The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.

The Hammersmith Score optimises patient selection and predicts for overall survival in early-phase cancer trial participants independent of tumour burden.

INTRODUCTION: As tumour response rates are increasingly demonstrated in early-phase cancer trials (EPCT), optimal patient selection and accurate prognostication is paramount. Hammersmith Score (HS), a simple prognostic index derived on routine biochemical measures (Albumin <35g/L, Lactate Dehydrogenase (LDH) >450 IU/L, Sodium <135mmol/L) is a validated predictor of response and survival in EPCT participants. HS has not been validated in the cancer immunotherapy era. METHODS: We retrospectively analysed characteristics and outcomes of unselected referrals to our early-phase unit (12/2019-12/2022). Independent predictors for overall survival (OS) were identified from univariable and multivariable models. HS was calculated for 66 eligible trial participants and compared with the Royal Marsden Score (RMS) to predict OS. Multivariable logistic regression and c-index was used to compare predictive ability of prognostic models. RESULTS: Of 212 referrals, 147 patients were screened and 82 patients treated in EPCT. Prognostic stratification by HS identifies significant difference in median OS and HS was confirmed as a multivariable predictor for OS (HR: HS 1 vs. 0 2.51, 95%CI: 1.01-6.24, p=0.049; HS 2/3 vs. 0: 10.32, 95%CI: 2.15-49.62, p=0.004; C-index 0.771) with superior multivariable predictive ability than RMS (HR: RMS 2 vs. 0/1 5.46, 95%CI: 1.12-26.57, p=0.036; RMS 3 vs. 0/1 6.83, 95%CI: 1.15-40.53, p<0.001; C-index 0.743). CONCLUSIONS: HS is a validated prognostic index for patients with advanced cancer treated in the context of modern EPCTs, independent of tumour burden. HS is a simple, inexpensive prognostic tool to optimise referral for EPCT.

Adult hypertension referral pathway and therapeutic management: British and Irish Hypertension Society position statement.

In the UK, most adults with hypertension are managed in Primary Care. Referrals to Secondary Care Hypertension Specialists are targeted to patients in whom further investigations are likely to change management decisions. In this position statement the British and Irish Hypertension Society provide clinicians with a framework for referring patients to Hypertension Specialists. Additional therapeutic advice is provided to optimise patient management whilst awaiting specialist review. Our aim is to ensure that referral criteria to Hypertension Specialists are consistent across the UK and Ireland to ensure equitable access for all patients.

A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia.

Background: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. Methods: Systematic literature searches were conducted in MEDLINE, Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. Results: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life. One study reported baseline erythrocyte sedimentation rate (ESR) predicted LDN response (≥30% reduction in fibromyalgia symptoms) and a second study showed plasma concentrations of inflammatory biomarkers were lower after LDN treatment. To our knowledge, there are no brain imaging studies reporting the effect of LDN in patients with fibromyalgia. All studies were based on small sample sizes, were restricted to women and the risk of bias was assessed to be high. There is also some evidence of publication bias. Conclusion: The strength of evidence from randomized controlled trials to support the use of LDN among patients with fibromyalgia is low. Two small studies suggest ESR and cytokines may be involved in the mechanism by which LDN exerts its effects. Two trials (INNOVA and FINAL) are currently in progress, but further work is needed among men and different ethnic groups.

Management of hypertensive crisis: British and Irish Hypertension Society Position document.

Patients with hypertensive emergencies, malignant hypertension and acute severe hypertension are managed heterogeneously in clinical practice. Initiating anti-hypertensive therapy and setting BP goal in acute settings requires important considerations which differ slightly across various diagnoses and clinical contexts. This position paper by British and Irish Hypertension Society, aims to provide clinicians a framework for diagnosing, evaluating, and managing patients with hypertensive crisis, based on the critical appraisal of available evidence and expert opinion.

Direction of attentional focus in prosthetic training: Current practice and potential for improving motor learning in individuals with lower limb loss.

OBJECTIVE: Adopting an external focus of attention has been shown to benefit motor performance and learning. However, the potential of optimizing attentional focus for improving prosthetic motor skills in lower limb prosthesis (LLP) users has not been examined. In this study, we investigated the frequency and direction of attentional focus embedded in the verbal instructions in a clinical prosthetic training setting. METHODS: Twenty-one adult LLP users (8 female, 13 male; 85% at K3 level; mean age = 50.5) were recruited from prosthetic clinics in the Southern Nevada region. Verbal interactions between LLP users and their prosthetists (mean experience = 10 years, range = 4-21 years) during prosthetic training were recorded. Recordings were analyzed to categorize the direction of attentional focus embedded in the instructional and feedback statements as internal, external, mixed, or unfocused. We also explored whether LLP users' age, time since amputation, and perceived mobility were associated with the proportion of attentional focus statements they received. RESULTS: We recorded a total of 20 training sessions, yielding 904 statements of instruction from 338 minutes of training. Overall, one verbal interaction occurred every 22.1 seconds. Among the statements, 64% were internal, 9% external, 3% mixed, and 25% unfocused. Regression analysis revealed that female, older, and higher functioning LLP users were significantly more likely to receive internally-focused instructions (p = 0.006, 0.035, and 0.024, respectively). CONCLUSIONS: Our results demonstrated that verbal instructions and feedback are frequently provided to LLP users during prosthetic training. Most verbal interactions are focused internally on the LLP users' body movements and not externally on the movement effects. IMPACT STATEMENT: While more research is needed to explore how motor learning principles may be applied to improve LLP user outcomes, clinicians should consider adopting the best available scientific evidence during treatment. Overreliance on internally-focused instructions as observed in the current study may hinder prosthetic skill learning.

Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer.

Importance: Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. Objective: To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. Design, Setting, and Participants: This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials. Main Outcomes and Measures: Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. Results: Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P < .001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P = .76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P < .001). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001) was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy (HR, 3.4; 95% CI, 1.9-6.1; P < .001) and response to ICI therapy (HR, 8.2; 95% CI, 4.0-16.9; P < .001) were associated with OS independent of tumor site, disease burden, and performance status. Conclusions and Relevance: Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients' gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

Patient-led decision making: Measuring autonomy and respect in Canadian maternity care.

OBJECTIVE: The Changing Childbirth in British Columbia study explored women's preferences and experiences of maternity care, including women's role in decision-making. METHODS: Following content validation by community members, we administered a cross-sectional online survey exploring novel topics, including drivers for interventions, and experiences of autonomy, respect, or mistreatment during maternity care. Using the Mothers Autonomy in Decision-Making (MADM) scale as an outcome measure in a mixed-effects analysis, we examined differential experiences by socio-demographic and prenatal risk profile, type of care provider, interventions received, and nature of communication with care providers. RESULTS: A geographically representative sample of Canadian women (n = 2051) reported on 3400 pregnancies. Most women (95.2%) preferred to be the lead decision-maker during care. Patients of physicians had significantly lower autonomy (MADM) scores than midwifery clients as did women who felt pressured to accept interventions. Women who had a difference in opinion with their provider, and those who felt their provider seemed rushed reported the lowest MADM scores. CONCLUSION: Women's autonomy is significantly altered by model of maternity care, the nature of interactions with care providers, and women's ability for self-determination. PRACTICE IMPLICATIONS: If health professionals acquire skills in person-centred decision-making experience of autonomy among pregnant women may improve.

The Mother's Autonomy in Decision Making (MADM) scale: Patient-led development and psychometric testing of a new instrument to evaluate experience of maternity care.

OBJECTIVE: To develop and validate a new instrument that assesses women's autonomy and role in decision making during maternity care. DESIGN: Through a community-based participatory research process, service users designed, content validated, and administered a cross-sectional quantitative survey, including 31 items on the experience of decision-making. SETTING AND PARTICIPANTS: Pregnancy experiences (n = 2514) were reported by 1672 women who saw a single type of primary maternity care provider in British Columbia. They described care by a midwife, family physician or obstetrician during 1, 2 or 3 maternity care cycles. We conducted psychometric testing in three separate samples. MAIN OUTCOME MEASURES: We assessed reliability, item-to-total correlations, and the factor structure of the The Mothers' Autonomy in Decision Making (MADM) scale. We report MADM scores by care provider type, length of prenatal appointments, preferences for role in decision-making, and satisfaction with experience of decision-making. RESULTS: The MADM scale measures a single construct: autonomy in decision-making during maternity care. Cronbach alphas for the scale exceeded 0.90 for all samples and all provider groups. All item-to-total correlations were replicable across three samples and exceeded 0.7. Eigenvalue and scree plots exhibited a clear 90-degree angle, and factor analysis generated a one factor scale. MADM median scores were highest among women who were cared for by midwives, and 10 or more points lower for those who saw physicians. Increased time for prenatal appointments was associated with higher scale scores, and there were significant differences between providers with respect to average time spent in prenatal appointments. Midwifery care was associated with higher MADM scores, even during short prenatal appointments (<15 minutes). Among women who preferred to lead decisions around their care (90.8%), and who were dissatisfied with their experience of decision making, MADM scores were very low (median 14). Women with physician carers were consistently more likely to report dissatisfaction with their involvement in decision making. DISCUSSION: The Mothers Autonomy in Decision Making (MADM) scale is a reliable instrument for assessment of the experience of decision making during maternity care. This new scale was developed and content validated by community members representing various populations of childbearing women in BC including women from vulnerable populations. MADM measures women's ability to lead decision making, whether they are given enough time to consider their options, and whether their choices are respected. Women who experienced midwifery care reported greater autonomy than women under physician care, when engaging in decision-making around maternity care options. Differences in models of care, professional education, regulatory standards, and compensation for prenatal visits between midwives and physicians likely affect the time available for these discussions and prioritization of a shared decision making process. CONCLUSION: The MADM scale reflects person-driven priorities, and reliably assesses interactions with maternity providers related to a person's ability to lead decision-making over the course of maternity care.

Inadequate prenatal care utilization and risks of infant mortality and poor birth outcome: a retrospective analysis of 28,729,765 U.S. deliveries over 8 years.

OBJECTIVE: To evaluate the association between adequacy of prenatal care utilization and risk of fetal and neonatal mortality and adverse outcomes. METHODS: We conducted a population-based cohort study using the Center for Disease Control and Prevention's Linked Birth-Infant Death and Fetal Death data on all deliveries in the United States between 1995 and 2002. Inclusion criteria were singleton births ≥22 weeks of gestation with no known congenital malformation. Inadequate prenatal care was defined according to the Adequacy of Prenatal Care Utilization Index, and its effect on fetal and neonatal death was estimated using unconditional logistic regression analysis adjusting for maternal age, race, education, and other confounding variables. RESULTS: During our 8-year study period, 32,206,417 births occurred, 28,729,765 (89.2%) of which met inclusion criteria. Inadequate prenatal care utilization occurred in 11.2% of expectant mothers, more commonly among women ≤20 years, black non-Hispanic and Hispanic women, and those without high school education. Relative to adequate care, inadequate care was associated with increased risk of prematurity 3.75 (3.73 to 3.77), stillbirth 1.94 (1.89 to 1.99), early neonatal dearth 2.03 (1.97 to 2.09), late neonatal death 1.67 (1.59 to 1.76), and infant death 1.79 (1.76 to 1.82). CONCLUSION: Risk of prematurity, stillbirth, early and late neonatal death, and infant death increased linearly with decreasing care. Given the population effect of this association, public health initiatives should target program expansion to ensure timely and adequate access, particularly for women ≤20 years, Black non-Hispanic and Hispanic women, and those without high school education.