Discovery of quinazoline HPK1 inhibitors with high cellular potency.

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.

Psychological predictors of consumer-level virtual reality technology adoption and usage.

In recent years, virtual reality (VR) technology has been mainstreamed for at-home use, with various consumer-oriented devices released by media firms such as Meta, Google, Samsung, and HTC. The present research investigates the role of psychological traits-including immersive tendencies, absorption, sensation seeking, need for cognition, neophobia, and belief in science-as well as trait levels of individual innovativeness, self-perception of social well-being, and owner demographics, in predicting VR adoption rates and sustained use over time. Separate analyses were conducted for different classes of VR device (fixed, mobile, and standalone devices). In general, psychological factors generally emerged as more determinative of adoption than did demographics. Users' immersive tendencies predicted earlier adoption of VR technology while absorption was associated with later adoption, with both predictive of higher overall initial usage of different types of devices. Additionally, perceiving oneself as socially successful was associated with higher initial VR usage, while a tendency to see one's emotions as influenced by in-person rather than online contacts was negatively associated with usage. Finally, belief in science predicted greater consistency in usage over time while higher levels of absorption were associated with unstable usage patterns. These findings expand upon the limited work previously investigating the role of individual differences in adoption of VR and mark the promise of psychometrics for understanding the diffusion and continued usage of consumer-facing VR devices.

The Search for Consumers of Web-Based Raw DNA Interpretation Services: Using Social Media to Target Hard-to-Reach Populations.

BACKGROUND: In recent years, there has been a proliferation of third-party Web-based services available to consumers to interpret raw DNA from direct-to-consumer genetic testing companies. Little is known about who uses these services and the downstream health implications. Identifying this hard-to-reach population of consumers for research raised questions about the most effective recruitment methods to undertake. Past studies have found that Web-based social media survey distribution can be cost-effective for targeting hard-to-reach populations, yet comparative efficacy information across platforms is limited. OBJECTIVE: The aim of this study was to identify the most effective Web-based strategies to identify and recruit the target population of direct-to-consumer genetic testing users who also made use of third-party interpretation services to analyze their raw genetic data. Web-based survey recruitment methods varying by social media platform and advertising method were compared in terms of cost-effectiveness and demographics of survey respondents. METHODS: A total of 5 Web-based survey distribution conditions were examined: 4 paid advertising services and 1 unpaid service. For the paid services, a 2x2 quasi-experimental design compared social media platforms (Facebook vs Twitter) and advertising tracking metrics (by click vs by conversion). The fifth unpaid comparison method consisted of study postings on the social media platform, Reddit, without any paid advertising. Links to identical Web-based versions of the study questionnaire were posted for 10 to 14 days for each of the distribution conditions, which allowed tracking the number of respondents that entered and completed the questionnaire by distribution condition. RESULTS: In total, 438 individuals were recruited to the study through all conditions. A nearly equivalent number of participants were recruited from paid campaigns on Facebook (n=159) and Twitter (n=167), with a smaller sample recruited on Reddit (n=112). Significantly more participants were recruited through conversion-tracking (n=222) than through click-tracking campaigns (n=104; Z=6.5, P<.001). Response rates were found to be partially driven by organic sharing of recruitment materials among social media users. Conversion tracking was more cost-effective than click tracking across paid social media platforms. Significant differences in terms of gender and age distributions were noted between the platforms and between the tracking metrics. CONCLUSIONS: Web-based recruitment methods were effective at recruiting participants from a hard-to-reach population in a short time frame. There were significant differences in the effectiveness of various paid advertising techniques. Recruitment through Web-based communities also appeared to perform adequately, yet it may be limited by the number of users accessible in open community groups. Future research should evaluate the impact of organic sharing of recruitment materials because this appeared to play a substantial role in the observed effectiveness of different methods.

Correction: The Search for Consumers of Web-Based Raw DNA Interpretation Services: Using Social Media to Target Hard-to-Reach Populations.

[This corrects the article DOI: 10.2196/12980.].

Oxygen saturation targeting by pulse oximetry in the extremely low gestational age neonate: a quixotic quest.

PURPOSE OF REVIEW: A collaboration of comparative effectiveness research trials of pulse oximeter saturation (SpO2) targeting in extremely low-gestational-age neonates have begun to report their aggregate results. We examine the results of those trials, collectively referred to as the Neonatal Oxygenation Prospective Meta-analysis or NeOProM. We also discuss the uncertainties that remain and the clinical challenges that lie ahead. RECENT FINDINGS: The primary outcome from NeOProM was a composite of death or disability at 18-24 months corrected age. In 2016 the last of these reports was published. Although there were no differences in the primary outcome overall, analyses of secondary outcomes and data subsets following a pulse oximeter revision show significant treatment differences between targeting a lower compared with a higher SpO2. SUMMARY: NeOProM represents the largest collaborative clinical research study of SpO2 targets in extremely low-gestational-age neonates. Although aggregate results give us some insight into the feasibility and efficacy of SpO2 targeting in this population, many questions remain. A patient-level analysis, tracking individual outcomes based on actual SpO2 experienced, may shed some light on these questions. However, finding a single optimal SpO2 range seems unlikely.

Respiratory Infections in the U.S. Military: Recent Experience and Control.

This comprehensive review outlines the impact of military-relevant respiratory infections, with special attention to recruit training environments, influenza pandemics in 1918 to 1919 and 2009 to 2010, and peacetime operations and conflicts in the past 25 years. Outbreaks and epidemiologic investigations of viral and bacterial infections among high-risk groups are presented, including (i) experience by recruits at training centers, (ii) impact on advanced trainees in special settings, (iii) morbidity sustained by shipboard personnel at sea, and (iv) experience of deployed personnel. Utilizing a pathogen-by-pathogen approach, we examine (i) epidemiology, (ii) impact in terms of morbidity and operational readiness, (iii) clinical presentation and outbreak potential, (iv) diagnostic modalities, (v) treatment approaches, and (vi) vaccine and other control measures. We also outline military-specific initiatives in (i) surveillance, (ii) vaccine development and policy, (iii) novel influenza and coronavirus diagnostic test development and surveillance methods, (iv) influenza virus transmission and severity prediction modeling efforts, and (v) evaluation and implementation of nonvaccine, nonpharmacologic interventions.

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams.

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

Is the robotic approach feasible for repair of iatrogenic injuries of the lower ureter?

OBJECTIVES: To analyze the robotic approach as treatment of iatrogenic ureteral injuries. METHODS: Medical records were reviewed for patients undergoing robotic-assisted laparoscopic ureteral reimplantation at the University of Missouri from 2009 to 2014. Patient charts were analyzed for demographics, prior abdominal surgeries, circumstances of injury, outcomes, and other relevant information. RESULTS: Nine patients met inclusion criteria. The average age was 44.6. Patients had an average of 4.3 abdominal surgeries. Injury occurred during hysterectomy (open, laparoscopic, or vaginal) in eight patients (88.9 %), five cases were laparoscopic, two utilized robotic assistance, and one injury occurred during uterosacral vault suspension. All cases were related to gynecological procedures. On average, ureteral injury was detected 17.2 days after the initial surgery and repaired 62.3 days after initial operation. The average surgical repair time was 295.9 min (range 168-498) with an average blood loss of 77.2 mL (range 20-150). Four patients required a psoas hitch, with one receiving both a psoas hitch and a Boari flap. Postoperatively, patients had an average hospital stay of 2.7 days. One patient had ileus for greater than 3 days, and another was readmitted within 30 days for pain control and antiemetics following stent removal. One patient underwent open reimplantation 3 years after original surgery for development of ureteral stricture. At follow-up, all patients had returned to baseline renal function. CONCLUSIONS: Robotic approach is feasible and a safe option for distal iatrogenic ureteral injuries occurring during gynecological procedures. Prior abdominal surgery or delayed repair does not preclude a robotic approach.

The VPS33B-binding protein VPS16B is required in megakaryocyte and platelet α-granule biogenesis.

Patients with platelet α or dense δ-granule defects have bleeding problems. Although several proteins are known to be required for δ-granule development, less is known about α-granule biogenesis. Our previous work showed that the BEACH protein NBEAL2 and the Sec1/Munc18 protein VPS33B are required for α-granule biogenesis. Using a yeast two-hybrid screen, mass spectrometry, coimmunoprecipitation, and bioinformatics studies, we identified VPS16B as a VPS33B-binding protein. Immunoblotting confirmed VPS16B expression in various human tissues and cells including megakaryocytes and platelets, and also in megakaryocytic Dami cells. Characterization of platelets from a patient with arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome containing mutations in C14orf133 encoding VPS16B revealed pale-appearing platelets in blood films and electron microscopy revealed a complete absence of α-granules, whereas δ-granules were observed. Soluble and membrane-bound α-granule proteins were reduced or undetectable, suggesting that both releasable and membrane-bound α-granule constituents were absent. Immunofluorescence microscopy of Dami cells stably expressing GFP-VPS16B revealed that similar to VPS33B, GFP-VPS16B colocalized with markers of the trans-Golgi network, late endosomes and α-granules. We conclude that VPS16B, similar to its binding partner VPS33B, is essential for megakaryocyte and platelet α-granule biogenesis.

Position statement on fetal myelomeningocele repair.

Following the promising multicenter randomized trial results of in utero fetal myelomeningocele repair; we anticipate that an increasing number of tertiary care centers may want to offer this therapy. It is essential to establish minimum criteria for centers providing open fetal myelomeningocele repair to ensure optimal maternal and fetal/pediatric outcomes, as well as patient safety both short- and long-term; and to advance our knowledge of the role and benefit of fetal surgery in the management of fetal myelomeningocele. The fetal myelomeningocele Maternal-Fetal Management Task Force was initially convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development to discuss the implementation of maternal fetal surgery for myelomeningocele. The decision was made to develop the optimal practice criteria presented in this document for the purpose of medical and surgical leadership. These criteria are not intended to be used for legal or regulatory purposes.

A Multifunctional, Low Cost and Sustainable Neonatal Database System.

Continuous improvement in the clinical performance of neonatal intensive care units (NICU) depends on the use of locally relevant, reliable data. However, neonatal databases with these characteristics are typically unavailable in NICUs using paper-based records, while in those using electronic records, the inaccuracy of data and the inability to customize commercial data systems limit their usability for quality improvement or research purposes. We describe the characteristics and uses of a simple, neonatologist-centered data system that has been successfully maintained for 30 years, with minimal resources and serving multiple purposes, including quality improvement, administrative, research support and educational functions. Structurally, our system comprises customized paper and electronic components, while key functional aspects include the attending-based recording of diagnoses, integration into clinical workflows, multilevel data accuracy and validation checks, and periodic reporting on both data quality and NICU performance results. We provide examples of data validation methods and trends observed over three decades, and discuss essential elements for the successful implementation of this system. This database is reliable and easily maintained; it can be developed from simple paper-based forms or used to supplement the functionality and end-user customizability of existing electronic medical records. This system should be readily adaptable to NICUs in either high- or limited-resource environments.

Results from tandem Phase 1 studies evaluating the safety, reactogenicity and immunogenicity of the vaccine candidate antigen Plasmodium falciparum FVO merozoite surface protein-1 (MSP1(42)) administered intramuscularly with adjuvant system AS01.

BACKGROUND: The development of an asexual blood stage vaccine against Plasmodium falciparum malaria based on the major merozoite surface protein-1 (MSP1) antigen is founded on the protective efficacy observed in preclinical studies and induction of invasion and growth inhibitory antibody responses. The 42 kDa C-terminus of MSP1 has been developed as the recombinant protein vaccine antigen, and the 3D7 allotype, formulated with the Adjuvant System AS02A, has been evaluated extensively in human clinical trials. In preclinical rabbit studies, the FVO allele of MSP142 has been shown to have improved immunogenicity over the 3D7 allele, in terms of antibody titres as well as growth inhibitory activity of antibodies against both the heterologous 3D7 and homologous FVO parasites. METHODS: Two Phase 1 clinical studies were conducted to examine the safety, reactogenicity and immunogenicity of the FVO allele of MSP142 in the adjuvant system AS01 administered intramuscularly at 0-, 1-, and 2-months: one in the USA and, after evaluation of safety data results, one in Western Kenya. The US study was an open-label, dose escalation study of 10 and 50 µg doses of MSP142 in 26 adults, while the Kenya study, evaluating 30 volunteers, was a double-blind, randomized study of only the 50 µg dose with a rabies vaccine comparator. RESULTS: In these studies it was demonstrated that this vaccine formulation has an acceptable safety profile and is immunogenic in malaria-naïve and malaria-experienced populations. High titres of anti-MSP1 antibodies were induced in both study populations, although there was a limited number of volunteers whose serum demonstrated significant inhibition of blood-stage parasites as measured by growth inhibition assay. In the US volunteers, the antibodies generated exhibited better cross-reactivity to heterologous MSP1 alleles than a MSP1-based vaccine (3D7 allele) previously tested at both study sites. CONCLUSIONS: Given that the primary effector mechanism for blood stage vaccine targets is humoral, the antibody responses demonstrated to this vaccine candidate, both quantitative (total antibody titres) and qualitative (functional antibodies inhibiting parasite growth) warrant further consideration of its application in endemic settings. TRIAL REGISTRATIONS: Clinical Trials NCT00666380.

Surfactant delivery by aerosol inhalation - past, present, and future.

Surfactant replacement therapy (SRT) by nebulization to spontaneously breathing patients has been regarded as the Holy Grail since surfactant deficiency was first identified as the cause for neonatal respiratory distress syndrome. It avoids neonatal endotracheal intubation, a procedure that is often difficult and occasionally harmful. Unapproved alternatives to endotracheal tube placement for liquid surfactant instillation, such as LISA (thin catheter intubation) and SALSA (supraglottic airway insertion) have significant merit but are still invasive, leaving nebulized SRT as the only truly non-invasive method. In the past 60 years, we have learned much about the potential - and limitations - of nebulized SRT. In this review, we examine the promises and pitfalls of nebulized SRT, discuss what we know about neonatal aerosol drug delivery and recap some of the most recent randomized clinical trials of nebulized SRT. We conclude with a discussion of what is known and the next steps needed if this type of SRT is to become a regular part of clinical care.

Towards estimating the carbon footprint of external beam radiotherapy.

PURPOSE: The National Health Service (NHS) in the United Kingdom (UK) is aiming to be carbon net zero by 2040 to help limit the dangerous effects of climate change. Radiotherapy contributes to this with potential sources quantified here. METHOD: Activity data for 42 patients from within the breast IMRT and prostate VMAT pathways were collected. Data for 20 prostate patients was also collected from 3 other centres to enable cross centre comparison. A process-based, bottom-up approach was used to calculate the carbon footprint. Additionally, patients were split into pre-COVID and COVID groups to assess the impact of protocol changes due to the pandemic. RESULTS: The calculated carbon footprint for prostate and breast pre-COVID were 148 kgCO2e and 101 kgCO2e respectively, and 226 kgCO2e and 75 kgCO2e respectively during COVID. The energy usage by the linac during treatment for a total course of radiotherapy for prostate treatments was 2-3 kWh and about 1 kWh for breast treatments. Patient travel made up the largest proportion (70-80%) of the calculated carbon footprint, with linac idle power second with âˆ¼ 10% and PPE and SF6 leakage were both between 2 and 4%. CONCLUSION: These initial findings highlight that the biggest contributor to the external beam radiotherapy carbon footprint was patient travel, which may motivate increased used of hypofractionation. Many assumptions and boundaries have been set on the data gathered, which limit the wider application of these results. However, they provide a useful foundation for future more comprehensive life cycle assessments.

Postnatal Corticosteroids to Prevent or Treat Chronic Lung Disease Following Preterm Birth.

The American Academy of Pediatrics continues to provide guidance on the use of postnatal corticosteroids to manage or prevent chronic lung disease following preterm birth (formerly referred to as bronchopulmonary dysplasia). Since the last revision of such guidance in 2010, several prospective randomized trials have been published. This revision provides a review of those studies as well as updated recommendations, which include the use of systemic low-dose corticosteroid in preterm neonates with or at high risk for chronic lung disease. High-dose dexamethasone (≥0.5 mg/kg per day) is not recommended. New evidence suggests that inhaled corticosteroids may confer benefit if provided with surfactant as a vehicle, but safety data are lacking. Evidence remains insufficient to make any recommendations regarding routine use of postnatal corticosteroids in preterm infants. Neonatologists and other hospital care providers must continue to use their clinical judgment in individual patients, balancing the potential adverse effects of corticosteroid treatment with those of chronic lung disease. The decision to use postnatal corticosteroids for this purpose should be made together with the infant's parents, and the care providers should document their discussions with parents in the patient's medical record.

Photoacoustic imaging is a novel tool to measure finger artery structure and oxygenation in patients with SSc.

Systemic sclerosis (SSc)-related digital ischaemia is a major cause of morbidity, resulting from a combination of microvascular and digital artery disease. Photoacoustic imaging offers a newly available, non-invasive method of imaging digital artery structure and oxygenation. The aim of this study was to establish whether photoacoustic imaging could detect and measure vasculopathy in digital arteries, including the level of oxygenation, in patients with SSc and healthy controls. 22 patients with SSc and 32 healthy controls (HC) underwent photoacoustic imaging of the fingers. Vascular volume and oxygenation were assessed across eight fingers at the middle phalanx. In addition, oxygenation change during finger occlusion was measured at the non-dominant ring finger and the vascular network was imaged along the length of one finger for qualitative assessment. There was no statistically significant difference in vascular volume between patients with SSc and HC (mean of eight fingers; SSc, median 118.6 IQR [95.0-130.5] vs. HC 115.6 [97.8-158.9]) mm3. However, baseline oxygenation (mean 8 fingers) was lower in SSc vs. HC (0.373 [0.361-0.381] vs. 0.381 [0.373-0.385] arbitrary sO2 units respectively; p = 0.03). Hyperaemic oxygenation response following occlusion release was significantly lower in SSc compared to HC (0.379 [0.376-0.381] vs. 0.382 [0.377-0.385]; p = 0.03). Whilst vascular volume was similar between groups, digital artery oxygenation was decreased in patients with SSc as compared to HC, indicative of functional deficit. Photoacoustic imaging offers an exciting new method to image the vascular network in patients with SSc and the possibility to capture oxygenation as a functional measure.

Care Levels for Fetal Therapy Centers.

Fetal therapies undertaken to improve fetal outcome or to optimize transition to neonate life often entail some level of maternal, fetal, or neonatal risk. A fetal therapy center needs access to resources to carry out such therapies and to manage maternal, fetal, and neonatal complications that might arise, either related to the therapy per se or as part of the underlying fetal or maternal condition. Accordingly, a fetal therapy center requires a dedicated operational infrastructure and necessary resources to allow for appropriate oversight and monitoring of clinical performance and to facilitate multidisciplinary collaboration between the relevant specialties. Three care levels for fetal therapy centers are proposed to match the anticipated care complexity, with appropriate resources to achieve an optimal outcome at an institutional and regional level. A level I fetal therapy center should be capable of offering fetal interventions that may be associated with obstetric risks of preterm birth or membrane rupture but that would be very unlikely to require maternal medical subspecialty or intensive care, with neonatal risks not exceeding those of moderate prematurity. A level II center should have the incremental capacity to provide maternal intensive care and to manage extreme neonatal prematurity. A level III therapy center should offer the full range of fetal interventions (including open fetal surgery) and be able manage any of the associated maternal complications and comorbidities, as well as have access to neonatal and pediatric surgical intervention including indicated surgery for neonates with congenital anomalies.

Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans.

In animals, effective immune responses against malignancies and against several infectious pathogens, including malaria, are mediated by T cells. Here we show that a heterologous prime-boost vaccination regime of DNA either intramuscularly or epidermally, followed by intradermal recombinant modified vaccinia virus Ankara (MVA), induces high frequencies of interferon (IFN)-gamma-secreting, antigen-specific T-cell responses in humans to a pre-erythrocytic malaria antigen, thrombospondin-related adhesion protein (TRAP). These responses are five- to tenfold higher than the T-cell responses induced by the DNA vaccine or recombinant MVA vaccine alone, and produce partial protection manifest as delayed parasitemia after sporozoite challenge with a different strain of Plasmodium falciparum. Such heterologous prime-boost immunization approaches may provide a basis for preventative and therapeutic vaccination in humans.