Is Droxidopa Safe and Effective in Reducing Symptoms of Neurogenic Orthostatic Hypotension?

Objective: The objective of this selective EBM review is to determine whether or not droxidopa is safe and effective in reducing the symptoms of neurogenic orthostatic hypotension. Study Design: Systemic review of three English-language primary studies, conducted in 2014 or later. Data Sources: Three double-blind, randomized trials comparing the safety and efficacy of droxidopa to placebo in patients with diagnosed neurogenic orthostatic hypotension, found via PubMed in peer-reviewed journals. Outcomes Measured: Improvement of symptoms was measured utilizing patient responses to the Orthostatic Hypotension Questionnaire (OHQ), which consists of a six item Orthostatic Hypotension Symptom Assessment (OSHA) and the four item Orthostatic Hypotension Daily Activity Scale (OHDAS), each measured on a 1-10 scale. Also utilized was the patient-rated Clinical Global Impression (CGI) severity and improvement 7-point scales. Safety was measured through incidence of adverse effects during the randomized trial. Results: Biaggioni, et al, exhibited 46% of droxidopa recipients describing themselves as much or very much improved according to CGI ratings, compared to 27.5% of those receiving placebo, although with a p-score of 0.384. Hauser, et al, exhibited mean improvement in OSHA item 1 at week 1 as 2.3 for droxidopa, compared to 1.3 in the control group, with a p-value of 0.018. Kaufmann, et al, exhibited improvement of greater than 3 units in composite OHQ score in 27.2% of droxidopa recipients compared to 11.4% of placebo recipients, with a p score of 0.016. Numbers needed to harm were presented for each studied, obtained through measurement of adverse effects of experiment vs control during randomized trial, and consisted of -13 in Biaggioni, et al, 38 in Hauser, et al, and 28 in Kaufmann, et al. Conclusions: These results indicate that droxidopa showed statistical improvement in symptoms in two studies and numerical improvement in another, in addition to being relatively well tolerated. However, the difference in end points measured in each studies and inconsistencies in study design prevent any strong conclusion, and further study is required

Heat Transfer Experiments on a Pulse Detonation Driven Combustor

Heat transfer experiments were conducted using a heat exchanger behind a pulse detonation combustor and a Garrett automotive turbocharger at the Air Force Research Lab (AFRL). The equivalence ratio and purge fraction were held at 1.0 and 0.9, respectively, while the frequency of operation was varied from 10 to 12 Hz in 1 Hz movements, and the fill fraction was varied from 0.5 to 0.8 in 0.1 increments. Temperature measurements were calculated using an energy balance allowing for the calculation of heat exchanger inlet enthalpy. The heat exchanger inlet enthalpy was estimated to be the exit enthalpy of the turbocharger it was coupled to. The representative turbine inlet enthalpy was calculated using compressor work and radiation from the turbine. Turbine inlet and exit temperatures were also measured directly using J-type and K-type thermocouples and compared to calculated values using the heat exchanger approach. Turbine work was calculated from the change in enthalpy from the inlet to the exit. This data was compared with average values of time accurate data from published work. Compressor and turbine work was also presented and compared with recently attained values. Efficiency was presented for varying pressure ratios. The efficiency measurements were compared with time accurate efficiency measurements from on-going work

Community Voices: Integrating Local and International Partnerships through Storytelling

This essay describes a new global service-learning project focused on integrating local and international partnerships through storytelling. Providence College faculty and students partnered with a local organization, CityArts, and an international organization, Waves of Hope, to empower young people to share their stories through a community lens. Using art and literacy in transnational contexts, the voices and images depict beauty and justice in communities, while also representing a more collaborative model of engagement

Acting Locally in a Flat World: Global Citizenship and the Democratic Practice of Service-Learning

This paper series seems especially significant this year, as Campus Compact celebrates an important milestone. The context has certainly changed over the decades since the founding of Campus Compact twenty years ago. For while Campus Compact has grown impressively to more than 950 member campuses with 31 state offices under the leadership of Elizabeth Hollander, there is also a sense that service-learning is at a crossroads. At least one dimension for educators to consider is the connection between the local and the global, and the importance of global citizenship and democratic practices which promote global citizenship. To be engaged and relevant requires that service-learning includes a large vision, along with democratic practices for acting locally with global intentions. The flattened world which Thomas Friedman has popularly termed for the rapid rise of globalization since the start of the 21st century has important implications for service-learning educators trying to implement John Dewey\u27s vision of building democratic, neighborly communities. It requires us to ask: if democracy begins at home, what does this mean in the context of an increasingly global society

Genome Mining of Plant NPFs Reveals Varying Conservation of Signature Motifs Associated With the Mechanism of Transport

Nitrogen is essential for all living species and may be taken up from the environment in different forms like nitrate or peptides. In plants, members of a transporter family named NPFs transport nitrate and peptides across biological membranes. NPFs are phylogenetically related to a family of peptide transporters (PTRs) or proton-coupled oligopeptide transporters (POTs) that are evolutionarily conserved in all organisms except in Archaea. POTs are present in low numbers in bacteria, algae and animals. NPFs have expanded in plants and evolved to transport a wide range of substrates including phytohormones and glucosinolates. Functional studies have shown that most NPFs, like POTs, operate as symporters with simultaneous inwardly directed movement of protons. Here we focus on four structural features of NPFs/POTs/PTRs that have been shown by structural and functional studies to be essential to proton-coupled symport transport. The first two features are implicated in proton binding and transport: a conserved motif named ExxER/K, located in the first transmembrane helix (TMH1) and a D/E residue in TMH7 that has been observed in some bacterial and algal transporters. The third and fourth features are two inter-helical salt bridges between residues on TMH1 and TMH7 or TMH4 and TMH10. To understand if the mechanism of transport is conserved in NPFs with the expansion to novel substrates, we collected NPFs sequences from 42 plant genomes. Sequence alignment revealed that the ExxER/K motif is not strictly conserved and its conservation level is different in the NPF subfamilies. The proton binding site on TMH7 is missing in all NPFs with the exception of two NPFs from moss. The two moss NPFs also have a positively charged amino acid on TMH1 that can form the salt bridge with the TMH7 negative residue. None of the other NPFs we examined harbor residues that can form the TMH1–TMH7 salt bridge. In contrast, the amino acids required to form the TMH4–TMH10 salt bridge are highly conserved in NPFs, with some exceptions. These results support the need for further biochemical and structural studies of individual NPFs for a better understanding of the transport mechanism in this family of transporters

New Medicines for Tropical Diseases in Pregnancy: Catch-22

Nicholas White and colleagues discuss why it is so important to conduct clinical trials of malaria treatments in pregnancy

Functional Dyspepsia

Dyspepsia is a constellation of symptoms referable to the gastroduodenal region of the upper gastrointestinal tract. Functional dyspepsia, a relapsing and remitting disorder, is the most common cause of these symptoms. The current standard for the diagnosis of functional dyspepsia is the Rome III criteria, developed by the Rome III Committees, a multinational group of experts in the field, first convened in 1990, that meets regularly to review and revise the diagnostic criteria for all functional gastrointestinal disorders. In most patients with functional dyspepsia, the natural history is chronic and fluctuating, with periods of time when the patient is asymptomatic followed by episodes of symptom relapse. Data from population-based studies suggest that, during extended follow-up, approximately 15 to 20% of people with functional dyspepsia have persistent symptoms and 50% have resolution of symptoms; in the remaining 30 to 35% of patients symptoms will fluctuate and meet the criteria for another functional gastrointestinal disorder.81 Despite the chronic nature of functional dyspepsia, there is no evidence to suggest that it is associated with decreased survival

Conservative management versus open reduction and internal fixation for mid-shaft clavicle fractures in adults - The Clavicle Trial: Study protocol for a multicentre randomized controlled trial

Background: Clavicle fractures account for around 4% of all fractures and up to 44% of fractures of the shoulder girdle. Fractures of the middle third (or mid-shaft) account for approximately 80% of all clavicle fractures. Management of this group of fractures is often challenging and the outcome can be unsatisfactory. In particular it is not clear whether surgery produces better outcomes than non-surgical management. Currently there is much variation in the use of surgery and a lack of good quality evidence to inform our decision.Methods/Design: We aim to undertake a multicentre randomised controlled trial evaluating the effectiveness and safety of conservative management versus open reduction and internal fixation for displaced mid-shaft clavicle fractures in adults. Surgical treatment will be performed using the Acumed clavicle fixation system. Conservative management will consist of immobilisation in a sling at the side in internal rotation for 6 weeks or until clinical or radiological union. We aim to recruit 300 patients. These patients will be followed-up for at least 9 months. The primary endpoint will be the rate of non-union at 3 months following treatment. Secondary endpoints will be limb function measured using the Constant-Murley Score and the Disabilities of the Arm, Shoulder and Hand (DASH) Score at 3 and 9 months post-operatively.Discussion: This article presents the protocol for a multicentre randomised controlled trial. It gives extensive details of, and the basis for, the chosen methods, and describes the key measures taken to avoid bias and to ensure validity.Trial Registration: United Kingdom Clinical Research Network ID: 8665. The date of registration of the trial is 07/09/2006. The date the first patient was recruited is 18/12/2007. © 2011 Longo et al; licensee BioMed Central Ltd

Governing integrated health and social care: an analysis of experiences in three European countries

Purpose: Achieving greater health and social care integration is a policy priority in many countries, but challenges remain. We focused on governance and accountability for integrated care and explored arrangements that shape more integrated delivery models or systems in Italy, the Netherlands and Scotland. We also examined how the COVID-19 pandemic affected existing governance arrangements. Design/methodology/approach: A case study approach involving document review and semi-structured interviews with 35 stakeholders in 10 study sites between February 2021 and April 2022. We used the Transparency, Accountability, Participation, Integrity and Capability (TAPIC) framework to guide our analytical enquiry. Findings: Study sites ranged from bottom-up voluntary agreements in the Netherlands to top-down mandated integration in Scotland. Interviews identified seven themes that were seen to have helped or hindered integration efforts locally. Participants described a disconnect between what national or regional governments aspire to achieve and their own efforts to implement this vision. This resulted in blurred, and sometimes contradictory, lines of accountability between the centre and local sites. Flexibility and time to allow for national policies to be adapted to local contexts, and engaged local leaders, were seen to be key to delivering the integration agenda. Health care, and in particular acute hospital care, was reported to dominate social care in terms of policies, resource allocation and national monitoring systems, thereby undermining better collaboration locally. The pandemic highlighted and exacerbated existing strengths and weaknesses but was not seen as a major disruptor to the overall vision for the health and social care system. Research limitations: We included a relatively small number of interviews per study site, limiting our ability to explore complexities within sites. Originality: This study highlights that governance is relatively neglected as a focus of attention in this context but addressing governance challenges is key for successful collaboration