Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre, single‐arm, phase 2 study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106815/1/bjh12780.pd

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Dissociable Effects of Alzheimer Disease and White Matter Hyperintensities on Brain Metabolism

ImportanceCerebrovascular disease and Alzheimer disease (AD) frequently co-occur and seem to act through different pathways in producing dementia.ObjectiveTo examine cerebrovascular disease and AD markers in relation to brain glucose metabolism in patients with mild cognitive impairment.Design and settingCohort study among the Alzheimer Disease Neuroimaging Initiative clinical sites in the United States and Canada.ParticipantsTwo hundred three patients having amnestic mild cognitive impairment (74 of whom converted to AD) with serial imaging during a 3-year follow-up period.Main outcomes and measuresQuantified white matter hyperintensities (WMHs) represented cerebrovascular disease, and cerebrospinal fluid β-amyloid represented AD pathology. Brain glucose metabolism in temporoparietal and frontal brain regions was measured using positron emission tomography with fluorodeoxyglucose F18.ResultsIn converters, greater WMHs were associated with decreased frontal metabolism (-0.048; 95% CI, -0.067 to -0.029) but not temporoparietal metabolism (0.010; 95% CI, -0.010 to 0.030). Greater cerebrospinal fluid β-amyloid (per 10-pg/mL increase) was associated with increased temporoparietal metabolism (0.005; 95% CI, 0.000-0.010) but not frontal metabolism (0.002; 95% CI, -0.004 to 0.007) in the same patients. In nonconverters, similar relationships were observed except for a positive association of greater WMHs with increased temporoparietal metabolism (0.051; 95% CI, 0.027-0.076).Conclusions and relevanceThe dissociation of WMHs and cerebrospinal fluid β-amyloid in relation to regional glucose metabolism suggests that these pathologic conditions operate through different and independent pathways in AD that reflect dysfunction in different brain systems. The positive association of greater WMHs with temporoparietal metabolism suggests that these pathologic processes do not co-occur in nonconverters

Guidance for Product Category Rule Development

This guidance document is a response to an internationally recognized need for additional instruction on the development of rules specific to a category of products for making claims based on a life cycle assessment (LCA). The purpose is to supplement existing standards for LCA-based claims that require the development of product category rules (PCRs) or their equivalents. The aim is that PCRs can be developed in a consistent manner and used to support claims based on multiple standards. The scope of the Guidance is global. The Guidance embodies the efforts of individuals with expertise in LCA and LCA-based product claims from more over 40 organizations in 13 countries and regions under the name of The Product Category Rule Guidance Development Initiative. The Initiative received no financial support from any standard or other product claim program and this Guidance reflects no bias toward any particular standard or program. The Guidance is intended to be a living document and we hope that it will continue to improve as the application of product claims based on LCA expands and diversifies.JRC.H.8-Sustainability Assessmen

Challenges in the transition to model-based development

Practitioners of the art and science of pharmacometrics are well aware of the considerable effort required to successfully complete modeling and simulation activities for drug development programs. This is particularly true because of the current, ad hoc implementation wherein modeling and simulation activities are piggybacked onto traditional development programs. This effort, coupled with the failure to explicitly design development programs around modeling and simulation, will continue to be an important obstacle, to the successful transition to model-based drug development. Challenges with timely data availability, high data discard rates, delays in completing modeling and simulation activities, and resistance of development teams to the use of modeling and simulation in decision making are all symptoms of an immature process capability for performing modeling and simulation

The cost effectiveness of a quality improvement program to reduce maternal and fetal mortality in a regional referral hospital in Accra, Ghana

To evaluate the cost-effectiveness of a quality improvement intervention aimed at reducing maternal and fetal mortality in Accra, Ghana.Quasi-experimental, time-sequence intervention, retrospective cost-effectiveness analysis.Data were collected on the cost and outcomes of a 5-year Kybele-Ghana Health Service Quality Improvement (QI) intervention conducted at Ridge Regional Hospital, a tertiary referral center in Accra, Ghana, focused on systems, personnel, and communication. Maternal deaths prevented were estimated comparing observed rates with counterfactual projections of maternal mortality and case-fatality rates for hypertensive disorders of pregnancy and obstetric hemorrhage. Stillbirths prevented were estimated based on counterfactual estimates of stillbirth rates. Cost-effectiveness was then calculated using estimated disability-adjusted life years averted and subjected to Monte Carlo and one-way sensitivity analyses to test the importance of assumptions inherent in the calculations.Incremental Cost-effectiveness ratio (ICER), which represents the cost per disability-adjusted life-year (DALY) averted by the intervention compared to a model counterfactual.From 2007-2011, 39,234 deliveries were affected by the QI intervention implemented at Ridge Regional Hospital. The total budget for the program was $2,363,100. Based on program estimates, 236 (±5) maternal deaths and 129 (±13) intrapartum stillbirths were averted (14,876 DALYs), implying an ICER of$158 ($129-$195) USD. This value is well below the highly cost-effective threshold of $1268 USD. Sensitivity analysis considered DALY calculation methods, and yearly prevalence of risk factors and case fatality rates. In each of these analyses, the program remained highly cost-effective with an ICER ranging from$97-$218.QI interventions to reduce maternal and fetal mortality in low resource settings can be highly cost effective. Cost-effectiveness analysis is feasible and should regularly be conducted to encourage fiscal responsibility in the pursuit of improved maternal and child health

A brain-based definition of death and criteria for its determination after arrest of circulation or neurologic function in Canada: a 2023 clinical practice guideline [Une definition cerebrale du deces et des criteres pour sa determination apres l'arret de la circulation ou de la fonction neurologique au Canada: des lignes directrices de pratique clinique 2023]

This 2023 Clinical Practice Guideline provides the biomedical definition of death based on permanent cessation of brain function that applies to all persons, as well as recommendations for death determination by circulatory criteria for potential organ donors and death determination by neurologic criteria for all mechanically ventilated patients regardless of organ donation potential. This Guideline is endorsed by the Canadian Critical Care Society, the Canadian Medical Association, the Canadian Association of Critical Care Nurses, Canadian Anesthesiologists’ Society, the Canadian Neurological Sciences Federation (representing the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian Association of Child Neurology, Canadian Society of Neuroradiology, and Canadian Stroke Consortium), Canadian Blood Services, the Canadian Donation and Transplantation Research Program, the Canadian Association of Emergency Physicians, the Nurse Practitioners Association of Canada, and the Canadian Cardiovascular Critical Care Society.</p