The effects of intervention with intravenous edaravone in Study 19 on hospitalization, tracheostomy, ventilation, and death in patients with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Intravenous (IV) edaravone is a US Food and Drug Administration-approved treatment for amyotrophic lateral sclerosis (ALS), shown in clinical trials to slow physical functional decline. In this study we compared the effect of IV edaravone (edaravone-first group) versus placebo followed by IV edaravone (placebo-first group) on survival and additional milestone events. METHODS: This work is a post hoc analysis of Study 19/MCI186-19, which was a randomized, placebo-controlled, phase 3 study investigating IV edaravone versus placebo. Study 19 and its 24-week extension have been described previously (NCT01492686). Edaravone-first versus placebo-first group time to events for specific milestone(s) were analyzed post hoc. Time-to-event composite endpoints were time to death; time to death, tracheostomy, or permanent assisted ventilation (PAV); and time to death, tracheostomy, PAV, or hospitalization. RESULTS: The risk for death, tracheostomy, PAV, or hospitalization was 53% lower among patients in the edaravone-first vs placebo-first groups (hazard ratio = 0.47 [95% confidence interval 0.25 to 0.88], P = .02). The overall effect of IV edaravone on ALS progression could be seen in the significant separation of time-to-event curves for time to death, tracheostomy, PAV, or hospitalization. ALS survival composite endpoint analyses (ALS/SURV) suggested a treatment benefit (least-squares mean difference) for the edaravone-first versus the placebo-first group at week 24 (0.15 ± 0.05 [95% confidence interval 0.06 to 0.25], P < .01) and week 48 (0.11 ± 0.05 [95% confidence interval 0.02 to 0.21], P = .02). DISCUSSION: These analyses illustrate the value of timely and continued IV edaravone treatment, as earlier initiation was associated with a lower risk of death, tracheostomy, PAV, or hospitalization in patients with ALS.

Slowing the loss of physical function in amyotrophic lateral sclerosis with edaravone: Post hoc analysis of ALSFRS-R item scores in pivotal study MCI186-19.

INTRODUCTION: Phase 3 study MCI186-19 demonstrated less loss of physical function with edaravone versus placebo, as measured by the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score. A 1-point drop in an individual ALSFRS-R item may be clinically meaningful. We assessed ALSFRS-R item score changes to identify clinical features protected by edaravone treatment. METHODS: Time-to-event analysis was used to assess the cumulative probabilities of reductions in ALSFRS-R item scores and Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) subdomain scores. RESULTS: Edaravone use was accompanied by: (1) delayed drop of ≥1 point in ALSFRS-R item score for four items: salivation, walking, climbing stairs, orthopnea (unadjusted), or for two items: walking, climbing stairs (after Bonferroni correction for multiple comparisons); (2) delayed score transition from 4 or 3 at baseline to ≤2 for five items: swallowing, eating motion, walking, climbing stairs, orthopnea (unadjusted), or for one item: climbing stairs (after Bonferroni correction for multiple comparisons); and (3) delayed worsening of ALSAQ-40 domain scores representing daily living/independence, eating and drinking (unadjusted). DISCUSSION: These post-hoc analyses identified the ALSFRS-R item scores and ALSAQ-40 domain scores that were associated with preserved gross motor function and health-related quality of life, respectively, after edaravone treatment. Limitations of post-hoc analyses should be considered when interpreting these results. We recommend that clinical trials employing the ALSFRS-R include this type of analysis as a pre-specified secondary outcome measure.

Assessment of management approaches for hyperemesis gravidarum and nausea and vomiting of pregnancy: a retrospective questionnaire analysis.

BACKGROUND: Hyperemesis gravidarum is the most severe form of nausea and vomiting of pregnancy, or morning sickness. 2% of pregnancies in the United States are affected by hyperemesis gravidarum. The condition is characterized by severe vomiting in pregnant people, especially during the first trimester, often leading to hypovolemia and weight loss. The standard of care for hyperemesis and nausea and vomiting of pregnancy is commonly ineffective. We hypothesize that based on patient experience; the current treatment guidelines for hyperemesis are not clinically effective. Our objective was to identify the efficacy of the various management approaches that are currently in place for hyperemesis and nausea and vomiting of pregnancy. METHODS: A questionnaire was designed based on diagnostic criteria, standard demographic identifiers, and common medications for the treatment of hyperemesis gravidarum. This questionnaire was distributed online to through hyperemesis and nausea and vomiting of pregnancy support groups, personal social media, and institutional email. RESULTS: In our study, most participants diagnosed with hyperemesis gravidarum trialed at least three medications, most of which were ineffective and/or had severe side effects. The most used medication for treatment of hyperemesis gravidarum is ondansetron, a standard antiemetic, with fatigue and constipation being the most reported side effects. All data in the dataset was coded as categorical and analyzed using contingency tables using Mantel-Haenszel Chi square tests. CONCLUSIONS: The data presented in this research provides insight into the suffering that patients with these diagnoses face day-to-day due to the lack of efficacious, well-tolerated treatment options. Establishing this gap in treatment can facilitate the development of effective treatments that will provide relief for thousands of patients.

Localization of the Interaction Site of Herpes Simplex Virus Glycoprotein D (gD) on the Membrane Fusion Regulator, gH/gL.

A cascade of protein-protein interactions between four herpes simplex virus (HSV) glycoproteins (gD, gH/gL, and gB) drive fusion between the HSV envelope and host membrane, thereby allowing for virus entry and infection. Specifically, binding of gD to one of its receptors induces a conformational change that allows gD to bind to the regulatory complex gH/gL, which then activates the fusogen gB, resulting in membrane fusion. Using surface plasmon resonance and a panel of anti-gD monoclonal antibodies (MAbs) that sterically blocked the interaction, we previously showed that gH/gL binds directly to gD at sites distinct from the gD receptor binding site. Here, using an analogous strategy, we first evaluated the ability of a panel of uncharacterized anti-gH/gL MAbs to block binding to gD and/or inhibit fusion. We found that the epitopes of four gD-gH/gL-blocking MAbs were located within flexible regions of the gH N terminus and the gL C terminus, while the fifth was placed around gL residue 77. Taken together, our data localized the gD binding region on gH/gL to a group of gH and gL residues at the membrane distal region of the heterodimer. Surprisingly, a second set of MAbs did not block gD-gH/gL binding but instead stabilized the complex by altering the kinetic binding. However, despite this prolonged gD-gH/gL interaction, "stabilizing" MAbs also inhibited cell-cell fusion, suggesting a unique mechanism by which the fusion process is halted. Our findings support targeting the gD-gH/gL interaction to prevent fusion in both therapeutic and vaccine strategies against HSV.IMPORTANCE Key to developing a human HSV vaccine is an understanding of the virion glycoproteins involved in entry. HSV employs multiple glycoproteins for attachment, receptor interaction, and membrane fusion. Determining how these proteins function was resolved, in part, by structural biology coupled with immunological and biologic evidence. After binding, virion gD interacts with a receptor to activate the regulator gH/gL complex, triggering gB to drive fusion. Multiple questions remain, one being the physical location of each glycoprotein interaction site. Using protective antibodies with known epitopes, we documented the long-sought interaction between gD and gH/gL, detailing the region on gD important to create the gD-gH/gL triplex. Now, we have identified the corresponding gD contact sites on gH/gL. Concurrently we discovered a novel mechanism whereby gH/gL antibodies stabilize the complex and inhibit fusion progression. Our model for the gD-gH/gL triplex provides a new framework for studying fusion, which identifies targets for vaccine development.

Cultural impediments to learning to cooperate: An experimental study of high- and low-caste men in rural India.

We report experimental findings on how individuals from different cultures solve a repeated coordination game of common interest. The results overturn earlier findings that fixed pairs are almost assured to coordinate on an efficient and cooperative equilibrium. Subjects in the prior experiments were US university students, whereas the subjects in our study are men drawn from high and low castes in rural India. Most low-caste pairs quickly established an efficient and cooperative convention, but most high-caste pairs did not. The largest difference in behavior occurred when a player suffered a loss because he had tried to cooperate but his partner did not: In this situation, high-caste men were far less likely than low-caste men to continue trying to cooperate in the next period. Our interpretation is that for many high-caste men, the loss resulting from coordination failure triggered retaliation. Our results are robust to controls for education and wealth, and they hold by subcaste as well as by caste status. A survey we conducted supports the ethnographic evidence that more high-caste than low-caste men prefer to retaliate against a slight. We find no evidence that caste differences in trust or self-efficacy explain the caste gap in cooperation in our experiment. Our findings are of general interest because many societies throughout the world have cultures that lead individuals to (mis)perceive some actions as insults and to respond aggressively and dysfunctionally.

Surface Plasmon Resonance Reveals Direct Binding of Herpes Simplex Virus Glycoproteins gH/gL to gD and Locates a gH/gL Binding Site on gD.

Herpes simplex virus (HSV) requires fusion between the viral envelope and host membrane. Four glycoproteins, gD, gH/gL, and gB, are essential for this process. To initiate fusion, gD binds its receptor and undergoes a conformational change that hypothetically leads to activation of gH/gL, which in turn triggers the fusion protein gB to undergo rearrangements leading to membrane fusion. Our model predicts that gD must interact with both its receptor and gH/gL to promote fusion. In support of this, we have shown that gD is structurally divided into two "faces": one for the binding receptor and the other for its presumed interaction with gH/gL. However, until now, we have been unable to demonstrate a direct interaction between gD and gH/gL. Here, we used surface plasmon resonance to show that the ectodomain of gH/gL binds directly to the ectodomain of gD when (i) gD is captured by certain anti-gD monoclonal antibodies (MAbs) that are bound to a biosensor chip, (ii) gD is bound to either one of its receptors on a chip, and (iii) gD is covalently bound to the chip surface. To localize the gH/gL binding site on gD, we used multiple anti-gD MAbs from six antigenic communities and determined which ones interfered with this interaction. MAbs from three separate communities block gD-gH/gL binding, and their epitopes encircle a geographical area on gD that we propose comprises the gH/gL binding domain. Together, our results show that gH/gL interacts directly with gD, supporting a role for this step in HSV entry.IMPORTANCE HSV entry is a multistep process that requires the actions of four glycoproteins, gD, gH/gL, and gB. Our current model predicts that gD must interact with both its receptor and gH/gL to promote viral entry. Although we know a great deal about how gD binds its receptors, until now we have been unable to demonstrate a direct interaction between gD and gH/gL. Here, we used a highly sensitive surface plasmon resonance technique to clearly demonstrate that gD and gH/gL interact. Furthermore, using multiple MAbs with defined epitopes, we have delineated a domain on gD that is independent of that used for receptor binding and which likely represents the gH/gL interaction domain. Targeting this interaction to prevent fusion may enhance both therapeutic and vaccine strategies.

Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs.

Herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit antigen is included in many preclinical candidate vaccines. The rationale for including gD2 is to produce antibodies that block crucial gD2 epitopes involved in virus entry and cell-to-cell spread. HSV-2 gD2 was the only antigen in the Herpevac Trial for Women that protected against HSV-1 genital infection but not HSV-2. In that trial, a correlation was detected between gD2 ELISA titers and protection against HSV-1, supporting the importance of antibodies. A possible explanation for the lack of protection against HSV-2 was that HSV-2 neutralization titers were low, four-fold lower than to HSV-1. Here, we evaluated neutralization titers and epitope-specific antibody responses to crucial gD2 epitopes involved in virus entry and cell-to-cell spread as correlates of immune protection against genital lesions in immunized guinea pigs. We detected a strong correlation between neutralizing antibodies and protection against genital disease. We used a high throughput biosensor competition assay to measure epitope-specific responses to seven crucial gD2 linear and conformational epitopes involved in virus entry and spread. Some animals produced antibodies to most crucial epitopes while others produced antibodies to few. The number of epitopes recognized by guinea pig immune serum correlated with protection against genital lesions. We confirmed the importance of antibodies to each crucial epitope using monoclonal antibody passive transfer that improved survival and reduced genital disease in mice after HSV-2 genital challenge. We re-evaluated our prior study of epitope-specific antibody responses in women in the Herpevac Trial. Humans produced antibodies that blocked significantly fewer crucial gD2 epitopes than guinea pigs, and antibody responses in humans to some linear epitopes were virtually absent. Neutralizing antibody titers and epitope-specific antibody responses are important immune parameters to evaluate in future Phase I/II prophylactic human vaccine trials that contain gD2 antigen.

Characterizing Epitope Binding Regions of Entire Antibody Panels by Combining Experimental and Computational Analysis of Antibody: Antigen Binding Competition.

Vaccines and immunotherapies depend on the ability of antibodies to sensitively and specifically recognize particular antigens and specific epitopes on those antigens. As such, detailed characterization of antibody-antigen binding provides important information to guide development. Due to the time and expense required, high-resolution structural characterization techniques are typically used sparingly and late in a development process. Here, we show that antibody-antigen binding can be characterized early in a process for whole panels of antibodies by combining experimental and computational analyses of competition between monoclonal antibodies for binding to an antigen. Experimental "epitope binning" of monoclonal antibodies uses high-throughput surface plasmon resonance to reveal which antibodies compete, while a new complementary computational analysis that we call "dock binning" evaluates antibody-antigen docking models to identify why and where they might compete, in terms of possible binding sites on the antigen. Experimental and computational characterization of the identified antigenic hotspots then enables the refinement of the competitors and their associated epitope binding regions on the antigen. While not performed at atomic resolution, this approach allows for the group-level identification of functionally related monoclonal antibodies (i.e., communities) and identification of their general binding regions on the antigen. By leveraging extensive epitope characterization data that can be readily generated both experimentally and computationally, researchers can gain broad insights into the basis for antibody-antigen recognition in wide-ranging vaccine and immunotherapy discovery and development programs.

Dynamics of a Viscous Droplet in Return Bends of Microfluidic Channels.

Return bends are frequently encountered in microfluidic systems. In this study, a three-dimensional spectral boundary element method for interfacial dynamics in Stokes flow has been adopted to investigate the dynamics of viscous droplets in rectangular return bends. The droplet trajectory, deformation, and migration velocity are investigated under the influence of various fluid properties and operational conditions, which are depicted by the Capillary number, viscosity ratio, and droplet size, as well as the dimensions of the return bend. While the computational results provide information for the design of return bends in microfluidic systems in general, the computational framework shows potential to guide the design and operation of a droplet-based microfluidic delivery system for cell seeding.

Global sensing of the antigenic structure of herpes simplex virus gD using high-throughput array-based SPR imaging.

While HSV-2 typically causes genital lesions, HSV-1 is increasingly the cause of genital herpes. In addition, neonatal HSV infections are associated with a high rate of mortality and HSV-2 may increase the risk for HIV or Zika infections, reinforcing the need to develop an effective vaccine. In the GSK Herpevac trial, doubly sero-negative women were vaccinated with a truncated form of gD2 [gD2(284t)], then examined for anti-gD serum titers and clinical manifestations of disease. Surprisingly, few vaccinees were protected against genital HSV-2 but 86% were protected from genital HSV-1. These observations suggest that subtle differences in gD structure might influence a protective response. To better understand the antigenic structure of gD and how it impacts a protective response, we previously utilized several key anti-gD monoclonal antibodies (mAbs) to dissect epitopes in vaccinee sera. Several correlations were observed but the methodology limited the number of sera and mAbs that could be tested. Here, we used array-based surface plasmon imaging (SPRi) to simultaneously measure a larger number of protein-protein interactions. We carried out cross-competition or "epitope binning" studies with 39 anti-gD mAbs and four soluble forms of gD, including a form [gD2(285t)] that resembles the Herpevac antigen. The results from these experiments allowed us to organize the mAbs into four epitope communities. Notably, relationships within and between communities differed depending on the form of gD, and off-rate analysis suggested differences in mAb-gD avidity depending on the gD serotype and length. Together, these results show that gD1 and gD2 differ in their structural topography. Consistent with the Herpevac results, several mAbs that bind both gD1 and gD2 neutralize only HSV-1. Thus, this technology provides new insights into the antigenic structure of gD and provides a rationale as to how vaccination with a gD2 subunit may lead to protection from HSV-1 infection.

Provisional best practices guidelines for the evaluation of bulbar dysfunction in amyotrophic lateral sclerosis.

INTRODUCTION: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics. METHODS: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain. DISCUSSION: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531-531, 2019.

Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia.

Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by motor-neuron degeneration in the brain and spinal cord. Most cases of ALS are sporadic but about 5-10% are familial. Mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP, also known as TDP43) and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS)) account for approximately 30% of classic familial ALS. Mutations in several other genes have also been reported as rare causes of ALS or ALS-like syndromes. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin 2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin 2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.

Six-Minute Walk Test as a Measure of Walking Capacity in Ambulatory Individuals With Amyotrophic Lateral Sclerosis.

OBJECTIVE: To determine the validity of the 6-minute walk test (6MWT) as an outcome measure to evaluate walking capacity in ambulatory patients with amyotrophic lateral sclerosis (ALS). DESIGN: Observational study. SETTING: Multidisciplinary ALS clinic at an academic medical center. PARTICIPANTS: Patients with ALS (N=186) who ambulate without (stage I) or with (stage II) an assistive device. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Walking distance obtained from the 6MWT. RESULTS: Participants performed the 6MWT, 25-foot walk test (25FWT), Timed Up and Go (TUG) test, lower extremity maximum voluntary isometric contraction (MVIC), ALS Functional Rating Scale-Revised (ALSFRS-R), and forced vital capacity (FVC). Walking capacity was reduced to 66% predicted of healthy subjects (75.2%±22% in stage I; 42.6%±22% in stage II). The 6MWT correlated with all other outcome measures in ambulatory patients with ALS (25FWT: r=-.74, P≤.0001; TUG test: r=-.80, P≤.0001; MVIC: r=.64, P≤.0001; percent predicted FVC: r=.25, P≤.0007; ALSFRS-R: r=.52, P≤.0001; ALSFRS-R gross motor subscore: r=.71, P≤.0001). When ambulatory patients with ALS were stratified by stage of ambulation, the 6MWT was associated with all other outcome measures in stage I (25FWT: r=-.56, P≤.0001; TUG test: r=-.66, P≤.0001; MVIC: r=.51, P≤.0001; percent predicted FVC: r=.40, P≤.02; ALSFRS-R: r=.52, P≤.0001; ALSFRS-R gross motor subscore: r=.61, P≤.0001). In stage II, the 6MWT correlated with the 25FWT (r=-.83, P≤.0001), TUG test (r=-.77, P≤.0001), MVIC (r=.47, P≤.0001), and ALSFRS gross motor subscore (r=.61, P≤.0001), but not with percent predicted FVC (r=.09, P≤.513) or ALSFRS-R (r=.21, P≤.141). CONCLUSIONS: The 6MWT is a valid measure of walking capacity of ambulatory patients with ALS that is associated with measures of lower extremity muscle strength and function in both stages of ambulation. The discordance between the 6MWT with the ALSFRS-R and percent predicted FVC in stage II ambulatory patients with ALS indicates that the 6MWT is an independent measure of ambulatory function in both stages of ambulation. The 6MWT may provide a quantitative, simple, and inexpensive outcome measure of walking capacity for early stage clinical trials in ambulatory patients with ALS.

Investigating the strategic antecedents of agility in humanitarian logistics.

This study investigates the strategic antecedents of operational agility in humanitarian logistics. It began by identifying the particular actions to be taken at the strategic level of a humanitarian organisation to support field-level agility. Next, quantitative data (n=59) were collected on four strategic-level capabilities (being purposeful, action-focused, collaborative, and learning-oriented) and on operational agility (field responsiveness and flexibility). Using a quantitative analysis, the study tested the relationship between organisational capacity building and operational agility and found that the four strategic-level capabilities are fundamental building blocks of agility. Collectively they account for 52 per cent of the ability of humanitarian logisticians to deal with ongoing changes and disruptions in the field. This study emphasises the need for researchers and practitioners to embrace a broader perspective of agility in humanitarian logistics. In addition, it highlights the inherently strategic nature of agility, the development of which involves focusing simultaneously on multiple drivers.

Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition. METHODS: In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983. FINDINGS: Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group. INTERPRETATION: Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease. FUNDING: Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center.

LPS modification promotes maintenance of Yersinia pestis in fleas.

Yersinia pestis, the causative agent of plague, can be transmitted by fleas by two different mechanisms: by early-phase transmission (EPT), which occurs shortly after flea infection, or by blocked fleas following long-term infection. Efficient flea-borne transmission is predicated upon the ability of Y. pestis to be maintained within the flea. Signature-tagged mutagenesis (STM) was used to identify genes required for Y. pestis maintenance in a genuine plague vector, Xenopsylla cheopis. The STM screen identified seven mutants that displayed markedly reduced fitness in fleas after 4 days, the time during which EPT occurs. Two of the mutants contained insertions in genes encoding glucose 1-phosphate uridylyltransferase (galU) and UDP-4-amino-4-deoxy-l-arabinose-oxoglutarate aminotransferase (arnB), which are involved in the modification of lipid A with 4-amino-4-deoxy-l-arabinose (Ara4N) and resistance to cationic antimicrobial peptides (CAMPs). These Y. pestis mutants were more susceptible to the CAMPs cecropin A and polymyxin B, and produced lipid A lacking Ara4N modifications. Surprisingly, an in-frame deletion of arnB retained modest levels of CAMP resistance and Ara4N modification, indicating the presence of compensatory factors. It was determined that WecE, an aminotransferase involved in biosynthesis of enterobacterial common antigen, plays a novel role in Y. pestis Ara4N modification by partially offsetting the loss of arnB. These results indicated that mechanisms of Ara4N modification of lipid A are more complex than previously thought, and these modifications, as well as several factors yet to be elucidated, play an important role in early survival and transmission of Y. pestis in the flea vector.

National health accounts data from 1996 to 2010: a systematic review.

OBJECTIVE: To collect, compile and evaluate publicly available national health accounts (NHA) reports produced worldwide between 1996 and 2010. METHODS: We downloaded country-generated NHA reports from the World Health Organization global health expenditure database and the Organisation for Economic Co-operation and Development (OECD) StatExtract website. We also obtained reports from Abt Associates, through contacts in individual countries and through an online search. We compiled data in the four main types used in these reports: (i) financing source; (ii) financing agent; (iii) health function; and (iv) health provider. We combined and adjusted data to conform with OECD's first edition of A system of health accounts manual, (2000). FINDINGS: We identified 872 NHA reports from 117 countries containing a total of 2936 matrices for the four data types. Most countries did not provide complete health expenditure data: only 252 of the 872 reports contained data in all four types. Thirty-eight countries reported an average not-specified-by-kind value greater than 20% for all data types and years. Some countries reported substantial year-on-year changes in both the level and composition of health expenditure that were probably produced by data-generation processes. All study data are publicly available at http://vizhub.healthdata.org/nha/. CONCLUSION: Data from NHA reports on health expenditure are often incomplete and, in some cases, of questionable quality. Better data would help finance ministries allocate resources to health systems, assist health ministries in allocating capital within the health sector and enable researchers to make accurate comparisons between health systems.

Personal responsibility or shared responsibility: What is the appropriate role of the law in obesity prevention?

Sensitive to allegations of "nanny state" paternalism, Australian governments support the doctrine that combating obesity is a matter of personal responsibility. Policy-makers endorse the "holistic" approach to obesity prevention, with a view to managing both sides of the nutritional energy equation. This paradigm allows the food and drinks industry to deflect its contributory responsibility for the epidemic and to avoid more stringent regulatory intervention beyond existing self-regulatory and corporate social responsibility regimes. This article argues that the industry must bear shared responsibility for the extent of the obesity crisis, although it cannot bear sole responsibility It defends the public interest case for more invasive, government-led regulation, reframing the crisis as one of public not individual burdens. Mindful of the political risk associated with unfocused calls for regulatory intervention, it articulates a set of regulatory principles to ensure that the interests of consumers and industry are properly acknowledged prior to further regulatory intervention. Finally, the article clarifies the subject, object and content of possible regulatory initiatives, offering an evaluation of their efficacy, practicality and fairness.

Power Wheelchair Use in Persons With Amyotrophic Lateral Sclerosis: Changes Over Time.

The objectives of this study were to survey persons with Amyotrophic Lateral Sclerosis (ALS) at 1 and 6 months after receiving power wheelchairs to determine long-term use, comfort, and function as well as the power wheelchair's impact on daily tasks and quality of life. A 33-question survey and Psychosocial Impact of Assistive Devices Scale (PIADS) were sent 1 month after getting a new power wheelchair; a follow-up survey was sent at 6 months. Based on satisfaction and feature use survey results, at 1 month, 81% of users found the power wheelchair overall comfort to be high, 88% found their overall mobility to be improved, and 95% found it easy to use. Their quality of life increased and pain decreased at 1 and 6 months. According to the PIADS, the power wheelchair gave users increased ability to participate and sense of competence. This study has important results for the ALS community, as it is the first to assess power wheelchair users at 1 and 6 months after power wheelchair procurement. The results demonstrate the impact the power wheelchair has on mobility, psychosocial issues, functional abilities, and quality of life for a person with ALS.