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X-linked agammaglobulinemia (XLA) is a monogenic primary immune deficiency characterized by very low levels of immunoglobulins and greatly increased risks for recurrent and severe infections. Patients with XLA have a loss-of-function mutation in the Bruton's tyrosine kinase (BTK) gene and fail to produce mature B lymphocytes. Gene editing in the hematopoietic stem cells of XLA patients to correct or replace the defective gene should restore B cell development and the humoral immune response. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 platform to precisely target integration of a corrective, codon-optimized BTK complementary DNA (cDNA) cassette into its endogenous locus. This process is driven by homologous recombination and should place the transgenic BTK under transcriptional control of its endogenous regulatory elements. Each integrated copy of this cDNA in BTK-deficient K562 cells produced only 11% as much BTK protein as the wild-type gene. The donor cDNA was modified to include the terminal intron of the BTK gene. Successful integration of the intron-containing BTK donor led to a nearly twofold increase in BTK expression per cell over the base donor. However, this donor variant was too large to package into an adeno-associated viral vector for delivery into primary cells. Donors containing truncated variants of the terminal intron also produced elevated expression, although to a lesser degree than the full intron. Addition of the Woodchuck hepatitis virus posttranscriptional regulatory element led to a large boost in BTK transgene expression. Combining these modifications led to a BTK donor template that generated nearly physiological levels of BTK expression in cell lines. These reagents were then optimized to maximize integration rates into human hematopoietic stem and progenitor cells, which have reached potentially therapeutic levels in vitro. The novel donor modifications support effective gene therapy for XLA and will likely assist in the development of other gene editing-based therapies for genetic disorders.

Abstract Background Influenza poses concerns about epidemic respiratory infection. Interventions designed to prevent the spread of respiratory infection within family physician (FP) offices could potentially have a significant positive influence on the health of Canadians. The main purpose of this paper is to estimate the explicit costs of such an intervention. Methods A cost analysis of a respiratory infection control was conducted. The costs were estimated from the perspective of provincial government. In addition, a threshold analysis was conducted to estimate a threshold value of the intervention's effectiveness that could generate potential savings in terms of averted health-care costs by the intervention that exceed the explicit costs. The informational requirements for these implicit costs savings are high, however. Some of these elements, such as the cost of hospitalization in the event of contacting influenza, and the number of patients passing through the physicians' office, were readily available. Other pertinent points of information, such as the proportion of infected people who require hospitalization, could be imported from the existing literature. We take an indirect approach to calculate a threshold value for the most uncertain piece of information, namely the reduction in the probability of the infection spreading as a direct result of the intervention, at which the intervention becomes worthwhile. Results The 5-week intervention costs amounted to a total of $52,810.71, or $131,094.73 prorated according to the length of the flu season, or $512,729.30 prorated for the entire calendar year. The variable costs that were incurred for this 5-week project amounted to approximately $923.16 per participating medical practice. The (fixed) training costs per practice were equivalent to $73.27 for the 5-week intervention, or $28.14 for 13-week flu season, or $7.05 for an entire one-year period. Conclusion Based on our conservative estimates for the direct cost savings, there are indications that the outreach facilitation intervention program would be cost effective if it can achieve a reduction in the probability of infection on the order of 0.83 (0.77, 1.05) percentage points. A facilitation intervention initiative tailored to the environment and needs of the family medical practice and walk-in clinics is of promise for improving respiratory infection control in the physicians' offices.

Abstract Background The identification of patients' health needs is pivotal in optimising the quality of health care, increasing patient satisfaction and directing resource allocation. Health needs are complex and not so easily evaluated as health-related quality of life (HRQL), which is becoming increasingly accepted as a means of providing a more global, patient-orientated assessment of the outcome of health care interventions than the simple medical model. The potential of HRQL as a surrogate measure of healthcare needs has not been evaluated. Objectives and method A generic (Short Form-12; SF-12) and a disease-specific questionnaire (Seattle Angina Questionnaire; SAQ) were tested for their potential to predict health needs in patients with acute coronary disease. A wide range of healthcare needs were determined using a questionnaire specifically developed for this purpose. Results With the exception of information needs, healthcare needs were highly correlated with health-related quality of life. Patients with limited enjoyment of personal interests, weak financial situation, greater dependency on others to access health services, and dissatisfaction with accommodation reported poorer HRQL (SF-12: p < 0.001; SAQ: p < 0.01). Difficulties with mobility, aids to daily living and activities requiring assistance from someone else were strongly associated with both generic and disease-specific questionnaires (SF-12: r = 0.46-0.55, p < 0.01; SAQ: r = 0.53-0.65, p < 0.001). Variables relating to quality of care and health services were more highly correlated with SAQ components (r = 0.33-0.59) than with SF-12 (r = 0.07-0.33). Overall, the disease-specific Seattle Angina Questionnaire was superior to the generic Short Form-12 in detecting healthcare needs in patients with coronary disease. Receiver-operator curves supported the sensitivity of HRQL tools in detecting health needs. Conclusion Healthcare needs are complex and developing suitable questionnaires to measure these is difficult and time-consuming. Without a satisfactory means of measuring these needs, the extent to which disease impacts on health will continue to be underestimated. Further investigation on larger populations is warranted but HRQL tools appear to be a reasonable proxy for healthcare needs, as they identify the majority of needs in patients with coronary disease, an observation not previously reported in this patient group.

Abstract Objectives To assess satisfaction of survivors of coronary artery diseases (CAD) with healthcare services and to determine whether specific components of standard health-related quality of life (HRQL) assessment tools might identify areas of satisfaction and dissatisfaction. Method A specific tool developed to provide a comprehensive assessment of healthcare needs was administered concomitantly with generic and specific HRQL instruments, on 242 patients with CAD, admitted to an acute coronary unit during a single year. Results 92.5% of patients confirmed their trust in and satisfaction with the care given by their General Practitioner; even so, one third experienced difficulty getting an appointment and a quarter wanted more time for each consultation or prompt referral to a specialist when needed. Around a third expressed dissatisfaction with advice from the practice nurse or hospital consultant. Overall 54% were highly satisfied with services, 33% moderately satisfied and 13% dissatisfied. Cronbach's alpha was 0.87; the corrected total-item correlation ranged between 0.55–0.75, with trivial 'floor' score and low 'ceiling' effect. Several domains in all three HRQL tools correlated with items relating to satisfaction. The Seattle Angina Questionnaire Treatment Score correlated significantly with all satisfaction items and with the global satisfaction score. Conclusion Cardiac patients' demanded better services and advice from, and more time with, health professionals and easier surgery access. The satisfaction tool showed acceptable psychometric properties. In this patient group, disease-specific HRQL tools seem more appropriate than generic tools for surveys of patient satisfaction.

Abstract Defining needs is difficult due to the inherent complexity of the concept of 'need', so it is not surprising that numerous definitions have been proposed. 'Health' consists of a wide range of characteristics so 'health needs' ought to include personal and social care, health care, accommodation, finance, education, employment and leisure, transport and access. Target-driven standards in areas of health care with a high political profile appear to be replacing the concept of universal provision and clinical need; this major change in clinical care warrants a re-evaluation of health care outcomes. Identifying who might benefit from this new approach to health care is equally important if scarce resources are to be fully and appropriately utilised. If the goal of care is 'optimal health', the key marker of success ought to be to ascertain individual patients' health care needs (HCN) and tailor services accordingly. Wide variation in the description of 'needs' directly affects policies and services intended to meet a population's health care needs. Consequently, the definition of 'needs' has important implications for healthcare provision- the more constrained the definition, the less healthcare will be made available and vice versa. This paper describes some common definitions of needs and discusses their respective benefits and disadvantages in terms of health care provision and their potential impact on health policy.

Abstract Background Improving the quality of health care services requires tailoring facilities to fulfil patients' needs. Satisfying patients' healthcare needs, listening to patients' opinions and building a closer provider-user partnership are central to the NHS. Few published studies have discussed cardiovascular patients' health needs, but they are not comprehensive and fail to explore the contribution of outcome to needs assessment. Method A comprehensive self-administered health needs assessment (HNA) questionnaire was developed for concomitant use with generic (Short Form-12 and EuroQOL) and specific (Seattle Angina Questionnaire) health-related quality of life (HRQL) instruments on 242 patients admitted to the Acute Cardiac Unit, Nottingham. Results 38% reported difficulty accessing health facilities, 56% due to transport and 32% required a travelling companion. Mean HRQOL scores were lower in those living alone (P < 0.05) or who reported unsatisfactory accommodation. Dissatisfaction with transport affected patients' ease of access to healthcare facilities (P < 0.001). Younger patients ( Conclusions Patients wanted more social (suitable accommodation, companionship, social visits) and physical (help aids, access to healthcare services, house work) support. The construct validity and intra-class reliability of the HNA tool were confirmed. Our results indicate a gap between patients' health needs and available services, highlighting potential areas for improvement in the quality of services.

Abstract Background Health-related quality of life (HRQL) assessment is an important measure of the impact of a wide range of disease process on an individual. To date, no HRQL tool has been evaluated in an Iranian population with cardiovascular disorders, specifically myocardial infarction, a major cause of mortality and morbidity. The MacNew Heart Disease Health-related Quality of Life instrument is a disease-specific HRQL questionnaire with satisfactory validity and reliability when applied cross-culturally. Method A Persian version of MacNew was prepared by both forward and backward translation by bilinguals after which a feasibility test was performed. Consecutive patients (n = 51) admitted to a coronary care unit with acute myocardial infarction were recruited for measurement of their HRQL with retest one month after discharge in the follow-up clinic. Principal components analysis, intra-class correlation reliability, internal consistency, and test-retest reliability were assessed. Results Trivial rates of missing data confirmed the acceptability of the tool. Principal component analysis revealed that the three domains, emotional, social and physical, performed as well as in the original studies. Internal consistency was high and comparable to other studies, ranging from 0.92 for the emotional and physical domains, to 0.94 for the social domain, and to 0.95 for the Global score. Domain means of 5, 5.3 and 4.9 for emotional, physical and social respectively indicate that our Iranian population has similar emotional and physical but worse social HRQL scores. Test-retest analysis showed significant correlation in emotional and physical domains (P < 0.05). Conclusion The Persian version of the MacNew questionnaire is comparable to the English version. It has high internal consistency and reasonable reproducibility, making it an appropriate specific quality of life tool for population-based studies and clinical practice in Iran in patients who have survived an acute myocardial infraction. Further studies are needed to confirm its validity in larger populations with cardiovascular disease.

We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41-76). Fifty percent of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics and Genomics standards, including variants in APP, C9orf72, CSF1R, and MAPT Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2-5) in ABCA7, AKAP9, GBA, PLD3, SORL1, and TREM2 All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two APOE ε4 alleles. One patient had two APOE ε4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) in ABI3, ADAM10, ARSA, GRID2IP, MME, NOTCH3, PLCD1, PSEN1, TM2D3, TNK1, TTC3, and VPS13C, also often along with other variants. In summary, genome sequencing for early-onset dementia frequently identified multiple established or possible contributory alleles. These observations add support for an oligogenic model for early-onset dementia.

Mating signals are targets of conspecific signal recognition and sexual selection but are also subject to abiotic temperature effects and to biotic interspecific eavesdroppers. In crickets, the male calling song becomes faster at warmer temperatures, and female crickets' recognition of male song tracks temperature in a coordinated manner, termed "temperature coupling." But, female crickets are not the only ecologically relevant listeners: some cricket species are parasitized by Ormia ochracea , a parasitoid fly which finds its cricket hosts by eavesdropping on male cricket song. How temperature affects parasitoid fly phonotaxis to song is largely unexplored, with only one previous study conducted under field conditions. Here, we explore 6 possible patterns of thermal effects on fly responses to cricket song, including temperature coupling, using field playbacks of synthetic Gryllus lineaticeps songs designed to be species-typical at various temperatures. We find that temperature does affect fly response, but that the temperature deviation of songs from ambient does not impact numbers of flies caught. We extend this finding by comparing the temperatures of the air (where flies search for their hosts) and the ground (where their host crickets signal) to show that temperature coupling is unlikely to be effective given microhabitat variation and differential rates of cooling in the evening hours when flies are most active. Our results can be interpreted more broadly to suggest (1) temperature effects on intraspecific communication systems may be more tightly coupled than are effects on interspecific eavesdropping and (2) variation in thermal microhabitats in the field make it difficult to translate laboratory physiological responses to natural selection in the wild. [ABSTRACT FROM AUTHOR]

The restructuring of Britain's civil service is understood mainly as a Thatcher- and Blair-era event rooted in neoliberal economic policies. Yet its roots reach back to the late 1960s and early 1970s. During that time, senior civil servants turned to American management strategy to advance the government's efforts to scale back the size of the service. This article explores these efforts via the activities of the Treasury's Management Services Division and its Head, John N. Archer. In 1969, Archer made a month-long visit to the United States to study American management techniques. Over the next few years, he and his colleagues attempted to implement one of these techniques in particular—Office Work Measurement—throughout the service. Derived from scientific management, OWM would, they believed, help cut the number of positions in the service. In tracing these efforts, the discussion sheds light on an under-analysed episode in Britain's civil service reform history. In turn, it argues that the OWM quest of the early 1970s played a heretofore under-emphasised role in the government's embrace of 'managerialism' and the implementation of civil service reforms. [ABSTRACT FROM AUTHOR]

Objectives Rituximab is used for remission induction and the prevention of relapse in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the incidence of safety events and compared time to first serious adverse event (SAE) between a rituximab cohort and a cohort treated with non-rituximab therapies in a real-life setting. Methods Rituximab surveillance study in vasculitis was a retrospective observational study of patients with AAV who received rituximab (MabThera) or other treatments between 2003 and 2017 at a specialist vasculitis clinic. The primary endpoint was time to first SAE. Results 392 patients were enrolled: 247 in the rituximab and 145 in the control cohorts with a total follow up of 2217 person-years (mean study duration 5.7 years). Mean age was 61 years, 77% had granulomatosis with polyangiitis (GPA). There were differences in baseline characteristics (disease duration and prior immunosuppressive use) between groups. 134/247 patients (54%) in the rituximab and 58/145 (40%) of controls experienced at least one SAE. Time to first SAE was shorter in the rituximab group (hazard ratio (HR) 1.55, 95% CI 1.07–2.26, P  = 0.022). Predictors of first SAE were higher vasculitis damage index and the presence of chronic pulmonary or kidney disease. The risk of serious infection was higher in the rituximab group (relative risk (RR) 2.12, 95% CI 1.31–3.43). Conclusion Over 40% of patients with AAV experienced at least one SAE. Although shorter time to first SAE and higher risk of infection were observed in the rituximab group, baseline imbalances necessitate a careful interpretation of these results. [ABSTRACT FROM AUTHOR]

The use of allogeneic hematopoietic stem cells (HSCs) to treat genetic blood cell diseases has become a clinical standard but is limited by the availability of suitable matched donors and potential immunologic complications. Gene therapy using autologous HSCs should avoid these limitations and thus may be safer. Progressive improvements in techniques for genetic correction of HSCs, by either vector gene addition or gene editing, are facilitating successful treatments for an increasing number of diseases. We highlight the progress, successes, and remaining challenges toward the development of HSC gene therapies and discuss lessons they provide for the development of future clinical stem cell therapies.