Nurse-Led Medicines' Monitoring for Patients with Dementia in Care Homes: A Pragmatic Cohort Stepped Wedge Cluster Randomised Trial

Background

People with dementia are susceptible to adverse drug reactions (ADRs). However, they are not always closely monitored for potential problems relating to their medicines: structured nurse-led ADR Profiles have the potential to address this care gap. We aimed to assess the number and nature of clinical problems identified and addressed and changes in prescribing following introduction of nurse-led medicines’ monitoring.

Design

Pragmatic cohort stepped-wedge cluster Randomised Controlled Trial (RCT) of structured nurse-led medicines’ monitoring versus usual care.

Setting

Five UK private sector care homes

Participants

41 service users, taking at least one antipsychotic, antidepressant or anti-epileptic medicine.

Intervention

Nurses completed the West Wales ADR (WWADR) Profile for Mental Health Medicines with each participant according to trial step.

Outcomes

Problems addressed and changes in medicines prescribed.

Data Collection and Analysis

Information was collected from participants’ notes before randomisation and after each of five monthly trial steps. The impact of the Profile on problems found, actions taken and reduction in mental health medicines was explored in multivariate analyses, accounting for data collection step and site.

Results

Five of 10 sites and 43 of 49 service users approached participated. Profile administration increased the number of problems addressed from a mean of 6.02 [SD 2.92] to 9.86 [4.48], effect size 3.84, 95% CI 2.57–4.11, P <0.001. For example, pain was more likely to be treated (adjusted Odds Ratio [aOR] 3.84, 1.78–8.30), and more patients attended dentists and opticians (aOR 52.76 [11.80–235.90] and 5.12 [1.45–18.03] respectively). Profile use was associated with reduction in mental health medicines (aOR 4.45, 1.15–17.22).

Conclusion

The WWADR Profile for Mental Health Medicines can improve the quality and safety of care, and warrants further investigation as a strategy to mitigate the known adverse effects of prescribed medicines.

Trial Registration

ISRCTN 48133332     

Intraocular Pressure Rise in Subjects with and without Glaucoma during Four Common Yoga Positions

Purpose

To measure changes in intraocular pressure (IOP) in association with yoga exercises with a head-down position.

Methods

The single Center, prospective, observational study included 10 subjects with primary open-angle glaucoma and 10 normal individuals, who performed the yoga exercises of Adho Mukha Svanasana, Uttanasana, Halasana and Viparita Karani for two minutes each. IOP was measured by pneumatonometry at baseline and during and after the exercises.

Results

All yoga poses were associated with a significant (P<0.01) rise in IOP within one minute after assuming the yoga position. The highest IOP increase (P<0.01) was measured in the Adho Mukha Svanasana position (IOP increase from 17±3.2 mmHg to 28±3.8 mmHg in glaucoma patients; from 17±2.8 mmHg to 29±3.9 mmHg in normal individuals), followed by the Uttanasana position (17±3.9 mmHg to 27±3.4 mmHg (glaucoma patients) and from 18±2.5 mmHg to 26±3.6 mmHg normal individuals)), the Halasana position (18±2.8 mmHg to 24±3.5 mmHg (glaucoma patients); 18±2.7 mmHg to 22±3.4 mmHg (normal individuals)), and finally the Viparita Kirani position (17±4 mmHg to 21±3.6 mmHg (glaucoma patients); 17±2.8 to 21±2.4 mmHg (normal individuals)). IOP dropped back to baseline values within two minutes after returning to a sitting position. Overall, IOP rise was not significantly different between glaucoma and normal subjects (P = 0.813), all though glaucoma eyes tended to have measurements 2 mm Hg higher on average.

Conclusions

Yoga exercises with head-down positions were associated with a rapid rise in IOP in glaucoma and healthy eyes. IOP returned to baseline values within 2 minutes. Future studies are warranted addressing whether yoga exercise associated IOP changes are associated with similar changes in cerebrospinal fluid pressure and whether they increase the risk of glaucoma progression.

Trial Registration

ClinicalTrials.gov #{"type":"clinical-trial","attrs":{"text":"NCT01915680","term_id":"NCT01915680"}}NCT01915680     

Unavoidable Human Errors of Tumor Size Measurement during Specimen Attachment after Endoscopic Resection: A Clinical Prospective Study

Objective

Objective evaluation of resected specimen and tumor size is critical because the tumor diameter after endoscopic submucosal dissection affects therapeutic strategies. In this study, we investigated whether the true tumor diameter of gastrointestinal cancer specimens measured by flexible endoscopy is subjective by testing whether the specimen is correctly attached to the specimen board after endoscopic submucosal dissection resection and whether the size differs depending on the endoscopist who attached the specimen.

Methods

Seventy-two patients diagnosed with early gastric cancer who satisfied the endoscopic submucosal dissection expanded-indication guideline were enrolled. Three endoscopists were randomly selected before every endoscopic submucosal dissection. Each endoscopist separately attached the same resected specimen, measured the maximum resection diameter and tumor size, and removed the lesion from the attachment board.

Results

The resected specimen diameters of the 3 endoscopists were 44.5±13.9 mm (95% Confidence Interval (CI): 23–67), 37.4±12.0 mm (95% CI: 18–60), and 41.1±13.3 mm (95% CI: 20–63) mm. Comparison among 3 groups (Kruskal Wallis H- test), there were significant differences (H = 6.397, P = 0.040), and recorded tumor sizes were 38.3±13.1 mm (95% CI: 16–67), 31.1±11.2 mm (95% CI: 12.5–53.3), and 34.8±12.8 (95% CI: 11.5–62.3) mm. Comparison among 3 groups, there were significant differences (H = 6.917, P = 0.031).

Conclusions

Human errors regarding the size of attached resected specimens are unavoidable, but it cannot be ignored because it affects the patient’s additional treatment and/or surgical intervention. We must develop a more precise methodology to obtain accurate tumor size.

Trial Registration

University hospital Medical Information Network UMIN No. 000012915     

Impact of Community Based Peer Support in Type 2 Diabetes: A Cluster Randomised Controlled Trial of Individual and/or Group Approaches

Background

Diabetes peer support, where one person with diabetes helps guide and support others, has been proposed as a way to improve diabetes management. We have tested whether different diabetes peer support strategies can improve metabolic and/or psychological outcomes.

Methods

People with type 2 diabetes (n = 1,299) were invited to participate as either ‘peer’ or ‘peer support facilitator’ (PSF) in a 2x2 factorial randomised cluster controlled trial across rural communities (130 clusters) in England. Peer support was delivered over 8–12 months by trained PSFs, supported by monthly meetings with a diabetes educator. Primary end point was HbA1c. Secondary outcomes included quality of life, diabetes distress, blood pressure, waist, total cholesterol and weight. Outcome assessors and investigators were masked to arm allocation. Main factors were 1:1 or group intervention. Analysis was by intention-to-treat adjusting for baseline.

Results

The 4 arms were well matched (Group n = 330, 1:1(individual) n = 325, combined n = 322, control n = 322); 1035 (79•7%) completed the mid-point postal questionnaire and 1064 (81•9%) had a final HbA1c. A limitation was that although 92.6% PSFs and peers were in telephone contact, only 61.4% of intervention participants attended a face to face session. Mean baseline HbA1c was 57 mmol/mol (7•4%), with no significant change across arms. Follow up systolic blood pressure was 2•3mm Hg (0.6 to 4.0) lower among those allocated group peer-support and 3•0mm Hg (1.1 to 5.0) lower if the group support was attended at least once. There was no impact on other outcomes by intention to treat or significant differences between arms in self-reported adherence or medication.

Conclusions

Group diabetes peer support over 8–12 months was associated with a small improvement in blood pressure but no other significant outcomes. Long term benefits should be investigated.

Trial Registration

ISRCTN.com ISRCTN6696362166963621     

The Effect of Preoperative Oral Carbohydrate or Oral Rehydration Solution on Postoperative Quality of Recovery: A Randomized,Controlled Clinical Trial

Background

Numerous studies have demonstrated the beneficial effects of preoperative administration of oral carbohydrate (CHO) or oral rehydration solution (ORS). However, the effects of preoperative CHO or ORS on postoperative quality of recovery after anesthesia remain unclear. Consequently, the purpose of the current study was to evaluate the effect of preoperative CHO or ORS on patient recovery, using the Quality of Recovery 40 questionnaire (QoR-40).

Methods

This prospective, randomized, controlled clinical trial included American Society of Anesthesiologists (ASA) physical status 1 and 2 adult patients, who were scheduled to undergo a surgical procedure of body surface. Subjects were randomized to one of the three groups: 1) preoperative CHO group, 2) preoperative ORS group, and 3) control group. The primary outcome was the global QoR-40 administered 24 h after surgery. Intraoperative use of vasopressor, intraoperative body temperature changes, and postoperative nausea and vomiting (PONV) were also evaluated.

Results

We studied 134 subjects. The median [interquartile range (IQR)] global QoR-40 scores 24 h after the surgery were 187 [177–197], 186 [171–200], and 184 [171–198] for the CHO, ORS, and control groups, respectively (p = 0.916). No significant differences existed between the groups regarding intraoperative vasopressor use during the surgery (p = 0.475).

Conclusions

Results of the current study indicated that the preoperative administration of either CHO or ORS did not improve the quality of recovery in patients undergoing minimally invasive body surface surgery.

Trial Registration

www.umin.ac.jp UMIN000009388 https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000011029&language=E     

The Effect of Neutral Peritoneal Dialysis Solution with Low Glucose-Degradation-Product on the Fluid Status and Body Composition – A Randomized Control Trial

Background

Previous studies report conflicting results on the benefit of peritoneal dialysis (PD) patients treated with low glucose degradation product (GDP) solution. The effects of low GDP solution on body fluid status and arterial pulse wave velocity (PWV) have not been studied.

Methods

We randomly assigned 68 incident PD patients to low GDP (Intervention Group) or conventional solutions (Control Group); 4 dropped off before they received the assigned treatment. Patients were followed for 52 weeks for changes in ultrafiltration, residual renal function, body fluid status and arterial PWV.

Result

After 52 weeks, Intervention Group had higher overhydration (3.1 ± 2.6 vs 1.9 ± 2.2 L, p = 0.045) and extracellular water volume (17.7 ± 3.9 vs 15.8 ± 3.1 L, p = 0.034) than Control Group. There was no significant difference in PWV between groups. There was no significant difference in residual renal function between the Groups. Intervention Group had lower ultrafiltration volume than Control Group at 4 weeks (0.45 ± .0.61 vs 0.90 ± 0.79 L/day, p = 0.013), but the difference became insignificant at later time points. Intervention Group had lower serum CRP levels than Control Group (4.17 ± 0.77 vs 4.91 ± 0.95 mg/dL, p < 0.0001).

Conclusion

Incident PD patients treated with low GDP solution have less severe systemic inflammation but trends of less ultrafiltration, and more fluid accumulation. However, the effects on ultrafiltration and fluid accumulation disappear with time. The long term effect of low GDP solution requires further study.

Trial Registration

ClinicalTrials.gov NCT00966615     

Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101)

Background

Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m² on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m² on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects.

Methods

We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2′,2′-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800–1,000 mg/m². Physical examination and adverse events were monitored for 12 weeks.

Results

Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43–83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy.

Conclusion

Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU.

Trial Registration

UMIN-CTR in (JPRN) UMIN000005109     

Intraocular Pressure Changes during Accommodation in Progressing Myopes,Stable Myopes and Emmetropes

Purpose

To investigate the changes of intraocular pressure (IOP) induced by 3-diopter (3 D) accommodation in progressing myopes, stable myopes and emmetropes.

Design

Cross-sectional study.

Participants

318 subjects including 270 myopes and 48 emmetropes.

Methods

195 progressing myopes, 75 stable myopes and 48 emmetropes participated in this study. All subjects had their IOP measured using iCare rebound tonometer while accommodative stimuli of 0 D and 3 D were presented.

Main Outcome Measures

IOP values without accommodation and with 3 D accommodation were measured in all subjects. Baseline IOPs and IOP changes were compared within and between groups.

Results

There was no significant difference in IOPs between progressing myopes, stable myopes and emmetropes when no accommodation was induced (17.47±3.46, 16.62±2.98 and 16.80±3.62 respectively, p>0.05). IOP experienced an insignificantly slight decrease after 3 D accommodation in three groups (mean change -0.19±2.16, -0.03±1.68 and -0.39±2.65 respectively, p>0.05). Subgroup analysis showed in progressing myopic group, IOP of children (<18 years old) declined with accommodation while IOP of adults (≥18 years) increased, and the difference was statistically significant (p = 0.008). However, after excluding the age factor, accommodation induced IOP changes of high progressing myopes (≤-6 D), low, moderate and non-myopes (>-6 D) was not significantly different after Bonferroni correction (p = 0.838).

Conclusions

Although no difference was detected between the baseline IOPs and accommodation induced IOP changes in progressing myopes, stable myopes and emmetropes, this study found accommodation could cause transient IOP elevation in adult progressing myopes.     

The Influence of Phacoemulsification on Surgical Outcomes of Trabeculectomy with Mitomycin-C for Uveitic Glaucoma

Purpose

To evaluate the influence of phacoemulsification after trabeculectomy on the postoperative intraocular pressure (IOP) in eyes with uveitic glaucoma (UG).

Setting

Kumamoto University Hospital, Kumamoto, Japan.

Design

A retrospective cohort study.

Methods

The medical records of patients with UG who had trabeculectomy with mitomycin-C (MMC) were reviewed. Complete and qualified surgical failures were defined by an IOP of ≥21 mmHg (condition A), ≥18 mmHg (condition B), or ≥15 mmHg (condition C) without and with glaucoma eye drops, respectively. Kaplan-Meier survival analysis, generalized by the Wilcoxon test, and the Cox proportional hazards model analysis were conducted. Post-trabeculectomy phacoemulsification was treated as a time-dependent variable. In 24 (30%) of the included 80 eyes, phacoemulsification was included, and they were divided into two groups: groups I (8 eyes with phacoemulsification within 1 year after trabeculectomy) and group II (16 eyes after 1 year following trabeculectomy).

Results

Multivariable Cox proportional hazards model analysis showed post-trabeculectomy phacoemulsification was a significant factor in both complete success and qualified success based upon condition C (P = 0.0432 and P = 0.0488, respectively), but not for the other conditions. Kaplan–Meier survival analyses indicated significant differences in success probabilities between groups I and group II for complete success and qualified success based upon condition C (P = 0.020 and P = 0.013, respectively). There was also a significant difference for qualified success based upon condition B (P = 0.034), while there was no significant difference for the other conditions.

Conclusion

Post-trabeculectomy phacoemulsification, especially within 1 year, can cause poor prognosis of IOP control of UG eyes after trabeculectomy with MMC.     

Efficacy of a Contact Lens Sensor for Monitoring 24-H Intraocular Pressure Related Patterns

Purpose

To study performance of a contact lens sensor (CLS) for 24-hour monitoring of IOP-related short-term patterns and compare with IOP obtained by pneumatonometry.

Methods

Prospective clinical trial. Thirty-one healthy volunteers and 2 glaucoma patients were housed for 24 hours in a sleep laboratory. One randomly selected eye was fitted with a CLS (Triggerfish, Sensimed, Switzerland), which measures changes in ocular circumference. In the contralateral eye, IOP measurements were taken using a pneumatonometer every two hours with subjects in the habitual body positions. Heart rate (HR) was measured 3 times during the night for periods of 6 minutes separated by 2 hours. Performance of CLS was defined in two ways: 1) recording the known pattern of IOP increase going from awake (sitting position) to sleep (recumbent), defined as the wake/sleep (W/S) slope and 2) accuracy of the ocular pulse frequency (OPF) concurrent to that of the HR interval. Strength of association between overall CLS and pneumatonometer curves was assessed using coefficients of determination (R²).

Results

The W/S slope was statistically significantly positive in both eyes of each subject (CLS, 57.0 ± 40.5 mVeq/h, p<0.001 and 1.6 ± 0.9 mmHg/h, p<0.05 in the contralateral eye). In all, 87 CLS plots concurrent to the HR interval were evaluated. Graders agreed on evaluability for OPF in 83.9% of CLS plots. Accuracy of the CLS to detect the OPF was 86.5%. Coefficient of correlation between CLS and pneumatonometer for the mean 24-h curve was R² = 0.914.

Conclusions

CLS measurements compare well to the pneumatonometer and may be of practical use for detection of sleep-induced IOP changes. The CLS also is able to detect ocular pulsations with good accuracy in a majority of eyes.

Trial Registration

ClinicalTrials.gov NCT01390779     

The Immediate Effect of Sildenafil on Right Ventricular Function in Patients with Heart Failure Measured by Cardiac Magnetic Resonance: A Randomized Control Trial

Background

Studies have demonstrated that phosphodiesterase 5 (PDE5) inhibition is associated with right ventricle (RV) functional improvement in patients with primary pulmonary hypertension. This study aims to demonstrate the immediate impact of Sildenafil, a PDE5 inhibitor, on RV function, measured by cardiovascular magnetic resonance (CMR), in patients with heart failure (HF).

Methods

We conducted a randomized double-blind controlled trial. Inclusion criteria: diagnosis of HF functional class I-III; left ventricle ejection fraction < 35%. Patients underwent CMR evaluation and were then equally randomly assigned to either 50 mg of Sildenafil or Placebo groups. One hour following drug administration, they were submitted to a second scan examination.

Results

26 patients were recruited from a tertiary reference center in Brazil and 13 were allocated to each study group. The median age was 61.5 years (50–66.5 years). Except for the increase in RV fractional area change following the administration of sildenafil (Sildenafil [before vs. after]: 34.3 [25.2–43.6]% vs. 42.9 [28.5–46.7]%, p = 0.04; Placebo [before vs. after]: 28.1 [9.2–34.8]% vs. 29.2 [22.5–38.8]%, p = 0.86), there was no statistically significant change in parameters. There was no improvement in left ventricular parameters or in the fractional area change of the pulmonary artery.

Conclusion

This study demonstrated that a single dose of Sildenafil did not significantly improve RV function as measured by the CMR.

Trial Registration

ClinicalTrials.gov NCT01936350     

Low Ambient Temperature and Intracerebral Hemorrhage: The INTERACT2 Study

Background

Rates of acute intracerebral hemorrhage (ICH) increase in winter months but the magnitude of risk is unknown. We aimed to quantify the association of ambient temperature with the risk of ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) participants on an hourly timescale.

Methods

INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of patients with spontaneous ICH (<6h of onset) and elevated systolic blood pressure (SBP, 150–220 mmHg) assigned to intensive (target SBP <140 mmHg) or guideline-recommended (SBP <180 mmHg) BP treatment. We linked individual level hourly temperature to baseline data of 1997 participants, and performed case-crossover analyses using a distributed lag non-linear model with 24h lag period to assess the association of ambient temperature and risk of ICH. Results were presented as overall cumulative odds ratios (ORs) and 95% CI.

Results

Low ambient temperature (≤10°C) was associated with increased risks of ICH: overall cumulative OR was 1.37 (0.99–1.91) for 10°C, 1.92 (1.31–2.81) for 0°C, 3.13 (1.89–5.19) for -10°C, and 5.76 (2.30–14.42) for -20°C, as compared with a reference temperature of 20°C.There was no clear relation of low temperature beyond three hours after exposure. Results were consistent in sensitivity analyses.

Conclusions

Exposure to low ambient temperature within several hours increases the risk of ICH.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00716079","term_id":"NCT00716079"}}NCT00716079     

Secreted Frizzled Related Protein 3 in Chronic Heart Failure: Analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)

Background

We have previously demonstrated an association between increased sFRP3 expression and adverse outcome in a population of HF irrespective of cause and left ventricular ejection fraction. In this study we evaluated the prognostic value of sFRP3 in older patients with chronic systolic HF of ischemic origin.

Methods

We evaluated sFRP3, by tertiles, as a risk factor for the primary endpoint (cardiovascular [CV] mortality, nonfatal myocardial infarction, nonfatal stroke), all-cause mortality, CV mortality, death from worsening HF (WHF), any coronary event, including sudden death, as well as hospitalizations for CV causes and WHF in 1444 patients from the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo.

Results

Kaplan-Meier curves for the primary endpoint, as well as all-cause- and CV mortality revealed a markedly better survival for patients with sFRP3 levels in the middle tertile of compared to the 1^st and 3^rd tertile. In multivariable Cox-regression, after full adjustment including high-sensitive CRP and NT-proBNP, a lower event rate for the primary end point, all cause and CV mortality was observed for patients with tertile 2 sFRP3 levels (HR 0.57 [0.44–0.74], 0.55 [0.44–0.74] and 0.52 [0.39–0.69]; p<0.001), as well as for the number of coronary events (HR 0.62 [0.47–0.82], p = 0.001) and sudden death (HR 0.55 [0.37–0.82], p = 0.002). Applying sFRP3 values to the fully adjusted regression model resulted in highly significant continuous net reclassification improvements for the primary endpoint, all cause and CV mortality, coronary events and sudden death (range 0.24–0.31; p≤0.002 for all).

Conclusions

Intermediate serum sFRP3 levels are associated with better survival and fewer CV events than low or high sFRP3 levels, independently of conventional risk factors, in older patients with chronic systolic HF of ischemic origin. Our study suggests that balanced Wnt activity might confer protective effects in a clinical HF setting.

Trial Registration

http://www.clinicaltrials.gov NCT00206310     

Risk Factors for Death in 632 Patients with Sickle Cell Disease in the United States and United Kingdom

Background

The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial.

Methods and Results

We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥3.0 m/s cuttof, which has a 67–75% positive predictive value for mean pulmonary artery pressure ≥25 mm Hg was used. Among 572 subjects, 11.2% had TRV≥3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV≥3.0 m/sec. At 24 months the cumulative survival was 83% with TRV≥3.0 m/sec and 98% with TRV<3.0 m/sec (p<0.0001). The hazard ratios for death were 11.1 (95% CI 4.1–30.1; p<0.0001) for TRV≥3.0 m/sec, 4.6 (1.8–11.3; p = 0.001) for NT-proBNP≥160 pg/mL, and 14.9 (5.5–39.9; p<0.0001) for both TRV≥3.0 m/sec and NT-proBNP≥160 pg/mL. Age >47 years, male gender, chronic transfusions, WHO class III–IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death.

Conclusions

A TRV≥3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable.

The study is registered in ClinicalTrials.gov with identifier

{"type":"clinical-trial","attrs":{"text":"NCT00492531","term_id":"NCT00492531"}}NCT00492531     

Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Na?ve Patients with Metastatic Uveal Melanoma

Purpose

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM.

Patients and Methods

We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months.

Results

Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7–8.1), median progression-free survival 2.8 months (95% CI 2.5–2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3–4 events (36%). One drug-related death due to pancytopenia was observed.

Conclusions

Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines.

Trial Registration

ClinicalTrials.gov NCT01355120     

Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia

Background

Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea.

Objectives

We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010.

Methods

An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648.

Results

Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003–1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00–1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23–4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34–0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15–35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17–0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels.

Conclusions

Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.     

Long-Term Outcomes and Prognostic Factors of Trabeculectomy following Intraocular Bevacizumab Injection for Neovascular Glaucoma

Purpose

To evaluate long-term outcomes and identify prognostic factors of trabeculectomy following intraocular bevacizumab injection for neovascular glaucoma.

Methods

Sixty-one eyes of 54 patients with neovascular glaucoma treated by trabeculectomy following intraocular bevacizumab injection were consecutively enrolled. Surgical success criteria were sufficient intraocular pressure (IOP) reduction (IOP ≤21 mmHg, ≥20% IOP reduction, no additional medications or glaucoma surgeries) without devastating complications (loss of light perception, phthisis bulbi, and endophthalmitis) or significant hypotony (IOP ≤5 mmHg continued ≥6 months and until the last follow-up visit or hypotony requiring intervention). Kaplan-Meier survival curves and Cox regression analysis were used to examine success rates and risk factors for surgical outcomes.

Results

The follow-up period after trabeculectomy was 45.0 ± 22.2 months (mean ± standard deviation). Surgical success rate was 86.9 ± 4.3% (± standard error), 74.0 ± 6.1%, and 51.3 ± 8.6% at 1, 3, and 5 years. Multivariate Cox regression analysis identified two risk factors; lower preoperative IOP (≤30 mmHg) for surgical failure and hypotony [hazard ratio (HR), 2.92, 6.64; 95% confidence interval (CI), 1.22 to 7.03, 1.47 to 30.0; P = 0.018, 0.014, respectively], and vitrectomy after trabeculectomy for surgical failure with or without hypotony criteria (HR, 2.32, 4.06; 95% CI, 1.02 to 5.28, 1.30 to 12.7; P = 0.045, 0.016, respectively).

Conclusions

The long-term outcomes of trabeculectomy following intraocular bevacizumab injection for neovascular glaucoma were favorable. Lower baseline IOP was associated with development of significant hypotony, while additional vitrectomy was related to insufficient IOP reduction.     

Impact of a Glaucoma Severity Index on Results of Trabectome Surgery: Larger Pressure Reduction in More Severe Glaucoma

Purpose

To stratify outcomes of trabectome-mediated ab interno trabeculectomy (AIT) by glaucoma severity using a simple and clinically useful glaucoma index. Based on prior data of trabectome after failed trabeculectomy, we hypothesized that more severe glaucoma might have a relatively more reduced facility compared to mild glaucoma and respond with a larger IOP reduction to trabecular meshwork ablation.

Methods

Patients with primary open angle glaucoma who had undergone AIT without any other same session surgery and without any second eye surgery during the following 12 months were analyzed. Eyes of patients that had less than 12 months follow up or were diagnosed with neovascular glaucoma were excluded. A glaucoma index (GI) was created to capture glaucoma severity based on visual field, number of preoperative medications, and preoperative IOP. Visual field (VF) was separated into 3 categories: mild, moderate, and advanced (assigned 1, 2, and 3 points, respectively). Preoperative number of medications (meds) was divided into 4 categories: ≤1, 2, 3 or ≥4, and assigned with a value of 1 to 4. Baseline IOP (IOP) was divided into 3 categories: <20 mmHg, 20–29 mmHg, and greater than 30 mmHg and assigned with 1 to 3 points. GI was defined as IOP × meds × VF and separated into 4 groups: <6 (Group 1), 6–12 (Group 2), >12–18 (Group 3) and >18 (Group 4). Linear regression was used to determine if there was an association between GI group and IOP reduction after one year or age, gender, race, diagnosis, cup to disc (C/D) ratio, and Shaffer grade.

Results

Out of 1340 patients, 843 were included in the analysis. The GI group distribution was GI1 = 164, GI2 = 202, GI3 = 260, and GI4 = 216. Mean IOP reduction after one year was 4.0±5.4, 6.4±5.8, 9.0±7.6, 12.0±8.0 mmHg for GI groups 1 to 4, respectively. Linear regression showed that IOP reduction was associated with GI group after adjusting for age, gender, race, diagnosis, cup to disc ratio, and Shaffer grade. Each GI group increase of 1 was associated with incremental IOP reductions of 2.95±0.29 mmHg. Success rate at 12 months was 90%, 77%, 77%, and 71% for GI groups 1 to 4. The log-rank test suggested significant differences between GI groups.

Conclusion

A simple glaucoma index, GI, was created to capture glaucoma severity and a relative resistance to treatment. A higher GI was associated with a larger IOP reduction in trabectome surgery. This indicates that there is a role for AIT beyond mild glaucoma and ocular hypertension.     

Multivitamin and Iron Supplementation to Prevent Periconceptional Anemia in Rural Tanzanian Women: A Randomized,Controlled Trial

Objective

Women’s nutritional status during conception and early pregnancy can influence maternal and infant outcomes. This study examined the efficacy of pre-pregnancy supplementation with iron and multivitamins to reduce the prevalence of anemia during the periconceptional period among rural Tanzanian women and adolescent girls.

Design

A double-blind, randomized controlled trial was conducted in which participants were individually randomized to receive daily oral supplements of folic acid alone, folic acid and iron, or folic acid, iron, and vitamins A, B-complex, C, and E at approximately single recommended dietary allowance (RDA) doses for six months.

Setting

Rural Rufiji District, Tanzania.

Subjects

Non-pregnant women and adolescent girls aged 15–29 years (n = 802).

Results

The study arms were comparable in demographic and socioeconomic characteristics, food security, nutritional status, pregnancy history, and compliance with the regimen (p>0.05). In total, 561 participants (70%) completed the study and were included in the intention-to-treat analysis. Hemoglobin levels were not different across treatments (median: 11.1 g/dL, Q1-Q3: 10.0–12.4 g/dL, p = 0.65). However, compared with the folic acid arm (28%), there was a significant reduction in the risk of hypochromic microcytic anemia in the folic acid and iron arm (17%, RR: 0.61, 95% CI: 0.42–0.90, p = 0.01) and the folic acid, iron, and multivitamin arm (19%, RR: 0.66, 95% CI: 0.45–0.96, p = 0.03). Inverse probability of treatment weighting (IPTW) to adjust for potential selection bias due to loss to follow-up did not materially change these results. The effect of the regimens was not modified by frequency of household meat consumption, baseline underweight status, parity, breastfeeding status, or level of compliance (in all cases, p for interaction>0.2).

Conclusions

Daily oral supplementation with iron and folic acid among women and adolescents prior to pregnancy reduces risk of anemia. The potential benefits of supplementation on the risk of periconceptional anemia and adverse pregnancy outcomes warrant investigation in larger studies.

Trial Registration

ClinicalTrials.gov NCT01183572     

Internet-Based Brief Intervention to Prevent Unhealthy Alcohol Use among Young Men: A Randomized Controlled Trial

Introduction

Alcohol use is one of the leading modifiable morbidity and mortality risk factors among young adults.

Study Design

2 parallel-group randomized controlled trial with follow-up at 1 and 6 months.

Setting/Participants

Internet based study in a general population sample of young men with low-risk drinking, recruited between June 2012 and February 2013.Intervention: Internet-based brief alcohol primary prevention intervention (IBI). The IBI aims at preventing an increase in alcohol use: it consists of normative feedback, feedback on consequences, calorific value alcohol, computed blood alcohol concentration, indication that the reported alcohol use is associated with no or limited risks for health. Intervention group participants received the IBI. Control group (CG) participants completed only an assessment.

Main Outcome Measures

Alcohol use (number of drinks per week), binge drinking prevalence. Analyses were conducted in 2014–2015.

Results

Of 4365 men invited to participate, 1633 did so; 896 reported low-risk drinking and were randomized (IBI: n = 451; CG: n = 445). At baseline, 1 and 6 months, the mean (SD) number of drinks/week was 2.4(2.2), 2.3(2.6), 2.5(3.0) for IBI, and 2.4(2.3), 2.8(3.7), 2.7(3.9) for CG. Binge drinking, absent at baseline, was reported by 14.4% (IBI) and 19.0% (CG) at 1 month and by 13.3% (IBI) and 13.0% (CG) at 6 months. At 1 month, beneficial intervention effects were observed on the number of drinks/week (p = 0.05). No significant differences were observed at 6 months.

Conclusion

We found protective short term effects of a primary prevention IBI.

Trial Registration

Controlled-Trials.com ISRCTN55991918