopalatopharyngoplasty ± palatal advancement. Full polysomnography (PSG) was performed preoperatively and at a mean of 145 days postoperatively. Pre- and postoperative PSG data were analyzed by two different but widely used scoring systems for the apnea-hypopnea index (AHI): The American Academy of Sleep Medicine (AASM) 1999 Chicago criteria and the AASM 2007 recommended criteria. RESULTS: Follow-up PSG data were available in 31 of 40 patients. Successful surgery was defined as a reduction in AHI(Rec) <20 with a 50% reduction from the patient's baseline, and in this group the surgical intervention was associated with a 72.2% success rate. If, however, differing AHI metrics are used or the absolute or percent reduction used to define a successful outcome is changed, then the rate of surgical success is shown to range from 39% to 92%. CONCLUSIONS: Different criteria for measuring AHI and defining success following OSA surgery can produce widely conflicting outcome data. Reported results following OSA surgery should be interpreted with this in mind. Using acceptable criteria, multilevel sleep surgery can be demonstrated to be of benefit to the majority of carefully selected patients.

Treating obstructive sleep apnea with hypoglossal nerve stimulation.

BACKGROUND: Reduced upper airway muscle activity during sleep is fundamental to obstructive sleep apnea (OSA) pathogenesis. Hypoglossal nerve stimulation (HGNS) counteracts this problem, with potential to reduce OSA severity. STUDY OBJECTIVES: To examine safety and efficacy of a novel HGNS system (HGNS, Apnex Medical, Inc.) in treating OSA. PARTICIPANTS: Twenty-one patients, 67% male, age (mean ± SD) 53.6 ± 9.2 years, with moderate to severe OSA and unable to tolerate continuous positive airway pressure (CPAP). DESIGN: Each participant underwent surgical implantation of the HGNS system in a prospective single-arm interventional trial. OSA severity was defined by apnea-hypopnea index (AHI) during in-laboratory polysomnography (PSG) at baseline and 3 and 6 months post-implant. Therapy compliance was assessed by nightly hours of use. Symptoms were assessed using the Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), Calgary Sleep Apnea Quality of Life Index (SAQLI), and the Beck Depression Inventory (BDI). RESULTS: HGNS was used on 89% ± 15% of nights (n = 21). On these nights, it was used for 5.8 ± 1.6 h per night. Nineteen of 21 participants had baseline and 6-month PSGs. There was a significant improvement (all P < 0.05) from baseline to 6 months in: AHI (43.1 ± 17.5 to 19.5 ± 16.7), ESS (12.1 ± 4.7 to 8.1 ± 4.4), FOSQ (14.4 ± 2.0 to 16.7 ± 2.2), SAQLI (3.2 ± 1.0 to 4.9 ± 1.3), and BDI (15.8 ± 9.0 to 9.7 ± 7.6). Two serious device-related adverse events occurred: an infection requiring device removal and a stimulation lead cuff dislodgement requiring replacement. CONCLUSIONS: HGNS demonstrated favorable safety, efficacy, and compliance. Participants experienced a significant decrease in OSA severity and OSA-associated symptoms. CLINICAL TRIAL INFORMATION: NAME: Australian Clinical Study of the Apnex Medical HGNS System to Treat Obstructive Sleep Apnea. REGISTRATION NUMBER: NCT01186926. URL: http://clinicaltrials.gov/ct2/show/NCT01186926.

Clinical equipoise in sleep surgery: investigating clinical trial targets.

OBJECTIVE: Surgical approaches for alleviating snoring and/or obstructive sleep apnea (OSA) have been questioned because of a lack of evidence from high-quality randomized controlled trials (RCTs). An ethical requirement for RCTs is that they must test questions where community equipoise (ie, uncertainty) exists as to the correct treatment. We aimed to measure perceived importance, community equipoise, and willingness to enroll patients in 5 potential trial targets among members of the Australian Society for Otolaryngology Head and Neck Surgery (ASOHNS). STUDY DESIGN, SETTING, AND SUBJECTS: All ASOHNS members were surveyed using a multistage mail, email, Internet, and phone-based questionnaire. METHODS: Equipoise was measured for each of the scenarios using a bidirectional linear scale comparing 2 treatments. Responses were categorized into 1 of 3 groups: (A) preferred treatment 1, (B) completely undecided, and (C) preferred treatment 2. The resulting proportions are called equipoise ratios: A:B:C. Using tick boxes, the authors queried the general clinical importance and willingness to enroll patients for all scenarios. RESULTS: A total of 167 of 313 surgeons responded (53.4%). Three of the 5 trial scenarios exhibited evidence of community equipoise, but 2 scenarios, radiofrequency ablation plus uvulopalatopharyngoplasty (UPPP) versus UPPP alone and upper-airway reconstruction versus mandibular advancement splint (MAS), did not have strong support for enrolling patients. Informal feedback indicates one of these may be feasible in a smaller number of specifically trained surgeons. CONCLUSION: We suggest 2 potential RCT targets: septoplasty and turbinate reduction versus conservative measures for snoring and airway reconstruction versus MAS for OSA, where importance, clinical equipoise, and willingness all exist.

Uvulopalatopharyngoplasty funded by the Australian government's Medicare scheme (1995-2007).

OBJECTIVE: To describe the provision, through the Australian state-funded Medicare system, of uvulopalatopharyngoplasty (UPPP) and its laser-assisted variation (LAUP) to the population of Australia between 1995 and 2007. STUDY DESIGN: Case series using a comprehensive national administrative database. SETTING: The Commonwealth of Australia. SUBJECTS AND METHODS: Subjects comprised the population of Australia. The raw numbers of procedures, reimbursement amounts in Australian dollars, and per capita adjustment nationwide and in each state/territory for UPPP and LAUP for each calendar year from 1995 to 2007 were downloaded from a publicly accessible database run by Medicare. RESULTS: The Australian federal government paid AUD 8.2 million for 19,534 UPPP procedures and AUD 1.1 million for 3270 LAUP procedures in the calendar years 1995 to 2007, inclusive. There is substantive variability between states in provision. Over time, provision of UPPP has declined slightly compared with population growth and overall Medicare provision. LAUP provision has declined markedly. CONCLUSION: Provision of UPPP under Medicare in Australia has declined slowly relative to population growth and overall growth in Medicare per capita provision. Laser-assisted UPPP (LAUP) has steadily declined and is now rarely used compared with the peak in its provision in the mid 1990s.

Upper airway reconstructive surgery long-term quality-of-life outcomes compared with CPAP for adult obstructive sleep apnea.

OBJECTIVE: To measure long-term quality-of-life (QOL) improvement following contemporary multilevel upper airway reconstruction surgery, compared with continuous positive airway pressure (CPAP) therapy. Secondary aims were to investigate factors determining clinical effectiveness and QOL impact of reported side effects. DESIGN: Cohort study. SUBJECTS AND METHODS: Consecutive, simultaneously treated adult patients with moderate-severe obstructive sleep apnea (OSA) having upper airway surgery (N=77) or CPAP (N=89) therapy were studied by questionnaire. Glasgow Benefit Inventory (GBI), change in snoring status and Epworth Sleepiness Scale (ESS), subjective CPAP compliance, and side effects in both groups were measured at mean+/-SEM 44.12+/-5.78 months (3.68+/-0.48 years) after commencement of therapy. RESULTS: No significant difference was seen between surgical outcomes for GBI, snoring, or ESS and CPAP controls. Multivariate analysis showed reduction in Respiratory Disturbance Index (RDI) predicted postoperative snoring and ESS, but not GBI outcomes. Snoring control and GBI were related to CPAP compliance (P<0.001). CPAP side effects (reported in 26%) significantly reduced the QOL benefit of treatment, independent of compliance. Surgical complications (occurring in 44%) did not affect QOL treatment benefit. CONCLUSION: Patients with poor CPAP compliance and/or significant side effects of CPAP therapy (45% of cases in this series) should be evaluated for contemporary upper airway reconstructive surgery.

Transpalatal advancement pharyngoplasty outcomes compared with uvulopalatopharygoplasty.

OBJECTIVE: Uvulopalatopharyngoplasty (UPPP) success rates in patients classified with Friedman stage 3 is reported as 8%. Surgical failure may result from persistent obstruction at the palate, which may be addressed by pharyngoplasty with palatal advancement (PA). The effectiveness of PA versus UPPP was evaluated by using polysomnographic outcomes in a retrospective cohort of patients classified with Friedman stage 3. METHODS: Surgical records were reviewed for PA (n = 47) and UPPP (n = 124). Clinical records were reviewed and reclassified by Friedman stage. Respiratory data were collected from overnight polysomnography. Statistical analysis was conducted of continuous variables (ANOVA), categorical variables (chi2), and adjusted odds ratios by using logistic regression. RESULTS: PA (n = 30) and UPPP (n = 44) did not differ in baseline apnea hypopnea index (AHI), age, or BMI. Both PA (48.3 +/- 24.6 to 19.8 +/- 16.8 events per hour, P < 0.000) and UPPP (47.9 +/- 30.0 to 30.9 +/- 24.2 events per hour, P < 0.000) improved with surgery. In the PA group, final AHI was lower (17.1 +/- 30.1 versus 28.5 +/- 25.6, P < 0.04) and postoperative change was greater (30.9 +/- 24.2 versus 19.8 +/- 16.8, P < 0.02). For patients with Friedman stage 3, odds ratio of having an AHI of <20 events per hour and a greater than 50% reduction with PA compared with UPPP was 3.80 (95% CI, 1.41-10.29, P < 0.013). Adjusted for age, body mass index, preoperative apnea severity, and tongue-base surgery, OR was 5.77 (95% CI of 1.80-17.98). CONCLUSIONS: Polysomnographic outcomes using AHI support the use of palatopharyngoplasty using palatal advancement as an effective treatment of obstructive sleep apnea. PA may offer benefit over UPPP alone in patients classified with Friedman stage 3.

New non-invasive sonographic modality for intracranial pressure/volume monitoring.

INTRODUCTION: The wide use of intracranial pressure and cerebral perfusion pressure monitoring has improved the management of patients with severe head injuries. The rare but worrying complications associated with the application of such monitoring makes the idea of a non-invasive method of monitoring very attractive. MATERIALS AND METHODS: A new non-invasive ultrasonographic technology was used to measure cerebral perfusion pressure in 27 normal volunteers. The average monitoring time was 45.3+/-0.2 min, and the average perfusion pressure recorded was 77.4+/-0.3 mmHg. No complications were reported during the procedure, which was performed while the subjects were in regular ward beds. CONCLUSION: The non-invasive character of this method could extend the use of cerebral perfusion pressure measurement to several other neurosurgical entities, such as hydrocephalus, pseudotumor cerebri, chronic headache, and spinal cord injuries.