Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides.

BACKGROUND: The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides. METHODS: HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses. RESULTS: We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele. CONCLUSION: The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.

The use of procedural kits may reduce unscheduled central line dressing changes: A matched pre-post intervention study.

Background: Unscheduled dressing changes for central venous lines (CVLs) have been shown to increase the risk of bloodstream infections. Objective: The objective of this study is to determine if the use of an innovative dressing change kit reduces the rate of unscheduled dressing changes. Methods: This pre-post interventional study took place at a large, academic, tertiary care center in metro Detroit, Michigan, the United States. We assessed the impact of the interventional dressing change procedure kit on the rate of unscheduled dressing changes for adult patients who underwent placement of a CVL inclusive of a central catheter, peripherally inserted central catheter, or hemodialysis catheter. Data was collected for the pre-intervention cohort through electronic health records (EHRs), while data for the post-intervention cohort were collected by direct observation by trained research staff in combination with EHR data. The primary outcome was the rate of unscheduled dressing changes. Secondary outcomes included rate of unscheduled dressing changes based on admission floor type, etiology of unscheduled dressing changes, and central line-associated bloodstream infections (CLABSIs). Results: The study included a convenience sample of 1548 CVLs placed between May 2018 and June 2022 with a matched analysis including 488 catheters in each of the pre- and post-intervention groups. The results showed that the unadjusted rate of unscheduled dressing evaluations was significantly reduced from the pre-intervention group (0.21 per day) to the post-intervention group (0.13 per day) (p < .001). The adjusted rate ratio demonstrated the same trend at 1.00 pre- and 0.60 post-intervention (p < .001). Stratifying the analysis based on the highest level of care showed that the intervention was effective in reducing the unadjusted rate of unscheduled dressing evaluations for both the advanced and regular medical floor subgroups pre- to post-intervention; the advanced subgroup had an reduction from 0.22 to 0.15 per day (p = .001), while the regular medical floor subgroup had a reduction from 0.21 to 0.09 per day (p < .001). CLABSIs were similar in both groups (0.6% vs 0.8%; p = 1.00) in pre- and post-intervention groups, respectively. Discussion: Procedural kits for central line dressing changes are effective in reducing unscheduled dressing changes and may have a role in reducing CLABSI. Further studies assessing the impact of dressing change kits on cost, procedural compliance, and the precise impact on CLABSI are needed.

Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

Diagnostic Performance of Diastolic Hyperemia-Free Ratio Compared With Invasive Fractional Flow Reserve for Evaluation of Coronary Artery Disease.

Hyperemic and nonhyperemic pressure ratios are frequently used to assess the hemodynamic significance of coronary artery disease and to guide the need for myocardial revascularization. However, there are limited data on the diagnostic performance of the diastolic hyperemia-free ratio (DFR). We evaluated the diagnostic performance of the DFR compared with invasive fractional flow reserve (FFR). We performed a prospective, single-center study of 308 patients (343 lesions) who underwent DFR and FFR for evaluation of visually estimated 40% to 90% stenoses. Diagnostic performance of the DFR compared with FFR was evaluated using linear regression, Bland-Altman analysis, and receiver operating characteristic curves. The overall diagnostic accuracy of the DFR was 83%; the accuracy rates were 86%, 40%, and 95% when the DFR was <0.86, 0.88 to 0.90, and >0.93, respectively. The sensitivity, specificity, positive predicative value, and negative predictive value were 60%, 91%, 71%, and 87%, respectively. The Pearson correlation coefficient was 0.75 (p <0.05). The Bland-Altman analysis showed a mean difference of 0.09, and the area under the receiver operating characteristic curve was 0.88 (95% confidence interval 0.84 to 0.92, p <0.05). In conclusion, the DFR has a good diagnostic performance compared with FFR but 17% of the measurements were discordant. The diagnostic accuracy of the DFR was only 40% when the DFR was 0.88 to 0.90, suggesting that FFR may be useful in these arteries.

Impact of Ambulatory Care Pharmacist-Led Management on Hemoglobin A1c Values among Patients with Uncontrolled Diabetes in a Primary Care Clinic vs Usual Care over Two Years.

Background: Literature has shown the positive impact of ambulatory care pharmacists on diabetes management, yet additional research on clinical outcomes compared to traditional care models is warranted. Objective: The objective of this study is to evaluate the impact of an ambulatory care pharmacist on glycemic control over two years compared to patients who received usual care. Methods: This retrospective cohort study matched patients with a baseline hemoglobin A1c (HgbA1c) ≥8% managed by the ambulatory care pharmacist to patients who received usual care. The primary outcome was the mean change in HgbA1c over two years. The secondary outcomes were to evaluate the difference in (1) the proportion of patients achieving HgbA1c <8%, (2) the proportion of patients achieving blood pressure <130/80 mmHg, (3) mean LDL, (4) the proportion of patients prescribed SGLT2 inhibitors, GLP-1RA, and sulfonylureas, and (5) severe hypoglycemia after two years. Results: Data for 180 patients was analyzed over two years. The mean HgbA1c was 10% at baseline vs 8.2% after two years (adjusted mean change -1.92) among pharmacist-managed patients, compared to 9.9% vs 9% respectively for usual care patients (adjusted mean change -0.98) (p=0.004). Among pharmacist-managed patients, 53.5% achieved HgbA1c <8% compared with 34.2% of usual care patients (p=0.014). There were no statistically significant differences in proportion of patients at goal blood pressure, mean LDL, or hypoglycemia between the two groups. After two years, 18.3% of pharmacist-managed and 5.8% of usual care patients were on an SGLT2 inhibitor (p=0.008), and 46.7% of pharmacist-managed and 9.2% of usual care patients were on a GLP-1RA (p<0.001). No difference was found in sulfonylurea utilization. Conclusion: Patients with HgbA1c >8% managed by an ambulatory care pharmacist had twice the HgbA1c reduction and significantly more utilization of GLP-1RA and SGLT2 inhibitors as compared to controls provided usual care.

Evaluation of Interprofessional Quality Improvement Interventions Led by an Ambulatory Care Pharmacist on Adherence to a Controlled Substance Agreement Policy.

Background: A controlled substance agreement (CSA) is a risk mitigation strategy for patients managed on controlled substance medications such as opioids and benzodiazepines. Limited literature exists to describe the role of the clinic pharmacy team to promote adherence to CSA monitoring parameters. Objective: The objective of this study is to evaluate the impact of interprofessional educational and clinical interventions led by an ambulatory care pharmacist on adherence to monitoring parameters within a CSA policy. Methods: This retrospective observational study included patients on long-term controlled substances who had a clinic visit every 3 months during the study period. The primary outcomes were the proportion of patients with a signed CSA in the electronic medical record (EMR), urine drug screen (UDS) completion, and documentation of review of the statewide prescription drug monitoring program (PDMP) in the EMR 8 months prior to as compared to 8 months after implementation of pharmacist interventions. Results: Among 79 patients (mean age 55.7 years, 65.8% female, 54.4% African American), 8.9% pre- vs 88.6% post-interventions had a signed CSA (p<0.001), 35.4% pre- vs 65.8% post-interventions had a UDS completed (p<0.001), and 32.9% pre- vs 57% post-interventions had documentation of PDMP review (p=0.002). Conclusion: Adherence to monitoring parameters within a CSA policy significantly improved after educational and clinical interventions led by an ambulatory care pharmacist.

Predicting HPV association using deep learning and regular H&E stains allows granular stratification of oropharyngeal cancer patients.

Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) represents an OPSCC subgroup with an overall good prognosis with a rising incidence in Western countries. Multiple lines of evidence suggest that HPV-associated tumors are not a homogeneous tumor entity, underlining the need for accurate prognostic biomarkers. In this retrospective, multi-institutional study involving 906 patients from four centers and one database, we developed a deep learning algorithm (OPSCCnet), to analyze standard H&E stains for the calculation of a patient-level score associated with prognosis, comparing it to combined HPV-DNA and p16-status. When comparing OPSCCnet to HPV-status, the algorithm showed a good overall performance with a mean area under the receiver operator curve (AUROC) = 0.83 (95% CI = 0.77-0.9) for the test cohort (n = 639), which could be increased to AUROC = 0.88 by filtering cases using a fixed threshold on the variance of the probability of the HPV-positive class - a potential surrogate marker of HPV-heterogeneity. OPSCCnet could be used as a screening tool, outperforming gold standard HPV testing (OPSCCnet: five-year survival rate: 96% [95% CI = 90-100%]; HPV testing: five-year survival rate: 80% [95% CI = 71-90%]). This could be confirmed using a multivariate analysis of a three-tier threshold (OPSCCnet: high HR = 0.15 [95% CI = 0.05-0.44], intermediate HR = 0.58 [95% CI = 0.34-0.98] p = 0.043, Cox proportional hazards model, n = 211; HPV testing: HR = 0.29 [95% CI = 0.15-0.54] p < 0.001, Cox proportional hazards model, n = 211). Collectively, our findings indicate that by analyzing standard gigapixel hematoxylin and eosin (H&E) histological whole-slide images, OPSCCnet demonstrated superior performance over p16/HPV-DNA testing in various clinical scenarios, particularly in accurately stratifying these patients.

Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer.

The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 SQLCs with 8p11-p12 amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1-8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain-deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency.

Exploring the artificial intelligence "Trust paradox": Evidence from a survey experiment in the United States.

Advances in Artificial Intelligence (AI) are poised to transform society, national defense, and the economy by increasing efficiency, precision, and safety. Yet, widespread adoption within society depends on public trust and willingness to use AI-enabled technologies. In this study, we propose the possibility of an AI "trust paradox," in which individuals' willingness to use AI-enabled technologies exceeds their level of trust in these capabilities. We conduct a two-part study to explore the trust paradox. First, we conduct a conjoint analysis, varying different attributes of AI-enabled technologies in different domains-including armed drones, general surgery, police surveillance, self-driving cars, and social media content moderation-to evaluate whether and under what conditions a trust paradox may exist. Second, we use causal mediation analysis in the context of a second survey experiment to help explain why individuals use AI-enabled technologies that they do not trust. We find strong support for the trust paradox, particularly in the area of AI-enabled police surveillance, where the levels of support for its use are both higher than other domains but also significantly exceed trust. We unpack these findings to show that several underlying beliefs help account for public attitudes of support, including the fear of missing out, optimism that future versions of the technology will be more trustworthy, a belief that the benefits of AI-enabled technologies outweigh the risks, and calculation that AI-enabled technologies yield efficiency gains. Our findings have important implications for the integration of AI-enabled technologies in multiple settings.

[ctHPV-DNA based precision oncology for patients with oropharyngeal cancer - Where are we?] / ctHPV-DNA-basierte Präzisionsonkologie für Patienten mit Oropharynxkarzinom ­ wo stehen wir?

Human papillomavirus (HPV) is an established etiologic factor for cancers in the head and neck region, specifically for Oropharyngeal Squamous Cell Carcinoma (OPSCC). The comparatively good overall survival justifies the current discussion regarding therapy de-escalation for patients with a low-risk profile. In addition to the immunohistochemistry-based biomarker p16INK4a, there is still a need for diagnostic and prognostic biomarkers that allow risk stratification and monitoring during therapy and follow-up of these patients. In recent years, liquid biopsy, especially in the form of plasma samples, has gained importance and is already used to monitor viral DNA in patients with Epstein-Barr virus-associated nasopharyngeal carcinoma. Circulating DNA (ctDNA) released by the tumor into the bloodstream is particularly suitable for a high specificity in detecting virus-associated tumors. Detection of viral E6 and E7 oncogenes in HPV-positive OPSCC is predominantly performed by droplet digital/quantitative PCR as well as next generation sequencing. Detection of circulating HPV-DNA derived from tumor cells (ctHPV-DNA) at diagnosis is associated with advanced tumor stage, locoregional and distant metastases. Longitudinal studies have further demonstrated that detectable and/or increasing ctHPV-DNA levels are associated with treatment failure and disease relapse. However, a standardization of the diagnostic procedure is necessary before introducing liquid biopsy into the clinical routine. In the future, this might allow a valid reflection of disease progression in HPV-positive OPSCC.

Impact of P16 Positivity on Clinical Outcomes in Nasopharyngeal Carcinoma: A Single Institution Study.

Introduction Nasopharyngeal carcinoma (NPC) is a rare malignancy with unique geographical distribution. It is prevalent in East and Southeast Asia and rare in non-endemic countries like the USA. P16 is a tumor suppressor gene and there are limited studies with inconsistent results describing the association of its positivity in immunohistochemistry and clinical outcomes. In this retrospective study, we compared progression-free survival (PFS) and overall survival (OS) based on p16 positivity in 60 patients with NPC. Materials and methods Patients aged above 18 years and followed between July 2015 and December 2020 were included in the study. P16 positivity was based on the immunohistochemistry of the biopsy sample. We compared PFS and OS among all p16-positive and negative patients, and then among patients with advanced disease (stage III or IV), and between p16-positive, negative, and unknown status patients. Results There were 15 p16-positive, and 28 p16-negative, with a median age of 54.3 years and 55.7 years respectively. Most patients in both groups were male, Caucasian, and had advanced disease (stage III or stage IV). Both median PFS (p=0.838) and OS (p=0.776) were 84 months in the p16-negative group but were not reached during the study period in the p16-positive group. Among advanced-stage patients, the PFS (p=0.873), and OS (p=0.773) of both groups were not statistically significant. P16 status was unknown for 17 patients, and PFS (p=0.785) and OS (p=0.901), when compared among patients with p16-positive, negative, and unknown status, were also statistically non-significant. Discussion and conclusion Our analysis suggests that p16 status does not predict clinical outcomes in NPC patients. Our sample size was limited but is larger than most studies describing this association. With different studies in the literature reporting disparate findings, we recommend larger prospective studies to better illustrate the impact of p16 positivity on clinical outcomes in NPC.

(Mis)Information on Digital Platforms: Quantitative and Qualitative Analysis of Content From Twitter and Sina Weibo in the COVID-19 Pandemic.

Background: Misinformation about COVID-19 on social media has presented challenges to public health authorities during the pandemic. This paper leverages qualitative and quantitative content analysis on cross-platform, cross-national discourse and misinformation in the context of COVID-19. Specifically, we investigated COVID-19-related content on Twitter and Sina Weibo-the largest microblogging sites in the United States and China, respectively. Objective: Using data from 2 prominent microblogging platform, Twitter, based in the United States, and Sina Weibo, based in China, we compared the content and relative prevalence of misinformation to better understand public discourse of public health issues across social media and cultural contexts. Methods: A total of 3,579,575 posts were scraped from both Sina Weibo and Twitter, focusing on content from January 30, 2020, within 24 hours of when WHO declared COVID-19 a "public health emergency of international concern," and a week later, on February 6, 2020. We examined how the use and engagement measured by keyword frequencies and hashtags differ across the 2 platforms. A 1% random sample of tweets that contained both the English keywords "coronavirus" and "covid-19" and the equivalent Chinese characters was extracted and analyzed based on changes in the frequencies of keywords and hashtags and the Viterbi algorithm. We manually coded a random selection of 5%-7% of the content to identify misinformation on each platform and compared posts using the WHO fact-check page to adjudicate accuracy of content. Results: Both platforms posted about the outbreak and transmission, but posts on Sina Weibo were less likely to reference topics such as WHO, Hong Kong, and death and more likely to cite themes of resisting, fighting, and cheering against coronavirus. Misinformation constituted 1.1% of Twitter content and 0.3% of Sina Weibo content-almost 4 times as much on Twitter compared to Sina Weibo. Conclusions: Quantitative and qualitative analysis of content on both platforms points to lower degrees of misinformation, more content designed to bolster morale, and less reference to topics such as WHO, death, and Hong Kong on Sina Weibo than on Twitter.

Navigating Paths to Wellness: A Strengths-Based Photovoice Study Conducted with One First Nation in Southern Ontario, Canada.

Research on substance use challenges in First Nations communities is often deficit-focused and can reinforce paternalistic stereotypes that lead to further discrimination. In this article, we report on findings of a strengths-based Photovoice project done in collaboration with a First Nations' community in southern Ontario, Canada to better understand experiences with substance use challenges in the community. We analyzed interview data collected with seventeen individuals who have lived experience or are supporting a loved one with lived experience with a substance use challenge. Participants described sources of strength that characterized their path to wellness, including strong family and social connections, cultural practices, identity, spirituality, day-to-day activities, and helpful supports and services. Furthermore, participants made several suggestions for improving services, including the need for integrated and flexible systems of care and trustful client-provider relationships. At its core, nurturing wellness involved a transformative process involving social and/or cultural connections. The stories shared by participants demonstrate the unique and varied strengths drawn from by individuals dealing with a substance use challenge.

Understanding Social Determinants of First Nations Health Using a Four-Domain Model of Health and Wellness Based on the Medicine Wheel: Findings from a Community Survey in One First Nation.

We examined the explanatory roles of social determinants of health (SDOH) for First Nations people using a four-domain model of health and wellness based on the Medicine Wheel (i.e., physical, mental, emotional, and spiritual health), including colonial-linked stressors (i.e., historical trauma, childhood adversities, racial discrimination) and cultural resilience factors (i.e., cultural strengths, traditional healing practices, social support). Data were collected in partnership with a First Nation in Ontario, Canada in 2013 through a community survey (n = 194). For each outcome (physical, mental, emotional, and spiritual health), a modified Poisson regression model estimated prevalence ratios for the SDOH, adjusting for age, sex, education, and marital status. Negative associations were found for historical trauma with physical, mental, emotional, and spiritual health; for childhood adversities with mental health; and for racial discrimination with physical, mental, and emotional health. Positive associations were found for cultural strengths with physical, mental, and emotional health and for social support with physical, mental, emotional, and spiritual health. We observed negative associations between use of traditional healing practices and mental and emotional health. Our findings suggest that these SDOH may play important roles in relation to wellness through associations with the domains of health modelled by the Medicine Wheel.

Role of demographics in non-invasive testing for colorectal cancer screening: do targeted cut-off values improve detection?

BACKGROUND: Fecal immunochemical test (FIT) is a yearly alternative colorectal screening modality for average risk individuals unwilling or unable to undergo invasive colorectal cancer (CRC) screening due to cost and accessibility. This study aims to determine whether FIT should be interpreted within the context of patient demographics and medical history. METHODS: Patients >50 years old who had a FIT followed by colonoscopy within 1 year were analyzed based on age, race, BMI, social and medical comorbidities. False positive (FP) and false negative (FN) FIT results within each patient demographic and medical history variable were determined by comparing with the gold standard of colonoscopy using Chi-square analysis. RESULTS: 1025 patients were reviewed. 21.8% of FIT results were positive. Factors which differed in positive FIT rates were age (p=0.003), smoking (p<0.001), alcohol (p=0.001), and hypertension (p<0.001). The difference in rates of FP and FN FIT outcomes among each variable underwent further sub-analysis. The FP was 66.8% and the FN rate was 12.8%. Higher FN outcomes were noted in those above 70, males and smokers, though the result was only statistically significant for males (p=0.009). Females were observed to have higher FP rates (p=0.019). CONCLUSIONS: Females had higher FP FIT rates compared to males, indicating that sex may influence FIT outcomes and should be accounted for when interpreting FIT results. This information can be utilized to identify populations at higher risk of FP or FN FIT results to target CRC screening. Additionally, recalculating the FP and FN rates for each variable may help determine new FIT targets.

Impact of Ambulatory Care Pharmacist-Led Diabetes Mellitus Management on Hemoglobin A1c Values Among Patients With Diabetes in a Primary Care Clinic Over Two Years.

Background: Previous evaluation in the literature of ambulatory care pharmacist management on glycosylated hemoglobin (HgbA1c) has been positive, but often limited to 6 to 12 months of follow up. Objective: The objective of this study is to evaluate the impact of an ambulatory care pharmacist on HgbA1c among patients with diabetes in a primary care clinic over two years. Methods: Retrospective chart review was conducted on patients with type 2 diabetes managed by the ambulatory care pharmacist. Patients with at least one HgbA1c value ≥7% in the two-year pre-intervention period were included. The primary outcome was the change in mean HgbA1c from baseline to two years post-intervention. The secondary outcome was the change in mean of all HgbA1c values over two years pre-intervention compared to two years post-intervention. Results: Data for 116 patients was analyzed two years prior to and two years after ambulatory care pharmacist service initiation. The mean HgbA1c at baseline pre-intervention was 8.8% compared to a mean HgbA1c of 7.8% two years post-intervention. A total of 12.9% of patients (n=15) had a baseline HgbA1c of less than 7% pre-intervention, compared to 42.2% of patients (n=49) two years post-intervention (p<0.001). The overall mean HgbA1c was 8.8% in the two-year pre-intervention period and 8.2% in the two-year post-intervention period (p<0.001). Among patients with an overall mean HgbA1c ≥8% in the pre-intervention period, the mean HgbA1c was 9.8% pre-intervention and 8.7% post-intervention. Conclusion: Ambulatory care pharmacist interventions demonstrated a significant impact on HgbA1c reduction over two years of follow up.

Clinical and physical efficiency of virtual reality games in soccer players with low back pain / Eficiencia de los juegos de realidad virtual en jugadores de futbol con dolor de espalda baja / Eficiência clínica e física de jogos de realidade virtual em jogadores de futebol com dor lombar

ABSTRACT Introduction: Virtual reality training (VRT) is an advanced technology that creates virtual games by a computer through specific software. It is a type of rehabilitation training commonly used in balance problems to treat musculoskeletal conditions. Objective: To determine and compare the effects of virtual reality games with those of core stabilization training on physical efficiency in soccer players with chronic low back pain. Methods: A randomized, double-blinded, controlled study was conducted on 60 LBP participants at a university hospital. The first group (n=20) received virtual reality (VR) training; the second group (n=20) received core stabilization (CS) training; and the third group (n=20) received conventional training exercises for four weeks. Scores of clinical and sports performance were measured at baseline, and after 4 weeks, 8 weeks and 6 months. Results: The baseline demographic and clinical characters did not show any significant differences (p>0.05) in the statistical analysis, which shows a homogenous population. Four weeks following the training, the VR training group showed more significant changes in clinical scores than the CS training and control groups (p≤0.001). The scores for sports performance also showed more significant improvement in the VR training group than in the other two groups (p≤0.001). The same improved clinical and sports performance changes were seen at 8 weeks and 6 months of follow-up in the VR training group, when compared to the other two groups (p≤0.001). Conclusion: This study suggests that training through virtual reality games results in long-term improvement in clinical and sports performance compared to other forms of training in soccer players with chronic low back pain.Level of evidence I b; Therapeutic studies - Investigation of treatment results.

RESUMEN Introducción: El entrenamiento de realidad virtual (VRT) es una tecnología avanzada, que crea juegos virtuales por computadora a través de un software específico. Es un tipo de entrenamiento de rehabilitación que se usa comúnmente en problemas de equilibrio para tratar afecciones musculoesqueléticas. Objetivo: Encontrar y comparar los efectos de los juegos de realidad virtual sobre el entrenamiento de estabilización central sobre la eficiencia física en jugadores de fútbol con dolor lumbar crónico. Métodos: Se realizó un estudio controlado, aleatorizado, doble ciego en 60 participantes con dolor lumbar en un hospital universitario. El primer grupo (n = 20) recibió entrenamiento de realidad virtual (VR), el segundo grupo (n = 20) recibió entrenamiento de estabilización central (CS) y el tercer grupo (n = 20) recibió ejercicios de entrenamiento convencionales durante cuatro semanas. Los puntajes de rendimiento clínico y deportivo se midieron al inicio del estudio, después de 4 semanas, 8 semanas y 6 meses. Resultados: Los caracteres demográficos y clínicos basales no mostraron ninguna diferencia significativa (p. 0,05) en el análisis estadístico lo que indica una población homogénea. Cuatro semanas después del entrenamiento, el grupo de entrenamiento de RV mostró cambios más significativos en las puntuaciones clínicas que los de entrenamiento de CS y los grupos de control (p≤0,001). Las puntuaciones de rendimiento deportivo también mostraron una mejora significativa en el grupo de entrenamiento de RV comparadas con los otros dos grupos (p≤0,001). Hubo los mismos cambios clínicos y de rendimiento deportivo a las 8 semanas y 6 meses de seguimiento en el grupo de entrenamiento de RV y en los otros dos grupos (p≤0,001). Conclusión: Nuestro estudio sugirió que el entrenamiento a través de juegos de realidad virtual mejoró el rendimiento clínico y deportivo más que otros entrenamientos en jugadores de fútbol con dolor lumbar crónico a largo plazo. Nivel de evidencia Ib; Estudios terapéuticos, investigación de los resultados del tratamiento.

RESUMO Introdução: O treinamento com realidade virtual (TRV) é uma tecnologia avançada que cria jogos virtuais para computador por meio de software específico. É um tipo de treinamento de reabilitação comumente usado em problemas de equilíbrio no tratamento de doenças musculoesqueléticas. Objetivo: Determinar e comparar os efeitos dos jogos de realidade virtual com o treinamento de estabilização central na eficiência física de jogadores de futebol com dor lombar crônica. Métodos: Estudo randomizado, duplo-cego e controlado realizado com 60 participantes com lombalgia em um hospital universitário. O primeiro grupo (n = 20) recebeu treinamento de realidade virtual (RV), o segundo grupo (n = 20) recebeu treinamento de estabilização central (EC) e o terceiro grupo (n = 20) recebeu exercícios de treinamento convencional por quatro semanas. Os escores de desempenho clínico e esportivo foram medidos no início do estudo e depois de 4 semanas, 8 semanas e 6 meses. Resultados: As características demográficas e clínicas basais não mostraram diferença significativa (p > 0,05) na análise estatística, o que indica população homogênea. Quatro semanas depois do treinamento, o grupo RV mostrou mudanças mais significativas nos escores clínicos do que os grupos EC e controle (p ≤ 0,001). Os escores de desempenho esportivo também mostraram melhora significativa no grupo RV do que nos outros dois grupos (p ≤ 0,001). As mesmas mudanças benéficas de desempenho clínico e esportivo foram observadas em 8 semanas e 6 meses de acompanhamento no grupo RV em comparação com os outros dois grupos (p ≤ 0,001). Conclusão: Este estudo sugere que o treinamento com jogos de realidade virtual resulta em melhora do desempenho clínico e esportivo a longo prazo do que outras formas de treinamento em jogadores de futebol com dor lombar crônica. Nível de evidência Ib; Estudos terapêuticos, Investigação dos resultados de tratamentos.

Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer.

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.