Effectiveness of first-line treatments in metastatic squamous non-small-cell lung cancer.

Background: Commonly used first-line (1L) chemotherapies for patients with advanced squamous-cell lung cancer (scc) include gemcitabine-platinum (gp), nab-paclitaxel-carboplatin (nabpc), and sb-paclitaxel-carboplatin (sbpc) regimens. However, no head-to-head trials have compared those treatments. In the present study, we compared the efficacy of 1L gp, nabpc, and sbpc in patients with scc and in patients with scc who subsequently received second-line (2L) immunotherapy. Methods: Medical records of patients who initiated the 1L treatments of interest between June 2014 and October 2015 were reviewed by 132 participating physicians. Kaplan-Meier curves were used to evaluate overall survival (os), progression-free survival (pfs), and treatment discontinuation (td), and then Cox proportional hazards regression was used to compare the results between the cohorts. Results: Medical records of 458 patients with scc receiving gp (n = 139), nabpc (n = 159), or sbpc (n = 160) as 1L therapy were reviewed. Median os was longer with nabpc (23.9 months) than with gp (16.9 months; adjusted hazard ratio vs. nabpc: 1.55; p < 0.05) and with sbpc (18.3 months; adjusted hazard ratio: 1.42; p = 0.10). No differences were observed in pfs (median pfs: 8.8, 8.0, and 7.6 months for gp, nabpc, and sbpc respectively; log-rank p = 0.76) or in td (median td: 5.5, 5.7, and 4.6 months respectively; p = 0.65). For patients who subsequently received 2L immunotherapy, no differences in os were observed (median os: 27.3, 25.0, and 23.0 months respectively; p = 0.59). Conclusions: In a nationwide sample of scc patients, longer median os was associated with 1L nabpc than with gp and sbpc. Median os for all 1L agents considered was similar in the subgroup of patients who sequenced to a 2L immunotherapy.

Impact of hidradenitis suppurativa on work loss, indirect costs and income.

BACKGROUND: Hidradenitis suppurativa (HS), a chronic cutaneous disease, can negatively affect work life. OBJECTIVES: This retrospective cohort study evaluates the indirect burden among employed patients with HS in the U.S.A. METHODS: Newly diagnosed and general patients with HS, who were employees (age 18-64 years) from a large claims database (Q1 1999 to Q1 2015), were matched 1 : 5 to controls. Income growth and risk of leaving the workforce were assessed among the newly diagnosed HS and control cohorts in the 5-year study period. Income, work loss days and indirect costs (absenteeism and disability) were assessed among the general HS and control cohorts in the 1-year study period. RESULTS: Newly diagnosed (n = 1003, mean age 39·5 years, 66·3% female) and general patients with HS (n = 1204, mean age 39·9 years, 69·1% female) were matched to 5015 and 6020 controls, respectively. Newly diagnosed patients with HS had significantly slower income growth ($324 per year) and higher risk of leaving the workforce (adjusted hazard ratio 1·65, 95% confidence interval 1·45-1·88) compared with controls (all P < 0·05). General patients with HS had more total days of work loss (18·4 vs. 7·7), higher annual total indirect costs ($2925 vs. $1483) and lower annual income ($54 925 vs. $62 357) than controls (all P < 0·001). CONCLUSIONS: Patients with newly diagnosed HS and general patients with HS experienced a greater indirect burden than matched controls.

Calcipotriol plus betamethasone dipropionate aerosol foam vs. apremilast, methotrexate, acitretin or fumaric acid esters for the treatment of plaque psoriasis: a matching-adjusted indirect comparison.

BACKGROUND: Plaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild-to-moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability and therapeutic options; particularly decisions on transition from topical to non-biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions. OBJECTIVE: To compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non-biologic systemic treatments based on aggregated patient characteristics and treatment outcomes. METHODS: Individual data from four Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching-adjusted indirect comparisons. Literature review identified non-biologic systemic treatment trials where methods, populations and outcomes align with Cal/BD foam trials. Of 3090 screened publications, four studies of apremilast, methotrexate, acitretin or fumaric acid esters (FAE) were included. RESULTS: After baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P < 0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P < 0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 vs. 12 weeks of methotrexate (50.8% vs. 33.5%; P < 0.001) or acitretin (50.9% vs. 31.7%; P = 0.009), and comparable response to FAE (42.4% vs. 47.0%; P = 0.451). CONCLUSIONS: Despite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate or acitretin, and comparable efficacy to FAE.

Comparative efficacy of biological treatments for moderate-to-severe psoriasis: a network meta-analysis adjusting for cross-trial differences in reference arm response.

BACKGROUND: Multiple biological therapies are approved for the treatment of moderate-to-severe psoriasis. OBJECTIVES: To assess the short-term efficacy of biological treatments for moderate-to-severe psoriasis via a network meta-analysis that adjusts for reference arm response rates. METHODS: Fifteen randomized trials of biological treatments for moderate-to-severe psoriasis were identified. Rates of response, assessed as 50%, 75% and 90% reductions in the Psoriasis Area and Severity Index (PASI), were compared using a network meta-analysis. To account for variation across trials, the model was adjusted for placebo responses, the relevance of which was assessed by testing its statistical significance, impact on model fit, and extent to which lack of adjustment confounded the efficacy estimates for biologics. RESULTS: Psoriasis Area and Severity Index 75 response rates for placebo arms ranged from 1·8% to 18·9%. The probability of achieving a PASI 75 response was 80·5% [95% credible interval (CrI) 74·8-85·7] with infliximab 5 mg kg(-1) ; 72·5% (95% CI 66·1-78·3) with ustekinumab 90 mg; 67·5% (95% CI 60·7-73·9) with ustekinumab 45 mg; 66·2% (95% CI 57·3-73·3) with adalimumab 40 mg; 51·9% (95% CI 45·7-58·4) with etanercept 50 mg; and 38·0% (95% CI 31·6-45·1) with etanercept 25 mg. Infliximab had the highest PASI 75 response. Adalimumab and both ustekinumab doses had significantly higher PASI 75 responses than both etanercept doses. There were no significant differences among adalimumab and ustekinumab doses. CONCLUSIONS: A model adjusted for reference arm response rates was found to fit clinical trial data significantly better than unadjusted models.

Assessing the validity, responsiveness and meaningfulness of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical endpoint for hidradenitis suppurativa treatment.

BACKGROUND: Quantification of disease severity supports the development of evidence-based treatments. Assessments to capture clinical improvement in hidradenitis suppurativa (HS) can be improved. OBJECTIVES: This study aimed to validate the Hidradenitis Suppurativa Clinical Response (HiSCR), which is defined as a ≥ 50% reduction in inflammatory lesion count (sum of abscesses and inflammatory nodules, AN), and no increase in abscesses or draining fistulas in HS when compared with baseline as a meaningful clinical endpoint for HS treatment. METHODS: Patients with ≥ 3 ANs at baseline in a Phase II adalimumab trial for HS were included for analysis. HiSCR achievers vs. nonachievers were assessed at week 16 and week 52. Criteria measures included physician-rated assessments [Hurley stage, modified Sartorius score (MSS), and HS Physician's Global Assessment] and patient-reported outcomes (PROs: visual analogue pain scale, Dermatology Life Quality Index, and Work Productivity and Activity Impairment questionnaire). Test-retest reliability, convergent validity, responsiveness and predictive validity of HiSCR, and its meaningfulness to patients were assessed. RESULTS: Among 138 eligible study participants, the majority were female (69·6%) with a mean age of 36·7 years. The mean (median) MSS was 125·2 (85·5) at baseline. Test-retest reliability of the AN count was 0·91. HiSCR was significantly correlated with improvements in all physician-rated and PRO measures (Spearman's rho between -0·61 and -0·27, all P < 0·001). Improvements of all PROs in HiSCR achievers exceeded the respective meaningful improvement thresholds. CONCLUSIONS: In patients with HS with ≥ 3 ANs, HiSCR achievers had significant improvements in physician-rated and patient-reported HS disease severity and impact. HiSCR is a valid and meaningful endpoint for assessing HS treatment effectiveness in controlling inflammatory manifestations in this population.

Effects of briakinumab treatment for moderate to severe psoriasis on health-related quality of life and work productivity and activity impairment: results from a randomized phase III study.

BACKGROUND: Psoriasis is known to have a significant negative impact on a patient's health-related quality of life, including social, recreational and work activities. OBJECTIVE: To evaluate the effects of briakinumab on quality of life and work productivity measures in patients with moderate to severe psoriasis. METHODS: Patients received either briakinumab (n = 981) or placebo (n = 484) during the 12-week induction phase of trial M06-890. At week 12, patients with a Physician's Global Assessment score of 'Clear' or 'Minimal' entered the 40-week maintenance phase and were to receive briakinumab every 4 weeks, briakinumab every 12 weeks, or placebo. At weeks 12 and 52, treatment groups were compared using mean change from baseline in health-related quality of life and Work Productivity and Activity Impairment Questionnaire scores and the percentage of patients with minimum clinically important differences. RESULTS: At week 12, more than half of the briakinumab-treated patients achieved improvements meeting or exceeding minimum clinically important differences for Dermatology Life Quality Index (75.9%), and psoriasis- (64.8%), and psoriatic arthritis-related (54.1%) pain scores; 48.4% achieved improvements for activity impairment. Although improvements in quality of life and work productivity measures were maintained at week 52 for both briakinumab regimens, responder rates were consistently greater in the every-4-week group than in the every-12-week group. CONCLUSION: Briakinumab treatment resulted in clinically significant improvements in quality of life and work productivity in adults with moderate to severe psoriasis. Maintenance therapy was associated with a more pronounced benefit for the every-4-week briakinumab regimen.

Hypoglycaemia and accident risk in people with type 2 diabetes mellitus treated with non-insulin antidiabetes drugs.

AIMS: To assess associations between hypoglycaemia and risk of accidents resulting in hospital visits among people with type 2 diabetes receiving antidiabetes drugs without insulin. METHODS: People with type 2 diabetes who were not treated with insulin were identified from a US-based employer claims database (1998-2010). Following initiation of an antidiabetes drug, the occurrence of accidents resulting in hospital visits was compared between people with, and without, claims for hypoglycaemia using multivariable Cox proportional hazard models adjusted for demographics, comorbidities, prior treatments and prior medical service use. Additional analyses were stratified by age 65 years or older. RESULTS: A total of N = 5582 people with claims for hypoglycaemia and N = 27,910 with no such claims were included. Accidents resulting in hospital visits occurred in 5.5 and 2.8% of people with, and without, hypoglycaemia, respectively. After adjusting for baseline characteristics, hypoglycaemia was associated with significantly increased hazards for any accident [hazard ratio (HR) 1.39, 95% CI 1.21-1.59, p < 0.001], accidental falls (HR 1.36, 95% CI 1.13-1.65, p < 0.001) and motor vehicle accidents (HR 1.82, 95% CI 1.18-2.80, p = 0.007). In age-stratified analyses, hypoglycaemia was associated with greater hazards of driving-related accidents in people younger than age 65 and falls in people aged 65 or older. CONCLUSIONS: In people with type 2 diabetes receiving antidiabetes drugs without insulin, hypoglycaemia was associated with a significantly higher risk of accidents resulting in hospital visits, including accidents related to driving and falls.

Phylogeny and biogeography of Hydra (Cnidaria: Hydridae) using mitochondrial and nuclear DNA sequences.

The polyp hydra is ubiquitous in freshwater and is highly variable, with many species names assigned to different strains. Types of hydra do fall into four morphologically recognizable groups but many of the species determinations are confusing. To assess the diversity of hydra we collected 101 strains from six continents and built a phylogeny using three genetic markers. Each of the four well-defined groups of species represents a clade in our phylogeny. The green hydra group diverged first, followed by the braueri group and finally the sister groups vulgaris and oligactis. Each of eight species easily definable by morphological criteria represents a distinct clade in our phylogeny. Hydra of two clades, the green and the vulgaris hydra, are found on all continents (except Antarctica) and many islands, whereas hydra of the other two groups (braueri and oligactis) are restricted to the Northern Hemisphere. Our best estimate of the time of origin of hydra is about 60 Ma, long after the breakage of Pangea into northern and southern landmasses. Hydra appear to have diversified in the Northern Hemisphere, and their current diversity is greatest here. Two species were then able to disperse to the Southern Hemisphere, perhaps due to their thermal tolerance.

Economic impact of switching from valsartan to other angiotensin receptor blockers in patients with hypertension.

BACKGROUND: The approaching availability of lower-cost generic angiotensin receptor blockers (ARBs) may affect formulary policies for patients maintained on the ARB valsartan. OBJECTIVE: Estimate the economic impact of switching from valsartan (including valsartan-based single-pill combinations) to other ARBs without apparent medical reasons. RESEARCH DESIGN AND METHODS: Patients with essential hypertension and at least 6 months of continuous valsartan treatment free of hospitalization, cardiovascular events, renal events or ARB-associated adverse events were identified from the MarketScan administrative claims database from January 1, 2004 to March 31, 2008. Those who subsequently switched to a different ARB with at least a 5% copayment decrease (switchers) were matched to those who did not switch (maintainers) according to propensity score quintiles and selected baseline characteristics. Refills were not required after the index fill for the switched-to ARB or maintained valsartan. Matched switchers and maintainers were compared in terms of medication discontinuation, healthcare resource use and costs during the 6 months following the index fill. RESULTS: A total of 99,926 valsartan maintainers and 2150 switchers (with a mean copayment decrease of $16.5 per month) were identified and matched. After matching, switching from versus maintaining valsartan was associated with an 8% higher risk of medication discontinuation (p < 0.008), 19.1 additional outpatient visits/100 patients (p = 0.002) and 9.3 additional hypertension-related inpatient days/100 patients (p = 0.030). Concurrently, switching from versus maintaining valsartan was associated with higher total medical costs by $748/patient (p < 0.001), driven largely by higher costs for hypertension-related medical services by $492/patient (p = 0.004). LIMITATIONS: Exact reasons for switching were not available and the study assessed only the short-term impacts of switching. CONCLUSIONS: Hypertension patients maintained on valsartan who switched to a different ARB with a lower copayment experienced substantial increases in medication discontinuation, healthcare resource use and costs compared to those who maintained valsartan treatment.

N-terminal pro B-type natriuretic peptide levels predict newly detected atrial fibrillation in a population-based cohort.

BACKGROUND: B-type natriuretic peptide (BNP) is secreted from cardiomyocytes and may reflect haemodynamic abnormalities predisposing to atrial fibrillation (AF). We aimed to investigate whether N-terminal pro BNP (NT-proBNP) is associated with newly detected AF in subjects obtained from the general population. METHODS: From the PREVEND programme (n=8592), we selected all subjects with an available baseline and four-year electrocardiogram and NTproBNP levels at baseline. We excluded subjects with AF at baseline and subjects with a serum creatinine >2.0 mg/dl. RESULTS: In total, 6494 subjects were eligible for the prospective analysis (aged 49+/-12 years, 49.7% men). At four years, AF was detected in 41 (0.6%) subjects. Median NT-proBNP levels at baseline in subjects with newly detected AF after four years was 62.2 (22.6 to 208.5) pg/ml as compared with 35.7 (15.9 to 68.7) pg/ml in those with sinus rhythm (p=0.001). Each 1 standard deviation increment in natural log transformed NT-proBNP was associated with a 54% (5% to 126%, p=0.028) increase in risk for AF after adjustment for other risk factors predisposing to AF. NT-proBNP levels above the sex-specific 80th percentile (97 pg/ml in women and 60 pg/ml in men) were associated with a multivariate odds ratio of 2.65 (1.22 to 5.76, p=0.01) for the occurrence of AF. CONCLUSION: Plasma levels of NT-proBNP predict newly detected AF in subjects obtained from the general population independent of cardiovascular risk factors predisposing to AF. (Neth Heart J 2008;16:73-8.).

Physiological importance of a circadian clock outside the suprachiasmatic nucleus.

Circadian clocks are widely distributed in mammalian tissues, but little is known about the physiological functions of clocks outside the suprachiasmatic nucleus of the brain. The retina has an intrinsic circadian clock, but its importance for vision is unknown. Here, we show that mice lacking Bmal1, a gene required for clock function, had abnormal retinal transcriptional responses to light and defective inner retinal electrical responses to light, but normal photoreceptor responses to light and retinas that appeared structurally normal as observed by light and electron microscopy. We generated mice with a retina-specific genetic deletion of Bmal1, and they had defects of retinal visual physiology essentially identical to those of mice lacking Bmal1 in all tissues and lacked a circadian rhythm of inner retinal electrical responses to light. Our findings indicate that the intrinsic circadian clock of the retina regulates retinal visual processing in vivo.

PATRI-paternity inference using genetic data.

PATRI is a new application for paternity analysis using genetic data that accounts for the sampling fraction of potential fathers.