Evaluation and Management of Buprenorphine Extended-Release Injection Thrombophlebitis: A Case Report.

INTRODUCTION: Buprenorphine extended-release subcutaneous injection (BUP-XR) is a medication used to treat opioid use disorder. It is a long-acting formulation of buprenorphine, which is a partial opioid agonist. Buprenorphine extended-release subcutaneous injection is injected into the subcutaneous space forming a depot that can last up to a month. The most common adverse effects of BUP-XR are injection site pain, erythema, and induration. CASE REPORT: A man in his late 30s presented to the emergency department 48 hours after BUP-XR injection with abdominal pain. He was found to have superficial venous thrombosis of an abdominal wall vessel extending near the deep venous system. He was subsequently started on apixaban for 30 days and cefadroxil for 7 days to reduce the risk of extension and infection. He fully recovered and has since restarted BUP-XR without further complications. CONCLUSIONS: Venous thrombosis is a rare but potentially life-threatening complication of BUP-XR. It is important for emergency and outpatient clinicians to be aware of adverse reactions associated with this medication. The patient was successfully treated with a 30-day course of apixaban and able to resume taking BUP-XR without further complications. Clinicians may want to consider supplementing BUP-XR with sublingual film after injection-related complications due to possible lower serum levels.

Family Physician's Satisfaction Report: Military 2021 vs. Civilian 2020 and 2022.

INTRODUCTION: In the Medscape 2020 Compensation Report, family physicians ranked low for feeling fairly compensated, choosing their specialty again and choosing medicine again. However, the Medscape data may not represent military family physicians. METHODS: A large survey was emailed to 2,562 military family physicians via a military professional organization list-serve from February to April 2021. The inquiry included 6 statements pertaining to professional satisfaction. The main outcome measures were proportions of "agree" and "strongly agree." The proportions were compared to the Medscape Compensation Report 2020 and 2022. Statistical analysis was completed with a two-tailed Z-score for 2 populations. RESULTS: Sixty-one percent of military family physicians feel fairly compensated compared to 54% of civilian family physicians in 2020 and 55% in 2022 (P = .065, .119). Eighty-six percent of military family physicians would reselect medicine compared to 74% of civilian family physicians in 2020 and 73% in 2022 (P < .001 for both). Eighty percent of military family physicians would reselect their specialty again compared to 70% of civilians in 2020 and 68% in 2022 (P = .004, P = .001, respectively). CONCLUSIONS: Military family physicians were more likely to choose medicine generally and family medicine specifically again. Military family physicians and civilian family physicians do not statistically differ in feeling fairly compensated. A strong majority of military family physicians are satisfied with their military-sponsored medical education.

Habitat suitability of biocrust communities in a cold desert ecosystem.

Drylands are unique among terrestrial ecosystems in that they have a significant proportion of primary production facilitated by non-vascular plants such as colonial cyanobacteria, moss, and lichens, i.e., biocrusts, which occur on and in the surface soil. Biocrusts inhabit all continents, including Antarctica, an increasingly dynamic continent on the precipice of change. Here, we describe in-situ field surveying and sampling, remote sensing, and modeling approaches to assess the habitat suitability of biocrusts in the Lake Fryxell basin of Taylor Valley, Antarctica, which is the main site of the McMurdo Dry Valleys Long-Term Ecological Research Program. Soils suitable for the development of biocrusts are typically wetter, less alkaline, and less saline compared to unvegetated soils. Using random forest models, we show that gravimetric water content, electrical conductivity, and snow frequency are the top predictors of biocrust presence and biomass. Areas most suitable for the growth of dense biocrusts are soils associated with seasonal snow patches. Using geospatial data to extrapolate our habitat suitability model to the whole basin predicts that biocrusts are present in 2.7 × 105 m2 and contain 11-72 Mg of aboveground carbon, based on the 90% probability of occurrence. Our study illustrates the synergistic effect of combining field and remote sensing data for understanding the distribution and biomass of biocrusts, a foundational community in the carbon balance of this region. Extreme weather events and changing climate conditions in this region, especially those influencing snow accumulation and persistence, could have significant effects on the future distribution and abundance of biocrusts and therefore soil organic carbon storage in the McMurdo Dry Valleys.

Quantitative analysis of radiosensitizing effect for magnetic hyperthermia-radiation combined therapy on prostate cancer cells.

BACKGROUND: Magnetic hyperthermia (MHT) has emerged as a promising therapeutic approach in the field of radiation oncology due to its superior precision in controlling temperature and managing the heating area compared to conventional hyperthermia. Recent studies have proposed solutions to address clinical safety concerns associated with MHT, which arise from the use of highly concentrated magnetic nanoparticles and the strong magnetic field needed to induce hyperthermic effects. Despite these efforts, challenges remain in quantifying therapeutic outcomes and developing treatment plan systems for combining MHT with radiation therapy (RT). PURPOSE: This study aims to quantitatively measure the therapeutic effect, including radiation dose enhancement (RDE) in the magnetic hyperthermia-radiation combined therapy (MHRT), using the equivalent radiation dose (EQD) estimation method. METHODS: To conduct EQD estimation for MHRT, we compared the therapeutic effects between the conventional hyperthermia-radiation combined therapy (HTRT) and MHRT in human prostate cancer cell lines, PC3 and LNCaP. We adopted a clonogenic assay to validate RDE and the radiosensitizing effect induced by MHT. The data on survival fractions were analyzed using both the linear-quadradic model and Arrhenius model to estimate the biological parameters describing RDE and radiosensitizing effect of MHRT for both cell lines through maximum likelihood estimation. Based on these parameters, a new survival fraction model was suggested for EQD estimation of MHRT. RESULTS: The newly designed model describing the MHRT effect, effectively captures the variations in thermal and radiation dose for both cell lines (R2 > 0.95), and its suitability was confirmed through the normality test of residuals. This model appropriately describes the survival fractions up to 10 Gy for PC3 cells and 8 Gy for LNCaP cells under RT-only conditions. Furthermore, using the newly defined parameter r, the RDE effect was calculated as 29% in PC3 cells and 23% in LNCaP cells. EQDMHRT calculated through this model was 9.47 Gy for PC3 and 4.71 Gy for LNCaP when given 2 Gy and MHT for 30 min. Compared to EQDHTRT, EQDMHRT showed a 26% increase for PC3 and a 20% increase for LNCaP. CONCLUSIONS: The proposed model effectively describes the changes of the survival fraction induced by MHRT in both cell lines and adequately represents actual data values through residual analysis. Newly suggested parameter r for RDE effect shows potential for quantitative comparisons between HTRT and MHRT, and optimizing therapeutic outcomes in MHRT for prostate cancer.

Personalized Treatment of Recurrent, Metastatic Head and Neck Cancer Guided by Patient-Derived Xenograft Models.

Recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) is associated with a poor prognosis and short survival duration. There is an urgent need to identify personalized predictors of drug response to guide the selection of the most effective therapy for each individual recurrence. We tested the feasibility of patient-derived xenografts (PDX) for guiding their RMHNSCC salvage treatment. Fresh tumor samples from eligible, consented patients were implanted into mice. Established tumors were expanded in mouse PDX cohorts to identify responses to candidate salvage drug treatments in parallel testing. Patients alive and suitable for chemotherapy were treated based on responses determined by PDX testing. Nine patient tumors were successfully engrafted in mice with an average time of 89.2±41.7 days. Four patients' PDX models underwent parallel drug testing. Two patients received PDX-guided therapy. In one of these patients, single agents of cetuximab and paclitaxel demonstrated the best responses in the PDX model, and this patient exhibited sequential partial responses to each drug, including a 17-month clinical response to cetuximab. The main limitation of PDX testing for RMHNSCC was the time delay in obtaining testing results. Despite this, parallel PDX testing may be feasible for a subset of patients and appears to correlate with clinical benefit.

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer.

Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.

Antibacterial and mechanism of action studies of boxazomycin A.

Boxazomycins A-C are potent broad-spectrum antibiotics isolated from Actinomycetes strain G495-1 in 1987. We now report that boxazomycin A inhibits bacterial growth by selectively inhibiting protein synthesis, its effect is bacteriostatic, and it is equally active against drug resistant bacterial strains. No cross-resistance to protein synthesis inhibitors was observed suggesting that its inhibition is distinct from clinical protein synthesis inhibitors. We also report in vivo efficacy in a Staphylococcus aureus murine infection model supported by corresponding pharmacokinetic studies.

A comparison of timing and patterns of treatment failure, and survival outcomes after progression between HPV+ and HPV- patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas.

BACKGROUND: We aimed to analyze and compare the timing and patterns of treatment failure, and survival after progression between HPV-positive (HPV+) and HPV-negative (HPV-) patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas (OPSCC). METHODS: A retrospective review was performed of all patients undergoing primary chemoradiation for OPSCC between 2008 and 2021. Demographic and clinical data were collected. Kaplan-Meier estimates for overall survival (OS), and time to recurrence/metastases (TTR) were compared using the log-rank test, with Cox regression used for multivariable modeling comparing HPV+ and HPV- patients. RESULTS: HPV- patients developed recurrence or metastases at earlier time points than HPV+ patients (8.8 vs. 15.2 months, p < 0.05), due to earlier local/locoregional recurrence and distant metastases, but not isolated regional recurrences. HPV- distant metastases exclusively occurred in a single organ, most commonly the lungs or bone, while HPV+ metastases frequently had multi-organ involvement in a wide variety of locations (p < 0.05). Once progression (recurrence/metastases) was diagnosed, HPV+ patients experienced superior survival to HPV- patients on univariate and multivariate analysis, largely due to improved outcomes after treatment of local/locoregional recurrences (p < 0.05). There were no differences in survival after isolated regional recurrences or distant metastases. CONCLUSION: HPV+ OPSCC patients relapse later compared to HPV- patients in local/locoregional and distant sites. HPV+ patients with local/locoregional recurrence experience superior survival after recurrence, which does not hold true for isolated regional recurrences or distant metastases. These data can be useful to inform prognosis and guide treatment decisions in patients with recurrent OPSCC.

Outcomes for potentially Resectable patients undergoing primary chemoradiation treatment for T1-T2 HPV Negative oropharyngeal squamous cell carcinoma.

BACKGROUND: Transoral surgical resectability (TOS) is a prognostic factor for patients with HPV+ T1-2 oropharyngeal squamous cell carcinoma (OPSCC) disease undergoing radiotherapy (RT), but it is unclear whether this holds for HPV-negative (HPV-) patients. We aimed to compare outcomes of potential TOS-candidates vs. non-TOS candidates, among patients who underwent RT/CRT for early T-stage HPV- OPSCC. METHODS: For patients treated with RT/CRT for early T-stage HPV-negative OPSCC between 2014 and 2021, pretreatment imaging was reviewed by four head-and-neck surgeons, masked to clinical outcomes, to assess primary-site suitability for TOS. Extracapsular extension (ECE) was assessed by a head-and-neck neuroradiologist. We compared outcomes based on surgical resectability relating to: (1) the primary site tumor alone, and (2) the primary site plus the absence/presence of ECE (overall assessment). Kaplan-Meier curves for overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were compared using the log-rank test. RESULTS: Seventy patients were included in the analysis. The primary site was TOS-favorable in 46/70 (66%). Based on the overall assessment, 41/70 (58.6%) were TOS-favorable. The 3-year OS, DSS and PFS for primary site TOS-favorable versus unfavorable were OS: 76.9% versus 37.4%; DSS: 78.1% versus 46.2%, PFS: 69.9% versus 41.3%, (log-rank test = 0.01, 0.03, 0.04; respectively). Additionally, patients with an overall assessment of TOS favorability demonstrated better survival outcomes compared with TOS-unfavorable patients (OS: 77.3% vs. 46.2%; DSS: 78.2% vs. 56.5%, PFS: 72.3% vs. 42.1%, log-rank test = 0.01, 0.04, 0.01; respectively). CONCLUSION: Patients with TOS-favorable HPV-negative early T-stage OPSCC have superior survival outcomes than TOS-unfavorable patients.

Linked Exposures Across Databases: an exposure common data elements aggregation framework to facilitate clinical exposure review.

Understanding the health outcomes of military exposures is of critical importance for Veterans, their health care team, and national leaders. Approximately 43% of Veterans report military exposure concerns to their VA providers. Understanding the causal influences of environmental exposures on health is a complex exposure science task and often requires interpreting multiple data sources; particularly when exposure pathways and multi-exposure interactions are ill-defined, as is the case for complex and emerging military service exposures. Thus, there is a need to standardize clinically meaningful exposure metrics from different data sources to guide clinicians and researchers with a consistent model for investigating and communicating exposure risk profiles. The Linked Exposures Across Databases (LEAD) framework provides a unifying model for characterizing exposures from different exposure databases with a focus on providing clinically relevant exposure metrics. Application of LEAD is demonstrated through comparison of different military exposure data sources: Veteran Military Occupational and Environmental Exposure Assessment Tool (VMOAT), Individual Longitudinal Exposure Record (ILER) database, and a military incident report database, the Explosive Ordnance Disposal Information Management System (EODIMS). This cohesive method for evaluating military exposures leverages established information with new sources of data and has the potential to influence how military exposure data is integrated into exposure health care and investigational models.

Development and Validation of the Veteran Military Occupational and Environmental Exposure Assessment Tool.

INTRODUCTION: Military exposures may present a cumulative load and increased individual susceptibility to negative health outcomes. Currently, there are no comprehensive and validated environmental exposure assessment tools covering the full spectrum of occupational and environmental exposures for Veterans. The Veterans Affairs (VA) War Related Illness and Injury Study Center in Washington, DC, developed the Veteran Military Occupational and Environmental Exposure Assessment Tool (VMOAT) to establish a structured, comprehensive self-report tool that captures military and non-military occupational and environmental exposures. The VMOAT is clinically insightful, modular, and flexible for adding novel exposures, meeting the needs of modern evolving threats and exposures in both clinical and research settings. This manuscript reviews the ongoing development and validation plans for the VMOAT. MATERIALS AND METHODS: The VMOAT is a self-reported structured questionnaire, and VMOAT 1.0 was developed to cover an individual's 3 life phases (pre, during, post-military service); 5 exposure domains (chemical, physical, biological, injuries including ergonomic, and psychological stress exposures, plus military preventive health measures); and 64 specific exposures nested within exposure categories. VMOAT 1.0 addresses exposure dose (frequency, duration, proximity, route), and can be administered online via VA approved Qualtrics survey software. VMOAT 1.0 to 2.0 updates began in December 2022 with changes focused on readability, streamlining the exposure history, refining the exposure metrics, and improving the skip logic embedded within the survey design. RESULTS: The initial VMOAT 1.0 development included face and construct validation with expert internal and external academic and military collaborators, undergoing an iterative 5-cycle review as well as sample testing among a small group of Veterans. The VMOAT 1.0 was used in Institutional Review Board (IRB)-approved longitudinal study, which has been examined preliminarily to compare the VMOAT 1.0 with other exposure assessments and to compare responses of Explosive Ordnance Disposal Veterans, a high occupational exposure cohort, to non-Explosive Ordnance Disposal Veterans. Ongoing VMOAT 2.0 updates will include integration of experiences from piloting the VMOAT 1.0 as well as additional face and content validation and survey cognitive testing with Veterans. VMOAT 2.0 data will improve the development of exposure-informed models using composite survey data to create scored- and scale-based exposure metrics for specific exposures and exposure domains. These data will highlight the effectiveness of the VMOAT as a structured comprehensive occupational and environmental exposure assessment instrument. CONCLUSIONS: VMOAT development supports the 2022 Promise to Address Comprehensive Toxics Act and fits into the existing VA exposure assessment approach as a standardized, comprehensive self-reported exposure assessment tool. It can be utilized as a stand-alone instrument or supplemented by clinician interviews in research or specialty evaluation programs. The collected VMOAT self-report information on military occupational and environmental exposures will allow direct evaluation with objective measures of exposure and health outcomes. These data outcomes have a high potential to guide the DoD and VA environmental exposure risk mitigation and risk communication efforts.

HPV16 Intratypic Variants in Head and Neck Cancers: A North American Perspective.

Human papillomavirus (HPV) is the major causative agent for cervical and many head and neck cancers (HNCs). HPVs randomly acquire single nucleotide polymorphisms (SNPs) that may become established via positive selection. Within an HPV type, viral isolates differing by <2% in the L1 region are termed "variants" and classified based on combinations of SNPs. Studies in cervical cancer demonstrate clear differences between HPV16 intratypic variants in terms of persistence of infection, tumor histology, cancer risk, and death. Much less is known about the frequency of HPV16 variants in HNC, and their effects on clinical outcomes. We combined HPV16 positive (HPV16+) HNC samples from a local Southwestern Ontario, Canada cohort with those from the Cancer Genome Atlas to create a larger North American cohort of 149 cases with clinical data and determined the distribution of intratypic variants and their impact on clinical outcomes. Most isolates were lineage A, sublineage A1, or A2, with roughly half exhibiting the T350G polymorphism in E6. Univariable analysis identified significant differences between 350T and 350G intratypic variants in clinical T, N, and O staging, as well as disease-free survival. Multivariable analysis failed to identify any clinical factor as a statistically significant covariate for disease-free survival differences between 350T and 350G. Significant differences in several measures of B-cell mediated immune response were also observed between 350T and 350G intratypic variants. We suggest that HPV genetic variation may be associated with HNC clinical characteristics and may have prognostic value.