Veterans Affairs Radiation Oncology Quality Surveillance Program and American Society for Radiation Oncology Quality Measures Initiative.

PURPOSE: Ensuring high quality, evidence-based radiation therapy for patients is of the upmost importance. As a part of the largest integrated health system in America, the Department of Veterans Affairs National Radiation Oncology Program (VA-NROP) established a quality surveillance initiative to address the challenge and necessity of providing the highest quality of care for veterans treated for cancer. METHODS AND MATERIALS: As part of this initiative, the VA-NROP contracted with the American Society for Radiation Oncology to commission 5 Blue Ribbon Panels for lung, prostate, rectal, breast, and head and neck cancers experts. This group worked collaboratively with the VA-NROP to develop consensus quality measures. In addition to the site-specific measures, an additional Blue Ribbon Panel comprised of the chairs and other members of the disease sites was formed to create 18 harmonized quality measures for all 5 sites (13 quality, 4 surveillance, and 1 aspirational). CONCLUSIONS: The VA-NROP and American Society for Radiation Oncology collaboration have created quality measures spanning 5 disease sites to help improve patient outcomes. These will be used for the ongoing quality surveillance of veterans receiving radiation therapy through the VA and its community partners.

Vitamin D Status and Severe COVID-19 Disease Outcomes in Hospitalized Patients.

BACKGROUND: Vitamin D deficiency may increase the risk of severe COVID-19 disease. OBJECTIVES: To determine if 25-hydroxyvitamin D [25(OH)D] levels in patients hospitalized for COVID-19 were associated with the clinical outcomes of days on oxygen, duration of hospitalization, ICU admission, need for assisted ventilation, or mortality. METHODS: We conducted a retrospective study of 92 patients admitted to the hospital with SARS-CoV-2 infection between April 16, 2020 and October 17, 2020. Multivariable regression was performed to assess the independent relationship of 25(OH)D values on outcomes, adjusting for significant covariates and the hospitalization day the level was tested. RESULTS: About 15 patients (16.3%) had 25(OH)D levels <20 ng/mL. Only 1 patient (3.4%) who had documented vitamin D supplementation prior to admission had 25(OH)D <20 ng/mL. Serum 25(OH)D concentrations were not significantly associated with any of our primary outcomes of days on oxygen, duration of hospitalization, intensive care unit (ICU) admission, need for mechanical ventilation, or mortality in any of the adjusted multivariable models. Adjusting for the hospital day of 25(OH)D sampling did not alter the relationship of 25(OH)D with any outcomes. CONCLUSION: Vitamin D status was not related to any of the primary outcomes reflecting severity of COVID-19 in hospitalized patients. However, our sample size may have lacked sufficient power to demonstrate a small effect of vitamin D status on these outcomes.

Advancing precision medicine with personalized drug screening.

Personalized drug screening (PDS) of approved drug libraries enables rapid development of specific small-molecule therapies for individual patients. With a multidisciplinary team including clinicians, researchers, ethicists, informaticians and regulatory professionals, patient treatment can be optimized with greater efficacy and fewer adverse effects by using PDS as an approach to find remedies. In addition, PDS has the potential to rapidly identify therapeutics for a patient suffering from a disease without an existing therapy. From cancer to bacterial infections, we review specific maladies addressed with PDS campaigns. We predict that PDS combined with personal genomic analyses will contribute to the development of future precision medicine endeavors.

Gypenoside UL4-Rich Gynostemma pentaphyllum Extract Exerts a Hepatoprotective Effect on Diet-Induced Nonalcoholic Fatty Liver Disease.

Nonalcoholic steatohepatitis (NASH) arises from nonalcoholic fatty liver disease (NAFLD) as a consequence of oxidative stress. Gynostemma pentaphyllum extract (GPE) is proven to be beneficial for patients suffering from NAFLD. However, the precise mechanism by which GPE confers these benefits remains largely unknown. The purpose of this study was to investigate the underlying mechanism and to determine whether supplementation with the newly discovered GPE gypenoside UL4 mitigates NASH progression. Male c57BL/6 mice were fed a normal chow diet, a methionine choline-deficient (MCD) diet, or an MCD diet supplemented with various doses of UL4-rich GPE for eight weeks. GPE supplementation suppressed oxidative stress induced by the MCD diet by increasing levels of sirtuin 6 and phase 2 anti-oxidant enzymes in mouse liver and HepG2 cells. Additionally, GPE supplementation prevented diet-induced hepatic fat accumulation, hepatocellular injury, inflammation, and fibrosis in mice fed the MCD diet. These results indicate the possible therapeutic potential of dietary supplementation of UL4-rich GPE in preventing the development of fatty liver and its progression to NASH.

Epigallocatechin-3-Gallate-Rich Green Tea Extract Ameliorates Fatty Liver and Weight Gain in Mice Fed a High Fat Diet by Activating the Sirtuin 1 and AMP Activating Protein Kinase Pathway.

The prevalence of metabolic diseases has risen globally in parallel with the obesity epidemic over the past few decades. Green tea has been reported to have metabolically beneficial effects on obesity; however, the mechanism by which green tea regulates lipid metabolism is not clearly understood. Male c57BL/6 mice were fed a normal chow diet, a high-fat diet (HFD), or an HFD supplemented with various doses of epigallocatechin gallate-rich green tea extract (GTE) for 12 weeks. GTE supplementation reduced body weight gain, prevented hepatic fat accumulation, decreased hypertriglyceridemia, and improved hyperglycemia and insulin resistance in HFD-fed mice. The underlying mechanisms of these beneficial effects of GTE might involve the upregulation of sirtuin 1 and AMP activated protein kinase (AMPK) and the downregulation of enzymes related to de novo lipogenesis. Consistent with the in vivo findings, GTE increased the expression and activity of sirtuin 1, enhanced the binding of sirtuin 1 to liver kinase B1 (LKB1) and subsequent deacetylation of LKB1, and reduced triglyceride accumulation in HepG2 cells. These results suggest the possible therapeutic potential of dietary epigallocatechin gallate-rich GTE supplementation for preventing the development and progression of hepatic steatosis and obesity.

Should doctors strike?

Last year in June, British doctors went on strike for the first time since 1975. Amidst a global economic downturn and with many health systems struggling with reduced finances, around the world the issue of public health workers going on strike is a very real one. Almost all doctors will agree that we should always follow the law, but often the law is unclear or does not cover a particular case. Here we must appeal to ethical discussion. The General Medical Council, in its key guidance document for practising doctors, Good Medical Practice, claims that 'Good doctors make the care of their patients their first concern'. Is this true? And if so, how is this relevant to the issue of striking? One year on since the events, we carefully reflect and argue whether it was right for doctors to pursue strike action, and call for greater discussion of ethical issues such as the recent strikes, particularly among younger members of the profession.

Novel and emerging nonpositive airway pressure therapies for sleep apnea.

CPAP therapy has remained the standard of care for the treatment of sleep apnea for nearly 4 decades. Its overall effectiveness, however, has been limited by incomplete adherence despite many efforts to improve comfort. Conventional alternative therapies include oral appliances and upper airway surgeries. Recently, several innovative alternatives to CPAP have been developed. These novel approaches include means to increase arousal thresholds, electrical nerve stimulation, oral vacuum devices, and nasal expiratory resistive devices. We will review the physiologic mechanisms and the current evidence for these novel treatments.

Asian upper lid blepharoplasty: an update on indications and technique.

This article (1) briefly reviews the topographical and surgical anatomy of the Asian upper eyelid, (2) provides guidelines for preoperative assessment and postoperative management for upper Asian blepharoplasty, (3) describes the senior author's surgical technique for external incisional approach to upper eyelid crease formation, and (4) discusses potential pitfalls and complications.

The distal left Malone antegrade continence enema--is it better?

PURPOSE: The Malone antegrade continence enema is used for refractory fecal dysfunction in the pediatric neuropathic population. While various locations along the colon have been described, the optimal site for achieving efficient enemas remains unknown. We reviewed our experience with the Malone antegrade continence enema procedure and investigated functional outcomes and complications associated with proximal and distal locations. MATERIALS AND METHODS: We performed an institutional review board approved, retrospective chart review of 109 consecutive MACE procedures done by a single surgeon from 2000 to 2012. Preoperative patient characteristics, intraoperative techniques and postoperative outcomes were reviewed and statistical analysis was performed. RESULTS: Included in analysis were 90 patients treated with a total of 109 MACE procedures. Average age at operation was 13.8 years. Myelomeningocele was the most common diagnosis. Most patients underwent simultaneous urinary reconstruction. Stomal complications were most common (49% of patients). We compared the outcomes of proximal (cecal) MACE in 48 cases and distal (sigmoid colon) MACE in 55. Location did not affect the overall efficiency of fecal continence. Flush time was shorter for distal than for proximal MACE stomas (37.2 vs 61.2 minutes, p <0.001). Of the patients 15 underwent a total of 20 complete MACE revisions, including 12 proximal and 6 distal MACEs. As a channel, appendix was associated with a higher but not statistically significant stomal complication rate compared to colon (42% vs 25%). CONCLUSIONS: A cecal, transverse or colonic location for MACE results in acceptable outcomes. Distal MACE is associated with significantly shorter flush time and possibly fewer stomal complications. Stomal complications remain a frustrating reality of the MACE procedure.

Solving the puzzle of strong French coffee, palpitation and dizziness.

A 38-year-old gentleman presented to the emergency department at the University Hospital in Geneva with nausea, rapid palpitation and presyncope. This was followed by a poor night's sleep, a day of strenuous walking in the city and drinking a large quantity of strong French coffee. 12-lead ECG revealed tachycardia with slightly increased QRS duration of right bundle branch block pattern and left axis deviation. Without the electrophysiological (EP) study, the patient was diagnosed with supraventricular tachycardia. On return to Edinburgh, he was investigated under the EP study, which confirmed fascicular tachycardia, a rare and uncommon presentation of ventricular tachycardia. The patient was successfully treated with radiofrequency catheter ablation therapy, which is curative in over 80% of the cases. This case highlights the importance of referring patients with repeatedly presenting arrhythmic episodes to undergo EP study. This will avoid putting them at unnecessary future risk, while offering the opportunity to definitely diagnose and provide curative therapy.

Synthesis of methyl ketones by metabolically engineered Escherichia coli.

Methyl ketones are a group of highly reduced platform chemicals with widespread applications in the fragrance, flavor and pharmacological industries. Current methods for the industrial production of methyl ketones include oxidation of hydrocarbons, but recent advances in the characterization of methyl ketone synthases from wild tomato have sparked interest towards the development of microbial platforms for the industrial production of methyl ketones. A functional methyl ketone biosynthetic pathway was constructed in Escherichia coli by over-expressing two genes from Solanum habrochaites: shmks2, encoding a 3-ketoacyl-ACP thioesterase, and shmks1, encoding a beta-decarboxylase. These enzymes enabled methyl ketone synthesis from 3-ketoacyl-ACP, an intermediate in the fatty acid biosynthetic cycle. The production of 2-nonanone, 2-undecanone, and 2-tridecanone by MG1655 pTH-shmks2-shmks1 was initially detected by nuclear magnetic resonance and gas chromatography-mass spectrometry analyses at levels close to 6 mg/L. The deletion of major fermentative pathways leading to ethanol (adhE), lactate (ldhA), and acetate (pta, poxB) production allowed for the carbon flux to be redirected towards methyl ketone production, doubling total methyl ketone concentration. Variations in methyl ketone production observed under different working volumes in flask experiments led to a more detailed analysis of the effects of oxygen availability on methyl ketone concentration in order to determine optimal levels of oxygen. The methyl ketone concentration achieved with MG1655 ∆adhE ∆ldhA ∆poxB ∆pta pTrcHis2A-shmks2-shmks1, the best performer strain in this study, was approximately 500 mg/L, the highest reported for an engineered microorganism. Through the establishment of optimal operating conditions and by executing rational metabolic engineering strategies, we were able to increase methyl ketone concentrations by almost 75-fold from the initial confirmatory levels.

Experimental approaches for the treatment of malignant gliomas.

Malignant gliomas, which include glioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over the past 30 years, the standard treatment for these tumors has evolved to include maximal safe surgical resection, radiation therapy and temozolomide chemotherapy. While the median survival of patients with glioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for the vast majority of patients. There has, however, been recent substantial progress in our mechanistic understanding of tumor development and growth. The translation of these genetic, epigenetic and biochemical findings into therapies that have been tested in clinical trials is the subject of this review.

A botanical extract from channel flow inhibits cell proliferation, induces apoptosis, and suppresses CCL5 in human endometriotic stromal cells.

Growing evidence suggests that medicinal herbs have direct actions on endometrial cells. By screening multiple herbs using an in vitro model of endometriosis, we found that a commonly used herbal formula exerted considerable antiproliferative effects. Our purpose was to investigate the effects of this antiendometriosis herbal mixture on cell proliferation, apoptosis, and CCL5 expression and secretion in endometriotic stromal cells in vitro. Isolated normal endometrial, eutopic, and ectopic endometriotic stromal cells were cultured under established conditions. Cell proliferation, apoptosis, and CCL5 gene expression protein secretion was evaluated after incubation with different concentrations of an antiendometriosis herbal mixture extract. Cell proliferation was assessed by cell counting, (3)H-thymidine incorporation, and MTS assays. Apoptosis was determined by blotting using anti-cleaved caspase 3 antibodies and by a TUNEL assay. CCL5 gene expression and protein secretion were determined by transient transfection of gene promoter reporters and ELISAs in cell supernatants. Extracts of a traditional herbal mixture dose-dependently decreased cell proliferation in normal, eutopic, and ectopic endometriotic stromal cells. (3)H-Thymidine uptake and MTS confirmed these findings. The herbal extracts induced apoptosis, as evidenced by activation of caspase 3 and the presence of TUNEL-positive cells after treatment. The herbal extracts also suppressed CCL5 gene transcription and protein secretion in endometriotic stromal cells, even when corrected for cell number. Extracts from a medicinal herbal mixture have direct effects on cell proliferation, apoptosis, and CCL5 production in endometriotic stromal cells. Our findings support the further investigation of novel, potentially safe and well-tolerated botanical products as future endometriosis treatments.

Real-time MR imaging of adeno-associated viral vector delivery to the primate brain.

We are developing a method for real-time magnetic resonance imaging (MRI) visualization of convection-enhanced delivery (CED) of adeno-associated viral vectors (AAV) to the primate brain. By including gadolinium-loaded liposomes (GDL) with AAV, we can track the convective movement of viral particles by continuous monitoring of distribution of surrogate GDL. In order to validate this approach, we infused two AAV (AAV1-GFP and AAV2-hAADC) into three different regions of non-human primate brain (corona radiata, putamen, and thalamus). The procedure was tolerated well by all three animals in the study. The distribution of GFP determined by immunohistochemistry in both brain regions correlated closely with distribution of GDL determined by MRI. Co-distribution was weaker with AAV2-hAADC, although in vivo PET scanning with FMT for AADC activity correlated well with immunohistochemistry of AADC. Although this is a relatively small study, it appears that AAV1 correlates better with MRI-monitored delivery than does AAV2. It seems likely that the difference in distribution may be due to differences in tissue specificity of the two serotypes.

Standard PET/CT of the chest during shallow breathing is inadequate for comprehensive staging of lung cancer.

UNLABELLED: The incidence of malignancy associated with subcentimeter pulmonary nodules (micronodules) in patients with malignant disease has been reported to be as high as 58%. Thus, detection of small lung nodules is important for appropriate staging of lung cancer. Because of respiratory motion, small parenchymal lung lesions can be missed on CT acquired during shallow breathing. Micronodules are usually too small to be characterized reliably with 18F-FDG PET. We aimed to determine the incidence of missed pulmonary micronodules on PET/CT studies acquired during shallow breathing. METHODS: The study included 142 consecutive cancer patients (62 male and 80 female; mean age, 54 y) who underwent whole-body PET/CT during shallow breathing and breath-hold CT of the chest during maximal inspiration. CT findings were reviewed independently, and noncalcified nodules missed on the shallow-breathing scan were evaluated for size, location, and metabolic activity. RESULTS: Breath-hold chest CT detected an additional 125 parenchymal lung nodules (mean size, 3.4 +/- 1.6 mm; range, 1-9 mm) in 48 (34%) of the 142 patients. In these patients, 3 nodules, on average, were missed during shallow breathing. In 18 patients (13%), micronodules were identified exclusively on breath-hold images. None of the missed nodules demonstrated 18F-FDG uptake. CONCLUSION: Acquisition of standard PET/CT chest images during shallow breathing is inadequate for comprehensive cancer staging.