Notes

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palsy is required. These studies should clarify the optimal standard treatment regarding weight-bearing exercises, vitamin D and calcium supplementation, and should include fracture frequency as a primary outcome.
Adequate dosing of antimicrobials is critical to properly treat infections and limit development of resistance and adverse effects. Limited guidance exists for antimicrobial dosing adjustments in patients requiring extracorporporeal membrane oxygenation (ECMO) therapy. A systematic review was conducted to delineate the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in critically ill adult patients requiring ECMO.

Medline, EMBASE, Global Health, and All EBM Reviews databases were searched. Grey literature was examined. All studies reporting PK/PD parameters of antimicrobials in critically ill adults treated with ECMO were included, except for case reports and congress abstracts. Ex vivo studies were included. Two independent reviewers applied the inclusion and exclusion criteria. Reviewers were then paired to independently abstract data and evaluate methodological quality of studies using the ROBINS-I tool and the compliance with ClinPK guidelines. Patients' and studies' characteristics, key PK/PD findings, details of ECMO circuits and co-treatments were summarized qualitatively. Dosing recommendations were formulated based on data from controlled studies.

Thirty-two clinical studies were included; most were observational and uncontrolled. Fourteen ex vivo studies were analysed. Information on patient characteristics and co-treatments was often missing. The effect of ECMO on PK/PD parameters of antimicrobials varied depending on the studied drugs. Few dosing recommendations could be formulated given the lack of good quality data.

Limited data exist on the PK/PD of antimicrobials during ECMO therapy. Rigorously designed and well powered populational PK studies are required to establish empiric dosing guidelines for antimicrobials in patients requiring ECMO support.

CRD42018099992 (Registered July 24th 2018).
CRD42018099992 (Registered July 24th 2018).
The aim of this study was to evaluate the cost effectiveness of cladribine compared with alemtuzumab, natalizumab, and ocrelizumab for the treatment of highly active multiple sclerosis (HAD-MS) from the perspective of the Chilean health care public sector.

A Markov model was used to compare costs and quality-adjusted life-years (QALYs) over a 45-year time horizon using a 3% discount rate for costs and outcomes. Natural history of the disease was modeled in terms of progression of disability according to the Expanded Disability Status Scale (EDSS). A network meta-analysis was used as a source of comparative effectiveness for disability progression and annual relapse rates. Differences in costs and outcomes were modeled for only 10 years due to high temporal uncertainty. Ocrelizumab was assumed to have the same efficacy as cladribine due to lack of data. Direct costs were taken from national tariffs and expressed in 2019 US dollars. Utilities for EDSS health states were obtained from the literature. Second-ladribine is a new oral alternative to treat patients with HAD-MS that is expected to produce higher QALYs than all evaluated alternatives. In the context of a conservative analysis, cladribine cannot be considered cost effective for the Chilean health care public sector using a 1 GDP per capita threshold. However, under reasonable discount scenarios, cladribine becomes an attractive alternative for the health system.The medical affairs function represents one of the scientific interfaces in a pharmaceutical organization. Over the last two decades, medical affairs has evolved from being a support function to a strategic pillar within organizational business units. The COVID-19 pandemic has given rise to unforeseen circumstances resulting in a dramatic change in external stakeholder engagements, catapulting the medical affairs function into leading the way on scientific engagements and patient-centric endeavors. The changes in stakeholder interactions and behavior as a result of the pandemic last year are likely to persist in the foreseeable future for which medical affairs professionals need to enhance existing skill sets and acquire expertise in newer domains. In this paper, the transformation of the medical affairs team to a key strategic partner and the skills required to strengthen this transition, in the next normal of a post-COVID world, is explored.Psychosis occurs across a wide variety of dementias with differing etiologies, including Alzheimer's dementia, Parkinson's dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia. Pimavanserin, a selective serotonin 5-HT2A receptor (5-HT2AR) inverse agonist, has shown promising results in clinical trials by reducing the frequency and/or severity of hallucinations and delusions and the risk of relapse of these symptoms in patients with dementia-related psychosis. BX-795 order A literature review was conducted to identify mechanisms that explain the role of 5-HT2ARs in both the etiology and treatment of dementia-related psychosis. This review revealed that most pathological changes commonly associated with neurodegenerative diseases cause one or more of the following events to occur reduced synaptic contact of gamma aminobutyric acid (GABA)-ergic interneurons with glutamatergic pyramidal cells, reduced cortical innervation from subcortical structures, and altered 5-HT2AR expression levels. Each of these events promotes increased pyramidal cell hyperexcitability and disruption of excitatory/inhibitory balance, facilitating emergence of psychotic behaviors. The brain regions affected by these pathological changes largely coincide with areas expressing high levels of 5-HT2ARs. At the cellular level, 5-HT2ARs are most highly expressed on cortical glutamatergic pyramidal cells, where they regulate pyramidal cell excitability. The common effects of different neurodegenerative diseases on pyramidal cell excitability together with the close anatomical and functional connection of 5-HT2ARs to pyramidal cell excitability may explain why suppressing 5-HT2AR activity could be an effective strategy to treat dementia-related psychosis.
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