Dual Checkpoint Aptamer Immunotherapy: Unveiling Tailored Cancer Treatment Targeting CTLA-4 and NKG2A.

Recent strides in immunotherapy have illuminated the crucial role of CTLA-4 and PD-1/PD-L1 pathways in contemporary oncology, presenting both promises and challenges in response rates and adverse effects. This study employs a computational biology tool (in silico approach) to craft aptamers capable of binding to dual receptors, namely, inhibitory CTLA4 and NKG2A, thereby unleashing both T and NK cells and enhancing CD8+ T and NK cell functions for tumor cell lysis. Computational analysis highlighted AYA22T-R2-13 with HADDOCK scores of -78.2 ± 10.2 (with CTLA4), -60.0 ± 4.2 (with NKG2A), and -77.5 ± 5.6 (with CD94/NKG2A). Confirmation of aptamer binding to targeted proteins was attained via ELISA and flow cytometry methods. In vitro biological functionality was assessed using lactate dehydrogenase (LDH) cytotoxicity assay. Direct and competitive assays using ELISA and flow cytometry demonstrated the selective binding of AYA22T-R2-13 to CTLA4 and NKG2A proteins, as well as to the cell surface receptors of IL-2-stimulated T cells and NK cells. This binding was inhibited in the presence of competition from CTLA4 or NKG2A proteins. Remarkably, the blockade of CTLA4 or NKG2A by AYA22T-R2-13 augmented human CD8 T cell- and NK cell-mediated tumor cell lysis in vitro. Our findings highlight the precise binding specificity of AYA22T-R2-13 for CTLA4-B7-1/B7-2 (CD80/CD86) or CD94/NKG2A-HLA-E interactions, positioning it as a valuable tool for immune checkpoint blockade aptamer research in murine tumor models. These in vitro studies establish a promising foundation for further enhancing binding capacity and establishing efficacy and safety in animal models. Consequently, our results underscore the potential of AYA22T-R2-13 in cancer immunotherapy, offering high specificity, low toxicity, and the potential for cost-effective production.

Photodynamic bone stabilization for traumatic and pathologic fractures: a systematic review of utilization, complications, and patient-reported outcomes.

INTRODUCTION: The photodynamic bone stabilization system (PBSS) was was developed in 2010, and in 2018 gained FDA approval in the United States. Given its relative novelty, our analysis sought to analyze the available literature exploring the indications, outcomes, and complications of the PBSS. METHODS: We performed a systematic review (PROSPERO registration of study protocol: CRD42022363065, October 8th, 2022). PubMed, EBSCOHost, and Google Scholar electronic databases were queried to identify articles evaluating PBSS in the treatment of pathologic or traumatic fractures between January 1 2010 and 15 October 2022. The quality of the included studies was assessed using the Methodological Index for Nonrandomized Studies tool. RESULTS: Our initial search yielded 326 publications, which were then screened for appropriate studies that aligned with the purpose of our review. A total of thirteen studies, comprising seven case series, four case reports, and two cohort studies. The total sample size of the included studies consisted of 345 patients, with 242 females (70%) and 103 males (30%). The implants were most commonly utilized in the humerus (41%), radius (12%), and metacarpal (12%). The most common complications were related to broken implants (5%) and dislocation (1%). Most studies reported complete fracture healing and return of full strength and range of motion. CONCLUSION: Despite being a relatively novel technology, PBSS appears to be a viable option for fracture stabilization. Most studies included in our analysis reported complete fracture healing and return of function with minimal complications.

Impact of external beam radiation on total shoulder arthroplasty outcomes: a propensity-matched cohort study.

BACKGROUND: External beam radiation therapy has a number of deleterious effects on the body, and a number of post-operative complications have been reported for several surgeries including total knee arthroplasty. However, few studies have investigated the impact of external beam radiation therapy for total shoulder arthroplasty (TSA). Our study aimed to assess the systemic and joint complications associated with TSA in patients with prior radiation exposures, as well as evaluate the surgical outcomes of radiation patients compared to non-radiation TSA patients. MATERIALS AND METHODS: A retrospective cohort analysis was conducted using the TriNetX Analytics Network. A 1:1 propensity score matching function was utilized to create two cohorts with matched baseline characteristics within the TriNetX network. Comparisons of the primary and secondary outcomes between the two cohorts were made using odds ratios. A p value of < 0.05 was determined to be significant. RESULTS: A total of 75,510 patients that received TSA were identified with 1505 having a history of radiation therapy (RT) and 73,605 with no radiation therapy (non-RT). After propensity matching, both groups contained 1484 patients. RT patients were at higher risk for developing prosthetic joint infection, acute renal failure, altered mental state, cerebrovascular event, DVT, PE, pneumonia, respiratory failure, and UTI compared to non-RT patients at different time points (p < 0.5). CONCLUSION: Patients with prior history of external beam radiation undergoing TSA had a higher risk of systemic complications and prosthetic joint infection compared to patients without a prior history. These complications suggest a more complicated post-operative management course for these patients.

The Surgical Management of Migraines and Chronic Headaches: A Cross-sectional Review of American Insurance Coverage.

BACKGROUND: Migraine headache can be an extremely debilitating condition, with pharmacotherapy for prophylaxis or treatment of acute symptoms being unsuccessful in a large proportion of patients. Surgical management of migraine has recently gained popularity as an alternative to pharmacotherapy for severe disease. However, the novel nature of these procedures may lead to variable insurance coverage, limiting access to care. METHODS: A cross-sectional analysis of 101 US insurance companies was conducted. Companies were chosen based on greatest market share and enrollment per state. A Web-based search or phone call identified whether each company had a publicly available policy on nonsurgical or surgical management of migraine or headache. For companies with an available policy, coverage was categorized into covered, covered on a case-by-case basis, or never covered, with criteria required for coverage collected and categorized. RESULTS: Of the 101 evaluated insurers, significantly fewer companies had a policy on surgical treatment for migraine or headache (n = 52 [52%]) compared with nonsurgical treatment (n = 78 [78%]) (P < 0.001). For companies with a policy, the most frequently covered nonsurgical treatments were biofeedback (n = 23 [92%]) and botulism toxin injections (n = 61 [88%]). Headaches were an approved indication for occipital nerve stimulation in 4% (n = 2) of company policies and nerve decompression in 2% (n = 1) of policies. Migraines were never offered preauthorized coverage for surgical procedures. CONCLUSION: Approximately half of US insurance companies have a publicly available policy on surgical management of migraine or headache. Surgical treatment was seldom covered for the indication of headache and would never receive preauthorized coverage for migraine. Lack of coverage may create challenges in accessing surgical treatment. Additional prospective, controlled studies are necessary to further support the efficacy of surgical treatment.

Recurrent repeat expansions in human cancer genomes.

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases1,2. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer3-8. Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study.

The Markup on Orthopaedic Services: An Analysis of 2014-2019 Medicare Data and the Potential for Surprise Billing.

BACKGROUND: Markups on charges for medical services have the potential to result in "surprise billing," especially for out-of-network and uninsured patients. Although previously analyzed in other surgical subspecialties, the distribution and level of cost-to-charge ratios (CCRs) for orthopaedic services have yet to be studied. Therefore, our analysis sought to evaluate the CCRs for orthopaedic surgery services provided to Medicare beneficiaries throughout the United States. METHODS: Orthopaedic services provided to Medicare Part B beneficiaries between 2014 and 2019 were identified in the Physician & Other Practitioners database of the Centers for Medicare & Medicaid Services (CMS). CCRs, representing the ratio between the actual payment provided by CMS and the charge submitted by the provider, were calculated for each service. Descriptive statistics were calculated for CCRs at the national, state, and service-code levels. The coefficient of variation (CoV) was utilized to evaluate variability in CCRs across services and states. Additionally, Mann-Kendall tests were performed to evaluate trends in CCRs for included services over the time frame. RESULTS: Our analysis included an annual mean of 47,247,928 services provided by a mean of 23,185 orthopaedic surgeons over the study period. In the non-facility setting, there was a decrease in median CCRs for orthopaedic surgery services (0.29 to 0.27; p = 0.024). No changes were demonstrated for facility-based services. Service codes related to trigger finger procedures (0.18 to 0.17; p = 0.004), physical therapy (0.40 to 0.36; p = 0.035), and new patient visits (0.52 to 0.46; p = 0.035) demonstrated significant decreases in median CCRs. Only shoulder arthroscopy demonstrated a significant increase in median CCR (0.09 to 0.10; p = 0.003). High dispersion in CCRs was demonstrated for 16 (80%) of the 20 evaluated services. Wide variations in CCRs were demonstrated across individual states (median, 0.57; interquartile range width, 0.53). CONCLUSIONS: Our analysis demonstrated low and variable CCRs for commonly performed orthopaedic services in the U.S. These findings serve to inform and help improve related price transparency policies. Additionally, our analysis encourages increased efforts at preventing these low CCRs from limiting care in vulnerable populations.

Adjuvant Radiation after Primary Resection of Atypical Lipomatous Tumors of the Extremity Reduces Local Recurrence but Increases Complications: A Multicenter Evaluation.

Background: Radiation after resection of an atypical lipomatous tumor (ALT) is controversial. This study evaluates local control and complications after the first resection of ALTs of the extremity with or without adjuvant radiation. Methods: A dual institution, retrospective review of patients treated from 1995 to 2020 with first-time resection of an ALT in the extremity was performed. In total, 102 patients underwent adjuvant radiation (XRT group) and 68 patients were treated with surgery alone (no-XRT group). The median follow-up time was 4.6 years (interquartile range (IQR) 2.0-7.3 years). The median radiation dose was 60 Gy (IQR 55-66 Gy). Univariable and multivariable analyses evaluated the association of patient, tumor, and treatment variables with recurrence and complications. Kaplan-Meier analysis evaluated local recurrence-free survival (LRFS) and time to complication. Results: The overall incidence of local recurrence was 1% (1/102) in the XRT group and 24% (16/68) in the no-XRT group (p < 0.001). The median time-to-recurrence was 8.2 years (IQR 6.5-10.5 years). In the XRT and the no-XRT groups, 5-yr LRFS was 98% and 92% (p=0.21) and 10-yr LRFS was 98% and 41% (p < 0.001), respectively. The absence of radiation (HR = 23.63, 95% CI (3.09-180.48); p < 0.001) and R2 surgical resection margins (HR = 11.04, 95% CI (2.07-59.03); p < 0.001) incurred a 23-fold and 11-fold increased risk of local recurrence, respectively, while tumor size, depth, location, and neurovascular involvement were not found to be independent predictors of recurrence. The complication rate was 37% (38/102) in the XRT group and 10% (7/68) in the no-XRT group (p < 0.001). Eight patients (8/102, 8%) required surgical management for complication in the XRT group compared with two patients (2/68, 3%) in the no-XRT group (p=0.10). Higher radiation dose had a modest correlation with increased severity of complication (ρ=0.24; p=0.02). Conclusions: Adjuvant radiation after first-time resection of an ALT of the extremity was associated with a significantly reduced risk of local recurrence but a three-fold increase in complication rate. These data support a 10-year follow-up for these patients and inform a notable clinical trade-off if considering adjuvant radiation for this tumor with recurrent potential.

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma.

BACKGROUND: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study developed C-CAR088, a novel second-generation humanized anti-BCMA CAR T-cell therapy, and assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM. METHODS: Patients received lymphodepletion with three doses of cyclophosphamide (300 mg/m2) and three doses of fludarabine (30 mg/m2) on days -5, -4, and -3, followed by an infusion of C-CAR088 on day 0. Doses of 1.0×106, 3.0×106, and 6.0×106 CAR T cells/kg (±20%) were tested in the dose-escalation cohorts and expansion cohorts. The primary endpoint was treatment safety, including the rate of treatment-emergent adverse events after cell infusion. Secondary endpoints were the overall response rate and progression-free survival. The exploratory endpoints were the quantification of C-CAR088 CAR T cells, selection of cytokines and chemokines in blood, and measurement of tumor BCMA expression. RESULTS: As of July 2, 2021, 31 patients had been infused with C-CAR088. Any grade cytokine release syndrome (CRS) occurred in 29 patients (93.5%), and grade 3 CRS occurred in 3 patients (9.7%). One patient from the high-dose group (4.5-6.0×106 CAR T cells/kg) developed grade 1 neurotoxicity. No dose-limiting toxicities were observed in any dose group, and all adverse events were reversible after proper management. The overall response, stringent complete response, complete response (CR), and very good partial response rates were 96.4%, 46.4%, 10.7%, and 32.1%, respectively. The CR rate in the medium-dose (3.0×106 CAR T cells/kg) and high-dose (4.5-6.0×106 CAR T cells/kg) groups was 54.5% and 71.4%, respectively. In the CR group, 15 (93.7%) patients achieved minimal residual disease (MRD) negativity (test sensitivity >1/10-5). All seven patients with double-hit or triple-hit multiple myeloma achieved MRD-negative CR. CONCLUSIONS: The present study demonstrated that C-CAR088 had a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM. TRIAL REGISTRATION NUMBER: NCT03815383, NCT03751293, NCT04295018, and NCT04322292.

A Herbal Mixture of Sesami Semen Nigrum and Longan Arillus Induces Neurite Outgrowth in Cultured Neurons and Shows Anti-Depression in Chronic Mild Stress-Induced Rats.

Medicinal food homology is referring to a group of food itself being considered as herbal medicine without a boundary of usage. Under the guidance of this food/medicine principle, the current study aims to develop anti-depressant from this food/medicine catalog. The herbal mixture of Sesami Semen Nigrum and Longan Arillus was evaluated in cultured PC12 rat pheochromocytoma cells, rat primary cortical neurons, and in chronic mild stress (CMS)-induced depressive rat model. The combination of two ethanolic extracts of Sesami Semen Nigrum and Longan Arillus in 1 : 1 ratio mimicked the function of nerve growth factor (NGF) and synergistically induced neurite outgrowth of PC12 cells. Besides, the expression and phosphorylation of tropomyosin receptor kinase A (TrkA) of the cultured cells were also elevated. This neurotrophic activity of herbal mixture was further supported by the increased expressions of biomarkers for neurogenesis and synaptogenesis in cortical neurons. Moreover, the depressed rats were soothed by the intake of herbal mixture, showing improved performance in behavior tests, as well as reversed levels of neurotransmitters and neurotrophic factors. Our results provide a new way to make full use of the current food/medicine resources, as to accelerate the development of therapeutics for depression.

Hyaluronic Acid Injections for Knee Osteoarthritis: Has Utilization Among Medicare Beneficiaries Changed Between 2012 and 2018?

BACKGROUND: The utilization of hyaluronic acid (HA) for the management of knee osteoarthritis (OA) remains controversial, and more information is needed regarding how its utilization and financial burden have changed over recent years. The purpose of our analysis was to evaluate changes in overall utilization and health-care costs associated with HA injections among Medicare beneficiaries over a contemporary time frame. METHODS: The 2012 to 2018 Medicare Fee-for-Service Provider Utilization and Payment Public Use Files (PUFs) were utilized for our analysis. Organized by Healthcare Common Procedure Coding System (HCPCS) codes, these files capture 100% of Medicare Part B claims. Payment and utilization data were collected for all HCPCS codes corresponding to injection of an HA formulation. The number of services involving HA as well as the total cost of HA administration in 2020 U.S. dollars were tabulated. Mann-Kendall trend tests were used to evaluate trends in utilization for providers nationally and when segregated by specialty. RESULTS: Total HA utilization increased significantly from 2012 (n = 1,090,503) through 2018 (n = 1,209,489; p = 0.04). Although orthopaedic surgeons did not demonstrate significant changes in total utilization rates (p = 0.23), the average number of services per orthopaedic surgeon increased significantly (p = 0.02). Reflecting a substantial growth in the number of advanced practice providers (APPs) providing injections, there was a significant increase in utilization and associated costs among physician assistants (p < 0.01) and nurse practitioners (p < 0.01). Total costs associated with HA services increased significantly from $290.10 million to $325.02 million (p < 0.01). CONCLUSIONS: Despite the 2013 American Academy of Orthopaedic Surgeons clinical practice guideline recommending against the clinical utility of these injections, HA services continued to be widely implemented among Medicare beneficiaries. Although there were variations across specialties when evaluating overall utilization rates as well as rates per provider, APPs largely contributed to the increase seen in the U.S. over this study period. More data are needed to support continued implementation and spending on this low-value care.

Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Are You Covered?

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a locally aggressive T-cell lymphoma that can develop following breast implantation. In 2017, and updated in 2019, the National Comprehensive Cancer Network (NCCN) recommended total capsulectomy with implant removal as definitive therapy. OBJECTIVES: The aim of this study was to evaluate the US insurance coverage for the management of BIA-ALCL and compare it to the NCCN recommendations. METHODS: A cross-sectional analysis of US insurance policies for coverage of BIA-ALCL treatment was conducted. Insurance companies were selected based on their market share and state enrollment. Medical necessity criteria were abstracted from the publicly available policies. RESULTS: Of the 101 companies assessed, only 30 (30%) had a policy for the management of BIA-ALCL. Of those policies, all (n = 30, 100%) provided coverage of the implant removal of the breast diagnosed with BIA-ALCL. For the contralateral breast implant, 20 policies (67%) covered their removal, but significantly fewer did so if the implant was placed for cosmetic reasons vs medically necessary (n = 13 vs n = 20, 43% vs 67%; P = 0.0026). Twenty-one policies (70%) covered an implant reinsertion, but fewer would do so if the implant was cosmetic rather than medically necessary (n = 5, 17% vs 70%; P < 0.0001). CONCLUSIONS: There was notable intercompany variation in the coverage of BIA-ALCL treatment, some of which is unnecessarily based on whether the original reason for the breast implant was cosmetic or medically necessary. This variability may significantly reduce access to definitive treatment in patients with a BIA-ALCL diagnosis.

Estrogen and sex-dependent loss of the vocal learning system in female zebra finches.

Sex hormones alter the organization of the brain during early development and coordinate various behaviors throughout life. In zebra finches, song learning is limited to males, with the associated song learning brain pathways only maturing in males and atrophying in females. While this atrophy can be prevented by treating females with exogenous estrogen during early post-hatch development, the requirement of estrogen during normal male song system development is uncertain. For the first time in songbirds, we administered exemestane, a potent third generation estrogen synthesis inhibitor, from the day of hatching until adulthood in order to reassess the role of estrogen in song circuit development. We examined the behavior, brain anatomy, and transcriptomes of individual song nuclei in these pharmacologically manipulated animals. We found that males with long-term exemestane treatment had diminished male-specific plumage and impaired song learning, but minimal effect on song nuclei sizes and their specialized transcriptome. Consistent with prior findings, females with long-term estrogen treatment retained a functional song system with song nuclei that had specialized gene expression similar, but not identical to males. We also observed that different song nuclei responded to estrogen manipulation differently, with Area X in the striatum being the most altered by estrogen modulation. These findings support the hypothesis that song learning is an ancestral trait in both sexes that was subsequently suppressed in females of some species and that estrogen has come to play a critical role in modulating this suppression as well as refinement of song learning.

Dynamic readmission prediction using routine postoperative laboratory results after radical cystectomy.

OBJECTIVE: To determine if the addition of electronic health record data enables better risk stratification and readmission prediction after radical cystectomy. Despite efforts to reduce their frequency and severity, complications and readmissions following radical cystectomy remain common. Leveraging readily available, dynamic information such as laboratory results may allow for improved prediction and targeted interventions for patients at risk of readmission. METHODS: We used an institutional electronic medical records database to obtain demographic, clinical, and laboratory data for patients undergoing radical cystectomy. We characterized the trajectory of common postoperative laboratory values during the index hospital stay using support vector machine learning techniques. We compared models with and without laboratory results to assess predictive ability for readmission. RESULTS: Among 996 patients who underwent radical cystectomy, 259 patients (26%) experienced a readmission within 30 days. During the first week after surgery, median daily values for white blood cell count, urea nitrogen, bicarbonate, and creatinine differentiated readmitted and nonreadmitted patients. Inclusion of laboratory results greatly increased the ability of models to predict 30-day readmissions after cystectomy. CONCLUSIONS: Common postoperative laboratory values may have discriminatory power to help identify patients at higher risk of readmission after radical cystectomy. Dynamic sources of physiological data such as laboratory values could enable more accurate identification and targeting of patients at greatest readmission risk after cystectomy. This is a proof of concept study that suggests further exploration of these techniques is warranted.

Characterizing the Benign Prostatic Hyperplasia Literature: A Bibliometric Analysis.

OBJECTIVE: To characterize the current landscape and future directions of academic benign prostatic hyperplasia (BPH) by using bibliometric analysis. METHODS: We used the Web of Science Core Collection to conduct a bibliometric analysis of leading BPH articles. Bibliometric analyses are quantitative approaches examining the impact of academic literature. We used the following search terms and Boolean logic "("benign prostat*") AND (hyperplasia OR enlarg*)" and characterized the 100 most-cited BPH articles through 2018 including citations, journal, author, year, and country. RESULTS: The top 100 BPH articles were published between 1978 and 2012. Citations ranged from 153 to 2171 across 27 different journals, including 10 urology-specific journals. The Journal of Urology was the most published journal (n = 25), followed by European Urology (n = 17), and Urology (n = 15). In general, the oldest 10 articles focused on BPH etiology/pathogenesis, while the newest 10 focused on treatment. The 1990's was the most productive decade with nearly half of the top 100 articles (n = 44). Twenty-six different countries contributed to the top 100 articles, with the US (n = 74), Italy (n = 19), and Canada (n = 12) being the most common. CONCLUSION: This study represents the first bibliometric analysis of the leading BPH articles impacting the academic literature. The focus has evolved from BPH pathogenesis to treatment, perhaps reflecting a shift in research funding and capacity. These findings may guide research priorities for this increasingly common condition.

Characterising 'bounce-back' readmissions after radical cystectomy.

OBJECTIVE: To examine predictors of early readmissions after radical cystectomy (RC). Factors associated with preventable readmissions may be most evident in readmissions that occur within 3 days of discharge, commonly termed 'bounce-back' readmissions, and identifying such factors may inform efforts to reduce surgical readmissions. PATIENTS AND METHODS: We utilised the Healthcare Cost and Utilization Project's State Inpatient Databases to examine 1867 patients undergoing RC in 2009 and 2010, and identified all patients readmitted within 30 days of discharge. We assessed differences between patients experiencing bounce-back readmission compared to those readmitted 8-30 days after discharge using logistic regression models and also calculated abbreviated LACE scores to assess the utility of common readmissions risk stratification algorithms. RESULTS: The 30-day and bounce-back readmission rates were 28.4% and 5.6%, respectively. Although no patient or index hospitalisation characteristics were significantly associated with bounce-back readmissions in adjusted analyses, bounce-back patients did have higher rates of gastrointestinal (14.3% vs 6.7%, P = 0.02) and wound (9.5% vs 3.0%, P < 0.01) diagnoses, as well as increased index and readmission length of stay (5 vs 4 days, P = 0.01). Overall, the median abbreviated LACE score was 7, which fell into the moderate readmission risk category, and no difference was observed between readmitted and non-readmitted patients. CONCLUSION: One in five readmissions after RC occurs within 3 days of initial discharge, probably due to factors present at discharge. However, sociodemographic and clinical factors, as well as traditional readmission risk tools were not predictive of this bounce-back. Effective strategies to reduce bounce-back readmission must identify actionable clinical factors prior to discharge.

Determinants of quality prostate cancer survivorship care across the primary and specialty care interface: Lessons from the Veterans Health Administration.

BACKGROUND: With over 3 million US prostate cancer survivors, ensuring high-quality, coordinated cancer survivorship care is important. However, implementation of recommended team-based cancer care has lagged, and determinants of quality care across primary and specialty care remain unclear. Guided by the theoretical domains framework (TDF), we explored multidisciplinary determinants of quality survivorship care in an integrated delivery system. METHODS: We conducted semistructured interviews with primary (4) and specialty (7) care providers across 6 Veterans Health Administration clinic sites. Using template analysis, we coded interview transcripts into the TDF, mapping statements to specific constructs within each domain. We assessed whether each construct was perceived a barrier or facilitator, examining results for both primary care providers (PCPs) and prostate cancer specialists. RESULTS: Cancer specialists and PCPs identified 2 primary TDF domains impacting their prostate cancer survivorship care: Knowledge and Environmental context and resources. Both groups noted knowledge (about survivorship care) and procedural knowledge (about how to deliver survivorship care) as positive determinants or facilitators, whereas resources/material resources (to deliver survivorship care) was noted as a negative determinant or barrier to care. Additional domains more commonly referenced by cancer specialists included Social/professional role and identity and Goals, while PCPs reported the domain Beliefs about capabilities as relevant. CONCLUSIONS: We used the TDF to identify several behavioral domains acting as determinants of high-quality, team-based prostate cancer survivorship care. These results can inform prostate cancer survivorship care plan content, and may guide tailored, multidisciplinary implementation strategies to improve survivorship care across the primary and specialty care interface.

De-implementation of low value castration for men with prostate cancer: protocol for a theory-based, mixed methods approach to minimizing low value androgen deprivation therapy (DeADT).

BACKGROUND: Men with prostate cancer are often castrated with long-acting injectable drugs termed androgen deprivation therapy (ADT). Although many benefit, ADT is also used in patients with little or nothing to gain. The best ways to stop this practice are unknown, and range from blunt pharmacy restrictions to informed decision-making. This study will refine and pilot two different de-implementation strategies for reducing ADT use among those unlikely to benefit in preparation for a comparative effectiveness trial. METHODS/DESIGN: This innovative mixed methods research program has three aims. Aim 1: To assess preferences and barriers for de-implementation of chemical castration in prostate cancer. Guided by the theoretical domains framework (TDF), urologists and patients from facilities with the highest and lowest castration rates across the VA will be interviewed to identify key preferences and de-implementation barriers for reducing castration as prostate cancer treatment. This qualitative work will inform Aim 2 while gathering rich information for two proposed pilot intervention strategies. Aim 2: To use a discrete choice experiment (DCE), a novel barrier prioritization approach, for de-implementation strategy tailoring. The investigators will conduct national surveys of urologists to prioritize key barriers identified in Aim 1 for stopping incident castration as localized prostate cancer treatment using a DCE experiment design. These quantitative results will identify the most important barriers to be addressed through tailoring of two pilot de-implementation strategies in preparation for Aim 3 piloting. Aim 3: To pilot two tailored de-implementation strategies to reduce castration as localized prostate cancer treatment. Building on findings from Aims 1 and 2, two de-implementation strategies will be piloted. One strategy will focus on formulary restriction at the organizational level and the other on physician/patient informed decision-making at different facilities. Outcomes will include acceptability, feasibility, and scalability in preparation for an effectiveness trial comparing these two widely varying de-implementation strategies. DISCUSSION: Our innovative approach to de-implementation strategy development is directly aligned with state-of-the-art complex implementation intervention development and implementation science. This work will broadly advance de-implementation science for low value cancer care, and foster participation in our de-implementation evaluation trial by addressing barriers, facilitators, and concerns through pilot tailoring. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03579680 , First Posted July 6, 2018.

Oncogenes and tumor suppressor genes: comparative genomics and network perspectives.

BACKGROUND: Defective tumor suppressor genes (TSGs) and hyperactive oncogenes (OCGs) heavily contribute to cell proliferation and apoptosis during cancer development through genetic variations such as somatic mutations and deletions. Moreover, they usually do not perform their cellular functions individually but rather execute jointly. Therefore, a comprehensive comparison of their mutation patterns and network properties may provide a deeper understanding of their roles in the cancer development and provide some clues for identification of novel targets. RESULTS: In this study, we performed a comprehensive survey of TSGs and OCGs from the perspectives of somatic mutations and network properties. For comparative purposes, we choose five gene sets: TSGs, OCGs, cancer drug target genes, essential genes, and other genes. Based on the data from Pan-Cancer project, we found that TSGs had the highest mutation frequency in most tumor types and the OCGs second. The essential genes had the lowest mutation frequency in all tumor types. For the network properties in the human protein-protein interaction (PPI) network, we found that, relative to target proteins, essential proteins, and other proteins, the TSG proteins and OCG proteins both tended to have higher degrees, higher betweenness, lower clustering coefficients, and shorter shortest-path distances. Moreover, the TSG proteins and OCG proteins tended to have direct interactions with cancer drug target proteins. To further explore their relationship, we generated a TSG-OCG network and found that TSGs and OCGs connected strongly with each other. The integration of the mutation frequency with the TSG-OCG network offered a network view of TSGs, OCGs, and their interactions, which may provide new insights into how the TSGs and OCGs jointly contribute to the cancer development. CONCLUSIONS: Our study first discovered that the OCGs and TSGs had different mutation patterns, but had similar and stronger protein-protein characteristics relative to the essential proteins or control proteins in the whole human interactome. We also found that the TSGs and OCGs had the most direct interactions with cancer drug targets. The results will be helpful for cancer drug target identification, and ultimately, understanding the etiology of cancer and treatment at the network level.

A comparative study of disease genes and drug targets in the human protein interactome.

BACKGROUND: Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. RESULTS: In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. CONCLUSIONS: The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing.