In-office Transoral Hilar Sialolithotomy: A Cost-Effective and Patient-Centered Procedure.

Transoral sialolithotomy performed in-office under local anesthesia is routinely performed for distal submandibular stones. We demonstrate the senior author's novel practice of in-office transoral sialolithotomy for hilar and intraglandular stones. A review of cases performed by the senior author revealed similar rates of complication and stone recurrence as those reported in the literature from removal under general anesthesia. Laryngoscope, 2024.

Impact of COVID-19 on Perinatal Outcomes and Birth Locations in a Large US Metropolitan Area.

This was a population-based study to determine the impact of COVID-19 on birth outcomes in the Chicago metropolitan area, comparing pre-pandemic (April-September 2019) versus pandemic (April-September 2020) births. Multivariable regression models that adjusted for demographic and neighborhood characteristics were used to estimate the marginal effects of COVID-19 on intrauterine fetal demise (IUFD)/stillbirth, preterm birth, birth hospital designation, and maternal and infant hospital length of stay (LOS). There were no differences in IUFD/stillbirths or preterm births between eras. Commercially insured preterm and term infants were 4.8 percentage points (2.3, 7.4) and 3.4 percentage points (2.5, 4.2) more likely to be born in an academic medical center during the pandemic, while Medicaid-insured preterm and term infants were 3.6 percentage points less likely (-6.5, -0.7) and 1.8 percentage points less likely (-2.8, -0.9) to be born in an academic medical center compared to the pre-pandemic era. Infant LOS decreased from 2.4 to 2.2 days (-0.35, -0.20), maternal LOS for indicated PTBs decreased from 5.6 to 5.0 days (-0.94, -0.19), and term births decreased from 2.5 to 2.3 days (-0.21, -0.17). The pandemic had a significant effect on the location of births that may have exacerbated health inequities that continue into childhood.

Race and Ethnicity Independently Predict Adverse Outcomes Following Head and Neck Autograft Surgery.

OBJECTIVE: There is growing attention toward the implications of race and ethnicity on health disparities within otolaryngology. While race is an established predictor of adverse head and neck oncologic outcomes, there is paucity in the literature on studies employing national, multi-institutional data to assess the impact of race and ethnicity on head and neck autograft surgery. METHODS: Using the National Surgical Quality Improvement Program (NSQIP) database, trends in 30 days outcomes were assessed. Patients with ICD-10 codes for malignant head and neck neoplasms were isolated. Autograft surgeries were selected using Current Procedural Terminology (CPT) codes for free flap and pedicled flap reconstruction. Primary outcomes included surgical complications, reoperation, readmission, extended length of stay and operation time. Each binary categorical variable was compared to racial/ethnic identity via binary logistic regression. RESULTS: The study cohort consisted of 2447 patients who underwent head and neck autograft surgery (80.71% free flap reconstruction and 19.39% pedicled flap reconstruction). Black patients had significantly higher odds of overall surgical complications (odds ratio [OR] 1.583, 95% confidence interval [CI] 1.091, 2.298, p = 0.016) with much higher odds of perioperative blood transfusions (OR 2.291, 95% CI 1.532, 3.426, p = <.001). Hispanic patients were more likely to undergo reoperation within 30 days after surgery and were more likely to be hospitalized for more than 30 days post-operatively (OR 1.566, 95% CI 1.015, 2.418, p = 0.043 and OR 12.224, 95% CI 2.698, 55.377, p = 0.001, respectively). CONCLUSIONS: Race and ethnicity serve as independent predictors of complications in the post-operative period following head and neck autograft surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3595-3603, 2024.

Timeliness of Multimodal Care for At-Risk Breast Cancer Patients at a Safety Net Institution.

INTRODUCTION: Because limited data exist, we sought to evaluate timeliness of multimodal treatments in a safety net breast cancer population. METHODS: Breast cancer patients treated at a safety net hospital from 2016 to 2020 were analyzed retrospectively. Time intervals were defined as primary time (PT) from diagnosis to initiation of primary intervention, secondary time (ST) from completion of primary to initiation of secondary intervention, and tertiary time (TT) from completion of secondary to initiation of tertiary intervention. Variables included primary language, insurance type, and race. RESULTS: Of 223 patients, 99 (44.4%) primarily spoke Spanish, 29 (13.0%) were of Black race, and 184 (82.5%) had Medicaid or uninsured status. Median (IQR) age at diagnosis was 55 (48-62) years. Primary intervention was surgical in 127/216 (58.8%); secondary intervention was systemic in 38/169 (22.5%); and tertiary intervention was radiation in 67/80 (83.8%). Overall, median days (IQR) for PT were 69 (53, 98), ST were 65 (42, 95), and TT were 69 (43, 88). PT was significantly longer in Black [105 (76, 142) days] patients compared to non-Hispanic White patients [68 (51, 107) days, P = 0.031)] and White Hispanic patients [65 (53,91) days, P = 0.014]. There were no significant differences in PT, ST, or TT by spoken language or insurance type. CONCLUSIONS: Black patients remain at risk due to prolonged time to intervention. Spanish-speaking status was not associated with inferior timeliness or completion of multimodal care at a safety net hospital. Identifying safety net hospital barriers to achieving benchmarks for timely completion of all phases of multimodal care warrants further attention.

Open Bedside Tracheostomy: Safe and Cost Saving but Underutilized Nationally.

OBJECTIVE: To evaluate open bedside tracheostomy (OBT) and compare it with open operating room (OR) tracheostomy and bedside percutaneous dilatational tracheostomy (PDT) in complications and cost. To determine the tracheostomy practice patterns of academic otolaryngology programs. STUDY DESIGN: Retrospective cohort study and cross-sectional study. SETTING: Public hospital and tertiary care hospital. METHODS: Otolaryngology program directors were surveyed to determine their institutions' tracheostomy practice patterns and the factors preventing the implementation of open bedside tracheostomies. A retrospective chart review was done of tracheostomies performed at our institutions from 2009 to 2019 for prolonged mechanical ventilation. Complications, length of intubation, comorbidities, body mass index, demographics, mortality rates, and decannulation rates were recorded. A cost analysis between OBT and PDT was conducted. RESULTS: Data from 802 patients were analyzed for 449 OBTs, 206 PDTs, and 147 open OR tracheostomies. Complication rates were low. PDTs were more likely to have perioperative tracheal bleeding (P = .028) and mucus plugging (P = .006). OBTs were performed on sicker patients with a higher Charlson Comorbidity Index than PDT and OR tracheostomies. The cost of OBT was less than that of PDT. The survey response rate of tracheostomy practice patterns was 46%. The otolaryngologists at the responding programs all conducted OR tracheostomies, while 52.7% did OBTs and 30.9% PDTs. CONCLUSION: OBT can be done safely in patients with multiple comorbidities and has a cost that can be less than PDT. Despite these benefits, only 50% of academic institutions routinely performed OBT.

Family Stressors and Resources as Social Determinants of Health among Caregivers and Young Children.

Life course-informed theories of development suggest it is important to integrate information about positive and negative aspects of the social environment into studies of child and parental wellbeing, including both stressors that compromise health and resources that promote well-being. We recruited a sample of 169 pairs of caregivers and young children (birth to 5 years) from a community health clinic and administered survey questions to assess stressors and resources. We constructed inventories of stressors and resources and examined the relationships between these inventories and caregivers' depressive symptoms, anxiety symptoms, and sleep problems, and young children's medical diagnoses derived from electronic health records. Cumulative stressors and resources displayed bivariate and adjusted associations with caregivers' depressive symptoms, anxiety symptoms, and sleep problems. For depressive and anxiety symptoms, these associations were evident in models that included stressors and resources together. Caregivers with high stressors and low resources displayed the highest levels of depressive and anxiety symptoms and sleep problems. In terms of children's health outcomes, only modest trends were evident for developmental/mental health outcomes, but not other diagnostic categories. Future studies are needed to examine stressors and resources together in larger samples and in relation to prospectively assessed measures of child well-being.

Diagnostic performance of the second-generation molecular tests in the assessment of indeterminate thyroid nodules: A systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the diagnostic performance of the second-generation molecular tests in the diagnosis of thyroid nodules with indeterminate fine-needle aspiration biopsy results. METHODS: We searched PubMed, Google Scholar, Scopus, and Cochrane Library for studies published between January 2017 and March 2021. Inclusion criteria were indeterminate thyroid results from fine-needle aspiration (FNA) that included Bethesda categories III and IV, use of Afirma GSC, Thyroseq v3, and ThyGeNext as an index test, and conclusive histopathological results. Studies with no post-surgical diagnoses were excluded. For each included study, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were obtained. Sensitivity and specificity were pooled jointly using a bivariate binomial random-effects model. Statistical significance was indicated at p-value less than 0.05. RESULTS: Our search yielded 431 non-duplicate articles, of which 15 were included in the study (7 GSC, 6 Thyroseq v3, and 2 ThyGeNext). ThyGeNext studies were excluded from the meta-analysis due to the small sample size. Pooled data for GSC studies on 472 thyroid nodules showed a sensitivity of 96.6 (95% confidence interval: 89.7-98.9%), specificity of 52.9% (23.4-80.5%), PPV of 63% (51-74%), and NPV of 96% (94-98%). Pooled data for ThyroSeq studies on 530 thyroid nodules showed a sensitivity of 95.1% (91.1-97.4%), specificity of 49.6% (29.3-70.1%), PPV of 70% (55-83%), and NPV of 92% (86-97%). There was no statistically significant difference in diagnostic performances of the two tests (p-values for sensitivity = 0.89, specificity = 0.82, PPV = 0.43, NPV = 0.17). CONCLUSION: High sensitivity and high NPV in GSC and Thyroseq v3 have potential to help rule out malignancy among thyroid nodules with indeterminate cytology results. There was no difference in diagnostic performances between the two molecular tests indicating that either test is appropriate to determine the malignancy of thyroid nodules. Further long-term outcome data are warranted to make a clear recommendation.

Understanding the Role of Past Health Care Discrimination in Help-Seeking and Shared Decision-Making for Depression Treatment Preferences.

As a part of a larger, mixed-methods research study, we conducted semi-structured interviews with 21 adults with depressive symptoms to understand the role that past health care discrimination plays in shaping help-seeking for depression treatment and receiving preferred treatment modalities. We recruited to achieve heterogeneity of racial/ethnic backgrounds and history of health care discrimination in our participant sample. Participants were Hispanic/Latino (n = 4), non-Hispanic/Latino Black (n = 8), or non-Hispanic/Latino White (n = 9). Twelve reported health care discrimination due to race/ethnicity, language, perceived social class, and/or mental health diagnosis. Health care discrimination exacerbated barriers to initiating and continuing depression treatment among patients from diverse backgrounds or with stigmatized mental health conditions. Treatment preferences emerged as fluid and shaped by shared decisions made within a trustworthy patient-provider relationship. However, patients who had experienced health care discrimination faced greater challenges to forming trusting relationships with providers and thus engaging in shared decision-making processes.

The Impact Of Medicare's Mental Health Cost-Sharing Parity On Use Of Mental Health Care Services.

Before the implementation of cost-sharing parity in Medicare, beneficiaries faced higher cost sharing for mental health services than for other medical services. The Medicare Improvements for Patients and Providers Act of 2008 phased in cost-sharing reductions in Medicare for outpatient mental health services in the period 2010-14. Using data for 2006-15 from the Medical Expenditure Panel Survey and difference-in-differences analyses, we assessed whether this reduction in mental health cost sharing was associated with changes in specialty and primary care outpatient mental health visits and psychotropic medication fills. We compared people with Medicare and with private insurance before and after parity implementation. Medicare beneficiaries' use of psychotropic medication increased after the implementation of cost-sharing parity, but we did not detect a change in visits. Changes in the use of psychotropic medications were greater among people with probable serious mental illness and among Medicare beneficiaries who did not report having supplemental coverage. The increased medication use could signal improvements in mental health care access among Medicare beneficiaries, especially among the subgroups most likely to benefit from the policy change.

Cost effectiveness of in vitro fertilisation and preimplantation genetic testing to prevent transmission of BRCA1/2 mutations.

STUDY QUESTION: Is it cost-effective to use in vitro fertilisation and preimplantation genetic testing of monogenic defects (IVT/PGT-M) to prevent transmission of BRCA1/2 mutations to second-generation new births in comparison with naturally conceived births? SUMMARY ANSWER: In this cost-effectiveness analysis, we found that IVF/PGT-M is cost-effective for BRCA1 and BRCA2 mutation carriers if using a willingness to pay of $50 000 per quality-adjusted life-year (QALY). WHAT IS KNOWN ALREADY: Carriers of a BRCA1 or BRCA2 mutation have a significantly increased risk of several types of cancer throughout their lifetime. The cost of risk reduction, screening and treatment of cancer in this population is high. In addition, there is a 50% chance of passing on this genetic mutation to each child. One option to avoid transmission of an inherited deleterious gene to one's offspring involves in vitro fertilisation with preimplantation genetic testing. STUDY DESIGN, SIZE, DURATION: We implemented a state transition model comparing the healthcare impact of a cohort of healthy children born after IVF/PGT-M, who have a population risk of developing cancer, to a cohort of naturally conceived live-births, half of whom are carriers of the BRCA mutation. Transition probabilities are based on published sources, a lifetime horizon and a perspective of a provincial Ministry of Health in Canada. PARTICIPANTS/MATERIALS, SETTING, METHODS: The target population is the second-generation new births who have at least one parent with a known BRCA1 or BRCA2 mutation. MAIN RESULTS AND THE ROLE OF CHANCE: At a willingness-to-pay threshold of $50 000 per QALY, IVF/PGT-M is a cost-effective intervention for carriers of either BRCA mutation. For BRCA1, the incremental cost-effectiveness ratio (ICER) for IVF/PGT-M is $14 242/QALY. For BRCA2, the ICER of intervention is $12 893/QALY. Probabilistic sensitivity analysis results show that IVF/PGT-M has a 98.4 and 97.3% chance of being cost-effective for BRCA1 and BRCA2 mutation carriers, respectively, at the $50 000/QALY threshold. LIMITATIONS, REASONS FOR CAUTION: Our model did not include the short-term negative effect of IVF/PGT-M on the woman's quality of life; in addition, our model did not consider any ethical issues related to post-implantation genetic testing. WIDER IMPLICATIONS OF THE FINDINGS: In countries in which the healthcare of a large segment of the population is covered by a single payer system such as the government, it would be cost-effective for that payer to cover the cost of IVF/PGT-M for couples in which one member has a BRCA mutation, in order to avoid the future costs and disutility of managing offspring with an inherited BRCA mutation. STUDY FUNDING/COMPETING INTEREST(S): Dr Wong's research program was supported by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC), the Canadian Liver Foundation and an Ontario Ministry of Research, Innovation and Science Early Researcher Award. All authors declared no conflict of interests.

Disparities in Mental Health Care Utilization and Perceived Need Among Asian Americans: 2012-2016.

OBJECTIVE: The objective was to examine mental health treatment access disparities between Asians and whites in the United States as well as the role of perceived and objective need and barriers to treatment in these disparities. METHODS: Data are five annual cross-sections (2012-2016) of responses from Asian Americans and whites to the nationally representative National Survey on Drug Use and Health. Multivariate logistic regression analyses adjusting for sociodemographic factors were conducted to compare past-year treatment access rates between Asians and whites across three need subgroups: those with perceived need for treatment, those with past-year serious psychological distress, and those with a past-year major depressive episode. Barriers to treatment were compared between Asians and whites with perceived need. RESULTS: Asians were less likely than whites to have accessed mental health treatment in the past year in all analyses. Compared with Asians with need determined by structured diagnostic instruments, Asians with perceived need had higher rates of mental health care access, but even among respondents with perceived need, the disparity between whites and Asians remained. Regarding barriers to treatment, only one barrier (not knowing where to go for treatment) was more likely to be reported for Asians than whites. CONCLUSIONS: Differences between Asians and whites in perceived need for mental health treatment do not explain the wide disparities in mental health care access between these two groups. Clinical interventions improving the relevance and fit of mental health care and community-based outreach interventions increasing awareness of available services are needed to improve access to mental health treatment among Asians.

A qualitative assessment of business perspectives and tactics of tobacco and vape shop retailers in three communities in Orange County, CA, 2015-2016.

BACKGROUND: In response to the growing awareness and use of electronic nicotine delivery systems (ENDS), or e-cigarettes, the U.S. Food and Drug Administration asserted its regulatory authority over ENDS in May 2016. Federal, state, and local regulatory action on ENDS may have significant and unique impacts on specialty ENDS retailers, including tobacco and vape shops. The purpose of this study is to describe the commercial motivations of vape shops in minority communities as business entities whose financial interests and actions may be particularly impacted by regulation of ENDS. METHODS: Specialty tobacco and vape retail stores in three minority communities were identified through an online search and community canvassing. Key informant interviews were conducted with tobacco and vape shop owners or managers discussing the business interests and tactics of selling ENDS for their store. Interview data were coded and analyzed for major themes. RESULTS: Interviews with 18 tobacco shops and 9 vape shops were completed. Tobacco shops' reasons for carrying e-cigarettes were business oriented, focused on maintaining their customer base. In comparison, vape shops opened because of the owner's positive experiences with e-cigarettes and belief in the potential of e-cigarettes to help people quit or reduce smoking. Tobacco shops mainly see their customers as using e-cigarettes to quit smoking whereas vape shops reported their customers using e-cigarettes for more varied reasons. Tobacco shops are much more limited in their marketing than vape shops, which rely heavily on social media and experimentation with other forms of marketing. CONCLUSIONS: Tobacco shops and vape shops differ in their rationale and approaches to the business of e-cigarettes. Vape shops engage in a wide range of activities that stabilize their financial interest and increase their influence with customers and within the vape community. In order for regulatory policymaking and tobacco control interventions to maximize effectiveness, the actions of vape shops in promoting ENDS use and influencing policy debates must be taken into account.

Examining racial/ethnic differences in patterns of benzodiazepine prescription and misuse.

BACKGROUND: Benzodiazepines (BZDs) are widely prescribed during psychiatric treatment. Unfortunately, their misuse has led to recent surges in overdose emergency visits and drug-related deaths. METHODS: Electronic health record data from a large healthcare system were used to describe racial/ethnic, sex, and age differences in BZD use and dependence. Among patients with a BZD prescription, we assessed differences in the likelihood of subsequently receiving a BZD dependence diagnosis, number of BZD prescriptions, receiving only one BZD prescription, and receiving 18 or more BZD prescriptions. We also estimated multivariate hazard models and generalized linear models, assessing racial/ethnic differences after adjustment for covariates. RESULTS: In both unadjusted and adjusted analyses, Whites were more likely than Blacks, Hispanics, and Asians to have a BZD dependence diagnosis and to receive a BZD prescription. Racial/ethnic minority groups received fewer BZD prescriptions, were more likely to have only one BZD prescription, and were less likely to have 18 or more BZD prescriptions. We identified greater BZD misuse among older patients but no sex differences. CONCLUSIONS: Findings from this study add to the emerging evidence of high relative rates of prescription drug abuse among Whites. There is a concern, given their greater likelihood of having only one BZD prescription, that Blacks, Hispanics, and Asians may be discontinuing BZDs before their clinical need is resolved. Research is needed on provider readiness to offer racial/ethnic minorities BZDs when indicated, patient preferences for BZDs, and whether lower prescription rates among racial/ethnic minorities offer protection against the progression from prescription to addiction.

Social Discrimination and Health Care: A Multidimensional Framework of Experiences among a Low-Income Multiethnic Sample.

The study aims to describe the perceived discriminatory health care treatment experiences and its impact on care among minority urban-dwelling adults. Semistructured qualitative interviews (N = 51) were conducted with patients from community-based health care settings, and systematic, grounded theory approach was used. Three distinct themes emerged: (a) the sources of discriminatory experiences, (b) its impact on health care, and (c) the provider/organization recommendations to address discriminatory practices. The study highlights the relevance of perceived discrimination in avoidance of health care services, nonadherence to treatment, and adverse health-related sequelae by low-income urban-dwelling adults with little access to health care.

A Public Health Approach in Responding to the Spread of Helium Suicide in Hong Kong.

BACKGROUND: The use of the helium suicide method has been increasing in popularity in Hong Kong since 2012. We have learned a valuable lesson in curbing the spread of charcoal burning (CB) suicide in the past 15 years and hope to prevent the helium suicide method from taking off in the community. AIMS: To document what actions have been taken to contain the spread of the helium suicide method and review the preliminary impact of these actions. METHOD: We adopted a public health approach by engaging stakeholders from multiple sectors, including the police force, the fire services department, coroners, pathologists, mass media, and online media outlets. RESULTS: A monitoring system was established by compiling data extracted from news reports, coroners' reports, and police investigations. Risk and protective factors were identified. Intervention strategies were developed to strengthen protective factors and minimize risk factors. This novel suicide method has not spread as rapidly as the CB suicide method. The preliminary outcomes suggest our actions to be effective. LIMITATIONS: The count of helium suicides in 2015 might be low. The impacts of the interventions are only estimated and require additional empirical verifications. CONCLUSION: The public health approach of engaging multiple partners in the early phase of a potential epidemic can be a good guide to meeting the challenges posed by any new suicide methods that emerge in the future.

Cost-effectiveness of prophylactic granulocyte colony-stimulating factor for febrile neutropenia in breast cancer patients receiving FEC-D.

5-fluorouracil, epirubicin, cyclophosphamide â†’ docetaxel (FEC-D) has been associated with higher-than-expected rates of febrile neutropenia (FN) that meet the current guideline threshold of 20 % for primary prophylaxis (PP) with granulocyte colony-stimulating factor (G-CSF). We examined the cost-effectiveness of FEC-D with varying strategies of G-CSF prophylaxis from the perspective of the public payer in Ontario, Canada. A state-transition model was developed to compare three strategies: FEC-D with secondary prophylaxis (SP) only, PP starting with the first cycle of D, and PP starting with the first cycle of FEC. Analysis was conducted for a hypothetical cohort of 50-year-old early-stage breast cancer patients undergoing adjuvant chemotherapy, at a 10-year horizon. Results were expressed in quality-adjusted life-years (QALYs) and 2013 Canadian dollars. Costs and benefits were discounted at 5 %. Event rates, costs, and utilities were derived from the literature. One-way and probabilistic sensitivity analyses were conducted. Using filgrastim, the incremental cost-effectiveness ratios (ICERs) for starting PP with the first cycle of D and starting PP with the first cycle of FEC, compared to using SP only, were $57,886/QALY and $116,186/QALY, respectively. With pegfilgrastim, the ICERs for the same strategies were $90,735/QALY and $149,483/QALY. Compared to using filgrastim SP only, starting PP with D had a 24 % chance of being cost-effective at a willingness-to-pay (WTP) threshold of $50,000/QALY, and a 99 % chance at a WTP threshold of $100,000/QALY. Results were sensitive to FN-related parameters, such as the risk of FN per cycle with D and the associated mortality, but were robust to uncertainty in parameters related to breast cancer, such as the utilities and hazard of relapse. FEC-D with PP starting with the first cycle of D is most likely to be cost-effective, especially with increased risk of FN and mortality from FN.

"Geography of suicide in Hong Kong: spatial patterning, and socioeconomic correlates and inequalities".

Past urban research on Western nations tends to show high suicide rates in inner city and socioeconomically deprived areas. However, little is known about geographic variations in suicide in non-Western cities. We used Bayesian hierarchical models to estimate smoothed standardised mortality ratios (2005-2010) for suicide in people aged 10 years or above in each geographic unit in Hong Kong at two levels, i.e. large street block (n = 1639; median population = 1860) and small tertiary planning unit group (n = 204; median population = 14,850). We further analysed their associations with a range of area socioeconomic characteristics and a deprivation index. The "city centre" of Hong Kong, a generally non-deprived area, showed mostly below average suicide rates. However, there were high rates concentrating in some socioeconomically deprived, densely populated areas, including some inner city areas, across the city. Males had greater geographic variations in rates than females, except the elderly group. The use of smaller geographic units revealed finer detailed suicide distribution than the use of larger units, and showed that suicide rates were associated with indicators of socioeconomic deprivation (population with non-professional jobs and low median household income), and social fragmentation (proportions of unmarried adults and divorced/separated adults), but not with Gini coefficient. Sex/age groups had different associations with suicide rates. Areas in the most deprived quintile had a suicide rate more than two times higher than the least deprived. The association between suicide and deprivation was stronger in males than females and more marked in the younger populations compared to the elderly. The spatial distribution of suicide in Hong Kong showed distinct patterning and a stronger association with income compared to findings from Western countries. Suicide prevention strategies should consider tackling the marked socioeconomic gradient in suicide and high risk in young and middle-aged males living in deprived areas.

Metabolites in safety testing assessment in early clinical development: a case study with a glucokinase activator.

The present article summarizes Metabolites in Safety Testing (MIST) studies on a glucokinase activator, N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319), which is under development for the treatment of type 2 diametes mellitus. Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Because M1 accounted for 65% of the drug-related material at steady state, an authentic standard was synthesized and used for comparison of steady-state exposures in humans and the 3-month safety studies in rats and dogs at the no-observed-adverse-effect level. Although circulating levels of M1 were very low in beagle dogs and female rats, adequate coverage was obtained in terms of total maximal plasma concentration (∼7.7× and 1.8×) and area under the plasma concentration-time curve (AUC; 3.6× and 0.8× AUC) relative to the 100- and 300-mg doses, respectively, in male rats. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC50 = 0.17 µM; M1: EC50 = 4.69 µM). Furthermore, M1 did not inhibit major human P450 enzymes (IC50 > 30 µM), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling. Insights gained from this analysis should lead to a more efficient and focused development plan for fulfilling MIST requirements with PF-04937319.

A semi-quantitative approach to compare high-sensitivity power Doppler sonography and conventional power Doppler sonography in the assessment of thyroid vascularity.

BACKGROUND: Ultrasound is a useful imaging tool in the assessment of thyroid glands, and Doppler ultrasound helps in the evaluation of thyroid vascularity. This study was undertaken to evaluate the difference in the thyroid vascularity demonstrated on the state-of-the-art high-sensitivity power Doppler sonography (HSPDS) and the conventional power Doppler sonography (PDS), and to investigate the feasibility of using a customized algorithm with image-processing software for semi-quantitative assessment of thyroid vascularity. METHODS: A total of 25 healthy volunteers were included in the study, and each subject had two thyroid ultrasound examinations with HSPDS and PDS, respectively. High sensitivity and conventional power Doppler sonograms of the thyroid glands were taken and recorded. To evaluate the vascularity of thyroid lobes quantitatively, a customized algorithm using the software Matlab was developed and used to analyze the ultrasound images. The vascularity of thyroid lobe (i.e., region of interest, ROI) was expressed as the vascular index (VI), which is the ratio of the number of color pixels to the total number of pixels within the ROI. RESULTS: Results showed that thyroid vascularity was detected in all thyroid lobes on both HSPDS and PDS. The mean VI of the thyroid lobes on HSPDS (right lobe, 0.31 +/- 0.08; left lobe, 0.32 +/- 0.07) was significantly higher than on PDS (right lobe, 0.18 +/- 0.09; left lobe, 0.16 +/- 0.08) (p < 0.05). There was no significant difference in the VI between the right and left thyroid lobes (p >0.05). On HSPDS, 96% of the thyroid lobes showed a VI <0.5, while 96% of thyroid lobes had a VI <0.3 on PDS. CONCLUSIONS: HSPDS is more sensitive than PDS in the detection of thyroid vascularity. The developed algorithm can quantify the color pixels on power Doppler sonograms, which is useful for objective assessment of thyroid vascularity.