The Silent Issue in Intel v. Sulyma: Does ERISA Section 413(2) Operate to Time-Bar Otherwise Timely Suits Challenging Subsequent Breaches of the Same Character?

In its recent opinion in Intel v. Sulyma, the U.S. Supreme Court clarified what qualifies as the “actual knowledge” required to trigger ERISA’s three-year statutory period. The Court’s opinion, however, left open whether establishing “actual knowledge” by a plaintiff in one case serves to time-bar otherwise timely suits that challenge subsequent breaches of the same character. This article argues that, under the continuing fiduciary duty analysis that the Court set forth in Tibble v. Edison, such suits should not be deemed untimely

Effect of Raloxifene Treatment on Osteocyte Apoptosis in Postmenopausal Women

Increased osteocyte apoptosis, as the result of estrogen deficiency, could play a role in the decrease of bone mass and bone strength seen in postmenopausal osteoporosis. We investigated whether treatment with raloxifene of postmenopausal women with osteoporosis affects osteocyte apoptosis. Transiliac bone biopsies were obtained from 26 osteoporotic women at baseline and after 2 years of treatment with placebo or raloxifene. Immunohistochemical detection of cleaved caspase-3 was performed on sections from nondecalcified bone biopsies to visualize apoptosis. In the trabecular bone total osteocytes, positively stained osteocytes and empty lacunae were counted and percent positive cells and percent empty lacunae determined. Statistical evaluation was performed by Wilcoxon’s paired t-test and Spearman’s rank correlations. There was no significant difference in percentage positive osteocytes between baseline and follow-up biopsies in both the placebo and the raloxifene groups. The percentage empty lacunae increased significantly in the placebo group (11.20 ± 1.43 vs. 9.00 ± 2.25, P = 0.014) but not in the raloxifene group. At baseline in both groups combined, there was a negative correlation between indices of bone remodeling and the percentage positive osteocytes (bone formation rate/bone volume r = −0.67, P = 0.001). We found no direct evidence for an effect of raloxifene treatment on osteocyte apoptosis, but small effects of raloxifene treatment cannot be excluded. The percent of apoptotic osteocytes was dependent on the level of bone remodeling in an individual

Brokerage Windows in 401(k) Plans: The Total Abdication of Fiduciary Responsibility

This article addresses the fiduciary issues raised by the current practice of plan fiduciaries of not only disclaiming any fiduciary responsibility for brokerage window investments, but also abdicating any role (fiduciary or otherwise) in assessing even the general suitability of those investments for a retirement plan, and concludes that the practice is in plain and notorious violation of what ERISA requires of fiduciaries

Property as a Legal Concept: PartI The two paradigms of property and freedom of expression

A retrospective study of 310 patients with carcinoma of the head of the pancreas or periampullary region was performed. Preoperative bile drainage by placement of a stent reduced the number of postoperative complications, especially bleeding (P = 0·03). The operative mortality rate was nil in patients with periampullary cancer aged under 70 years and 23 per cent in those over 70 years of age (P < 0·001). In the last 2 years of the study, the mortality rate following resection decreased to 2 per cent. Tumour-containing resection margins did not influence survival after resection (P = 0·48). Tumour dimension of pancreatic and periampullary canc

Training specialists to write appropriate reply letters to general practitioners about patients with medically unexplained physical symptoms; A cluster-randomized trial.

Objective: To evaluate effects of a communication training for specialists on the quality of their reply letters to general practitioners (GPs) about patients with medically unexplained physical symptoms (MUPS). Methods: Before randomization, specialists included ≤3 MUPS patients in a multi-center cluster-randomized trial. In 14 h of MUPS-specific communication training, 2.5 h focused on reply letters. Letters were discussed with regard to reporting and answering GPs' referral questions and patients' questions, and to reporting findings, explaining MUPS with perpetuating factors and giving advice. After the training, all doctors again included ≤3 MUPS patients. Reply letters to GPs were assessed for quality and blindly rated on a digital scale. Results: We recruited 478 MUPS patients and 123 specialists; 80% of the doctors wrote ≥1 reply letters, 285 letters were assessed. Trained doctors reported (61% versus 37%, OR=2.55, F(1281)=6.60, pgroup*time=.01) and answered (63% versus 33%, OR=3.31, F(1281)=5.36, pgroup*time=.02) patients' questions more frequently than untrained doctors. Conclusion: Training improves reply letters with regard to patients' questions, but not with regard to the following: GPs' referral questions, somatic findings, additional testing, explaining, and advice. Practice implications: Training specialists to write appropriate reply letters needs more focus on explanation and advice

GPs views on transfer of information about terminally ill patients to the out-of-hours co-operative

<p>Abstract</p> <p>Background</p> <p>In the Netherlands, the increase in of out-of-hours care that is provided by GP co-operatives is challenging the continuity of care for the terminally ill in general practice. Aim of this study is to investigate the views of general practitioners (GPs) on the transfer of information about terminally ill patients to the GP co-operatives. GPs were asked to give their view from two different perspectives: as a GP in their daily practice and as a locum in the GP co-operative.</p> <p>Methods</p> <p>Retrospective web based questionnaire sent to all 424 GPs in the Amsterdam region.</p> <p>Results</p> <p>With a response rate of 42%, 177 physicians completed the questionnaire. Transfer of information to the GP co-operative about most of their terminally ill patients was reported by 82% of the GPs and 5% did not do so for any of their patients. A faster than foreseen deterioration of the patient's situation was the most frequently reported reason for not transferring information.</p> <p>Of those who transferred information to the GP co-operative, more than 95% reported that they provided information about the diagnosis and terminally ill status of the patient. Information about medication, patient wishes regarding treatment, and prognosis was reported by respectively 90%, 87%, and 74% of the GPs. Less than 50% of the GPs reported that they transferred information about the patient's awareness of both the diagnosis and the prognosis, about the psychosocial context, and intolerances.</p> <p>In their role as locum, over 90% of the GPs wanted to receive information about the diagnosis, the terminally ill status of the patient, the medication and the patient's wishes regarding treatment.</p> <p>Conclusions</p> <p>Although most GPs reported that they transferred information about their terminally ill patients to the GP co-operative, the content of this information varies considerably. Only 21% of the GPs, working out of hours as a locum, were satisfied with the quality of the information transferred.</p

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized

ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis

Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients.Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, slow vital capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6–18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France.Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019

The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis

Background Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients’ safety and management. Objectives To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. Methods Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®. Results The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue. Conclusions MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients