ChatGPT for improving postoperative instructions in multiple fields of plastic surgery.

BACKGROUND: Clear discharge instructions are vital for patients and caregivers to manage postoperative care at home. However, they often exceed the sixth-grade reading level recommended by national associations. It was hypothesized that ChatGPT could help rewrite instructions to this level for increased accessibility and comprehension. This study aimed to assess the readability, understandability, actionability, and safety of ChatGPT rewritten postoperative instructions in four plastic surgery subspecialties: breast, craniofacial, hand, and aesthetic surgery. METHODS: Postoperative instructions from four index procedures in plastic surgery were obtained. ChatGPT was used to rewrite at the sixth- and fourth-grade reading levels. Readability was determined by seven readability indexes, understandability and actionability by the Patient Education Materials Assessment Tool for printable materials questionnaire, and safety by the primary surgeons. RESULTS: Overall, the average readability of the original postoperative instructions ranged between the seventh and eighth grade levels. Only one of the sixth-grade ChatGPT instructions was lowered to the sixth-grade level. Of the fourth-grade ChatGPT instructions, all were reduced to the sixth-grade-level or below, but none achieved the fourth-grade level. Understandability scores increased as reading levels decreased, whereas actionability scores decreased for fourth-grade rewrites. Safety was not compromised in all rewrites. CONCLUSIONS: ChatGPT can adapt postoperative instructions to a more readable sixth-grade level without compromising safety. This study suggests prompting ChatGPT to write one to two grade levels lower than the desired reading level. While understandability increased for all ChatGPT rewrites, actionability decreased for fourth-grade-level instructions. Sixth-grade remains the optimal reading level for postoperative instructions. This study demonstrates that ChatGPT can help improve patient care by improving the readability of postoperative instructions.

TRPM2 enhances ischemic excitotoxicity by associating with PKCγ.

N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate excitotoxicity significantly contributes to ischemic neuronal death and post-recanalization infarction expansion. Despite tremendous efforts, targeting NMDARs has proven unsuccessful in clinical trials for mitigating brain injury. Here, we show the discovery of an interaction motif for transient receptor potential melastatin 2 (TRPM2) and protein kinase Cγ (PKCγ) association and demonstrate that TRPM2-PKCγ uncoupling is an effective therapeutic strategy for attenuating NMDAR-mediated excitotoxicity in ischemic stroke. We demonstrate that the TRPM2-PKCγ interaction allows TRPM2-mediated Ca2+ influx to promote PKCγ activation, which subsequently enhances TRPM2-induced potentiation of extrasynaptic NMDAR (esNMDAR) activity. By identifying the PKCγ binding motif on TRPM2 (M2PBM), which directly associates with the C2 domain of PKCγ, an interfering peptide (TAT-M2PBM) is developed to disrupt TRPM2-PKCγ interaction without compromising PKCγ function. M2PBM deletion or TRPM2-PKCγ dissociation abolishes both TRPM2-PKCγ and TRPM2-esNMDAR couplings, resulting in reduced excitotoxic neuronal death and attenuated ischemic brain injury.

Toward quantitative intrafractional monitoring in paraspinal SBRT using a proprietary software application: clinical implementation and patient results.

Objective.We report on paraspinal motion and the clinical implementation of our proprietary software that leverages Varian's intrafraction motion review (IMR) capability for quantitative tracking of the spine during paraspinal SBRT. The work is based on our prior development and analysis on phantoms.Approach.To address complexities in patient anatomy, digitally reconstructed radiographs (DRR's) that highlight only the spine or hardware were constructed as tracking reference. Moreover, a high-pass filter and first-pass coarse search were implemented to enhance registration accuracy and stability. For evaluation, 84 paraspinal SBRT patients with sites spanning across the entire vertebral column were enrolled with prescriptions ranging from 24 to 40 Gy in one to five fractions. Treatments were planned and delivered with 9 IMRT beams roughly equally distributed posteriorly. IMR was triggered every 200 or 500 MU for each beam. During treatment, the software grabbed the IMR image, registered it with the corresponding DRR, and displayed the motion result in near real-time on auto-pilot mode. Four independent experts completed offline manual registrations as ground truth for tracking accuracy evaluation.Main results.Our software detected ≥1.5 mm and ≥2 mm motions among 17.1% and 6.6% of 1371 patient images, respectively, in either lateral or longitudinal direction. In the validation set of 637 patient images, 91.9% of the tracking errors compared to manual registration fell within ±0.5 mm in either direction. Given a motion threshold of 2 mm, the software accomplished a 98.7% specificity and a 93.9% sensitivity in deciding whether to interrupt treatment for patient re-setup.Significance.Significant intrafractional motion exists in certain paraspinal SBRT patients, supporting the need for quantitative motion monitoring during treatment. Our improved software achieves high motion tracking accuracy clinically and provides reliable guidance for treatment intervention. It offers a practical solution to ensure accurate delivery of paraspinal SBRT on a conventional Linac platform.

Interpretable machine learning-based predictive modeling of patient outcomes following cardiac surgery.

BACKGROUND: The clinical applicability of machine learning predictions of patient outcomes following cardiac surgery remains unclear. We applied machine learning to predict patient outcomes associated with high morbidity and mortality after cardiac surgery and identified the importance of variables to the derived model's performance. METHODS: We applied machine learning to the Society of Thoracic Surgeons Adult Cardiac Surgery Database to predict postoperative hemorrhage requiring reoperation, venous thromboembolism (VTE), and stroke. We used permutation feature importance to identify variables important to model performance and a misclassification analysis to study the limitations of the model. RESULTS: The study dataset included 662,772 subjects who underwent cardiac surgery between 2015 and 2017 and 240 variables. Hemorrhage requiring reoperation, VTE, and stroke occurred in 2.9%, 1.2%, and 2.0% of subjects, respectively. The model performed remarkably well at predicting all 3 complications (area under the receiver operating characteristic curve, 0.92-0.97). Preoperative and intraoperative variables were not important to model performance; instead, performance for the prediction of all 3 outcomes was driven primarily by several postoperative variables, including known risk factors for the complications, such as mechanical ventilation and new onset of postoperative arrhythmias. Many of the postoperative variables important to model performance also increased the risk of subject misclassification, indicating internal validity. CONCLUSIONS: A machine learning model accurately and reliably predicts patient outcomes following cardiac surgery. Postoperative, as opposed to preoperative or intraoperative variables, are important to model performance. Interventions targeting this period, including minimizing the duration of mechanical ventilation and early treatment of new-onset postoperative arrhythmias, may help lower the risk of these complications.

Incidence of immune checkpoint inhibitor mediated cardiovascular toxicity: A systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICI) are a novel class of anti-cancer therapy becoming increasingly associated with fatal cardiovascular toxicities (CVTs). The aim is to determine the incidence of CVTs in cohorts treated with ICIs as sole anti-cancer therapy. METHODS: A systematic literature search of scientific and medical databases was performed using PRISMA principles to identify relevant cohorts (PROSPERO registration CRD42021272470). Data for specific CVTs (pericardial disease, myocarditis, heart failure, arrhythmia, myocardial infarction/ischaemia and angina), CVT-related death and CV risk factors were extracted. Presence of CVTs in ICI-monotherapy versus combination-ICI therapy, and programmed death 1/programmed death ligand 1- (PD1/PDL1-) versus cytotoxic T-lymphocyte-associated protein 4- (CTLA4-) inhibitor groups were dichotomised and meta-analysed using random-effect models. RESULTS: Forty-eight studies (11,207 patients) were identified, from which 146 CVTs were observed (incidence 1.30%). ICI-monotherapy led to more CVTs than combination therapy (119/9009; 1.32% vs. 18/2086; 0.86%). Across monotherapies, PD1/PDL1-inhibitors had lower incidence of CVTs compared to CTLA4-inhibitors (62/6950; 0.89% vs. 57/2059; 2.77%). Based on eight studies that were meta-analysed, no significant difference was observed comparing monotherapy versus combination-ICI therapy (RR-0.69, 95% CI -1.47 to 0.09) for all CVTs, or PD1/PDL1- to CTLA4-inhibitors (RR-0.27, 95% CI -2.06 to 1.53), for all CVTs including CVT-death. CV risk factors could not be attributed to an ICI group as data was population based rather than individual based. CONCLUSION: ICI-mediated CVTs are rare and potentially fatal. The role of CV risk factors in their development remains unclear.

Alterations in gut microbiota of esophageal squamous cell carcinoma patients.

BACKGROUND AND AIM: Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of esophageal cancer worldwide. Patients with ESCC display an altered esophageal microbiota compared with healthy individuals; however, little is known about the gut microbiota in ESCC. METHODS: Here, we characterized the fecal microbiota of 15 ESCC patients and 16 healthy control subjects using 16S rRNA gene sequencing. RESULTS: After controlling for potential confounders, significant alterations in both taxonomic and functional composition of the gut microbiota in ESCC patients were observed. By contrast, alpha diversity of the gut microbiota did not significantly differ between the cases and controls. We observed an enrichment of potentially pro-inflammatory and/or carcinogenic bacteria, such as Butyricimonas, Veillonella, and Streptococcus, and a depletion of butyrate-producing and/or potentially anti-inflammatory bacteria, such as Butyricicoccus, Lachnospiraceae NK4A136 group, and Eubacterium eligens group, in the gut microbiota of ESCC patients. The log-ratios of Streptococcus to Butyricicoccus and Streptococcus to Lachnospiraceae NK4A136 group of the gut microbiota were identified as potential diagnostic biomarkers for ESCC, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.863 (95% confidence interval: 0.707-1.000) and 0.825 (0.673-0.977), respectively. The diagnostic performance of both microbial biomarkers was validated in another ESCC cohort. CONCLUSIONS: This pilot study has revealed an altered gut microbiota in ESCC patients and has paved the way for large-scale prospective cohort studies to examine the causative relationship between ESCC and gut dysbiosis.

Regulation of Drug Transport Proteins-From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium.

Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response.

Prediction of Hepatobiliary Clearances and Hepatic Concentrations of Transported Drugs in Humans Using Rosuvastatin as a Model Drug.

To assess efficacy and toxicity of a drug in humans, it is important to measure the tissue concentration of a drug at the target site. For a drug that is transported into or out of the tissue, the tissue unbound steady-state concentration can be dramatically different from its corresponding unbound steady-state plasma concentration. Because routine measurement of drug tissue concentrations is not possible, using rosuvastatin as a model transporter substrate drug, we compared the ability of the proteomics-informed relative expression factor (REF) approach and sandwich-cultured human hepatocytes (SCH) to accurately predict rosuvastatin human hepatobiliary clearances and hepatic concentrations. REF-predicted rosuvastatin biliary clearance (CLbile ), estimated using BCRP-overexpressing, MDR1-overexpressing, and MRP2-overexpressing vesicles, together with our previously published REF-predicted rosuvastatin hepatic sinusoidal uptake clearance (CLuptake ) and physiologically scaled sinusoidal passive uptake and efflux clearance (CLs,efflux ), were used to predict rosuvastatin hepatic concentrations. For SCH, the estimated rosuvastatin CLbile , CLuptake , and CLs,efflux were scaled using physiological scaling. The REF-predicted CLbile (6.39 ± 1.56 mL/minute) and hepatic rosuvastatin area under the concentration-time curve (AUC) fell within our a priori defined success criterion, i.e., within twofold of the observed positron emission tomography-imaged values. In contrast, as expected, SCH dramatically overpredicted (predicted/observed ratio P/O = 8.38-10.41) rosuvastatin CLbile , and underpredicted hepatic AUC (P/O = 0.08-0.14). For both approaches, predictions were improved by using the parallel tube model vs. well-stirred model. Overall, using rosuvastatin as a model drug, this study demonstrates the success of the REF approach in predicting in vivo CLbile and hepatic concentration of drugs, and highlights the shortcomings of the SCH approach in making such predictions.

Prevalence of thyroid malignancy and hormonal dysfunction following radiation exposure in childhood.

INTRODUCTION: Childhood radiation exposure is a known risk factor for thyroid malignancy and dysfunction. However, local data are limited and there is no consensus on the modality and frequency of screening in this high-risk group. METHODS: Retrospective analysis study evaluating patients with childhood radiation exposure in 2006-2016 and minimum of 1-year follow-up. RESULTS: Of the 132 childhood cancer survivors in the study, thyroid malignancy was detected in 2 cases (1.5%) and thyroid nodules in 13 (9.8%). The earliest thyroid malignancy was detected 5 years post-radiotherapy via ultrasound. Of the 84 patients who had screening thyroid function test, 26 (31.0%) were detected with abnormal test results post-radiation, majority being subclinical hypothyroidism. CONCLUSION: Regular screening via clinical examination for thyroid nodules should be performed at least annually. Where feasible and if resources permit, consideration should be given to using ultrasound for thyroid nodule(s) and malignancy screening at 5 years post-radiation therapy. Screening for thyroid dysfunction can be considered from 6-12 months post-radiotherapy.

Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake of Glucuronide Metabolites of Androgens.

We previously established that androgen glucuronides are effluxed by multidrug resistance-associated proteins 2 and 3. However, no data exist on the mechanism of hepatic uptake of these metabolites. The first goal of this study was to explore the role of hepatic uptake transporters and characterize transport kinetics of glucuronides of testosterone (TG), dihydrotestosterone (DHTG), androsterone (AG), and etiocholanolone (EtioG) using cell lines overexpressing organic anion transporting polypeptides (OATP1B1, OATP1B3, and OATP2B1). Using a quantitative proteomics-guided approach, we then estimated the fractional contribution of individual OATPs in hepatic uptake of these glucuronides. The transport screening assays revealed that the glucuronides were primarily taken up by OATP1B1 and OATP1B3. The K m values for OATP1B1-mediated uptake were low for EtioG (6.2 µM) as compared with AG, TG, and DHTG (46.2, 56.7, and 71.3 µM, respectively), whereas the K m value for OATP1B3-mediated uptake for EtioG, AG, DHTG, and TG were 19.8, 29.3, 69.6, and 110.4 µM, respectively. Both OATP1B1 and OATP1B3 exhibited the highest transport rate toward AG as compared with other glucuronides. When adjusted for the transporter abundance in human livers, EtioG and DHTG were predicted to be transported by both OATP1B1 and OATP1B3, whereas TG and AG were preferentially (>68%) transported by OATP1B3. Collectively, this report elucidates the mechanisms of hepatic uptake of androgen glucuronides. Perturbation of these processes by genetic polymorphisms, disease conditions, or drug interactions can lead to changes in enterohepatic recycling of androgens. TG and AG can be further investigated as potential biomarkers of OATP1B3 inhibition. SIGNIFICANCE STATEMENT: This is the first study to elucidate the mechanism of hepatic uptake of androgen glucuronides and estimate the fractional contribution of individual OATPs using quantitative proteomics. Our results show that both OATP1B1 and OATP1B3 are responsible for the hepatic uptake of major circulating testosterone glucuronides. The apparent higher selectivity of OATP1B3 toward testosterone glucuronide and androsterone glucuronide can be leveraged for establishing these metabolites as clinical biomarkers of OATP1B3 activity.

Contribution of Uptake and Efflux Transporters to Oral Pharmacokinetics of Furosemide.

Furosemide is a widely used diuretic for treating excessive fluid accumulation caused by disease conditions like heart failure and liver cirrhosis. Furosemide tablet formulation exhibits variable pharmacokinetics (PK) with bioavailability ranging from 10 to almost 100%. To explain the variable absorption, we integrated the physicochemical, in vitro dissolution, permeability, distribution, and the elimination parameters of furosemide in a physiologically-based pharmacokinetic (PBPK) model. Although the intravenous PBPK model reasonably described the observed in vivo PK data, the reported low passive permeability failed to capture the observed data after oral administration. To mechanistically justify this discrepancy, we hypothesized that transporter-mediated uptake contributes to the oral absorption of furosemide in conjunction with passive permeability. Our in vitro results confirmed that furosemide is a substrate of intestinal breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), and organic anion transporting polypeptide 2B1 (OATP2B1), but it is not a substrate of P-glycoprotein (P-gp) and MRP2. We then estimated the net transporter-mediated intestinal uptake and integrated it into the PBPK model under both fasting and fed conditions. Our in vitro data and PBPK model suggest that the absorption of furosemide is permeability-limited, and OATP2B1 and MRP4 are important for its permeability across intestinal membrane. Further, as furosemide has been proposed as a probe substrate of renal organic anion transporters (OATs) for assessing clinical drug-drug interactions (DDIs) during drug development, the confounding effects of intestinal transporters identified in this study on furosemide PK should be considered in the clinical transporter DDI studies.

A short report on current fertility preservation strategies for boys.

BACKGROUND: Advances in cancer treatment have led to improved long-term survival after childhood cancer, but often at a price of impaired future fertility. Fertility preservation (FP) in male children and early adolescents poses unique challenges as efficacy is unproven. OBJECTIVES: To describe characteristics of testicular tissue cryopreservation (TTCP) specimens taken from paediatric and adolescent patients, stratified by age, and prior chemotherapy, if any, and to demonstrate evidence for germ cells. MATERIALS AND METHODS: Retrospective review of gonadal biopsies and clinical records of patients consented into the Royal Children's Hospital FP programme between 1987 and 2015. Tissue was sliced into blocks, with one section sent for histopathology prior to cryopreservation. In boys ≥12 years where spermatogenesis could be expected, a portion of tissue was disaggregated completely to look for mature sperm and if found, additional tissue was dissected and the resulting suspension frozen. RESULTS: Testicular tissue cryopreservation specimens in 44 males (0.3-16.8 years) provided an average of 7.8 slices per patient. All the specimens were taken at the same time as another necessary surgical procedure, under one general anaesthesic. There was only one complication of scrotal wound dehiscence. Seven of the forty-four (15.9%) patients had chemotherapy prior to testicular biopsy, while the rest were chemotherapy naïve. Five of these were prepubertal, and two were pubertal patients. Eleven subjects had tissue dissected with mature sperm found in eight. Of these eight patients where sperm were found, all were pubertal with testicular size of more than 10 mL and showing histological evidence of spermatogenesis. No histologic specimen demonstrated any malignant cells. CONCLUSIONS: Testicular tissue cryopreservation can be performed in young patients without delay, preferably prior to cancer treatment. As testicular tissue contains germ cells from which haploid spermatozoa are ultimately derived, future technologies may allow their utilization for fertility in humans. This may be the only hope for biological offspring in some patients undergoing fertility compromising treatment. Retrieval of mature sperm from some pubertal patients, however, offers realistic hope to these patients of future fertility.

Thyroid carcinoma in children, adolescents and adults, both spontaneous and after childhood radiation exposure.

UNLABELLED: Thyroid carcinoma is the most common second malignancy for childhood cancer survivors. Radiation exposure is linked to risk. Thyroid nodules in children have a high risk for malignancy, whether spontaneous or after radiation. Due to the extremely limited available paediatric data, we sought to review a series of patients with thyroid carcinoma, seen over 25 years. Forty-six patients were identified. Thirty-nine (84.8 %) had papillary thyroid carcinoma, five (10.9 %) follicular carcinoma and 2 (4.3 %) medullary thyroid carcinoma (MEN2B). Thirty-three (71.7 %) had childhood radiation exposure (17 females) with thyroid malignancy occurring 6-37 years later. The smallest nodule size found on surveillance to have thyroid malignancy was 4 mm. Thyroid cancer in patients 16 years and under was seen in 22 patients (47.8 %). All had total thyroidectomy, with initial central node clearance from 2005. Diagnostic rTSH stimulated I(123) scan was followed by ablative I(131) if any uptake was seen. Sixteen (32.6 %) had metastases. Twenty-four (52.2 %) had I(131), four requiring multiple courses. Forty-two remain alive and well. CONCLUSION: Ultrasound screening is required for early diagnosis as small nodule size is not predictive of benign histology or absence of metastases. Central node clearance provides better outcome. Despite metastatic disease at presentation for some, prognosis is favourable. WHAT IS KNOWN: • Incidence of thyroid cancer has been increasing and radiation exposure in childhood cancer survivors is clearly linked to risk. • Published guidelines in many places can only provide very low level evidence due to extremely limited available paediatric data. What is New: • Paper provides good evidence to confirm existing views with the largest cohort of thyroid cancer reported to date in the paediatric age group in Australia, and the largest cohort in Australia where there have been specific high risks of radiation exposure. The only other reported larger studies have come from the Children's Oncology Group and Childhood Cancer Survivor Study [24]. • Using diagnostic rTSH stimulated I(123) scan 6 weeks after surgery helps to determine if radioactive iodine ablation is necessary and limits unnecessary bone marrow exposure for young patients in whom future leukaemia is of greater concern.

Age-Specific Regulation of Drug-Processing Genes in Mouse Liver by Ligands of Xenobiotic-Sensing Transcription Factors.

The xenobiotic-sensing transcription factors (xeno-sensors) AhR, CAR, and PXR upregulate the expression of many drug-processing genes (DPGs) in liver. Previous studies have unveiled profound changes in the basal expression of DPGs during development; however, knowledge on the ontogeny of the inducibility of DPGs in response to pharmacological activation of xeno-sensors is still limited. The goal of this study was to investigate the age-specific regulation of DPGs by prototypical xeno-sensor ligands: 2,3,7,8-tetrachlorodibenzodioxin (TCDD) for AhR; 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) for CAR; and pregnane-16α-carbonitrile (PCN) for PXR during mouse liver development. The basal mRNAs of most DPGs were low during neonatal age, but gradually increased to adult levels, whereas some DPGs (Cyp1a2, Cyp2b10, Cyp3a11, Gstm2, Gstm3, Papss2, and Oatp1a4) exhibited an adolescent-predominant expression pattern. The inducibility of DPGs was age-specific: 1) during neonatal age, the highest fold increase in the mRNA expression was observed for Cyp1a2, Sult5a1, and Ugt1a9 by TCDD; Cyp3a11 and Mrp2 by TCPOBOP; as well as Gstm2 and Gstm3 by PCN; 2) during adolescent age, the highest fold increase in the mRNA expression was observed for Ugt1a6 and Mrp4 by TCDD, Cyp2b10, Ugt2b34, and Ugt2b35 by TCPOBOP, as well as Gsta1, Gsta4, Sult1e1, Ugt1a1, Mrp3, and Mrp4 by PCN; 3) in adults, the highest fold increase in the mRNA expression was observed for Aldh1a1, Aldh1a7, and Ugt2b36 by TCPOBOP, as well as Papss2 and Oatp1a4 by PCN. In conclusion, the inducibility of hepatic DPGs following the pharmacological activation of xeno-sensors is age specific.

Early Trends Among Seven Recommendations From the Choosing Wisely Campaign.

IMPORTANCE: The Choosing Wisely campaign consists of more than 70 lists produced by specialty societies of medical practices or procedures of minimal clinical benefit to patients in most situations, with recommendations regarding judicious use. OBJECTIVE: To quantify the frequency and trends of some of the earliest Choosing Wisely recommendations using nationwide commercial health plan population-level data. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of claims data for members of Anthem-affiliated commercial health plans. The low-value services selected were (1) imaging tests for uncomplicated headache; (2) cardiac imaging without history of cardiac conditions; (3) low back pain imaging without red-flag conditions; (4) preoperative chest x-rays with unremarkable history and physical examination results; (5) human papillomavirus testing for women younger than 30 years; (6) use of antibiotics for acute sinusitis; and (7) use of prescription nonsteroidal anti-inflammatory drugs (NSAIDs) for members with hypertension, heart failure, or chronic kidney disease. MAIN OUTCOMES AND MEASURES: The number of members with medical and/or pharmacy claims for the included low-value services was assessed quarterly over a 2- to 3-year span through 2013. Trend changes in recommendations were evaluated across all quarters using Poisson regression with denominators as offsets. RESULTS: Two services had declines: Use of imaging for headache decreased from 14.9% to 13.4% (trend estimate, 0.99 [95% CI, 0.98-0.99]; P < .001), and cardiac imaging decreased from 10.8% to 9.7% (trend estimate, 0.99 [95% CI, 0.99-0.99]; P < .001). Two services had increases: Use of NSAIDs in select conditions increased from 14.4% to 16.2% (trend estimate, 1.02 [95% CI, 1.01-1.02]; P < .001), and human papillomavirus testing in younger women increased from 4.8% to 6.0% (trend estimate, 1.01 [95% CI, 1.00-1.01]; P < .001). Use of antibiotics for sinusitis remained stable (0.8% decrease from 84.5% to 83.7%; trend estimate, 1.00 [95% CI, 1.00-1.00]; P = .16). Use of preoperative chest x-rays (0.2% decrease, ending utilization 91.5%; trend estimate, 1.00 [95% CI, 1.00-1.00]; P = .70) and imaging for low back pain (53.7% utilization throughout study; P = .71) remained high with no statistically significant changes. CONCLUSIONS AND RELEVANCE: For this population-level analysis of 7 low-value services analyzed, changes were modest but showed a desirable decrease for 2 recommendations (imaging for headache, cardiac imaging for low-risk patients). The effect sizes were marginal, however, and although 4 of the 7 lists had statistically significant changes-unsurprising given the large sample size-the clinical significance is uncertain. These results suggest that additional interventions are necessary for wider implementation of Choosing Wisely recommendations.

Exogenous kisspeptin administration as a probe of GnRH neuronal function in patients with idiopathic hypogonadotropic hypogonadism.

CONTEXT: Idiopathic hypogonadotropic hypogonadism (IHH) results from defective synthesis, secretion, or action of GnRH. Kisspeptin is a potent stimulus for GnRH secretion. OBJECTIVE: We probed the functional capacity of the GnRH neuronal network in patients with IHH. PARTICIPANTS: Eleven subjects with congenital IHH (9 men and 2 women) and one male subject who underwent reversal of IHH were studied. Six of the twelve subjects had an identified genetic cause of their IHH: KAL1 (n = 1), FGFR1 (n = 3), PROKR2 (n = 1), GNRHR (n = 1). INTERVENTION: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 nmol/kg) and GnRH (75 ng/kg) both pre- and post-six days of treatment with exogenous GnRH (25 ng/kg sc every 2 h). RESULTS: All subjects with abiding IHH failed to demonstrate a GnRH-induced LH response to exogenous kisspeptin. In contrast, the subject who achieved reversal of his hypogonadotropism demonstrated a robust response to kisspeptin. CONCLUSIONS: The functional capacity of the GnRH neuronal network in IHH patients is impaired, as evidenced by their inability to respond to the same dose of kisspeptin that effects a robust GnRH-induced LH response in healthy men and luteal-phase women. This impairment is observed across a range of genotypes, suggesting that it reflects a fundamental property of GnRH neuronal networks that have not been properly engaged during pubertal development. In contrast, a patient who had experienced reversal of his hypogonadotropism responded to exogenous kisspeptin.

Synthesis, characterization, and biological studies of emissive rhenium-glutamine conjugates.

Two new rhenium complexes containing pyridine-triazole (pyta) and quinoline-triazole (quinta) ligands with attached glutamine-targeting agents have been characterized and tested for uptake in the HT-29 human colon adenocarcinoma cell line. The glutamine moiety in Re(CO)3Br(pyta) (1) and Re(CO)3Br(quinta) (2) remains pendant in solution. Both complexes exhibit absorptions in the 300-400-nm range with metal-to-ligand charge transfer (MLCT) character, as predicted by time-dependent density functional theory calculations. Geometrical analysis by theoretical calculations provides information on the cationic complexes 1 (+) and 2 (+) resulting from aquo for halide ligand exchange under aqueous conditions. The emissive properties of both complexes were studied under aqueous conditions, and the measured quantum yields were 0.46 % for 1 (+) and 0.18 % for 2 (+). The large Stokes shifts and oxygen sensitivity of the emission suggest a (3)MLCT process for both complexes. Cell studies in the HT-29 cell line demonstrate that both complexes are nontoxic over a large concentration range (0-1.4 mM). Preliminary uptake studies show that 2 (+), but not 1 (+), displays significant concentration-dependent uptake at 3 and 24 h.

Rates of complete colonic evaluation after incomplete colonoscopy and their associated factors: a population-based study.

BACKGROUND: With the increasing use of colonoscopy there is growing concern about the quality of these procedures. OBJECTIVE: To evaluate the rates of complete colonic evaluation after an incomplete colonoscopy and their associated factors. METHODS: Men and women > or =50 years old living in Ontario on January 1, 1997 who did not have a prior history of colorectal cancer, inflammatory bowel disease, or colonic resection comprised the inception cohort. Receipt of an incomplete colonoscopy between January 1, 1997 and December 31, 2002 was determined. Individuals were followed over 1 year and the time from incomplete colonoscopy to complete colonic evaluation was estimated using Kaplan-Meier analysis. A generalized estimating equations model was used to evaluate the association between patient, physician, and setting factors and complete colonic evaluation. RESULTS: Twenty thousand one hundred sixty-six individuals had an incomplete colonoscopy, of whom 29.4% underwent complete colonic evaluation within 1 year after the procedure. Women > or =80 years were less likely to undergo complete colonic evaluation (odds ratio: 0.89; 95% confidence interval: 0.79-0.99), as were those who had their colonoscopy in a private office or clinic (odds ratio: 0.77; 95% confidence interval: 0.67-0.89). CONCLUSIONS: Only 29.4% of individuals with an incomplete colonoscopy underwent complete colonic evaluation within 1 year after the procedure. Women > or =80 years and those who had their colonoscopy in a private office or clinic were less likely to undergo complete colonic evaluation. The quality of care provided to older women and colonoscopy practice in office settings may be suboptimal.

Risk factors for obstruction, perforation, or emergency admission at presentation in patients with colorectal cancer: a population-based study.

OBJECTIVES: Previous studies have shown that patients newly diagnosed with colorectal cancer (CRC) requiring emergency admission to hospital or those presenting with obstruction or perforation (defined here as OPE) have advanced disease. The objective was to conduct a population-based study among persons with a new diagnosis of CRC to identify factors associated with OPE in Ontario. METHODS: We analyzed data from the following databases: Canadian Institute for Health Information (CIHI), the Ontario Health Insurance Plan (OHIP), and the Registered Persons Database (RPDB). We identified all individuals > or = 20 yr of age with a new diagnosis of CRC (ICD-9 codes 153.0-153.4, 153.6-154.1) during 1996-2001 and defined the first admission for CRC as the index admission. We excluded those who received chemotherapy, radiotherapy, or palliative care prior to the index admission. We identified those with concomitant obstruction (ICD-9 code 560.9), perforation (ICD-9 code 569.8), or who were classified as emergency admission (referred to as OPE). Adjusted risk of OPE was calculated using logistic regression analysis. RESULTS: Between 1996 and 2001, we identified 41,356 persons with CRC, of whom 53.5% were men. In logistic regression analysis, female sex and low income were significantly associated with OPE, after adjusting for differences in age, cancer site, previous large bowel evaluation, comorbidity, having a regular source of primary care, and year of diagnosis. For men the adjusted odds ratio (OR) for OPE was 0.93 (95% confidence interval (CI) 0.88-0.99), and for the highest-income quintile the adjusted OR was 0.78 (95% CI 0.72-0.85). CONCLUSION: Among persons with a new diagnosis of CRC in Ontario, women and those who are poor are more likely to present with obstruction, perforation, or emergency admission to hospital. Population-based CRC screening is needed to address these adverse outcomes.