Addressing Intergenerational Inequity in Tobacco-Harm: What Helps Children of Smokers to Remain Nonsmokers?

INTRODUCTION: Children of people who smoke are more likely to take up smoking themselves. In Aotearoa New Zealand (NZ), adolescent smoking declined dramatically between 2000 and 2016 despite limited change in parental smoking, demonstrating that the cycle can be broken. AIMS AND METHODS: This study aimed to identify modifiable factors associated with never smoking in Year 10 students (14-15 years) who had at least one caregiver who smoked. We used data from the Youth Insights Survey (2016 and 2018, pooled, N = 5,422) and identified students with at least one caregiver (mother, father, grandparent, other caregiver) who smoked (N = 2,205). To investigate modifiable factors potentially associated with nonsmoking we used logistic regression with marginally adjusted prevalence estimates. RESULTS: Overall, 41% of students had at least one caregiver who smoked. In this group, the majority (65%) had never smoked themselves. After adjustment, never-smoking was more prevalent among students attending low-deprivation (more affluent) schools (73% had never smoked) compared to high-deprivation schools (44%); students not exposed to others' smoking inside the home (72%) or in cars (70%) in the past week compared to those exposed (59% and 51%, respectively); and students whose parents would be upset if they were caught smoking (68% vs 49% for those whose parents would not be upset), or who had high self-esteem (69% vs 55% for those with low self-esteem). CONCLUSIONS: Modifiable factors independently associated with non-smoking in adolescents with caregiver(s) who smoked were: nonexposure to smoking inside the home and in cars, parental expectations of nonsmoking, and high self-esteem. IMPLICATIONS: Even in countries like NZ with relatively low adult smoking rates, children's exposure to caregiver smoking may be prevalent, particularly in structurally disadvantaged populations. This study suggests that action to promote smokefree homes and cars, build high self-esteem in young people, and communicate expectations of non-smoking are likely to help children of people who smoke to remain nonsmokers. A comprehensive approach that also addresses "upstream" factors (eg, socioeconomic deprivation) and underlying causes of structural inequity (eg, institutional racism) is needed. Such policy and community action may help to break intergenerational cycles of tobacco use and health inequity.

A machine learning case study to predict rare clinical event of interest: imbalanced data, interpretability, and practical considerations.

Accurate prediction of a rare and clinically important event following study treatment has been crucial in drug development. For instance, the rarity of an adverse event is often commensurate with the seriousness of medical consequences, and delayed detection of the rare adverse event can pose significant or even life-threatening health risks to patients. In this machine learning case study, we demonstrate with an example originated from a real clinical trial setting how to define and solve the rare clinical event prediction problem using machine learning in pharmaceutical industry. The unique contributions of this work include the proposal of a six-step investigation framework that facilitates the communication with non-technical stakeholders and the interpretation of the model performance in terms of practical consequences in the context of patient screenings for conducting a future clinical trial. In terms of machine learning methodology, for data splitting into the training and test sets, we adapt the rare-event stratified split approach (from scikit-learn) to further account for group splitting for multiple records of a patient simultaneously. To handle imbalanced data due to rare events in model training, the cost-sensitive learning approach is employed to give more weights to the minor class and the metrics precision together with recall are used to capture prediction performance instead of the raw accuracy rate. Finally, we demonstrate how to apply the state-of-the-art SHAP values to identify important risk factors to improve model interpretability.

Increased Incidence of Legionellosis after Improved Diagnostic Methods, New Zealand, 2000-2020.

Legionellosis, notably Legionnaires' disease, is recognized globally and in New Zealand (Aotearoa) as a major cause of community-acquired pneumonia. We analyzed the temporal, geographic, and demographic epidemiology and microbiology of Legionnaires' disease in New Zealand by using notification and laboratory-based surveillance data for 2000‒2020. We used Poisson regression models to estimate incidence rate ratios and 95% CIs to compare demographic and organism trends over 2 time periods (2000-2009 and 2010-2020). The mean annual incidence rate increased from 1.6 cases/100,000 population for 2000-2009 to 3.9 cases/100,000 population for 2010-2020. This increase corresponded with a change in diagnostic testing from predominantly serology with some culture to almost entirely molecular methods using PCR. There was also a marked shift in the identified dominant causative organism, from Legionella pneumophila to L. longbeachae. Surveillance for legionellosis could be further enhanced by greater use of molecular typing of isolates.

Causal inference for longitudinal data based on historical controls.

Use of historical data has become a hot topic recently, considered to provide a way to reduce patient burden, lower drug development cost, and make innovative therapies available to patients earlier. In a single-arm study designed to examine the benefit of an experimental treatment, there is often a desire to compare the outcomes of patients receiving the new intervention with those receiving a control treatment, which can be extracted from sources such as historical trials or electronic medical records. Since the treatment is not randomly assigned, there is a need to adjust for the potential imbalance in key patient characteristics between the current study and historical controls. If the outcome of interest is measured longitudinally and subject to random missing, the required adjustment becomes more complicated. In this paper, we propose a doubly robust adjustment procedure specifically designed for longitudinal data analysis with missing data. The proposed method yields valid analysis results, if either the propensity score model or the mixed effects model for repeated measures (MMRM) regression model is correctly specified. An extensive numerical study is conducted to examine the performance of the proposed method. Data from a real clinical trial comparing with historical data are analyzed as an example applying the proposed procedure.

Rising Ethnic Inequalities in Acute Rheumatic Fever and Rheumatic Heart Disease, New Zealand, 2000-2018.

We describe trends in acute rheumatic fever (ARF), rheumatic heart disease (RHD), and RHD deaths among population groups in New Zealand. We analyzed initial primary ARF and RHD hospitalizations during 2000-2018 and RHD mortality rates during 2000-2016. We found elevated rates of initial ARF hospitalizations for persons of Maori (adjusted rate ratio [aRR] 11.8, 95% CI 10.0-14.0) and Pacific Islander (aRR 23.6, 95% CI 19.9-27.9) ethnicity compared with persons of European/other ethnicity. We also noted higher rates of initial RHD hospitalization for Maori (aRR 3.2, 95% CI 2.9-3.5) and Pacific Islander (aRR 4.6, 95% CI 4.2-5.1) groups and RHD deaths among these groups (Maori aRR 12.3, 95% CI 10.3-14.6, and Pacific Islanders aRR 11.2, 95% CI 9.1-13.8). Rates also were higher in socioeconomically disadvantaged neighborhoods. To curb high rates of ARF and RHD, New Zealand must address increasing social and ethnic inequalities.

Ethnically Disparate Disease Progression and Outcomes among Acute Rheumatic Fever Patients in New Zealand, 1989-2015.

We investigated outcomes for patients born after 1983 and hospitalized with initial acute rheumatic fever (ARF) in New Zealand during 1989-2012. We linked ARF progression outcome data (recurrent hospitalization for ARF, hospitalization for rheumatic heart disease [RHD], and death from circulatory causes) for 1989-2015. Retrospective analysis identified initial RHD patients <40 years of age who were hospitalized during 2010-2015 and previously hospitalized for ARF. Most (86.4%) of the 2,182 initial ARF patients did not experience disease progression by the end of 2015. Progression probability after 26.8 years of theoretical follow-up was 24.0%; probability of death, 1.0%. Progression was more rapid and ≈2 times more likely for indigenous Maori or Pacific Islander patients. Of 435 initial RHD patients, 82.2% had not been previously hospitalized for ARF. This young cohort demonstrated low mortality rates but considerable illness, especially among underserved populations. A national patient register could help monitor, prevent, and reduce ARF progression.

Current state of commercial point-of-care nucleic acid tests for infectious diseases.

The COVID-19 pandemic has put the spotlight on the urgent need for integrated nucleic acid tests (NATs) for infectious diseases, especially those that can be used near patient ("point-of-care", POC), with rapid results and low cost, but without sacrificing sensitivity or specificity of gold standard PCR tests. In the US, the Clinical Laboratory Improvement Amendments Certificate of Waiver (CLIA-waiver) is mandated by the Food and Drug Administration (FDA) and designated to any laboratory testing with high simplicity and low risk for error, suitable for application in the POC. Since the first issuance of CLIA-waiver to Abbot's ID NOW Influenza A&B in 2015, many more NAT systems have been developed, received the CLIA-waiver in the US or World Health Organization (WHO)'s pre-qualification, and deployed to the front line of infectious disease detection. This review highlights the regulatory process for FDA and WHO in evaluating these NATs and the technology innovation of existing CLIA-waived systems. Understanding the technical advancement and challenges, unmet needs, and the trends of commercialization facilitated through the regulatory processes will help pave the foundation for future development and technology transfer from research to the market place.

HIV detection from human serum with paper-based isotachophoretic RNA extraction and reverse transcription recombinase polymerase amplification.

The number of people living with HIV continues to increase with the current total near 38 million, of which about 26 million are receiving antiretroviral therapy (ART). These treatment regimens are highly effective when properly managed, requiring routine viral load monitoring to assess successful viral suppression. Efforts to expand access by decentralizing HIV nucleic acid testing in low- and middle-income countries (LMICs) has been hampered by the cost and complexity of current tests. Sample preparation of blood samples has traditionally relied on cumbersome RNA extraction methods, and it continues to be a key bottleneck for developing low-cost POC nucleic acid tests. We present a microfluidic paper-based analytical device (µPAD) for extracting RNA and detecting HIV in serum, leveraging low-cost materials, simple buffers, and an electric field. We detect HIV virions and MS2 bacteriophage internal control in human serum using a novel lysis and RNase inactivation method, paper-based isotachophoresis (ITP) for RNA extraction, and duplexed reverse transcription recombinase polymerase amplification (RT-RPA) for nucleic acid amplification. We design a specialized ITP system to extract and concentrate RNA, while excluding harsh reagents used for lysis and RNase inactivation. We found the ITP µPAD can extract and purify 5000 HIV RNA copies per mL of serum. We then demonstrate detection of HIV virions and MS2 bacteriophage in human serum within 45-minutes.

New Metrics Needed in the Evaluation of Hearing Hazard Associated With Industrial Noise Exposure.

OBJECTIVES: To evaluate (1) the accuracy of the International Organization for Standardization (ISO) standard ISO 1999 [(2013), International Organization for Standardization, Geneva, Switzerland] predictions of noise-induced permanent threshold shift (NIPTS) in workers exposed to various types of high-intensity noise levels, and (2) the role of the kurtosis metric in assessing noise-induced hearing loss (NIHL). DESIGN: Audiometric and shift-long noise exposure data were acquired from a population (N = 2,333) of screened workers from 34 industries in China. The entire cohort was exclusively divided into subgroups based on four noise exposure levels (85 ≤ LAeq.8h < 88, 88 ≤ LAeq.8h < 91, 91 ≤ LAeq.8h < 94, and 94 ≤ LAeq.8h ≤ 100 dBA), two exposure durations (D ≤ 10 years and D > 10 years), and four kurtosis categories (Gaussian, low-, medium-, and high-kurtosis). Predicted NIPTS was calculated using the ISO 1999 model for each participant and the actual measured NIPTS was corrected for age and sex also using ISO 1999. The prediction accuracy of the ISO 1999 model was evaluated by comparing the NIPTS predicted by ISO 1999 with the actual NIPTS. The relation between kurtosis and NIPTS was also investigated. RESULTS: Overall, using the average NIPTS value across the four audiometric test frequencies (2, 3, 4, and 6 kHz), the ISO 1999 predictions significantly (p < 0.001) underestimated the NIPTS by 7.5 dB on average in participants exposed to Gaussian noise and by 13.6 dB on average in participants exposed to non-Gaussian noise with high kurtosis. The extent of the underestimation of NIPTS by ISO 1999 increased with an increase in noise kurtosis value. For a fixed range of noise exposure level and duration, the actual measured NIPTS increased as the kurtosis of the noise increased. The noise with kurtosis greater than 75 produced the highest NIPTS. CONCLUSIONS: The applicability of the ISO 1999 prediction model to different types of noise exposures needs to be carefully reexamined. A better understanding of the role of the kurtosis metric in NIHL may lead to its incorporation into a new and more accurate model of hearing loss due to noise exposure.

Microbiota or placebo after antimicrobial therapy for recurrent Clostridioides difficile at home: A clinical trial with novel home-based enrollment.

INTRODUCTION: Clostridiodes difficile infection is the leading cause of infectious diarrhea in the United States, with substantial morbidity and mortality. Recurrent infection is especially challenging, with each recurrence increasing the likelihood of a successive recurrence, leading to cycles of prolonged symptoms, frequent antimicrobial use, and decreased quality of life. Fecal microbiota transplantation to prevent recurrent infection is a promising intervention with a large effect size in observational studies, but with conflicting results from randomized controlled trials. We are conducting a Veterans Affairs-wide randomized controlled trial utilizing centralized case identification, with enrollment and fecal microbiota transplant administration occurring at the participant's home. This type of trial design significantly improves trial efficiency, greatly decreases trial cost, increases consistency of trial administration, and most importantly makes nationwide clinical trials in less-common diseases possible. METHODS: This is a randomized comparison of capsule-delivered fecal microbiota transplant for the prevention of recurrent Clostridiodes difficile infection, administered after successful initial treatment of recurrent C. difficile infection with standard therapy. The primary endpoint is the incidence of recurrent C. difficile infection or death. Cases are identified by searching the Veterans Affairs Corporate Data Warehouse, with central study coordinators then reaching out to potential participants. Individuals meeting inclusion criteria and interested in participation are scheduled for in-home consent, randomization, and capsule administration, followed by telephone follow-up for 6 months. To mitigate risks of COVID-19, enrollment via video visits has been implemented. RESULTS: A total of 102 participants have been enrolled through January 2021. Centralized case identification and in-home enrollment has facilitated enrollment from 34 unique states, with 38% being from rural or highly rural areas. DISCUSSION: Centralized case identification and in-home enrollment is a feasible and innovative method of conducting randomized controlled trials in the Veterans Affairs system, improving access to clinical research for populations who may have difficulty engaging with the traditional model of clinical trials where enrollment is based at large hospitals in major metropolitan areas.

Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1).

PURPOSE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10- and 15-µg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations. DESIGN: Randomized, 20-month, multicenter, subject- and efficacy evaluator-masked, parallel-group, phase 3 clinical study. PARTICIPANTS: Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 am) of 22-32 mmHg after washout. METHODS: Study eyes received bimatoprost implant 10 µg (n = 198) or 15 µg (n = 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n = 198). Intraocular pressure was measured at hours 0 and 2 at each visit. MAIN OUTCOME MEASURES: Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). RESULTS: Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5-17.2, 16.5-17.0, and 17.1-17.5 mmHg through week 12 in the 10-µg implant, 15-µg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-µg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of ≥20% CECD loss was 10.2% (10-µg implant) and 21.8% (15-µg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit. CONCLUSIONS: Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-µg implant over the 15-µg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma.

Automated safety event monitoring using electronic medical records in a clinical trial setting: Validation study using the VA NEPHRON-D trial.

BACKGROUND/AIMS: Electronic medical records are now frequently used for capturing patient-level data in clinical trials. Within the Veterans Affairs health care system, electronic medical record data have been widely used in clinical trials to assess eligibility, facilitate referrals for recruitment, and conduct follow-up and safety monitoring. Despite the potential for increased efficiency in using electronic medical records to capture safety data via a centralized algorithm, it is important to evaluate the integrity and accuracy of electronic medical record-captured data. To this end, this investigation assesses data collection, both for general and study-specific safety endpoints, by comparing electronic medical record-based safety monitoring versus safety data collected during the course of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) clinical trial. METHODS: The VA NEPHRON-D study was a multicenter, double-blind, randomized clinical trial designed to compare the effect of combination therapy (losartan plus lisinopril) versus monotherapy (losartan) on the progression of kidney disease in individuals with diabetes and proteinuria. The trial's safety outcomes included serious adverse events, hyperkalemia, and acute kidney injury. A subset of the participants (~62%, n = 895) enrolled in the trial's long-term follow-up sub-study and consented to electronic medical record data collection. We applied an automated algorithm to search and capture safety data using the VA Corporate Data Warehouse which houses electronic medical record data. Using study safety data reported during the trial as the gold standard, we evaluated the sensitivity and precision of electronic medical record-based safety data and related treatment effects. RESULTS: The sensitivity of the electronic medical record-based safety for hospitalizations was 65.3% without non-VA hospitalization events and 92.3% with the non-VA hospitalization events included. The sensitivity was only 54.3% for acute kidney injury and 87.3% for hyperkalemia. The precision of electronic medical record-based safety data was 89.4%, 38%, and 63.2% for hospitalization, acute kidney injury, and hyperkalemia, respectively. Relative treatment differences under the study and electronic medical record settings were 15% and 3% for hospitalization, 123% and 29% for acute kidney injury, and 238% and 140% for hyperkalemia, respectively. CONCLUSION: The accuracy of using automated electronic medical record safety data depends on the events of interest. Identification of all-cause hospitalizations would be reliable if search methods could, in addition to VA hospitalizations, also capture non-VA hospitalizations. However, hospitalization is different from a cause-specific serious adverse event that could be more sensitive to treatment effects. In addition, some study-specific safety events were not easily identified using the electronic medical records. This limits the effectiveness of the automated central database search for purposes of safety monitoring. Hence, this data captured approach should be carefully considered when implementing endpoint data collection in future pragmatic trials.

Urea reduction ratio may be a simpler approach for measurement of adequacy of intermittent hemodialysis in acute kidney injury.

BACKGROUND: Assessment of adequacy of intermittent hemodialysis (IHD) is conventionally based upon urea kinetic models for calculation of single pool Kt/Vurea (Kt/V), with 1.2 accepted as minimum adequate clearance for thrice weekly IHD. In the Acute Renal Failure Trial Network (ATN) Study, adequacy of IHD in patients with acute kidney injury (AKI) was assessed using Kt/V. However, equations for Kt/V require volume of distribution of urea, which is highly variable in AKI. Therefore, simpler methods are needed to assess adequacy of IHD in AKI. We assessed correlation of urea reduction ratio (URR) with Kt/V and determined URR thresholds corresponding to Kt/V values to determine if URR could be a simpler means to assess the delivered dose of IHD. METHODS: Using patients who received IHD for 2.5-6 h and with pre-dialysis BUN ≥20 mg/dL, we plotted URR against Kt/V. We determined URR thresholds (0.60 to 0.75) corresponding to Kt/V ≥ 1.2, 1.3, and 1.4. We generated receiver operating characteristic (ROC) curves for increasing URR values for each level of Kt/V to identify the corresponding thresholds of URR. RESULTS: There was strong correlation between URR and Kt/V. ROC curves comparing URR with Kt/V ≥ 1.2, 1.3, and 1.4 had area under the curves (AUC) of 0.99. Sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.2 were 0.769 (95% CI: 0.745 to 0.793) and 0.999 (95% CI: 0.997 to 1.000), respectively and the sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.4 were 0.998 (95% CI: 0.995 to 1.000) and 0.791 (95% CI: 0.771 to 0.811), respectively. CONCLUSIONS: Targeting a URR ≥0.67 provides a simplified means of assessing adequacy of IHD in patients with AKI. Use of URR will enhance ability to assess delivery of small solute clearance and improve adherence with clinical practice guidelines in AKI.

The allosteric glycogen synthase kinase-3 inhibitor NP12 limits myocardial remodeling and promotes angiogenesis in an acute myocardial infarction model.

A key feature of acute myocardial infarction (AMI) is an alteration in cardiac architecture. Signaling events that result in the inhibition of glycogen synthase kinase-3 (GSK-3)ß represent an adaptive response that might limit the extent of adverse remodeling in the aftermath of AMI. Here, we report that an allosteric inhibitor of GSK-3ß, 4-benzyl-2-(naphthalene-1-yl)-1,2,4-thiadiazolidine-3,5-dione (NP12), lessens the magnitude of adverse myocardial remodeling and promotes angiogenesis. Male and female mice 8-10 weeks old were grouped (six animals in each group) into sham surgery (sham group), left anterior descending (LAD) ligation of the coronary artery followed by intramyocardial PBS injections (control group), and LAD ligation followed by NP12 administration (NP12 group). After 7 and 14 days, the extents of fibrosis and integrity of blood vessels were determined. Intramyocardial administration of NP12 increased phosphorylation of GSK-3ß, reduced fibrosis, and restored diastolic function in the mice that had experienced an AMI. Morphometric analyses revealed increased CD31+ and Ki67+ vascular structures and decreased apoptosis in these mice. NP12 administration mediated proliferation of reparative cells in the AMI hearts. In a time-course analysis, Wnt3a and NP12 stabilized ß-catenin and increased expression of both Nanog and VEGFR2. Moreover, NP12 increased the expression of ß-catenin and Nanog in myocardium from AMI mice. Finally, loss- and gain-of-function experiments indicated that the NP12-mediated benefit is, in part, Nanog-specific. These findings indicate that NP12 reduces fibrosis, reestablishes coronary blood flow, and improves ventricular function following an AMI. We conclude that NP12 might be useful for limiting ventricular remodeling after an AMI.

Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease.

Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.

Bimatoprost sustained-release intracameral implant reduces episcleral venous pressure in dogs.

OBJECTIVE: To determine the effect of a bimatoprost sustained-release intracameral implant (Bimatoprost SR) on episcleral venous pressure (EVP) in normal dogs. METHODS: Normotensive beagle dogs were randomized to receive Bimatoprost SR 30 µg (n = 7) or sham injection (needle insertion only, n = 7) in one eye on day 1. EVP was measured with an episcleral venomanometer through day 65. Episcleral aqueous outflow vessels were identified using fluorescence imaging following intracameral injection of indocyanine green in one additional animal. A separate cohort of dogs that had been trained for conscious intraocular pressure (IOP) measurements received Bimatoprost SR 30 µg (n = 8) in one eye; IOP was evaluated through day 66. RESULTS: Baseline mean EVP was 10.0 mmHg in the Bimatoprost SR group and 10.4 mmHg in the sham group. Eyes treated with Bimatoprost SR exhibited a transient increase in mean EVP that peaked at day 8, followed by a decrease to levels below baseline. From day 29 to day 65, the change in mean EVP from baseline ranged from -2.4 to -3.9 mmHg (P < 0.05 vs. sham). Baseline mean IOP in eyes treated with Bimatoprost SR was 14.9 mmHg, and a steady IOP reduction was maintained through day 66. Bimatoprost SR-treated eyes exhibited a selective, sustained dilation of aqueous outflow vessels that was not observed in sham-treated eyes. CONCLUSIONS: In normal dogs, Bimatoprost SR was associated with a transient increase in EVP followed by a sustained decrease. Changes in EVP were accompanied by a sustained dilation of aqueous outflow vessels.

The effects of essential oil mouthrinses with or without alcohol on plaque and gingivitis: a randomized controlled clinical study.

BACKGROUND: The efficacy of several variants of essential oil mouthrinses has been studied extensively. This is the first study to compare the anti-plaque and anti-gingivitis efficacy of two marketed essential oil mouthrinses: one is an alcohol containing mouthrinse and the other one is an alcohol-free mouthrinse. METHODS: This examiner-blind, parallel-group study randomized subjects to three groups: 1) Mechanical Oral Hygiene (MOH) only; 2) MOH plus Alcohol-Containing essential oil Mouthrinse (ACM); 3) MOH plus Alcohol-Free essential oil Mouthrinse (AFM). Primary endpoint was whole-mouth mean Modified Gingival Index (MGI) at six months. Secondary endpoints included whole-mouth mean MGI at one and three months, and whole-mouth mean Plaque Index (PI) and whole-mouth mean Bleeding Index (BI) at one, three and six months. Safety assessments were conducted at all time points. RESULTS: A total of 370 subjects were enrolled; 348 subjects completed the study. After six months, subjects using essential oil mouthrinses with or without alcohol showed significant reduction (p < 0.001) in gingivitis (28.2% and 26.7%, respectively) and significant reduction (p < 0.001) in plaque (37.8% and 37.0%, respectively), compared to those performing MOH only. Significant reductions in MGI, PI, and BI (p < 0.001) were observed at one and three months and also at six months for mean BI. No statistically significant differences were observed for all measured indices between ACM and AFM groups at any time point. Both mouthrinses were well tolerated. CONCLUSIONS: No significant differences were observed in the efficacy of ACM and AFM to reduce plaque and gingivitis, when used in addition to MOH, over six months. TRIAL REGISTRATION: The trial was registered on clinicaltrials.gov on November 30, 2016. The registration number is NCT02980497 .

Combined angiotensin inhibition for the treatment of diabetic nephropathy.

BACKGROUND: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Discovery of the imidazole-derived GPR40 agonist AM-3189.

As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.

Collaborating with a social housing provider supports a large cohort study of the health effects of housing conditions.

BACKGROUND: Despite the importance of adequate, un-crowded housing as a prerequisite for good health, few large cohort studies have explored the health effects of housing conditions. The Social Housing Outcomes Worth (SHOW) Study was established to assess the relationship between housing conditions and health, particularly between household crowding and infectious diseases. This paper reports on the methods and feasibility of using a large administrative housing database for epidemiological research and the characteristics of the social housing population. METHODS: This prospective open cohort study was established in 2003 in collaboration with Housing New Zealand Corporation which provides housing for approximately 5% of the population. The Study measures health outcomes using linked anonymised hospitalisation and mortality records provided by the New Zealand Ministry of Health. RESULTS: It was possible to match the majority (96%) of applicant and tenant household members with their National Health Index (NHI) number allowing linkage to anonymised coded data on their hospitalisations and mortality. By December 2011, the study population consisted of 11,196 applicants and 196,612 tenants. Half were less than 21 years of age. About two-thirds identified as Maori or Pacific ethnicity. Household incomes were low. Of tenant households, 44% containing one or more smokers compared with 33% for New Zealand as a whole. Exposure to household crowding, as measured by a deficit of one or more bedrooms, was common for applicants (52%) and tenants (38%) compared with New Zealanders as whole (10%). CONCLUSIONS: This project has shown that an administrative housing database can be used to form a large cohort population and successfully link cohort members to their health records in a way that meets confidentiality and ethical requirements. This study also confirms that social housing tenants are a highly deprived population with relatively low incomes and high levels of exposure to household crowding and environmental tobacco smoke.