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Aims Many patients with suspected non-ST-elevation (NSTE) acute coronary syndromes (ACS) are admitted, even those with initial high-sensitivity cardiac troponins (hs-cTn) values who meet rapid rule-out criteria for myocardial infarction (MI). We examined the clinical outcomes, resource utilization, and diagnostic yield of suspected NSTE-ACS patients, who presented with hs-cTnT values meeting these criteria but were nevertheless hospitalized. Methods and results Applying the 2020 European Society of Cardiology (ESC) rapid rule-out MI criteria, we identified consecutive patients with an initial value of hs-cTnT Conclusion Our findings support a policy of ED discharge of suspected NSTE-ACS patients meeting rapid MI rule-out criteria and subsequent ambulatory evaluation, sparing resource-consuming admissions. In-hospital and ensuing prognosis were better with lower initial hs-cTnT values.

The purpose of this article is to describe the protocol development, feasibility, and lessons learned in the postal mail delivery of sleep monitoring devices to study participants. The original study protocol included four in-person visits with distribution of a sleep monitoring device (Actiwatch) and return of the Actiwatch via the postal service in a self-addressed, stamped envelope. The COVID-19 pandemic limited in-person research contact thus requiring a remote study protocol for application and return of the Actiwatches using postal delivery. While there were postal delivery and return challenges, the overall return rate of 94.4% confirmed remote protocol feasibility. Key lessons learned were: consistent and frequent communication via telephone calls and/or text; confirming required postage; and use of package tracking labels. All these strategies contributed to successful postal delivery/return and concomitantly decreased the potential loss of data and valuable research equipment.

The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer's disease.We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

Objectives To analyze urinary stone composition in Israel and determine the effects of demographic parameters, such as gender, age, socioeconomic status, ethnicity, medical history and geographic region, on stone composition. Patients and Methods The stone composition of 10633 consecutive patients from an Israeli database was analyzed between 2014 and 2019 by a central laboratory using the Fouriertransform infrared spectroscopy. Chi-squared test was used to determine associations between stone composition and the different demographic parameters. Results Calcium oxalate (CaOx) monohydrate was the predominant stone type (51.9%). 5776 stones had pure component (54%) and 4,857 (46%) had mixed components. Men had a higher frequency of CaOx stones (89.6% vs. 85.6%), whereas women had a higher frequency of calcium phosphate, infection, and cystine stones (27.2%, 17.7%, and 0.9% vs. 17.2%, 7.5%, and 0.5%, respectively). Cystine stones were more abundant in Arabs (1.2% vs. 0.5% in the Jewish population). Lower socioeconomic status was associated with higher prevalence of calcium phosphate, uric acid, and infectious stones and a lower prevalence of CaOx stones. Uric acid stones were associated with medical conditions, such as diabetes, hypertension, ischemic heart disease, and obesity (28.3%, 24.9%, 25.7%, and 22.6% vs. 9.6%, 8.4%, 12.3%, and 10.3%, respectively). Conclusions The most common stone type was CaOx monohydrate. Stone types are highly influenced by patients’ demographics.

Several abnormalities of porphyrin metabolism leading to Porphyria Cutanea Tarda (PCT) have been described in early studies of End Stage Renal Disease (ESRD) patients, with a reported prevalence of 5-18%. We aimed to evaluate porphyrin levels and correlation to skin manifestations in modern dialysis era.The study cohort included adult hemodialysis patients from a single center tertiary medical center. All patients underwent a full skin examination, completed the Dermatology Life Quality Index questioner, and provided a blood sample for porphyrin levels assessment.A total of 94 adult hemodialysis patients were recruited to the study. No clinical PCT was diagnosed. Porphyrin levels did not correlate with any clinical or dialysis quality parameters.In modern hemodialysis era, possibly due to improved porphyrins' metabolism and dialysis removal, PCT is much less prevalent among hemodialysis patients than previously reported in the past.

Alpha 1 antitrypsin (A1AT) is the major human blood serine protease inhibitor. Transmembrane serine protease 2 (TMPRSS2), which is crucial for SARS-CoV-2 cell entry, is inhibited by A1AT. Therefore, we hypothesized that individuals with diminished levels of A1AT may be more prone to SARS-CoV-2 infection and severe COVID-19 disease. Our aim in this study was to evaluate the level of A1AT in hospitalized COVID-19 patients in comparison to hospitalized patients with non-COVID-19 pneumonia.We conducted an observational prospective study between October 2020 and April 2021 in Rabin Medical Centre in Israel. A1AT levels were measured from the routine serum samples of hospitalized patients with COVID-19 and non-COVID-19 pneumonia (control group). The primary outcome was A1AT level, secondary outcomes were clinical outcomes and predictors of morality.Overall, 145 patients were included in the study, 98 in the COVID-19 group and 47 in the control group. The median A1AT level was 222 mg/dL (interquartile range (IQR) 188-269) and 258 mg/dL (IQR 210-281) in the COVID-19 and control groups, respectively (Patients admitted due to severe COVID-19 had lower A1AT levels in comparison to patients admitted due to non-COVID pneumonia. This observation may suggest an association between mildly diminished A1AT and higher risk of SARS-CoV-2 infection with severe COVID-19 disease.

Label free and remote action potential detection in neurons can be of great importance in the neuroscience research field. This paper presents a novel label free imaging modality based on the detection of temporal vibrations of speckle patterns illuminating the sample. We demonstrated the feasibility of detecting action potentials originating from spontaneous and stimulated activity in cortical cell culture. The spatiotemporal vibrations of isolated cortical cells were extracted by illuminating the culture with a laser beam while the vibrations of the random back scattered secondary speckle patterns are captured by a camera. The postulated action potentials were estimated following correlation-based analysis on the captured vibrations, where the variance deviation of the signal from a Gaussian distribution is directly associated with the action potential events. The technique was validated in a series of experiments in which the optical signals were acquired concurrently with microelectrode array (MEA) recordings. Our results demonstrate the ability of detecting action potential events in mammalian cells remotely via extraction of acoustic vibrations.

Acute hepatic porphyria (AHP) attacks begin with abdominal pain and can progress to severe life-threatening conditions. Early diagnosis and treatment may prevent these complications. We investigated the difference between the severity of porphyria attacks before and after porphyria diagnosis. A retrospective study including AHP patients hospitalized for an acute attack in Israel during a 15-year period. Diagnosis of an attack was based on typical clinical symptoms accompanied by at least one documented elevated urinary porphobilinogen above fourfold of normal values. The primary outcome was intensive care unit (ICU) admissions. Secondary outcomes included the length of hospital stay, severe hyponatremia, seizures, and psychiatric symptoms. 42 attacks in 9 patients were included. Most attacks occurred in women (78.6%) and in acute intermittent porphyria patients (76.2%). The mean age of attack was 26.5 (± 6.3) years. Attacks following porphyria diagnosis had a lower prevalence of ICU admission (3.3% versus 75.0%, p

Background: Radical cystectomy (RC) is the standard treatment for muscle invasive bladder cancer (MIBC). Neoadjuvant chemotherapy (NAC) is associated with improved patient survival. The impact of NAC on nutritional status is understudied, while the association between malnutrition and poor surgical outcomes is well known. This study aims to examine the association between NAC, nutritional status impairment, and post-operative morbidity. Materials and Methods: We included MIBC patients who underwent RC and received NAC from multiple academic centers in Israel. Cross-sectional imaging was used to measure the psoas muscle area and normalized it by height (smooth muscle index, SMI). Pre- and post-NAC SMI difference was calculated (represents nutritional status change). The primary outcomes were post-RC ileus, infection, and a composite outcome of any complication. Logistic regression models were fit to identify independent predictors of the outcomes. Results: Ninety-one patients were included in the study. The median SMI change was −0.71 (−1.58, −0.06) cm2/m2. SMI decline was significantly higher in patients with post-RC complications (−18 vs. −203, p < 0.001). SMI change was an independent predictor of all complications, ileus, infection, and other complications. The accuracy of SMI change for predicting all complications, ileus, infection, and other complications was 0.85, 0.87, 0.75, and 0.86, respectively. Conclusions: NAC-related nutritional deterioration is associated with increased risk of complications after RC. Our results hint towards the need for nutritional intervention during NAC prior to RC.

The development of new cultivars is important for the profitability of the floriculture industry. There are a limited number of cultivars of Zantedeschia aethiopica, an iconic ornamental cut flower, garden plant, and potted plant, due to the incompatibility of interspecific crossings within the genus. Most present-day varieties are the result of spontaneous mutations or classical breeding within the species, followed by a long selection process. Breeders are very interested in the development of a time- and cost-effective method for producing new Z. aethiopica cultivars with novel characteristics. Here, Z. aethiopica mutants were generated by treating seeds with 100 Gy of X-ray radiation. The resulting putative mutants were selected based on particular flowering parameters and compared to non-irradiated, control plants. Over two growing seasons, characteristics such as early flowering, flower size and shape, yield and response to soft-rot disease were monitored and considerable variation was observed among the mutated lines. Out of 319 mutants, 20 lines were selected based on their phenotypes and then propagated and further analyzed. Within this group, only two phenotypes displayed at least five improved flowering properties under natural, Mediterranean conditions. The rest displayed two to four desired combinations of flowering traits, some with great commercial potential.

The microbial community inhabiting a plant’s root zone plays a crucial role in plant health and protection. To assess the ability of commercial plant growth-promoting products to enhance the positive effects of this environment, two products containing beneficial soil bacteria and a product containing plant extracts were tested on Zantedeschia aethiopica and Ornithogalum dubium. The products were tested in two different growing media: a soil and a soilless medium. The effects of these products on Pectobacterium brasiliense, the causal agent of soft rot disease, were also evaluated in vitro, and on naturally occurring infections in the greenhouse. The growing medium was found to have the strongest effect on the microbial diversity of the root-associated microbiome, with the next-strongest effect due to plant type. These results demonstrate that either a single bacterial strain or a product will scarcely reach the level that is required to influence soil microbial communities. In addition, the microbes cultured from these products, could not directly inhibit Pectobacterium growth in vitro. We suggest density-based and functional analyses in the future, to study the specific interactions between plants, soil type, soil microbiota and relevant pathogens. This should increase the effectiveness of bio-supplements and soil disinfestation with natural products, leading to more sustainable, environmentally friendly solutions for the control of bacterial plant diseases.

The visual analysis of letter strings is a separate cognitive process from the analysis of digit strings. Recent studies have hypothesized that these processes are not only separate but also qualitatively different, in that they may encode information specific to numbers or to words. To examine this hypothesis and to shed further light on the visual analysis of numbers, we asked adults to read aloud multi-digit strings presented to them for brief durations. Their performance was better in digits on the number’s left side than in digits farther to the right, with better performance in the two outer digits than their neighbors. This indicates the digits were processed serially, from left to right. Visual similarity of digits increased the likelihood of errors, and when a digit migrated to an incorrect position, it was most often to an adjacent location. Interestingly, the positions of 0 and 1 were encoded better than the positions of 2-9, and 2-9 were identified better when they were next to 0 or 1. To accommodate these findings, we propose a detailed model for the visual analysis of digit strings. The model assumes imperfect digit detectors in which a digit’s visual information leaks to adjacent locations, and a compensation mechanism that inhibits this leakage. Crucially, the compensating inhibition is stronger for 0 and 1 than for the digits 2-9, presumably because of the importance of 0 and 1 in the number system. This sensitivity to 0 and 1 makes the visual analyzer specifically adapted to numbers, not words, and may be one of the brain’s reasons to implement the visual analysis of numbers and words in two separate cognitive processes.

In this paper we propose a novel approach for remote speckle-based sensing of mechanical vibrations in the Hirudo medicinalis leech central nervous system (CNS) connective tissue. Using this method, spontaneous vibrations generated at the connective tissue following partial cut injury are continuously and remotely monitored. A laser beam illuminates the connective tissue and back scattered defocused patterns at the far field are captured by the camera. The spatialtemporal spontaneous vibrations of the connective are monitored by tracking the speckle spatial-temporal trajectory. After applying correlation-based analysis we were able to detect these vibrations of the connective tissue during recovery with respect to control measurements. This approach is the first step towards understanding the possible involvement of the tissue movements for the recovering process via mechanical vibrations sensing of the leech CNS connective tissue.

Objective: To describe patient characteristics at presentation, management, and fertility preservation rates among a cohort of Israeli children and adolescents with gender dysphoria (GD). Methods: We performed a retrospective chart review of 106 consecutive children and adolescents with GD (

Introduction Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). Methods In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. Results Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ 1–x and Aβ 1–40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. Conclusions Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Acoustic manipulation is an emerging non-invasive method enabling precise spatial control of cells in their native environment. Applying this method for organizing neurons is invaluable for neural tissue engineering applications. Here, we used surface and bulk standing acoustic waves for large-scale patterning of Dorsal Root Ganglia neurons and PC12 cells forming neuronal cluster networks, organized biomimetically. We showed that by changing parameters such as voltage intensity or cell concentration we were able to affect cluster properties. We examined the effects of acoustic arrangement on cells atop 3D hydrogels for up to 6 days and showed that assembled cells spontaneously grew branches in a directed manner towards adjacent clusters, infiltrating the matrix. These findings have great relevance for tissue engineering applications as well as for mimicking architectures and properties of native tissues.

Acute hepatic porphyria (AHP) attacks begin with abdominal pain and can progress to severe life-threatening conditions. Early diagnosis and treatment may prevent these complications. We investigated the difference between the severity of porphyria attacks before and after porphyria diagnosis. A retrospective study including AHP patients hospitalized for an acute attack in Israel during a 15-year period. Diagnosis of an attack was based on typical clinical symptoms accompanied by at least one documented elevated urinary porphobilinogen above fourfold of normal values. The primary outcome was intensive care unit (ICU) admissions. Secondary outcomes included the length of hospital stay, severe hyponatremia, seizures, and psychiatric symptoms. 42 attacks in 9 patients were included. Most attacks occurred in women (78.6%) and in acute intermittent porphyria patients (76.2%). The mean age of attack was 26.5 (± 6.3) years. Attacks following porphyria diagnosis had a lower prevalence of ICU admission (3.3% versus 75.0%, p 0.001), seizures (0% versus 50.0%, p 0.001), psychiatric symptoms (23.3% versus 66.7%, p = 0.01), severe hyponatremia (16.7% versus 83.3%, p 0.001), and median length of hospital stay (5 versus 11.0 days, p 0.001). These results remained significant after simple univariate logistic regression for ICU admission [odds ratio (OR) 0.01, 95% confidence interval (CI) 0.00-0.12], prolonged hospital stay (OR 0.08, 95% CI 0.01-0.41), seizures or neurological symptoms (OR 0.06, 95% CI 0.01-0.30), and severe hyponatremia (OR 0.02, 95% CI 0.00-0.20). Previously diagnosed AHP patients have a significantly milder attack course as compared to previously undiagnosed patients. Family screening following sentinel cases might prevent severe AHP attacks.

Visual Abstract, The search for therapeutic strategies to promote neuronal regeneration following injuries toward functional recovery is of great importance. Brief low-frequency electrical stimulation (ES) has been reported as a useful method to improve neuronal regeneration in different animal models; however, the effect of ES on single neuron behavior has not been shown. Here, we study the effect of brief ES on neuronal regeneration of the CNS of adult medicinal leeches. Studying the regeneration of selected sets of identified neurons allow us to quantify the ES effect per cell type at the single-cell level. Chains of the CNS that were subjected to cut injury were observed for 3 d, and the spontaneous regeneration was compared with the electrically stimulated injured chains. We show that the ES improves the efficiency of regeneration of Retzius cells, as larger masses of the total branching tree traverse the injury site with better directed growth with no effect on the average branching tree length. No antero-posterior polarity was found along regeneration within the leech CNS. Moreover, the microglial cell distribution was examined revealing more microglial cells in proximity to the stimulation site compared with non-stimulated. Our results lay a foundation for future ES-based neuroregenerative therapies.

Importance Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein–cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression. Objective To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. Design, Setting, and Participants AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging–Alzheimer’s Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. Interventions Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. Main Outcomes and Measures The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale–cognitive subscale. Secondary outcomes included Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. Results Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. Conclusions and Relevance Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. Trial Registration ClinicalTrials.gov identifiers:NCT02245737andNCT02783573

Objectives To examine adolescent attitudes toward accessing contraception through a new pharmacist prescribing model in the State of California. Study design In-depth telephone interviews were conducted in summer 2015 with 30 females ages 18 to 19 in California. Participants were recruited using a social media advertisement. Semi-structured interviews utilized open-ended questions to understand teens' experiences with pharmacies, experiences obtaining contraception, and views on pharmacist prescribing of contraception. Responses were transcribed and qualitatively analyzed using an independent-coder method to identify salient themes. Results Participants were ethnically diverse and primarily living in suburban areas. All participants had completed high school and many had completed one year of college. Nearly all participants were supportive of California's new law allowing pharmacist prescribing of contraception. Thematic analyses revealed that while participants were satisfied with traditional service providers and valued those relationships, they appreciated the benefit of increased access and convenience of going directly to a pharmacy. Participants expected increased access to contraception in pharmacies would lead to both personal and societal benefits. They expressed concerns regarding parental involvement, as well as confidentiality in the pharmacy environment and with insurance disclosures. Conclusion Older teens in California are very supportive of pharmacies and pharmacists as direct access points for contraception, but confidentiality concerns were noted. Policy makers and pharmacies can incorporate study findings when designing policies, services, and physical pharmacy spaces to better serve teens. Further research is warranted after pharmacies implement this new service to assess teen utilization and satisfaction as well as outcomes. Implication statement Several states recently passed legislation enabling pharmacists to prescribe contraception and other states are considering similar legislation. Older teens are interested in this additional method of contraceptive access and understanding their perspectives can help guide implementation by states and in individual pharmacies.

ObjectiveTo evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD).MethodsIn this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73.ResultsThe primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF β-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported.ConclusionsAlthough prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD.Clinicaltrials.gov identifierNCT 01343966.Classification of evidenceThis study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because

In an effort to increase access to contraception, the pharmacist scope of practice is being expanded to allow prescribing. While this is being accomplished in the United States by a variety of models, legislation that allows pharmacists to prescribe hormonal contraception under a statewide protocol is the most common. This study was designed to explore the outlooks of pharmacists regarding prescribing contraception in the period following the first state legislation and prior to statewide protocol development and availability. A qualitative study of community pharmacists in California using structured phone interviews explored their opinions regarding access to contraception in pharmacies and outlooks regarding prescribing. Data were analyzed using an inductive approach to identify themes. Among the thirty participants, the majority worked in a chain pharmacy. Themes were identified in five overarching domains: Pharmacist barriers, system barriers, patient issues, safety concerns, and pharmacist role. Most were unfamiliar with the new law, yet were interested in expanding access for patient benefit despite foreseeing challenges with implementing the service in community pharmacies. Barriers will need to be addressed and requisite training disseminated widely to facilitate successful implementation and thus improve access on a broad scale. Further research following protocol implementation is needed to understand service implementation, as well as patient utilization and satisfaction.

It has been recently demonstrated that while oligosaccharide moieties of μ heavy chains in the B-cell receptor (BCR) are of the complex type as expected, those of the pre-BCR on the surface of pre-B cells contain oligosaccharide moieties of the high-mannose type only. This is unique, because high-mannose glycans are generally restricted to the endoplasmic reticulum and not presented on the surface of mammalian cells. In the present study, we examined the processing of the unusually glycosylated μ heavy chains in pre-B cells. We demonstrate that the pre-BCR reaches the cell surface by a non-conventional brefeldin A-sensitive monensin-insensitive transport pathway. Although pre-BCR complexes consist of μ heavy chains with high-mannose oligosaccharide moieties, they are stably expressed in the plasma membrane and demonstrate turnover rates similar to those of the BCR. Thus, rapid internalization cannot account for their low surface expression, as previously postulated. Rather, we demonstrate that the low pre-BCR abundance in the plasma membrane results, at least in part, from insufficient production of surrogate light chains, which appears to be a limiting factor in pre-BCR expression.

To assess the real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease (AD) in Canada.Eighteen-month observational, prospective, multi-center, open-label study conducted on AD patients with Standardized Mini-Mental State Examination (SMMSE) score of 10-26 and Global Deterioration Scale (GDS) score of 4-6. Patients were treated with the rivastigmine transdermal patch (Exelon patch*) 5 cm² (4.6 mg/24 hours) or 10 cm² (9.5 mg/24 hours), once daily.Primary outcome was change in SMMSE from baseline to 18 months. Secondary outcomes included change in SMMSE at 6 and 12 months and change in GDS, Assessment of Patient Ability (APA-C), Overall Patient Assessment Rating (OPAR), caregiver-reported compliance and treatment satisfaction at 6, 12, and 18 months.Among the 1204 patients enrolled, 969 were included in the ITT analysis. Mean (SD) age was 80.2 (8.00) years, disease duration was 0.6 (1.26) years, 62.0% of patients were women, 80.4% were living in the community, and 69.3% were treatment naïve. Mean (SD) baseline SMMSE and GDS scores were 21.8 (3.98) and 4.2 (0.61), respectively. Over 18 months of treatment there were no clinically significant changes in SMMSE and GDS. The majority of patients showed improvement or no change in GDS, APA-C and OPAR over 18 months. The proportion with reported improvement in GDS, APA-C and OPAR was higher than the proportion that deteriorated. Compliance improved from baseline to 18 months and for 88.2% of patients caregivers preferred the transdermal patch to oral medications.The rivastigmine transdermal patch is effective in maintaining cognitive function over 18 months of treatment in patients with mild-to-moderate AD. The safety profile was comparable to the data in the Canadian product monograph. Lack of a comparator group is a potential limitation of the study.

Objectives Ponezumab is a humanized antiamyloid beta (Aβ) monoclonal antibody designed to treat Alzheimer disease (AD). Methods This randomized, double-blind, single-dose-escalation study evaluated the safety, pharmacokinetics, and pharmacodynamics of 0.1, 0.3, 1, 3, and 10 mg/kg ponezumab (n = 4, 4, 4, 6, and 8, respectively) versus placebo (n = 11) after a 2-hour intravenous infusion in subjects with mild-to-moderate AD. Cerebrospinal fluid (CSF) samples were obtained from the 1- and 10-mg/kg groups at baseline and at day 29. The subjects were followed for 1 year. Results All subjects completed the trial. Ponezumab was well tolerated with no drug-attributed serious adverse events. The most common adverse events were upper respiratory tract infection, headache, and back pain, all mild to moderate. One subject (10 mg/kg) experienced a mild hypersensitivity reaction. Another subject (0.1 mg/kg) demonstrated slight enlargement of a preexisting midbrain lesion. Electrocardiography and laboratory values (including CSF) were unremarkable. No evidence of new microhemorrhage, vasogenic edema, or meningoencephalitis was noted. Plasma maximum observed concentration increased approximately dose proportionally, and the area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUC(inf)) increased slightly more than dose proportionally. Mean terminal half-life was approximately 6 weeks. Two subjects (10 mg/kg) had measurable CSF ponezumab concentrations (~0.5% of plasma values) at day 29. Plasma Aβ(1-x) and Aβ(1-40) increased dose dependently, and mean CSF Aβ(1-x) increased 38% from baseline with 10 mg/kg (P = 0.002 vs placebo). Conclusions A 2-hour infusion of 0.1 to 10 mg/kg ponezumab was well tolerated in subjects with mild-to-moderate AD. Plasma pharmacokinetic profile was approximately linear. Plasma Aβ increased with dose, and CSF Aβ increased at the highest dose, suggesting that intravenous ponezumab alters central Aβ levels.

The loss of cognition associated with dementia affects an individual's ability to participate in even the most fundamental activities of daily living ADL. Assistive technology for cognition ATC has shown potential to support ADL completion, but few devices have undergone real-world deployments. The COACH is an existing ATC that has been shown in supervised trials to support older adults with dementia through the ADL of hand washing. This paper presents the results of a study of the COACH in a long-term, real-world, community-based deployment.The COACH was installed in a washroom at the Toronto Memory Program. The COACH was configured to run in an unsupervised state, interacting with users when they were not progressing through the task. Video was collected from an overhead camera, and was manually annotated to determine the system's capabilities. The trials were conducted from February to May, 2012.Twenty participants contributed forty-one hand washing trials. Results suggest that the COACH was able to identify completed task steps with 46.6% accuracy and the participants' true performance with 54.9% accuracy. This study clarifies the need for more robust, accurate and generalized user tracking, including the use of three-dimensional tracking, gesture, grip and rotation detection.

Summary The present standard of care for B cell non-Hodgkin's lymphoma includes the anti-CD20 monoclonal antibody rituximab. Although combination treatments with chemotherapy and rituximab improved the duration of remissions and overall survival in indolent B cell lymphoma, the disease is essentially incurable. Thus, new therapeutic approaches are needed. One such approach is active immunization. Given that rituximab depletes both malignant and normal B cells, it is expected to impair humoral immune responses in vaccinated patients. Hence, optimal vaccination strategies for rituximab-treated patients require induction of effector T cells, which can be achieved by dendritic cell (DC) vaccines. We have demonstrated in a mouse model that chemotherapy combined with DC vaccines was therapeutically effective. However, efficacy was related to tumour size at the onset of treatment, decreasing in correlation with increasing tumour burdens. We therefore examined whether, in spite of its low efficacy in advanced disease, DC vaccination may synergize with anti-CD20 antibodies to enhance therapy. Lymphoma-bearing mice were treated with cyclophosphamide, anti-CD20 antibodies and an intratumoral DC vaccine. Results clearly demonstrated the enhanced therapeutic effect of this combination treatment. Thus, under conditions of disseminated disease, when either anti-CD20 antibody treatment or vaccination showed insufficient efficacy, their combination resulted in synergism that mediated long-term survival. We demonstrated further that the combination of antibody and vaccine induced T cell-mediated anti-tumour immune responses with long-term memory. Combination treatments including tumour cell-loaded DC vaccines may therefore provide a strategy for enhancing therapy in rituximab-treated patients.

SUMMARY This qualitative study explores the perceptions of orthopaedic patients towards having to use a bed pan. Ten patients were interviewed both before and after either an elective hip or knee replacement. The main findings were that if nurses facilitated a discussion around the use of bed pans some anxiety could be relieved about their use. The research was conducted 15years ago and the author has re-visited the setting where it was conducted and found that patients continue to be anxious about using bed pans, even though they are now only confined to bed for only 24h following surgery.

Multiple myeloma is an incurable plasma cell malignancy. Immunotherapy in myeloma patients had limited success to date. We have previously demonstrated that dendritic cells (DCs) pulsed with autologous Ig Id induced Id-reactive CD8+ T cells and protection against a myeloma tumor challenge. In this work, we studied the therapeutic efficacy of chemotherapy combined with different formulations of DC-based vaccines in mice bearing large plasma cell tumors. The comparative study demonstrated that s.c. injection of DCs loaded with Id coupled to keyhole limpet hemocyanin, s.c. injection of DCs loaded with irradiated tumor cells, and intratumoral injection of naive DCs were similarly effective in mediating tumor regression and long-term survival. However, whereas the Id-keyhole limpet hemocyanin-DC vaccine was inefficient against myeloma cells that lost expression of the Ig H chain, intratumoral injection of naive DCs and s.c. injection of DCs loaded with irradiated tumor cells were highly effective against cells producing L chains only. This may be of particular importance for patients with L chain myeloma. Given that T cells respond primarily to peptides derived from H chain CDRs, attempts to treat L chain disease with myeloma protein-pulsed DCs may be futile. Vaccination with tumor cell-loaded DCs may, however, induce an effective antitumor response.

Objectives To assess pharmacist interest, comfort level, and perceived barriers regarding providing pharmacist-initiated access to hormonal contraceptives (i.e., tablets, patches, rings, injectables, emergency contraception [EC]). Design Descriptive, nonexperimental, cross-sectional study. Setting United States between November 2004 and January 2005. Participants 2,725 pharmacists working in community chain pharmacies (64%), community independent pharmacy (31%), and other practice settings, including hospitals and home care facilities (5%). Intervention Survey sent electronically by the American Pharmacists Association to a random sample of 14,142 of its 50,000 pharmacist members nationally. Main outcome measures Pharmacist interest and comfort level in providing pharmacy access to hormonal contraception (HC), perceived barriers and training needs, and familiarity with and provision of EC. Results 2,725 survey responses (19% response rate) were received. Pharmacists reported being very familiar with HC. The majority of respondents were comfortable and interested in providing direct access to HC in the pharmacy. Perceived barriers to providing HC in the pharmacy included lack of time, no mechanism of reimbursement for the service, and possible resistance from physicians. Conclusion Strong interest, comfort level, and capability from pharmacists, combined with a documented demand for direct pharmacy access from patients, indicate that pharmacy access to HC has the potential to meet patient needs and increase access to HC. Education about current clinical practice recommendations—which no longer require pelvic examinations and Papanicolaou (Pap) smears before hormonal contraception is initiated—may increase pharmacist support for providing hormonal methods directly.

Background: The prevalence of dementia is placing an increased burden on specialists. Methods: Canadian neurologists responded to a structured questionnaire to assess reasons for referral and services provided as well as to compare the neurologists' perceptions of their practice characteristics against cases seen over a 3-month period. Results: The audit confirmed the participants' perception that family practitioners are the main referral source (358/453, 79%). Sixty-two percent of patients had undergone clinical investigation for dementia prior to being seen by the neurologist; 39% (177/453) were on pharmacotherapy at the time of referral, 68% were initiated on pharmacotherapy by the neurologist. A fifth of the referrals did not meet clinical criteria for dementia, which may be directly related to the prevalence of prior workup that did not include mental status testing. Conclusions: Neurologists currently treat patients referred for dementia who may already have been adequately evaluated and treated by primary care providers.

Objectives To explore the potential of pharmacist-administered contraceptive injections and feasibility and acceptability among patients, pharmacists, and clinicians. Setting Throughout California, 27 pharmacists practicing in 26 community independent and chain pharmacies partnered with 19 clinics/physician offices. Practice description TIn spring 2003, Pharmacy Access Partnership launched a 2-year demonstration program in which established users of depot medroxyprogesterone acetate (e.g., Depo-Provera—Pfizer) hormonal contraception at participating clinics were given the option of returning to their regular clinic for reinjection or going to a participating pharmacist trained in injection technique and contraceptive management. Practice innovation Program feasibility and acceptability by patients, pharmacists, and clinicians were evaluated to offer insights into the potential of pharmacistadministered depot medroxyprogesterone injections. Intervention Intake forms collected during pharmacy reinjection visits, data from interviews with pharmacists and clinicians, and evaluations with patients. Main outcome measures To determine whether contraceptive reinjection at a pharmacy is feasible and acceptable for patients, pharmacists, and clinicians and to determine the characteristics of women most likely to use the service. Results A total of 69 women received 143 depot medroxyprogesterone injections during the project. Patients were ethnically and racially diverse and spanned a wide age range (19–45 years). Women 20 years of age or older used pharmacists’ services more frequently than did younger patients, perhaps because they were more familiar with the injections and they more often worked, therefore needing the expanded hours offered by the community pharmacy setting. Experiences of two pharmacies with successful programs are described. Conclusion The pharmacy option for reinjection is most viable for women who can comfortably manage their injection cycle, prefer not to have to schedule a clinic appointment quarterly, and do not require the ongoing attention and appointment supervision available from the clinic. To be successful, program promotion requires provider support, integration, and involvement at the clinic level.

Mental health problems during pregnancy can influence fetal growth. However, studies examining the influence of maternal mental health across the normal range of birth outcomes are uncommon. This study examined the associations between symptoms of maternal depression and anxiety during pregnancy on birth size among term Asian infants.One thousand forty-eight Asian pregnant women from a cohort Growing Up in Singapore Towards Healthy Outcomes were recruited between 2009 to 2010 at two Singaporean maternity hospitals. At 26 weeks gestation, depressive symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory II (BDI-II), and anxiety was measured with the Spielberger State-Trait Anxiety Inventory (STAI). Health personnel recorded birthweight, birthlength, gestational age, and head circumference at birth.Nine hundred forty-six women who delivered term infants had complete data. For this sample, the mean birthweight was 3146.6 g [standard deviation (SD) 399.0], the mean birthlength was 48.9 cm (SD 2.0). After controlling for several potential confounders, there was a significant negative association between STAI and birthlength [β = -0.248, confidence interval (CI) [-0.382, -0.115], P0.001] and a small negative association between EPDS and birthlength (β = -0.169, CI [-0.305, -0.033], P = 0.02). No associations were found between scores on the EPDS, BDI-II, and STAI with birthweight or head circumference.Our preliminary data suggest that among term infants, anxiety and depressive symptoms are not associated with birthweight, while anxiety and depressive symptoms are associated with a shorter birthlength.