Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.

PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

Soft, adhesive and conductive composite for electroencephalogram signal quality improvement.

Since electroencephalogram (EEG) is a very small electrical signal from the brain, it is very vulnerable to external noise or motion artifact, making it difficult to measure. Therefore, despite the excellent convenience of dry electrodes, wet electrodes have been used. To solve this problem, self-adhesive and conductive composites using carbon nanotubes (CNTs) in adhesive polydimethylsiloxane (aPDMS), which can have the advantages of both dry and wet electrodes, have been developed by mixing them uniformly with methyl group-terminated PDMS. The CNT/aPDMS composite has a low Young's modulus, penetrates the skin well, has a high contact area, and excellent adhesion and conductivity, so the signal quality is enhanced. As a result of the EEG measurement test, although it was a dry electrode, results comparable to those of a wet electrode were obtained in terms of impedance and motion noise. It also shows excellent biocompatibility in a human fibroblast cell test and a week-long skin reaction test, so it can measure EEG with high signal quality for a long period of time.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

Pathological complete response, long-term outcomes, and recurrence patterns in HER2-low versus HER2-zero breast cancer after neoadjuvant chemotherapy.

BACKGROUND: The interest in HER2-low breast cancer (BC) has increased in recent years with the development of novel anti-HER2 antibody-drug conjugates. Here, we investigated the clinical outcomes and relapse patterns of patients with HER2-low or -zero BCs in an Asian population. METHODS: We retrospectively identified HER2-low or -zero BC patients with stage I-III tumours who were treated with neoadjuvant chemotherapy and underwent curative surgery, between 2014 and 2018 at Asan Medical Center, Seoul, Korea. RESULTS: A total of 818 and 754 HER2-zero and HER2-low BC patients, respectively, were consecutively included in this analysis. The HER2-low group had more hormone receptor [HR]-positive patients (81% versus 56%, P < 0.001). The HER2-zero group had a higher proportion of patients who achieved pathological complete response (pCR) (14.7% versus 9.8%, P = 0.003); however, no significant differences of pCR rate by HER2 status were identified in the HR-positive (P = 0.4) and HR-negative groups (P = 0.3) when analysed separately. The HER2-low BC cases had higher 5-year overall survival (OS) and disease-free survival (DFS) rates (P < 0.001 for OS; P = 0.002 for DFS); however, no differences were observed in terms of OS and DFS by HER2 status in the HR-positive group (P = 0.21 for OS and P = 0.66 for DFS). CONCLUSIONS: Our current findings do not support that HER2-low BC had different biology and clinical features compared to HER2-zero BC in patients who treated with neoadjuvant chemotherapy. However, the prognostic impact of HER2-low status in BC remains controversial; thus warranting further research.

The effect of a methadone reformulation on opioid agonist treatment outcomes: A population-based study in British Columbia, Canada, 2013-14.

INTRODUCTION: The province of British Columbia, Canada, changed the existing oral anhydrous methadone solution to a 10-times more concentrated pre-mixed solution, Methadose®, on February 1, 2014. We aimed to assess the immediate effects of the methadone reformulation on missed doses, days off methadone, changes in medication dosing and dispensations of opioids for pain, and hospitalizations and mortality among all people receiving treatment at or near the time of the change. METHODS: We conducted a population-based retrospective cohort study including all individuals receiving at least one methadone dispensation in the 12 months prior to the study period. We executed a difference-in-differences analysis by estimating a multivariate regression model to compare outcomes in the three months before and after the reformulation (November 1, 2013 to April 30, 2014) versus a time-lagged control cohort with similar characteristics observed during an equivalent nonoverlapping interval. We used daily individual-level linked health administrative data capturing missed doses, days off methadone, changes in methadone dosing, concurrent dispensations of opioids for pain, hospitalizations, and mortality. We stratified the cohorts into three subgroups: (i) those receiving OAT for ≥12 months; (ii) those receiving OAT for <12 months; and (iii) those not receiving OAT at the start of the study period. We conducted sensitivity analyses and placebo tests to assess the robustness of our results. RESULTS: Among the 16,339 individuals receiving methadone during the study period, the reformulation was associated with more instances of methadone dose increases (34.5% [95% Confidence Interval (CI): 27.4%, 41.5%]). For those retained in treatment ≥12 months prior to the study period (n = 7449), the reformulation was associated with more instances of methadone dose increases (50.2% [39.5%, 60.8%]) and dispensations of opioids for pain (62.2% [40.8%, 83.5%]), as well as an increase in missed doses (41.9% [29.1%, 54.7%]) and days off methadone (62.6% [39.7%, 85.4%]). We found no statistically significant change in risk of hospitalization or mortality. Sensitivity analyses supported our results. CONCLUSION: Our results reinforce the need expressed by people receiving methadone for greater client involvement in the planning and implementation of regulatory changes that may impact client care, especially those patients with a relatively long treatment history.

Opioid Use Disorder and Perinatal Outcomes.

OBJECTIVES: Evidence on the perinatal health of mother-infant dyads affected by opioids is limited. Elevated risks of opioid-related harms for people with opioid use disorder (OUD) increase the urgency to identify protective factors for mothers and infants. Our objectives were to determine perinatal outcomes after an OUD diagnosis and associations between opioid agonist treatment and birth outcomes. METHODS: We conducted a population-based retrospective study among all women with diagnosed OUD before delivery and within the puerperium period in British Columbia, Canada, between 2000 and 2019 from provincial health administrative data. Controlling for demographic and clinical characteristics, we determined associations of opioid agonist treatment on birth weight, gestational age, infant disorders related to gestational age and birth weight, and neonatal abstinence syndrome via logistic regression. RESULTS: The population included 4574 women and 6720 live births. Incidence of perinatal OUD increased from 166 in 2000 to 513 in 2019. Compared with discontinuing opioid agonist treatment during pregnancy, continuous opioid agonist treatment reduced odds of preterm birth (adjusted odds ratio: 0.6; 95% confidence interval: 0.4-0.8) and low birth weight (adjusted odds ratio: 0.4; 95% confidence interval: 0.2-0.7). Treatment with buprenorphine-naloxone (compared with methadone) reduced odds of each outcome including neonatal abstinence syndrome (adjusted odds ratio: 0.6; 95% confidence interval: 0.4-0.9). CONCLUSIONS: Perinatal OUD in British Columbia tripled in incidence over a 20-year period. Sustained opioid agonist treatment during pregnancy reduced the risk of adverse birth outcomes, highlighting the need for expanded services, including opioid agonist treatment to support mothers and infants.

Characterizing opioid agonist treatment discontinuation trends in British Columbia, Canada, 2012-2018.

BACKGROUND: Given the elevated risk of mortality immediately following opioid agonist treatment (OAT) discontinuation, determining the frequency and timing of OAT discontinuation can help guide the planning of services to facilitate uninterrupted OAT. We sought to describe weekly and monthly trends in OAT episode discontinuations in British Columbia to determine the potential resource needs for implementing support services. METHODS: This population-based retrospective study utilized a provincial-level linkage of health administrative databases to identify all people with opioid use disorder (PWOUD) who received OAT between 01/2012-08/2018. We defined OAT episodes as continuous medication dispensations without interruptions in prescribed doses lasting ≥5 days for methadone and ≥6 days for buprenorphine/naloxone. We derived the percentage of PWOUD discontinuing OAT every month and we considered weekly discontinuations between 09/2017-08/2018, accounting for weeks during which monthly income assistance payments from social service programs occurred. RESULTS: Our study included 37,207 PWOUD discontinuing 158,027 OAT episodes. Discontinuations were relatively stable month-to-month, increasing from 10.6 % to 14.9 % (2012-2018). The monthly percentage of discontinuations was 21.2 % for buprenorphine/naloxone and 10.0 % for methadone. Weekly discontinuations were greater in income disbursement weeks (816; IQR: 752, 901) compared to other weeks (655; IQR: 615, 683; p < 0.01). CONCLUSIONS: We identified a high, and stable rate of monthly OAT discontinuations and a consistently higher rate of discontinuing treatment among PWOUD accessing buprenorphine/naloxone. There is an urgent need to develop the evidence base for interventions to support OAT engagement and to improve clinical management of OUD to address the opioid-related overdose crisis.

The cascade of care for opioid use disorder among youth in British Columbia, 2018.

BACKGROUND: Medication for opioid use disorder (MOUD) is associated with substantial reductions in the risk of mortality, and American and Canadian guidelines recommend it as part of the full range of available treatments for youth with opioid use disorder (OUD). We estimated the OUD cascade of care for all adolescents (ages 12-18) and young adults (19-24) with OUD in British Columbia, Canada (BC) in 2018. METHODS: Using a provincial-level linkage of six health administrative databases, we classified youth with OUD as adolescents (ages 12-18) or young adults (19-24) to compare with older adults (≥25) and described key factors known to influence engagement in health care. The eight-stage cascade of care included diagnosed with OUD, ever engaged in MOUD, recently in MOUD, currently in MOUD, and retained in MOUD for ≥1 month, ≥3 months, ≥12 months, ≥24 months. RESULTS: We identified 4048 youth diagnosed with OUD as of September 30, 2018 (6.3% of all people with OUD). Most were young adults, aged 19-24 (n = 3602; 89.0% of all youth), a majority of whom were males (n = 1984; 55.1%). In contrast, adolescents diagnosed with OUD (n = 446; 11.0% of all youth) were mostly females (n = 287; 64.4%). Compared to adolescents, there were more young adults diagnosed with OUD ever engaged in MOUD (71.4% v. 36.5%), currently on MOUD (29.3% v. 16.8%), and retained in care for ≥1 year (8.6% v. 2.0%). CONCLUSIONS: A high proportion of youth aged 12-24 diagnosed with OUD in a health care setting in British Columbia received MOUD yet continued engagement is infrequent, particularly for adolescents. Long-term treatment plans for youth need to consider including MOUD when appropriate as part of tailored, youth-friendly services.

Attributing health benefits to preventing HIV infections versus improving health outcomes among people living with HIV: an analysis in six US cities.

OBJECTIVE: Combination strategies generate health benefits through improved health outcomes among people living with HIV (PLHIV) and prevention of new infections. We aimed to determine health benefits attributable to improved health among PLHIV versus HIV prevention for a set of combination strategies in six US cities. DESIGN: A dynamic HIV transmission model. METHODS: Using a model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City (NYC) and Seattle, we assessed the health benefits of city-specific optimal combinations of evidence-based interventions implemented at publicly documented levels and at ideal (90% coverage) scale-up (2020-2030 implementation, 20-year study period). We calculated the proportion of health benefit gains (measured as quality-adjusted life-years) resulting from averted and delayed HIV infections; improved health outcomes among PLHIV; and improved health outcomes due to medication for opioid use disorder (MOUD). RESULTS: The HIV-specific proportion of total benefits ranged from 68.3% (95% credible interval: 55.3-80.0) in Seattle to 98.5% (97.5-99.3) in Miami, with the rest attributable to MOUD. The majority of HIV-specific health benefits in five of six cities were attributable HIV prevention, and ranged from 33.1% (26.1-41.1) in NYC to 83.1% (79.6-86.6) in Atlanta. Scaling up to ideal service levels resulted in three to seven-fold increases in additional health benefits, mostly from MOUD, with HIV-specific health gains primarily driven by HIV prevention. CONCLUSION: Optimal combination strategies generated a larger proportion of health benefits attributable to HIV prevention in five of six cities, underlining the substantial benefits of antiretroviral therapy engagement for the prevention of HIV transmission through viral suppression. Understanding to whom benefits accrue may be important in assessing the equity and impact of HIV investments.

Evaluation of risk mitigation measures for people with substance use disorders to address the dual public health crises of COVID-19 and overdose in British Columbia: a mixed-method study protocol.

INTRODUCTION: The COVID-19 pandemic was preceded by an ongoing overdose crisis and linked to escalating drug overdose deaths in British Columbia (BC). At the outset of these dual public health emergencies, the BC government announced interim Risk Mitigation Guidance (RMG) that permitted prescribing medication alternatives to substances, including opioids, alcohol, stimulants and benzodiazepines, an intervention sometimes referred to as 'safe supply'. This protocol outlines the approach for a study of the implementation of RMG and its impacts on COVID-19 infection, drug-related and systemic harms, continuity of care for people with substance use disorder (SUD), as well as their behavioural, psychosocial and well-being outcomes. METHODS AND ANALYSIS: We conducted a parallel mixed-method study that involved both analysis of population-level administrative health data and primary data collection, including a 10-week longitudinal observational study (target n=200), a cross-sectional survey (target n=200) and qualitative interviews (target n=60). We implemented a participatory approach to this evaluation, partnering with people with lived or living expertise of drug use, and researchers and public health decision-makers across the province. Linked population-level administrative databases will analyse data from a cohort of BC residents with an indication of SUD between 1996 and 2020. We will execute high-dimensional propensity score matching and marginal structural modelling to construct a control group and to assess the impact of RMG dispensation receipt on a collaboratively determined set of primary and secondary outcomes. ETHICS AND DISSEMINATION: Study activities were developed to adhere to the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, recommended COVID-19 research practices, and guided by the Truth and Reconciliation Commission's Calls to Action for public health, data governance and research ethics related to Indigenous people. Results will be disseminated incrementally, on an ongoing basis, through the consortium established for this study, then published in peer-reviewed journals.

Patent ductus arteriosus treatment trends and associated morbidities in neonates.

To evaluate national epidemiologic data on infants treated for patent ductus arteriosus (PDA) in Korea and analyze outcomes associated with different PDA treatments. We retrospectively evaluated data on 12,336 patients diagnosed with PDA (International Classification of Diseases-10 code: Q250) between 2015 and 2018 from the Health Insurance Review and Assessment database. Among them, 1623 patients underwent surgical ligation (code: O1671). We used birth certificate data from Statistics Korea to estimate the prevalence, diagnosis, and treatment of PDA. The prevalence of infants with PDA was 81 infants per 10,000 live births and 45.2% in very low birth weight (VLBW) infants, which increased from 2015 to 2018. PDA ligation was performed in 2571 infants and 22% VLBW infants. Medical treatment was administered to 4202 infants, which decreased significantly, especially in VLBW infants (62% to 53%). The proportion of treatment was as follows: conservative treatment (53.1%), intravenous ibuprofen (24.4%), surgery (20.4%), and oral ibuprofen (10.7%); that among 4854 VLBW infants was as follows: intravenous ibuprofen (46.3%), conservative treatment (33.2%), surgery (22.2%), and oral ibuprofen (14.2%). Surgical treatment had a significantly higher risk (odds ratio 1.36) of mortality than conservative treatment. Surgical and/or medical treatments were associated with a higher risk of morbidity. Recently, increased use of conservative management of PDA has contributed to improved neonatal outcomes in VLBW infants. Select patients may still benefit from surgical ligation following careful consideration.

High-b diffusivity of MS lesions in cervical spinal cord using ultrahigh-b DWI (UHb-DWI).

PURPOSE: The purpose of this study was to investigate UHb-rDWI signal in white matter tracts of the cervical spinal cord (CSC) and compare quantitative values between healthy control WM with both MS NAWM and MS WM lesions. METHODS: UHb-rDWI experiments were performed on (a) 7 MS patients with recently active or chronic lesions in CSC and on (b) 7 healthy control of similar age range and gender distribution to MS subjects. All MRI data were acquired using clinical 3T MRI system. Axial high-b diffusion images were acquired using 2D single-shot DW stimulated EPI with reduced FOV and a CSC-dedicated 8 channel array coil. High-b diffusion coefficient DH was estimated by fitting the signal-b curve to a double or single-exponential function. RESULTS: The high-b diffusivity DH values were measured as (0.767 ± 0.297) × 10-3 mm2/s in the posterior column lesions, averaged over 6 MS patients, and 0.587 × 10-3 mm2/s in the corticospinal tract for another patient. The averaged DH values of the 7 healthy volunteers from the posterior and lateral column were (0.0312 ± 0.0306) × 10-3 and (0.0505 ± 0.0205) × 10-3 mm2/s, respectively. UHb-rDWI signal-b curves of the MS patients revealed to noticeably behave differently to that of the healthy controls. The patient signal-b curves decayed with greater high-b decay constants to reach lower signal intensities relative to signal-b curves of the healthy controls. CONCLUSION: UHb-DWI of the CSC reveals a marked difference in signal-b-curves and DH values in MS lesions compared to NAWM and healthy control WM. Based on physical principles, we interpret these altered observations of quantitative diffusion values to be indicative of demyelination. Further studies in animal models will be required to fully interpret UHb-DWI quantitative diffusion values during demyelination and remyelination.

Preparation and characterization of a soluble eggshell membrane/agarose composite scaffold with possible applications in cartilage regeneration.

Articular hyaline cartilage is an extremely hydrated, not vascularized tissue with a low-cell density. The damage of this tissue can occur after injuries or gradual stress and tears (osteoarthritis), minor damages can be self-healed in several weeks, but major injuries may eventually require surgery. In fact, in this case, because of nature of the cartilage (the absence of cells and vascularization) it is difficult to expect its natural regeneration in a reasonable amount of time. In recent years, cell therapy, in which cells are directly transplanted, has attracted attention. In this study, a scaffold for implanting chondrocytes was prepared. The scaffold was made as a sponge using the eggshell membrane and agarose. The eggshell membrane is structurally similar to the extracellular matrix and nontoxic due to its many collagen components and has good biocompatibility and biodegradability. However, scaffolds made of collagen only has poor mechanical properties. For this reason, the disulfide bond of collagen extracted from the insoluble eggshell membrane was cut, converted into water-soluble, and then mixed with agarose to prepare a scaffold. Agarose is capable of controlling mechanical properties, has excellent biocompatibility, and is suitable for forming a hydrogel having a three-dimensional porosity. The scaffold was examined for Fourier-transform infrared, mechanical properties, biodegradability, and biocompatibility. In in vitro experiment, cytotoxicity, cell proliferation, and messenger RNA expression were investigated. The study demonstrated that the agarose/eggshell membrane scaffold can be used for chondrocyte transplantation.

Diagnosis of Opioid Use Disorder by Youths Assessed in Acute Care Settings in British Columbia, Canada.

OBJECTIVES: To describe trends in the number of youths diagnosed with opioid use disorder (OUD) and to identify factors associated with OUD diagnosis in acute care settings. STUDY DESIGN: Data from a population-based retrospective cohort study with linkage of 6 health administrative databases for 13 009 youth age 12-24 years identified with OUD between 2001 and 2018 in British Columbia, Canada were used to describe annual diagnoses. Using a multiple logistic regression model, we estimated the association between past-year health care utilization and OUD diagnosis in acute settings, controlling for sociodemographic and OUD-related comorbid conditions. RESULTS: Annual OUD diagnoses quadrupled between 2003 and 2017 (from 326 to 1473). Among the 6579 youth diagnosed with OUD between April 1, 2013 and September 30, 2018, 88.1% had past-year health system contacts. Youth age 12-18 had higher odds of OUD diagnosis in acute care (aOR 2.04; 95% CI 1.78, 2.34). Compared with no health care contact, youth receiving outpatient care only were less likely to be diagnosed with OUD in acute care (aOR 0.69; 95% CI 0.56, 0.84) and those with >1 urgent hospitalization were more likely to be diagnosed with OUD in acute care (aOR 1.87; 95% CI 1.40,2.49). CONCLUSIONS: More than 88% of youth had past-year health system contacts prior to diagnosis. Those age 12-18 years and with urgent hospitalizations in the year prior to diagnosis were more likely to have OUD diagnosed in acute care settings. Establishing an effective evidence-based system for early detection and intervention among youth with OUD must be a priority.

Main and Accessory Canal Filling Quality of a Premixed Calcium Silicate Endodontic Sealer According to Different Obturation Techniques.

The present study aimed to investigate the effects of different obturation techniques on the main and accessory canal filling quality of a premixed calcium silicate endodontic sealer (Endoseal TCS). We also highlighted the validity of the methods used for evaluating the canal filling quality. Thirty single-rooted premolars were used for the main canal filling and 75 were used for accessory canal filling. The canals were instrumented and randomly divided into three groups according to the filling techniques: (1) single-cone technique (SC), (2) single-cone with ultrasonic activation (SU), and (3) warm vertical compaction (WV). Voids in relation to the root canal fillings were assessed using cross-section images from microcomputed tomography (µCT) scans or transversely sectioned tooth specimens (n = 10). After demineralization and clearing of the teeth, the incidence, number, and completeness of the accessory canal fillings were evaluated (n = 25). One-way analysis of variance (ANOVA) and Tukey's post hoc test was used for the evaluation of the voids in the main root canal and the incidence and number of filled accessory canals. Pearson's chi-squared (χ2) test was used for the evaluation of the filling completeness (α = 0.05). In the stereomicroscopic evaluation of the sectioned specimen, the SC group had significantly higher void occurrence than the other groups (p < 0.05), although there was no difference between groups in the µCT evaluation. However, there was no difference between the SU and WV. There was no difference between all the groups regarding the incidence, number, and completeness of the accessory canal fillings. When the premixed calcium silicate sealer is used with SC, the ultrasonic activation is recommended to obtain a better main canal filling quality. In contrast, the obturation techniques did not affect the accessory canal filling. We also recommend using the sectioning method when the void formation in the root canal filling materials is evaluated.

The adherence-associated Fdp fasciclin I domain protein of the biohydrogen producer Rhodobacter sphaeroides is regulated by the global Prr pathway.

Expression of fdp, encoding a fasciclin I domain protein important for adherence in the hydrogen-producing bacterium Rhodobacter sphaeroides, was investigated under a range of conditions to gain insights into optimization of adherence for immobilization strategies suitable for H2 production. The fdp promoter was linked to a lacZ reporter and expressed in wild type and in PRRB and PRRA mutant strains of the Prr regulatory pathway. Expression was significantly negatively regulated by Prr under all conditions of aerobiosis tested including anaerobic conditions (required for H2 production), and aerobically regardless of growth phase, growth medium complexity or composition, carbon source, heat and cold shock and dark/light conditions. Negative fdp regulation by Prr was reflected in cellular levels of translated Fdp protein. Since Prr is required directly for nitrogenase expression, we propose optimization of Fdp-based adherence in R. sphaeroides for immobilized biohydrogen production by inactivation of the PrrA binding site(s) upstream of fdp.

Estimates of opioid use disorder prevalence from a regression-based multi-sample stratified capture-recapture analysis.

BACKGROUND: An epidemic of opioid overdose has spread across North America, with illicit drug-related overdose emerging as a leading cause of death in recent years. Estimates of opioid use disorder (OUD) prevalence at the level of the public health service delivery area are needed to project resource needs and identify priority areas for targeted intervention. Our objective is to estimate the annual prevalence of OUD in British Columbia (BC), Canada, from 2000 to 2017. METHODS: We performed a multi-sample stratified capture-recapture analysis to estimate OUD prevalence in BC. The analysis included individuals identified from 3 administrative databases for 2000-2011 and 4 databases for 2012-2017, linked at the individual level. Negative binomial regression models on the counts of individuals within these strata were used to estimate prevalence, adjusting for dependency between databases. RESULTS: OUD prevalence in BC among people aged 12 years or older was 1.00 % (N = 34,663 individuals) in 2000 and increased to 1.54 % (N = 61,080) in 2011. Between 2013 and 2017 prevalence increased from 1.57 % (95 % confidence interval: 1.56-1.58) to 1.92 % (1.89-1.95; N = 83,760; 82,492-84,855). The greatest increases in prevalence were observed among males 12-30 years old and 31-44 years old, with 43.2 % and 40.2 % increases from 2013 to 2017. CONCLUSIONS: In BC, the OUD prevalence was 1.92 % among people 12 years or older in 2017. We estimated that prevalence has nearly doubled since 2000, with the highest increases in prevalence observed among males under 45.

Ending the HIV Epidemic Among Persons Who Inject Drugs: A Cost-Effectiveness Analysis in Six US Cities.

BACKGROUND: Persons who inject drugs (PWID) are at a disproportionately high risk of HIV infection. We aimed to determine the highest-valued combination implementation strategies to reduce the burden of HIV among PWID in 6 US cities. METHODS: Using a dynamic HIV transmission model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City, and Seattle, we assessed the value of implementing combinations of evidence-based interventions at optimistic (drawn from best available evidence) or ideal (90% coverage) scale-up. We estimated reduction in HIV incidence among PWID, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) for each city (10-year implementation; 20-year horizon; 2018 $ US). RESULTS: Combinations that maximized health benefits contained between 6 (Atlanta and Seattle) and 12 (Miami) interventions with ICER values ranging from $94 069/QALY in Los Angeles to $146 256/QALY in Miami. These strategies reduced HIV incidence by 8.1% (credible interval [CI], 2.8%-13.2%) in Seattle and 54.4% (CI, 37.6%-73.9%) in Miami. Incidence reduction reached 16.1%-75.5% at ideal scale. CONCLUSIONS: Evidence-based interventions targeted to PWID can deliver considerable value; however, ending the HIV epidemic among PWID will require innovative implementation strategies and supporting programs to reduce social and structural barriers to care.

A later menopausal age is associated with a lower prevalence of physical frailty in community-dwelling older adults: The Korean Frailty and Aging Cohort Study (KFACS).

OBJECTIVES: The aim of this study was to determine whether age at menopause is associated with physical frailty. METHODS: This was a cross-sectional study that included 1264 women (70-84 years) from the Korean and Aging Cohort Study (KFACS) who had records of their ages at menarche and their ages at menopause and had experienced a natural menopause. We used Fried criteria to assess physical frailty status. The ages at menopause and menarche were collected using self-reported questionnaires. RESULTS: The prevalence of physical frailty decreased by 5.3 % with each year of increase in age at menopause after adjusting for age, marital status, years of education, diabetes mellitus, hypertension, polypharmacy, hospitalizations, falls, and hormone replacement therapy (p = 0.005). The prevalence of frailty significantly decreased by 4.1 % when the reproductive span increased by a year (p = 0.019). CONCLUSIONS: This study found that a later menopausal age was associated with a lower risk of frailty using Fried criteria. In addition, it showed that a longer reproductive span was associated with a lower prevalence of frailty.

Can the 'Ending the HIV Epidemic' initiative transition the USA towards HIV/AIDS epidemic control?

: Using a dynamic HIV transmission model calibrated for six USA cities, we projected HIV incidence from 2020 to 2040 and estimated whether an established UNAIDS HIV epidemic control target could be met under ideal implementation of optimal combination strategies previously defined for each city. Four of six cities (Atlanta, Baltimore, New York City and Seattle) were projected to achieve epidemic control by 2040 and we identified differences in reaching epidemic control across racial/ethnic groups.