Are high-cost drug funding mechanisms fit for purpose? A retrospective study of individual funding requests in an NHS tertiary hospital.

AIMS: To report on a retrospective study of individual funding request (IFR) submissions from a large tertiary hospital and describe gaps in current mechanisms for funding of high-cost medicines in England. METHODS: Data on the number and outcome of IFR submissions submitted to commissioners between 2014/15 and 2018/19 was extracted from the electronic patient health record and a local high-cost drug database. RESULTS: In total, 230 IFRs were submitted: 112 to NHS England and 118 to a Clinical Commissioning Group (CCG). The decline rate for IFRs was 71% for NHS England and 34% for CCGs. Lack of exceptionality was the primary reason cited for declining IFRs submitted between 2016-18 (n = 42/45; 93%). Half of the patients whose IFR was declined received treatment funded through other routes, the majority (13/23; 57%) from internal hospital budget. This was governed via a local high-cost drug panel. Positive clinical outcomes were observed in 50% (4/8) of patients who received NHS England IFR-funded treatment, 54% (19/35) who received CCG IFR-funded treatment and 91% (21/23) who were funded via other routes. CONCLUSION: The high rate of IFR decline signals inefficient use of resource expended in the IFR process. Gaps in access to high-cost medicines remain for patients with rare and refractory disease requiring urgent treatment, largely due to the demand for exceptionality from NHS commissioners. Local mechanisms address this unmet need but have limitations. An outcomes-based evaluation approach to commissioning and greater transparency of previous funding decisions by commissioners may improve efficiency and equity in the IFR system.

Skin microbiome alters attractiveness to Anopheles mosquitoes.

BACKGROUND: Some people produce specific body odours that make them more attractive than others to mosquitoes, and consequently are at higher risk of contracting vector-borne diseases. The skin microbiome can break down carbohydrates, fatty acids and peptides on the skin into volatiles that mosquitoes can differentiate. RESULTS: Here, we examined how skin microbiome composition of women differs in relation to level of attractiveness to Anopheles coluzzii mosquitoes, to identify volatiles in body odour and metabolic pathways associated with individuals that tend to be poorly-attractive to mosquitoes. We used behavioural assays to measure attractiveness of participants to An. coluzzii mosquitoes, 16S rRNA amplicon sequencing of the bacteria sampled from the skin and gas chromatography of volatiles in body odour. We found differences in skin microbiome composition between the poorly- and highly-attractive groups, particularly eight Amplicon Sequence Variants (ASVs) belonging to the Proteobacteria, Actinobacteria and Firmicutes phyla. Staphylococcus 2 ASVs are four times as abundant in the highly-attractive compared to poorly-attractive group. Associations were found between these ASVs and volatiles known to be attractive to Anopheles mosquitoes. Propanoic pathways are enriched in the poorly-attractive participants compared to those found to be highly-attractive. CONCLUSIONS: Our findings suggest that variation in attractiveness of people to mosquitoes is related to the composition of the skin microbiota, knowledge that could improve odour-baited traps or other next generation vector control tools.

Lower carbohydrate diets for adults with type 2 diabetes.

In May 2021, the Scientific Advisory Committee on Nutrition (SACN) published a risk assessment on lower carbohydrate diets for adults with type 2 diabetes (T2D)(). The purpose of the report was to review the evidence on 'low'-carbohydrate diets compared with the current UK government advice on carbohydrate intake for adults with T2D. However, since there is no agreed and widely utilised definition of a 'low'-carbohydrate diet, comparisons in the report were between lower and higher carbohydrate diets. SACN's remit is to assess the risks and benefits of nutrients, dietary patterns, food or food components for health by evaluating scientific evidence and to make dietary recommendations for the UK based on its assessment(). SACN has a public health focus and only considers evidence in healthy populations unless specifically requested to do otherwise. Since the Committee does not usually make recommendations relating to clinical conditions, a joint working group (WG) was established in 2017 to consider this issue. The WG comprised members of SACN and members nominated by Diabetes UK, the British Dietetic Association, Royal College of Physicians and Royal College of General Practitioners. Representatives from NHS England and NHS Health Improvement, the National Institute for Health and Care Excellence and devolved health departments were also invited to observe the WG. The WG was jointly chaired by SACN and Diabetes UK.

Implementation strategies for improving vitamin D status and increasing vitamin D intake in the UK: current controversies and future perspectives: proceedings of the 2nd Rank Prize Funds Forum on vitamin D.

A multi-disciplinary expert group met to discuss vitamin D deficiency in the UK and strategies for improving population intakes and status. Changes to UK Government advice since the 1st Rank Forum on Vitamin D (2009) were discussed, including rationale for setting a reference nutrient intake (10 µg/d; 400 IU/d) for adults and children (4+ years). Current UK data show inadequate intakes among all age groups and high prevalence of low vitamin D status among specific groups (e.g. pregnant women and adolescent males/females). Evidence of widespread deficiency within some minority ethnic groups, resulting in nutritional rickets (particularly among Black and South Asian infants), raised particular concern. Latest data indicate that UK population vitamin D intakes and status reamain relatively unchanged since Government recommendations changed in 2016. Vitamin D food fortification was discussed as a potential strategy to increase population intakes. Data from dose-response and dietary modelling studies indicate dairy products, bread, hens' eggs and some meats as potential fortification vehicles. Vitamin D3 appears more effective than vitamin D2 for raising serum 25-hydroxyvitamin D concentration, which has implications for choice of fortificant. Other considerations for successful fortification strategies include: (i) need for 'real-world' cost information for use in modelling work; (ii) supportive food legislation; (iii) improved consumer and health professional understanding of vitamin D's importance; (iv) clinical consequences of inadequate vitamin D status and (v) consistent communication of Government advice across health/social care professions, and via the food industry. These areas urgently require further research to enable universal improvement in vitamin D intakes and status in the UK population.

Easing the burden of multi-state genetic counseling licensure in the United States: Process, pitfalls, and possible solutions.

State-based genetic counseling licensure creates standardization, ensures high-quality care, and supports the credentialing of genetic counselors (GCs) in the United States. However, it also has the unintended consequence of requiring substantial time and resources from genetic counselors who need to obtain licensure in multiple states. There is a wide range of variability among state licensure applications, required supporting documentation, verification processes, and cost-all of which are barriers for genetic counselors. New licensure laws are being passed on a regular basis, further complicating this process. Resources may be available to some genetic counselors such as employer reimbursement and administrative support; however, access to this support is not universal. This paper reviews the current condition of genetic counseling multi-state licensure, including barriers, unique challenges, and possible solutions for increased efficiencies, based on the authors' experiences and examples found in other healthcare fields.

A social media microinfluencer intervention to reduce coronavirus disease 2019 vaccine hesitancy in underserved Tennessee communities: A protocol paper.

BACKGROUND: Central to effective public health policy and practice is the trust between the population served and the governmental body leading health efforts, but that trust has eroded in the years preceding the pandemic. Vaccine hesitancy among adults is also a growing concern across the United States. Recent data suggest that the trustworthiness of information about the coronavirus 2019 (COVID-19) vaccine was a larger concern than the vaccine's adverse effects or risks. OBJECTIVE: This study aims to describe the methods used to create a public health microinfluencer social media vaccine confidence campaign for the COVID-19 vaccine in underserved Tennessee communities. A secondary objective is to describe how the Social-Ecological Model (SEM) and Social Cognitive Theory may address vaccine hesitancy using community pharmacies. METHODS: In late 2020, 50 independent community pharmacies in underserved communities across Tennessee were involved in a public health project with the State of Tennessee Department of Health and the University of Tennessee Health Science Center College of Pharmacy. The project involved a 3-pronged, pharmacy-based COVID-19 vaccination outreach project, including (1) social media messaging (i.e., microinfluencer approach), (2) community partner collaboration, and (3) in-pharmacy promotion. Quantitative and qualitative data will assess the quality and effectiveness of the program. Social media outcomes will also be assessed to measure the impact of the microinfluencer social media training. RESULTS: Project implementation is planned for 6 months (January 2021 to June 2021) after an initial month of planning by the research team (December 2020) and preceding several months of assessment (July 2021 and beyond). CONCLUSIONS: Novel, theory-based approaches will be necessary to improve vaccine confidence. One approach to promoting public health, derived from the SEM, may be to use trusted microinfluencers on social media platforms, such as local community pharmacists and community leaders.

Comparative efficacy of cemiplimab versus other systemic treatments for advanced cutaneous squamous cell carcinoma.

Aim: To estimate the comparative efficacy of cemiplimab, a programmed cell death protein 1 inhibitor, versus EGFR inhibitors, pembrolizumab and platinum-based chemotherapy in terms of overall survival (OS) and progression-free survival. Patients & methods: We performed an indirect treatment comparison of cemiplimab and other available systemic therapies for patients with advanced cutaneous squamous cell carcinoma. Results: Cemiplimab was associated with benefits in OS (hazard ratios range: 0.07-0.52) and progression-free survival (hazard ratios range: 0.30-0.67) versus EGFR inhibitors and pembrolizumab (data from KEYNOTE-629). Cemiplimab was more efficacious versus platinum-based chemotherapy in terms of OS. Conclusion: Cemiplimab may offer improvements in survival for advanced cutaneous squamous cell carcinoma patients compared with existing systemic therapies.

Engineering the interactions between a plant-produced HIV antibody and human Fc receptors.

Plants can provide a cost-effective and scalable technology for production of therapeutic monoclonal antibodies, with the potential for precise engineering of glycosylation. Glycan structures in the antibody Fc region influence binding properties to Fc receptors, which opens opportunities for modulation of antibody effector functions. To test the impact of glycosylation in detail, on binding to human Fc receptors, different glycovariants of VRC01, a broadly neutralizing HIV monoclonal antibody, were generated in Nicotiana benthamiana and characterized. These include glycovariants lacking plant characteristic α1,3-fucose and ß1,2-xylose residues and glycans extended with terminal ß1,4-galactose. Surface plasmon resonance-based assays were established for kinetic/affinity evaluation of antibody-FcγR interactions, and revealed that antibodies with typical plant glycosylation have a limited capacity to engage FcγRI, FcγRIIa, FcγRIIb and FcγRIIIa; however, the binding characteristics can be restored and even improved with targeted glycoengineering. All plant-made glycovariants had a slightly reduced affinity to the neonatal Fc receptor (FcRn) compared with HEK cell-derived antibody. However, this was independent of plant glycosylation, but related to the oxidation status of two methionine residues in the Fc region. This points towards a need for process optimization to control oxidation levels and improve the quality of plant-produced antibodies.

Clinical experience with multigene carrier panels in the reproductive setting.

OBJECTIVES: Expanded carrier testing is acknowledged as an acceptable strategy for carrier testing by the American College of Obstetrics and Gynecology. Limited studies have investigated positivity rates of expanded carrier panels. We describe our experience with 3 commercial laboratory panels varying in size from 3 to 218 disorders. METHODS: We reviewed outcomes for 3 multigene carrier screening panels: trio (3 diseases), standard (23 diseases), and global (218 diseases). All panels used targeted genotype analysis of preselected mutations via next-generation sequencing. We calculated positivity rates for each panel. RESULTS: Positivity rates were 7.2% for Preparent Trio, 13.2% for Preparent Standard, and 35.8% for Preparent Global. The most frequent positive results in the global panel were (in descending order): abnormal hemoglobin electrophoresis, familial Mediterranean fever, cystic fibrosis, fragile X, glucose-6-phosphate dehydrogenase deficiency, alpha-thalassemia, and nonsyndromic hearing loss. CONCLUSIONS: While genetic diseases are individually rare, they are cumulatively common. Our experience illustrates that, with a panel of 218 diseases, the likelihood of identifying a carrier can be as high as 36%. Understanding panel positivity rates is one important factor for providers when choosing the right test for their practice, setting appropriate expectations for patients, and planning for follow-up counseling.

The ecological consequences of environmentally induced phenotypic changes.

Population dynamics and species persistence are often mediated by species traits. Yet many important traits, like body size, can be set by resource availability and predation risk. Environmentally induced changes in resource levels or predation risk may thus have downstream ecological consequences. Here, we assess whether quantity and type of resources affect the phenotype, the population dynamics, and the susceptibility to predation of a mixotrophic protist through experiments and a model. We show that cell shape, but not size, changes with resource levels and type, and is linked to carrying capacity, thus affecting population dynamics. Also, these changes lead to differential susceptibility to predation, with direct consequences for predator-prey dynamics. We describe important links between environmental changes, traits, population dynamics and ecological interactions, that underscore the need to further understand how trait-mediated interactions may respond to environmental shifts in resource levels in an increasingly changing world.

LILRB2 interaction with HLA class I correlates with control of HIV-1 infection.

Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10(-2)). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10(-11)-10(-9)) and African (p = 10(-5)-10(-3)) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.

Cost-Effectiveness of Eltrombopag versus Romiplostim for the Treatment of Chronic Immune Thrombocytopenia in England and Wales.

OBJECTIVES: To evaluate the cost-effectiveness of eltrombopag compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia in patients in England and Wales who are splenectomized or ineligible for splenectomy and are refractory to other treatments. METHODS: A Markov cohort model in which patients were administered a sequence of treatments was used to predict long-term outcomes associated with each treatment. The model was informed by data from the eltrombopag clinical trial program and the available literature. The analysis was conducted from the perspective of the UK National Health Service, and a lifetime time horizon was used. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Eltrombopag dominated romiplostim (i.e., eltrombopag was as effective as but less costly than romiplostim) in both splenectomized and nonsplenectomized patients, assuming a class effect for the two treatments. Eltrombopag also dominated romiplostim in most deterministic sensitivity analyses with the exception of when indirect efficacy estimates were incorporated into the model. In this analysis, eltrombopag no longer dominated romiplostim but remained cost-effective versus romiplostim at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Probabilistic sensitivity analysis demonstrated that there was a 99% and 92% chance of eltrombopag being cost-effective at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year in splenectomized and nonsplenectomized patients, respectively. CONCLUSIONS: Results of this study demonstrate that eltrombopag is cost-effective when compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia, representing good value for the UK National Health Service.

A link between dimerization and autophosphorylation of the response regulator PhoB.

Response regulator proteins within two-component signal transduction systems are activated by phosphorylation and can catalyze their own covalent phosphorylation using small molecule phosphodonors. To date, comprehensive kinetic characterization of response regulator autophosphorylation is limited to CheY, which follows a simple model of phosphodonor binding followed by phosphorylation. We characterized autophosphorylation of the response regulator PhoB, known to dimerize upon phosphorylation. In contrast to CheY, PhoB time traces exhibited an initial lag phase and gave apparent pseudo-first order rate constants that increased with protein concentration. Furthermore, plots of the apparent autophosphorylation rate constant versus phosphodonor concentration were sigmoidal, as were PhoB binding isotherms for the phosphoryl group analog BeF3(-). Successful mathematical modeling of the kinetic data necessitated inclusion of the formation of a PhoB heterodimer (one phosphorylated and one unphosphorylated monomer) with an enhanced rate of phosphorylation. Specifically, dimerization constants for the PhoB heterodimer and homodimer (two phosphorylated monomers) were similar, but the rate constant for heterodimer phosphorylation was ~10-fold higher than for the monomer. In a test of the model, disruption of the known PhoB(N) dimerization interface by mutation led to markedly slower and noncooperative autophosphorylation kinetics. Furthermore, phosphotransfer from the sensor kinase PhoR was enhanced by dimer formation. Phosphorylation-mediated dimerization allows many response regulators to bind to tandem DNA-binding sites and regulate transcription. Our data challenge the notion that response regulator dimers primarily form between two phosphorylated monomers and raise the possibility that response regulator heterodimers containing one phosphoryl group may participate in gene regulation.

Continuous femoral nerve block using 0.125% bupivacaine does not prevent early ambulation after total knee arthroplasty.

BACKGROUND: Continuous femoral nerve block has been shown to decrease opioid use, improve postoperative pain scores, and decrease length of stay. However, several studies have raised the concern that continuous femoral nerve block may delay patient ambulation and increase the risk of falls during the postoperative period. QUESTIONS/PURPOSES: This study sought to determine whether continuous femoral nerve block with a single-shot sciatic block prevented early ambulation after total knee arthroplasty (TKA) and whether the technique was associated with adverse effects. METHODS: Between January 2011 and January 2013, 77 consecutive patients undergoing primary TKAs at an orthopaedic specialty hospital received a continuous femoral nerve block for perioperative analgesia. The femoral block was placed preoperatively with an initial bolus and 76 (99%) patients received a single-shot sciatic nerve block performed at the same time. Fifty-eight percent (n = 45) received an initial bolus of 0.125% bupivacaine and 42% (n = 32) received 0.25% bupivacaine. All 77 patients received 0.125% bupivacaine infusion postoperatively with the continuous femoral nerve block. All patients were provided a knee immobilizer that was worn while they were out of bed and was used until 24 hours after removal of the block. All patients also used a front-wheeled walker to assist with ambulation. All 77 patients had complete records for assessing the end points of interest in this retrospective case series, including distance ambulated each day and whether in-hospital complications could be attributed to the patients' nerve blocks. RESULTS: Thirty-five patients (45%) ambulated for a mean distance of 19 ± 22 feet on the day of surgery. On postoperative Days 1 and 2, all 77 patients successfully ambulated a mean of 160 ± 112 and 205 ± 123 feet, respectively. Forty-eight patients (62%) had documentation of ascending/descending stairs during their hospital stay. No patient fell during the postoperative period, required return to the operating room, or readmission within 90 days of surgery. One patient experienced a transient foot drop related to the sciatic nerve block, which resolved by postoperative Day 1. CONCLUSIONS: Continuous femoral nerve block with dilute bupivacaine (0.125%) can be successfully used after TKA without preventing early ambulation. By taking active steps to prevent in-hospital falls, including the use of a knee immobilizer for ambulation while the block is in effect, patients can benefit from the analgesia provided by the block and still ambulate early after TKA. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Understanding factors associated with COVID-19 vaccination among health care workers using the Diffusion of Innovation Theory.

BACKGROUND: The COVID-19 vaccine was initially offered to frontline health care workers (HCWs), due to the high risk of contracting COVID-19 through occupational exposure to patients. Low HCW vaccine uptake can impact overall community-level vaccine uptake. This study used the Diffusion of Innovation (DOI) Theory to understand factors related to COVID-19 vaccine uptake in HCWs. METHODS: We surveyed Pennsylvanian HCWs (excluding Philadelphia) from August 2022 to February 2023. Survey questions inquired about demographics, COVID-19 vaccination status, reasons for receiving/declining the COVID-19 vaccine, and sources of information about the vaccine. RESULTS: Participants (n = 3,490) were 85% female, 89% White, and 93% (n = 3,255) reported receiving at least one dose of a COVID-19 vaccine. HCWs were categorized into adopter categories of the DOI Theory: innovators (56%), early adopters (9%), early majority (11%), late majority (7%), and laggards (17%). The major reason that prompted participants to get the vaccine was to protect them against COVID-19 infection (78%), while the major reason for declining the vaccine was due to concern about possible side effects from the vaccine (78%). CONCLUSIONS: We applied the DOI Theory to characterize adopters and identify factors related to COVID-19 vaccine uptake in HCWs. As updated COVID-19 vaccines are approved for the United States market, our findings may be used to improve vaccine education and communication among HCWs to support vaccine uptake.

HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding.

Leukocyte Ig-like receptors (LILRs) are a family of innate immune receptors predominantly expressed by myeloid cells that can alter the Ag presentation properties of macrophages and dendritic cells. Several LILRs bind HLA class I. Altered LILR recognition due to HLA allelic variation could be a contributing factor in disease. We comprehensively assessed LILR binding to >90 HLA class I alleles. The inhibitory receptors LILRB1 and LILRB2 varied in their level of binding to different HLA alleles, correlating in some cases with specific amino acid motifs. LILRB2 displayed the weakest binding to HLA-B*2705, an allele genetically associated with several autoimmune conditions and delayed progression of HIV infection. We also assessed the effect of HLA class I conformation on LILR binding. LILRB1 exclusively bound folded ß(2)-microglobulin-associated class I, whereas LILRB2 bound both folded and free H chain forms. In contrast, the activating receptor LILRA1 and the soluble LILRA3 protein displayed a preference for binding to HLA-C free H chain. To our knowledge, this is the first study to identify the ligand of LILRA3. These findings support the hypothesis that LILR-mediated detection of unfolded versus folded MHC modulates immune responses during infection or inflammation.

Alexithymia and posttraumatic stress disorder following epileptic seizure.

This study investigated (1) the incidence of posttraumatic stress disorder following epileptic seizure (post-epileptic seizure PTSD) and psychiatric co-morbidity and (2) the extent to which alexithymia traits related to the severity of the preceding outcomes. Seventy-one people with epilepsy participated in the study and completed the Posttraumatic Stress Diagnostic Scale, Hospital Anxiety and Depression Scale (HADS), and Toronto Alexithymia Scale. The control group comprised 71 people without epilepsy who completed the HADS. Fifty-one percent met the diagnostic criteria for full-PTSD; 30 % for partial-PTSD and 19 % for no-PTSD. The epilepsy group reported significantly more anxiety and depression than the control with demographic variables controlled for. Difficulty identifying feelings predicted post-epileptic seizure PTSD, anxiety and depression. It was positively correlated with post-epileptic seizure PTSD and depression, while it was negatively correlated with anxiety. People can develop PTSD and psychiatric co-morbid symptoms following epileptic seizures. The severity of these symptoms was related to difficulty in identifying internal feelings and emotions.

Impaired reversal learning in the Dlg2+/- rat model of genetic risk for psychiatric disorder: Important questions regarding the neuro-behavioral mechanisms of reversal learning.

In this issue, Griesius et al report that heterozygous Dlg2+/- rats showed a reversal learning impairment on a specific bowl-digging task, whereas other reversal tasks were unaffected. The study suggests that Dlg2 gene disruption, which has been linked to neuropsychiatric disorders, including schizophrenia, may cause relatively specific impairments in reversal learning, an important aspect of cognitive flexibility. The study draws attention to two important issues regarding the neuro-behavioral mechanisms of reversal learning, namely that hippocampal dysfunction, which is prominent in Dlg2+/- rats, may contribute to reversal learning impairments and that, depending on the task and previous experience, brain and behavioral mechanisms of reversal learning may differ.