Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized,Double-Blind Primary Endpoint

ObjectivePublished reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease.Materials and MethodsParticipants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life.ResultsThe study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period.ConclusionDirectional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.     

Occurrence of inadequate ACL healing after Dynamic Intraligamentary Stabilization and functional outcome—a multicentre case series

Introduction

Dynamic Intraligamentary Stabilization (DIS) is a technique for preservation, anatomical repair and stabilization of a freshly injured anterior cruciate ligament (ACL). The main purpose of this study was to evaluate the short-term re-operation rate when compared to traditional autograft reconstruction.

Methods

Four, from the developer independent, centres enrolled patients that underwent ACL repair by DIS, according to the specific indications given by MRI imaging at a minimum follow-up of 12 months. The re-operation rate was recorded as primary outcome. Secondary outcome measures were the postoperative antero-posterior knee laxity (using a portable Rolimeter®), as well as the Tegner, Lysholm and IKDC Scores.

Results

A total of 105 patients were investigated with a median follow-up of 21 months. Thirteen patients were lost to follow-up. Of the remaining 92 patients 15 (16.3%) had insufficient functional stability and required subsequent ACL reconstruction. These patients were excluded from further analysis, leaving 77 consecutive patients for a 12 months follow-up. The median age at time of surgery was 30 years for that group. At time of follow-up a median antero-posterior translation difference of 2 mm was measured. None of these patients reported subjective insufficiency (giving way), but in 14 patients (18.2%), the difference of antero-posterior translation was more than 3 mm. We found a median Tegner Score of 5.5, a median Lysholm Score of 95.0 and a median IKDC Score of 89.4.

Conclusion

The main finding of this multicentre study is a relevant re-operation rate of 16.3%. Another 18.2% showed objective antero-posterior laxity (≥ 3 mm) during testing raising the suspicion of postoperative non-healing. The failure rate of DIS in this study is higher than for reconstruction with an autologous tendon graft. However, our successfully treated patients had a good clinical and functional outcome based on antero-posterior knee laxity and clinical scores, comparable to patients treated by autograft reconstruction.

     

Timing of Palliative Care Referral Before and After Evidence from Trials Supporting Early Palliative Care

BackgroundEvidence from randomized controlled trials has demonstrated benefits in quality of life outcomes from early palliative care concurrent with standard oncology care in patients with advanced cancer. We hypothesized that there would be earlier referral to outpatient palliative care at a comprehensive cancer center following this evidence.Materials and MethodsAdministrative databases were reviewed for two cohorts of patients: the pre‐evidence cohort was seen in outpatient palliative care between June and November 2006, and the post‐evidence cohort was seen between June and November 2015. Timing of referral was categorized, according to time from referral to death, as early (>12 months), intermediate (>6 months to 12 months), and late (≤6 months from referral to death). Univariable and multivariable ordinal logistic regression analyses were used to determine demographic and medical factors associated with timing of referral.ResultsLate referrals decreased from 68.8% pre‐evidence to 44.8% post‐evidence; early referrals increased from 13.4% to 31.1% (p < .0001). The median time from palliative care referral to death increased from 3.5 to 7.0 months (p < .0001); time from diagnosis to referral was also reduced (p < .05). On multivariable regression analysis, earlier referral to palliative care was associated with post‐evidence group (p < .0001), adjusting for shorter time since diagnosis (p < .0001), referral for pain and symptom management (p = .002), and patient sex (p = .04). Late referrals were reduced to <50% in the breast, gynecological, genitourinary, lung, and gastrointestinal tumor sites.ConclusionsFollowing robust evidence from trials supporting early palliative care for patients with advanced cancer, patients were referred substantially earlier to outpatient palliative care.Implications for PracticeFollowing published evidence demonstrating the benefit of early referral to palliative care for patients with advanced cancer, there was a substantial increase in early referrals to outpatient palliative care at a comprehensive cancer center. The increase in early referrals occurred mainly in tumor sites that have been included in trials of early palliative care. These results indicate that oncologists’ referral practices can change if positive consequences of earlier referral are demonstrated. Future research should focus on demonstrating benefits of early palliative care for tumor sites that have tended to be omitted from early palliative care trials.     

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty‐nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early‐stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty‐two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28‐66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.     

Pharmacokinetic interactions of maraviroc with darunavir-ritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials

The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.     

Fasting augments lipid peroxidation during reperfusion after ischemia in the perfused rat liver

OBJECTIVE: To test the hypothesis that fasting would aggravate postischemic lipid peroxidation in a perfused rat liver model. DESIGN: Prospective, randomized study in a rat perfused liver model. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Livers isolated from fed and fasted male Sprague-Dawley rats (n = 16) were exposed to 2.5 hrs of normothermic (38 degrees C) ischemia followed by 2 hrs of reperfusion. MEASUREMENTS AND MAIN RESULTS: Lipid peroxidation was measured by chemiluminescence and thiobarbituric acid reactive substances (TBARS). Injury parameters, potassium, lactate dehydrogenase efflux, and oxygen extraction were measured every 30 mins. Chemiluminescence and TBARS were greater in the fasted ischemic group during reperfusion. (fasted vs. fed: chemiluminescence, 946.8+/-205.5 [SEM] vs. 98.1+/-8.2 counts per second, p = .0004; thiobarbituric acid reactive substances, 1.11+/-0.25 vs. 0.21+/-0.032 nM/g of liver wt/min, p = .0019). Potassium efflux in the fasted group was greater than in the fed group. (1.568+/-0.082 vs. 1.28+/-0.079 microEq/g liver weight/min, p = .0184). Fasted livers extracted less oxygen after ischemia (1.94+/-0.22 vs. 1.14+/-0.46 microM/g liver wt/min, p = .0048). Lactate dehydrogenase levels showed no significant differences. CONCLUSION: Fasting augmented lipid peroxidation markedly. Nutrition may be an important mechanism that protects organs from oxidative injury.     

ADHD and overweight in boys: cross-sectional study with birth weight as a controlled factor

Population studies indicate a strong relationship between birth weight (BW) and body size in later life. However, BW as a variable was never accounted for in studies on the relationship between attention-deficit/hyperactivity disorder (ADHD) and overweight. This study aims to assess the relationship between ADHD and overweight with control of birth weight and other confounding factors. Prevalence of overweight was compared in clinical sample of 219 boys with ADHD and 396 boys without ADHD, aged 6–18 years. The following factors were controlled: BW, parents income and education level, place of residence, ADHD type, selected comorbid disorders and stimulant treatment. Overweight and obesity were diagnosed according to the criteria proposed by the International Obesity Task Force. Logistic regression analysis was used to estimate the association between ADHD and the prevalence of overweight and obesity. Boys with ADHD differed significantly from the control group in distribution of low BW (8.2 vs. 3.0 %, χ ² = 8.23, p = 0.02). Low BW was associated with a lower prevalence of overweight than normal and high BW (0 vs. 12.14 %, χ ² = 4.12, p = 0.04). Overweight was observed significantly more often in boys with ADHD (17.3 vs. 8.3 %, χ ² = 11.23, p < 0.001) even after adjustment for BW and other variables (OR = 2.44, 95 % CI 1.38–4.29, p = 0.002) and after controlling for ADHD type, stimulant treatment and selected comorbid disorders. Independently to applied analysis, obesity was not associated with ADHD. Lower birth weight is over twice more often observed in boys with ADHD than in control group. Although this phenomenon may reduce the rate of overweight in the studied group, ADHD remains strongly associated with increased prevalence of overweight.