To test the hypothesis that transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) thalamotomy is effective, durable, and safe for patients with medication-refractory essential tremor ...(ET), we assessed clinical outcomes at 3-year follow-up of a controlled multicenter prospective trial.
Outcomes were based on the Clinical Rating Scale for Tremor, including hand combined tremor-motor (scale of 0-32), functional disability (scale of 0-32), and postural tremor (scale of 0-4) scores, and total scores from the Quality of Life in Essential Tremor Questionnaire (scale of 0-100). Scores at 36 months were compared with baseline and at 6 months after treatment to assess for efficacy and durability. Adverse events were also reported.
Measured scores remained improved from baseline to 36 months (all
< 0.0001). Range of improvement from baseline was 38%-50% in hand tremor, 43%-56% in disability, 50%-75% in postural tremor, and 27%-42% in quality of life. When compared to scores at 6 months, median scores increased for hand tremor (95% confidence interval CI 0-2,
= 0.0098) and disability (95% CI 1-4,
= 0.0001). During the third follow-up year, all previously noted adverse events remained mild or moderate, none worsened, 2 resolved, and no new adverse events occurred.
Results at 3 years after unilateral tcMRgFUS thalamotomy for ET show continued benefit, and no progressive or delayed complications. Patients may experience mild degradation in some treatment metrics by 3 years, though improvement from baseline remains significant.
NCT01827904.
This study provides Class IV evidence that for patients with severe ET, unilateral tcMRgFUS thalamotomy provides durable benefit after 3 years.
The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for ...medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial.
Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist. The Quality of Life in Essential Tremor Questionnaire (QUEST) was used to assess quality of life. CRST and QUEST scores at 48 and 60 months post-MRgFUS were compared to those at baseline to assess treatment efficacy and durability. All adverse events (AEs) were reported.
Forty-five and 40 patients completed the 4- and 5-year follow-ups, respectively. CRST scores for postural tremor (Part A) for the treated hand remained significantly improved by 73.3% and 73.1% from baseline at both 48 and 60 months posttreatment, respectively (both p < 0.0001). Combined hand tremor/motor scores (Parts A and B) also improved by 49.5% and 40.4% (p < 0.0001) at each respective time point. Functional disability scores (Part C) increased slightly over time but remained significantly improved through the 5 years (p < 0.0001). Similarly, QUEST scores remained significantly improved from baseline at year 4 (p < 0.0001) and year 5 (p < 0.0003). All previously reported AEs remained mild or moderate, and no new AEs were reported.
Unilateral MRgFUS thalamotomy demonstrates sustained and significant tremor improvement at 5 years with an overall improvement in quality-of-life measures and without any progressive or delayed complications. Clinical trial registration no.: NCT01827904 (ClinicalTrials.gov).
Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies.
We randomly assigned, in a 3:1 ratio, ...patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months.
Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness.
Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).
This study aimed to identify characteristics of patients with frequent obstetric triage visits ("superusers") compared to those with fewer visits and to evaluate the association of frequent obstetric ...triage visits with preterm birth and cesarean delivery.
This retrospective cohort included patients presenting to the obstetric triage unit at a tertiary care center from March through April 2014. Superusers were defined as individuals having four or more triage visits. Participant characteristics, including demographic, clinical, visit acuity, and health care characteristics of superusers and nonsuperusers, were summarized and compared. In the subset of patients where data were available regarding prenatal care, prenatal visit patterns were analyzed and compared between the two groups. The outcomes of preterm birth and cesarean were compared between groups using modified Poisson regression to control for confounding.
Of the 656 patients evaluated in the obstetric triage unit during the study period, 648 patients met the inclusion criteria. Factors associated with frequent triage use included race/ethnicity, multiparity, insurance status, high-risk pregnancy, and a prior preterm birth. Superusers were more likely to present at an earlier gestational age and had a higher proportion of visits for hypertensive disease. Patient acuity scores were not different between the groups. In the subset of patients receiving prenatal care at the institution, prenatal visit patterns were similar. The risk of preterm birth (adjusted risk ratio aRR: 1.06; 95% confidence interval CI: 0.66-1.70) did not differ between groups; however, the risk of a cesarean delivery was increased in superusers (aRR: 1.39; 95% CI: 1.01-1.92) when compared to nonsuperusers.
Superusers, compared to nonsuperusers, have distinct clinical and demographic characteristics and are more likely to be seen in the triage unit at earlier gestational ages. Superusers tended to have a higher proportion of visits for hypertensive disease and had an increased risk of cesarean delivery.
· Patients with frequent triage visits did not have an increased risk of preterm birth.. · Patients with frequent triage visits were more likely to undergo cesarean delivery.. · Acuity scales were similar for patients with frequent visits compared to those with few visits..
Raw produce is an increasingly recognized vehicle for salmonellosis. We investigated a nationwide outbreak that occurred in the United States in 2008.
We defined a case as diarrhea in a person with ...laboratory-confirmed infection with the outbreak strain of Salmonella enterica serotype Saintpaul. Epidemiologic, traceback, and environmental studies were conducted.
Among the 1500 case subjects, 21% were hospitalized, and 2 died. In three case-control studies of cases not linked to restaurant clusters, illness was significantly associated with eating raw tomatoes (matched odds ratio, 5.6; 95% confidence interval CI, 1.6 to 30.3); eating at a Mexican-style restaurant (matched odds ratio, 4.6; 95% CI, 2.1 to ∞) and eating pico de gallo salsa (matched odds ratio, 4.0; 95% CI, 1.5 to 17.8), corn tortillas (matched odds ratio, 2.3; 95% CI, 1.2 to 5.0), or salsa (matched odds ratio, 2.1; 95% CI, 1.1 to 3.9); and having a raw jalapeño pepper in the household (matched odds ratio, 2.9; 95% CI, 1.2 to 7.6). In nine analyses of clusters associated with restaurants or events, jalapeño peppers were implicated in all three clusters with implicated ingredients, and jalapeño or serrano peppers were an ingredient in an implicated item in the other three clusters. Raw tomatoes were an ingredient in an implicated item in three clusters. The outbreak strain was identified in jalapeño peppers collected in Texas and in agricultural water and serrano peppers on a Mexican farm. Tomato tracebacks did not converge on a source.
Although an epidemiologic association with raw tomatoes was identified early in this investigation, subsequent epidemiologic and microbiologic evidence implicated jalapeño and serrano peppers. This outbreak highlights the importance of preventing raw-produce contamination.
To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ...ovarian cancer.
Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria.
26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness.
Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months.
The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development.
•Weekly paclitaxel with lenvatinib shows encouraging activity in multiple, rare and difficulty to treat, histologic subtypes.•This regimen provides a new active option for patients with recurrent platinum resistant ovarian or endometrial cancer.•The combination is safe and side effects are manageable.•This regimen is also reasonable for patients who are not candidates for lenvatinib/pembrolizumab or other immunotherapy.
Contaminated food ingredients can affect multiple products, each distributed through various channels and consumed in multiple settings. Beginning in November 2008, we investigated a nationwide ...outbreak of salmonella infections.
A case was defined as laboratory-confirmed infection with the outbreak strain of Salmonella Typhimurium occurring between September 1, 2008, and April 20, 2009. We conducted two case-control studies, product "trace-back," and environmental investigations.
Among 714 case patients identified in 46 states, 166 (23%) were hospitalized and 9 (1%) died. In study 1, illness was associated with eating any peanut butter (matched odds ratio, 2.5; 95% confidence interval CI, 1.3 to 5.3), peanut butter-containing products (matched odds ratio, 2.2; 95% CI, 1.1 to 4.7), and frozen chicken products (matched odds ratio, 4.6; 95% CI, 1.7 to 14.7). Investigations of focal clusters and single cases associated with nine institutions identified a single institutional brand of peanut butter (here called brand X) distributed to all facilities. In study 2, illness was associated with eating peanut butter outside the home (matched odds ratio, 3.9; 95% CI, 1.6 to 10.0) and two brands of peanut butter crackers (brand A: matched odds ratio, 17.2; 95% CI, 6.9 to 51.5; brand B: matched odds ratio, 3.6; 95% CI, 1.3 to 9.8). Both cracker brands were made from brand X peanut paste. The outbreak strain was isolated from brand X peanut butter, brand A crackers, and 15 other products. A total of 3918 peanut butter-containing products were recalled between January 10 and April 29, 2009.
Contaminated peanut butter and peanut products caused a nationwide salmonellosis outbreak. Ingredient-driven outbreaks are challenging to detect and may lead to widespread contamination of numerous food products.
To evaluate in a randomized clinical trial systemic chemoendocrine therapy used as primary (neo-adjuvant) treatment before surgery in women with primary operable breast cancer.
Patients aged less ...than 70 years with clinically palpable, primary operable breast cancer diagnostically confirmed by fine-needle aspiration cytology (FNAC) and suitable for treatment with surgery, radiotherapy, cytotoxic chemotherapy, and tamoxifen were considered eligible. Patients randomized to neoadjuvant treatment received four cycles of chemo-therapy for 3 months before surgery followed by another four cycles after surgery, and were compared with patients randomized to adjuvant therapy who received eight cycles of chemotherapy over 6 months after surgery.
Of 212 patients who were randomized to receive either adjuvant (n = 107) or neoadjuvant (n = 105) chemoendocrine therapy, 200 are now assessable for response. The two groups are comparable for age, menopausal status, disease stage, and surgical requirements. The overall clinical response rate was 85%, with a complete histologic response rate of 10%. There was a significant reduction in the requirement for mastectomy in patients who received neoadjuvant treatment (13%) as compared with those who received adjuvant therapy (28%) (P < .005). Symptomatic and hematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy. The median follow-up period for patients in this trial is 28 months, during which time four patients have relapsed locally and 20, including one of the local relapses, have developed metastatic disease, 19 of whom have died. The follow-up period is too brief to evaluate relapse rate or survival duration.
This trial confirms previous reports of a high rate of response to neoadjuvant therapy, but is the first to include small primary cancers and to show, in the context of a randomized trial, a reduction in the requirement for mastectomy. Until disease-free and overall survival data are available from the larger National Surgical Adjuvant Breast and Bowel Project (NSABP)-18 trial, such neoadjuvant treatment cannot be recommended outside of a clinical trial.
Background Although anticoagulation therapy is accepted for most patients with atrial fibrillation, 2 different strategies exist for management of the cardiac rhythm: atrial fibrillation is allowed ...to persist while the ventricular rate is controlled; and atrial fibrillation is converted, and an attempt is made to maintain sinus rhythm. Methods The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study was a randomized clinical trial that compared these 2 strategies. We report the baseline characteristics of the patients enrolled in the AFFIRM Study. Results More than 7400 patients at more than 200 North American hospitals and clinics qualified for enrollment in the AFFIRM Study. A total of 4060 patients were enrolled in the AFFIRM Study. The average age of patients enrolled was 70 years, with 39% female and 89% white. Hypertension was present in 71%. Coronary artery disease was present in 38%. Echocardiography was performed in 3311 patients, and results showed normal ventricular function in 68% and normal left atrial size in 33%. Most patients with recurrent episodes had symptoms with atrial fibrillation. Approximately one third of patients were enrolled with a first episode of atrial fibrillation. Conclusion The AFFIRM Study enrolled 4060 predominantly elderly patients with atrial fibrillation to compare ventricular rate control with rhythm control. The patients in the AFFIRM Study were representative of patients at high risk for complications from atrial fibrillation, which indicates that the results of this large clinical trial will be relevant to patient care. (Am Heart J 2002;143:991-1001.)
This impressive collection celebrates the work of Peter Kershaw, a key figure in the field of Australian palaeoenvironmental reconstruction. Over almost half a century his research helped ...reconceptualize ecology in Australia, creating a detailed understanding of environmental change in the Late Pleistocene and Holocene. Within a biogeographic framework one of his exceptional contributions was to explore the ways that Aboriginal people may have modified the landscape through the effects of anthropogenic burning. These ideas have had significant impacts on thinking within the fields of geomorphology, biogeography, archaeology, anthropology and history. Papers presented here continue to explore the dynamism of landscape change in Australia and the contribution of humans to those transformations. The volume is structured in two sections. The first examines evidence for human engagement with landscape, focusing on Australia and Papua New Guinea but also dealing with the human/environmental histories of Europe and Asia. The second section contains papers that examine palaeoecology and present some of the latest research into environmental change in Australia and New Zealand. Individually these papers, written by many of Australia's prominent researchers in these fields, are significant contributions to our knowledge of Quaternary landscapes and human land use. But Peopled Landscapes also signifies the disciplinary entanglement that is archaeological and biogeographic research in this region, with archaeologists and environmental scientists contributing to both studies of human land use and palaeoecology. Peopled Landscapes reveals the interdisciplinary richness of Quaternary research in the Australasian region as well as the complexity and richness of the entangled environmental and human pasts of these lands. - Prof. Peter Hiscock, The Australian National University
