ACU193, a Monoclonal Antibody that Selectively Binds Soluble Aß Oligomers: Development Rationale, Phase 1 Trial Design, and Clinical Development Plan.

BACKGROUND: Alzheimer's disease is a large and growing unmet medical need. Clinical trial designs need to assess disease-related outcomes earlier to accelerate the development of better treatments for Alzheimer's disease. ACU193 is a monoclonal antibody that selectively targets amyloid ß oligomers, thought to be the most toxic species of Aß that accumulates early in AD and contributes to downstream pathological effects. Nonclinical data indicate that ACU193 can reduce the toxic effects of amyloid ß oligomers. ACU193 is currently being investigated in a phase 1 clinical trial designed with the properties described in this report. This phase 1 trial is designed to provide data to enable a go/no-go decision regarding the initiation of a subsequent phase 2/3 study. OBJECTIVES: To design a phase 1 study that assesses target engagement and incorporates novel measures to support more rapid development of a potential disease-modifying treatment for Alzheimer's disease. DESIGN: The INTERCEPT-AD trial for ACU193 is an ongoing randomized, placebo-controlled phase 1a/b study that assesses safety, tolerability, pharmacokinetics, target engagement, clinical measures, and several Alzheimer's disease biomarkers, including novel digital and imaging biomarkers. SETTING: For INTERCEPT-AD, brief inpatient stays for patients in the single ascending dose portion of the study, with the remainder of the evaluations being performed as outpatients at multiple clinical trial sites in the U.S. PARTICIPANTS: Patients with early Alzheimer's disease (mild cognitive impairment or mild dementia with a positive florbetapir positron emission tomography scan). INTERVENTION: ACU193 administered intravenously at doses of 2- 60 mg/kg. MEASUREMENTS: Safety assessments including magnetic resonance imaging for the presence of amyloid-related imaging abnormalities, clinical assessments for Alzheimer's disease including the Alzheimer's Disease Rating Scale-cognition and Clinical Dementia Rating scale, pharmacokinetics, a measure of target engagement, and digital and imaging biomarkers, including a computerized cognitive test battery and a measure of cerebral blood flow using arterial spin labelling magnetic resonance imaging. RESULTS: A phase 1 study design was developed for ACU193 that allows collection of data that will enable a go/no-go decision for initiation of a subsequent adaptive phase 2/3 study. CONCLUSIONS: A phase 1a/b trial and an overall clinical development plan for an Alzheimer's disease treatment can be designed that maintains patient safety, allows informed decision-making, and achieves an accelerated timeline by using novel biomarkers and adaptive study designs.

Development of a surgical assessment tool for national policy monitoring & evaluation in Ethiopia: A quality improvement study.

BACKGROUND: A baseline assessment of surgical capacity is recommended as a first-step to surgical system strengthening in order to inform national policy. In Ethiopia, the World Health Organization's Tool for Situational Analysis (WHO SAT) was adapted to assess surgical, obstetric, and anesthesia capacity as part of a national initiative: Saving Lives Through Safe Surgery (SaLTS). This study describes the process of adapting this tool and initial results. MATERIALS AND METHODS: The new tool was used to evaluate fourteen hospitals in the Southern Nations, Nationalities, and People's Region of Ethiopia between February and March 2017. Two analytic methods were employed. To compare this data to international metrics, the WHO Service Availability and Readiness Assessment (SARA) framework was used. To assess congruence with national policy, data was evaluated against Ethiopian SaLTS targets. RESULTS: Facilities had on average 62% of SARA items necessary for both basic surgery and comprehensive surgery. Primary, general, and specialized facilities offered on average 84%, 100%, and 100% of SARA basic surgeries, and 58%, 73% and 90% of SARA comprehensive surgeries, respectively. An average of 68% of SaLTS primary surgeries were available at primary facilities, 83% at general facilities, and 100% at specialized facilities. General and specialized hospitals offered an average of 80% of SaLTS general surgeries, while one specialized hospital offered 38% of SaLTS specialized surgeries. CONCLUSION: While the modified SaLTS Tool provided evaluation against Ethiopian national benchmarks, the resultant assessment was much lengthier than standard international tools. Analysis of results using the SARA framework allowed for comparison to global standards and provided insight into essential parts of the tool. An assessment tool for national surgical policy should maintain internationally comparable metrics and incorporation into existing surveys when possible, while including country-specific targets.

Framework for developing a national surgical, obstetric and anaesthesia plan.

Background: Emergency and essential surgical, obstetric and anaesthesia (SOA) care are now recognized components of universal health coverage, necessary for a functional health system. To improve surgical care at a national level, strategic planning addressing the six domains of a surgical system is needed. This paper details a process for development of a national surgical, obstetric and anaesthesia plan (NSOAP) based on the experiences of frontline providers, Ministry of Health officials, WHO leaders, and consultants. Methods: Development of a NSOAP involves eight key steps: Ministry support and ownership; situation analysis and baseline assessments; stakeholder engagement and priority setting; drafting and validation; monitoring and evaluation; costing; governance; and implementation. Drafting a NSOAP involves defining the current gaps in care, synthesizing and prioritizing solutions, and providing an implementation and monitoring plan with a projected cost for the six domains of a surgical system: infrastructure, service delivery, workforce, information management, finance and governance. Results: To date, four countries have completed NSOAPs and 23 more have committed to development. Lessons learned from these previous NSOAP processes are described in detail. Conclusion: There is global movement to address the burden of surgical disease, improving quality and access to SOA care. The development of a strategic plan to address gaps across the SOA system systematically is a critical first step to ensuring countrywide scale-up of surgical system-strengthening activities.

Antecedentes: En la actualidad, se reconoce que la atención quirúrgica, obstétrica y anestésica urgente y esencial (surgical, obstetric, and anaesthesia, SOA) es uno de los componentes de la cobertura sanitaria universal y un elemento necesario para el funcionamiento de un sistema de salud. Para mejorar la atención quirúrgica a nivel nacional, se necesita una planificación estratégica que aborde los seis dominios de un sistema quirúrgico. En este artículo, se detalla el proceso para el desarrollo de un plan nacional de cirugía, obstetricia y anestesia (national surgical, obstetric, and anaesthesia plan, NSOAP) basado en las experiencias de los principales proveedores, los funcionarios del Ministerio de Salud, los líderes de la Organización Mundial de la Salud y consultores. Métodos: El desarrollo de un NSOAP incluye ocho pasos clave: (1) apoyo y dependencia del ministerio, (2) análisis de la situación y evaluaciones de referencia, (3) compromiso de los agentes implicados y establecimiento de prioridades, (4) redacción y validación, (5) seguimiento y evaluación, (6) análisis de costes, (7) gobernanza y (8) implementación. Redactar un NSOAP implica definir los déficits actuales en la atención, sintetizar y priorizar soluciones, y proporcionar un plan de implementación y seguimiento con unos costes proyectados para los seis dominios de un sistema quirúrgico: infraestructura, prestación de servicios, personal, gestión de la información, finanzas y gobernanza. Resultados: Hasta la fecha, cuatro países han completado un NSOAP y 23 más se han comprometido con su desarrollo. Las lecciones aprendidas de estos procesos previos de NSOAP se describen con detalle. Conclusiones: Existe un movimiento global para abordar la carga de las enfermedades que precisan cirugía, mejorar la calidad y el acceso a la atención SOA. El desarrollo de un plan estratégico para la aproximación sistemáticamente los déficits en todo el sistema SOA es un primer paso crítico para garantizar la ampliación a nivel nacional de las actividades de fortalecimiento del sistema quirúrgico.

Associations between disordered eating and intimate partner violence mediated by depression and posttraumatic stress disorder symptoms in a female veteran sample.

OBJECTIVE: This study established a link between intimate partner violence (IPV) and eating disorders (EDs) via mediators of depression and posttraumatic stress disorder (PTSD) symptoms in female veterans. METHOD: A nationally representative sample of female veterans (N = 190, Mean age = 48.41 years) completed online surveys assessing IPV and symptoms of depression, PTSD, and EDs, at three time points from 2014 to 2017. RESULTS: Approximately 14.11% of participants met criteria for any ED (7.83% Bulimia Nervosa; 6.28% Binge Eating Disorder), and 49.42% reported lifetime histories of IPV. Eating disorder symptoms were significantly associated with lifetime IPV, PTSD and depression symptoms at the bivariate level. Mediation model results revealed that lifetime IPV was indirectly associated with EDDS scores, via PTSD symptoms and depression symptoms. CONCLUSION: Findings confirmed elevated rates of probable EDs and lifetime IPV among female veterans; significant associations between EDs, lifetime IPV, depression, and PTSD; and mediation of the association between IPV and EDs by PTSD and depression symptoms. Implications for screening, treatment and research are discussed.

Mixed-methods assessment of surgical capacity in two regions in Ethiopia.

BACKGROUND: Surgery is among the most neglected parts of healthcare systems in low- and middle-income countries. Ethiopia has launched a national strategic plan to address challenges in the surgical system. This study aimed to assess surgical capacity in two Ethiopian regions to inform priority areas for improvement. METHODS: A mixed-methods study was conducted using two tools adapted from the Lancet Commission's Surgical Assessment Tools: a quantitative Hospital Assessment Tool and a qualitative semistructured interview tool. Fifteen hospitals selected by the Federal Ministry of Health were surveyed in the Tigray and Amhara regions to assess the surgical system across five domains: service delivery, infrastructure, workforce, information management and financing. RESULTS: Service delivery was low across hospitals with a mean(s.d.) of 5(6) surgical cases per week and a narrow range of procedures performed. Hospitals reported varying availability of basic infrastructure, including constant availability of electricity (9 of 15) and running water (5 of 15). Unavailable or broken diagnostic equipment was also common. The majority of surgical and anaesthesia services were provided by non-physician clinicians, with little continuing education available. All hospitals tracked patient-level data regularly and eight of 15 hospitals reported surgical volume data during the assessment, but research activities were limited. Hospital financing specified for surgery was rare and the majority of patients must pay out of pocket for care. CONCLUSION: Results from this study will inform programmes to simultaneously improve each of the health system domains in Ethiopia; this is required if better access to and quality of surgery, anaesthesia and obstetric services are to be achieved.

Associations between healthcare use and disordered eating among female veterans.

OBJECTIVE: Individuals with eating disorders (EDs) have considerable medical and psychiatric comorbidity as well as increased healthcare use and associated costs. However, EDs remain largely undetected and understudied among veteran populations, and EDs are not routinely screened for or treated in Veterans Affairs (VA) medical settings. Research elucidating the links between disordered eating and VA and non-VA healthcare use is needed to inform policy and practice for ED screening and treatment. METHOD: Data regarding probable EDs and VA and non-VA healthcare use was obtained through a mail survey of 198 female veterans receiving care from VA. RESULTS: A total of 21 participants (10.6%) met probable criteria for subthreshold anorexia nervosa, bulimia nervosa, or binge-eating disorder. Negative binomial regression models revealed that female veterans with EDs reported higher frequency of VA mental healthcare use and substance use disorder treatment, above and beyond the association of comorbid PTSD and depression symptoms. DISCUSSION: These findings confirm the high probability that female veterans with EDs are utilizing significant VA mental health resources. Screening for EDs may be particularly important in VA medical and mental health settings.

Widespread neonatal brain damage following calcium channel blockade.

An abundance of evidence exists that shows calcium channel blockade promotes injury in cultured neurons. However, few studies have addressed the in vivo toxicity of such agents. We now show that the L-type calcium channel antagonist nimodipine promotes widespread and robust injury throughout the neonatal rat brain, in an age-dependent manner. Using both isolated neuronal as well as brain slice approaches, we address mechanisms behind such injury. These expanded studies show a consistent pattern of injury using a variety of agents that lower intracellular calcium. Collectively, these observations indicate that postnatal brain development represents a transitional period for still developing neurons, from being highly sensitive to reductions in intracellular calcium to being less vulnerable to such changes. These observations directly relate to current therapeutic strategies targeting neonatal brain injury.

Effects of stress and relaxation on capsaicin-induced pain.

A sizable body of research has been devoted to understanding the relationship between pain sensitivity and the psychological state of the individual. Considerable disagreement as to the direction of the association still exists. This study examines the effects of 2 experimental manipulations, cognitive/emotional stress and relaxation, on capsaicin-induced pain. Subjects were pretrained in relaxation and then randomized to experimental stress produced by a 20-minute Stroop test, relaxation (tape), or a control condition (neutral video), followed by a capsaicin injection in the forearm. Cardiovascular measures were taken at regular intervals, and cortisol, norepinephrine (NE), and self-reports of arousal (relaxation index) were taken immediately before and after the experimental task. The manipulation significantly interacted with sex to predict capsaicin-induced maximum pain. Women in the stress condition reported greater pain than both men in the stress condition and women in the relaxation condition. Pain was correlated negatively with task-induced changes in NE and cortisol and positively with self-reported arousal (decreased relaxation). However, separate analyses showed that some physiologic indexes of heightened arousal (increased blood pressure and NE) predicted lower pain only in men, whereas subjective increases in arousal predicted higher pain only in women. Multiple hierarchical regression analyses confirmed that physiologic and self-reported arousal predicted pain independently and in opposite directions, and a model including both accounted for 56% of the overall variance. These findings suggest that a unidimensional model of arousal may be insufficient to explain the effects of stress on pain and that these effects operate differently in men and women.

Effects of relaxation and stress on the capsaicin-induced local inflammatory response.

OBJECTIVE: Although stress is known to modulate the inflammatory response, there has been little experimental examination of the effects of stress and stress reduction on inflammation in humans. In particular, the effects of stress and relaxation on neurogenic inflammation have been minimally studied. This study examines the effects of three experimental manipulations: mental stress, relaxation, and control on the local inflammatory response evoked by the intradermal injection of capsaicin, the active ingredient in chili peppers. METHODS: Fifty subjects (28 men and 22 women) were pretrained in relaxation using an imagery-based relaxation tape and then randomized to experimental condition. Subjects participated in an evening reactivity session including 20 minutes of a stress (Stroop test), relaxation (tape), or control (video) manipulation, followed by a capsaicin injection in the forearm. Digitized flare measurements were taken for 1 hour postcapsaicin, and measurements of cardiovascular variables, cortisol, adrenocorticotrophic hormone, and norepinephrine were taken at regular intervals. RESULTS: The size of the maximum capsaicin-induced flare was significantly smaller in the relaxation condition than in the stress or control conditions, which did not differ from each other. Increases in norepinephrine, heart rate, and systolic blood pressure during the experimental task, but not after capsaicin, significantly predicted size of maximum flare and total area under the curve of flare measurements. CONCLUSIONS: These findings suggest that stress reduction may affect local inflammatory processes. Results are consistent with sympathetic modulation of the effects of relaxation on the flare response.

Antecedents and correlates of hypoplastic enamel defects of primary incisors.

Four hundred and fifty-five exfoliated primary incisors were obtained from children whose mothers provided information about a wide range of pre-, peri-, and postnatal characteristics of both the mother and child. These teeth then were examined for the presence of hypoplastic enamel defects (HED). The basic form of the null hypothesis tested was that children who had HED of a primary incisor did not differ from those who did not have such a defect. Of the primary incisors examined, 18.5% had HED (25.0% maxillary and 10.1% mandibular). The following items were found to be associated most strongly (P less than 0.003) with an increase in a child's risk of developing HED; 1) maternal antenatal history of smoking, higher prepregnancy weight, and failure to obtain prenatal care during the first trimester; 2) prematurity, low birth-weight and their associated correlates; and 3) postnatal measles infection. Left-handedness, maternal tea and Tylenol (McNeil Consumer Products Co., Fort Washington, PA) consumption, and failure to screen for undue lead burden were associated less prominently (P less than 0.05) with HED prevalence. Season of birth and serum and dentin lead levels were not related to the prevalence of HED. Many of these risk factors are also covariates of low socioeconomic status such as suboptimal nutrition and increased risk of infection. Additional investigation is needed to delineate the associations between specific pre- and perinatal nutritional and infectious factors, socioeconomic status, and HED development.

Patient-controlled analgesic administration. A comparison of steady-state morphine infusions with bolus doses.

The authors have shown previously that bone marrow transplant (BMT) patients who self-administered bolus doses of morphine gained equal oral mucositis pain relief while using less drug compared with similar patients receiving morphine by staff-controlled continuous infusion. In a follow-up study they compared the efficacy and side effects of morphine in two groups of marrow transplant patients who controlled their own analgesic administration either by conventional bolus-dose, patient-controlled analgesia (PCA) or by adjusting the rate of continuous morphine infusion to increase or decrease their plasma morphine concentration. Patients controlling their morphine infusion rates (pharmacokinetically based patient-controlled analgesia [PKPCA] group) obtained more relief from oral mucositis pain than did patients using conventional PCA. Patients in the PKPCA group used more morphine than PCA patients and achieved superior pain relief without significant increases in side effects (e.g., nausea, mood changes, sedation). The authors conclude that PKPCA improves the management of prolonged, severe pain in marrow transplant patients and that this approach to patient-controlled analgesia may be useful in other types of persistent pain.

Bacterial Symbionts in the Sugar Beet Root Maggot, Tetanops myopaeformis (von Röder).

Aerobic heterotrophic and facultative anaerobic bacteria were isolated from all developmental stages of the sugar beet root maggot, Tetanops myopaeformis (von Röder). Two distinct bacterial symbiotic relationships were observed. Serratia liquefaciens and Serratia marcescens were found to be associated with all developmental stages. Bacterial symbiont transmission occurred from one generation to the next. Symbionts were transferred from the male reproductive system to the female reproductive system, where both an internal infiltration of the egg chorion and an external smearing of the eggs occurred during oviposition. Pseudomonas maltophilia was found in association with the larval gut and the inner surface of the puparium. Electron microscopy of the inner puparial surface revealed symbionts within the chitinous wall. In vitro symbiont chitinase production was found, using both nephelometric (turbidimetric) and N-acetylglucosamine assays. A relationship appeared to exist between adult fly emergence and enzymatic chitin degradation of the puparium by the bacterial symbionts.

The anaerobic decomposition of benzoic acid during methane fermentation. IV. Dearomatization of the ring and volatile fatty acids formed on ring rupture.

A possible pathway for the anaerobic utilization of benzoic acid by a methanogenic consortium is suggested. Cyclohexane carboxylic acid and 1-cyclohexene-1-carboxylic acid have been identified as intermediates before ring rupture. Suprisingly, 3-cyclohexene-1-carboxylic acid interferes with utilization of other cyclic acids. In addition, isobutyric acid or short chain acids containing carbon-carbon double bonds could not be used without induction periods of a week or longer. A number of volatile fatty acids (heptanoic, valeric, butyric, propanoic, and acetic) have been identified and are suggested intermediates.

Inhibition of leukocyte candidacidal activity by serum from patients with disseminated candidiasis.

The effect of normal serum and serum for seven patients with disseminated candidiasis (DC) on candidacidal activity of normal human neutrophils (PMNL) was studied. PMNL incubated in DC serum had depressed candiacidal activity when compared to studies with normal serum. The candidacidal defect was not related to differences in particle uptake since phagocytic indices were similar with either normal or DC serum. DC serum did not affect PMNL bactericidal activity against Staphylococcus aureus. When Candida albicans (CA) was incubated in either normal or DC sera, washed, and added to PMNL in normal serum, pronounced inhibition of candidacidal activity was seen in all studies with CA previously incubated in DC serum. Dilution of DC serum or absorption of DC serum with heat-killed CA reversed the candidacidal defect. Ultrastructural studies of phagocytized CA demonstrated small ("tight") phagolysosomes and a delay in breakdown of an electron-dense coating on CA previously incubated in DC serum when compared to controls. Inhibition of leukocyte candidacidal activity appeared to be related to high titers of IgG antibodies against CA present in DC serum.