Cause Of Attrition Research Articles

From the Cover: High-Throughput Imaging of Cardiac Microtissues for the Assessment of Cardiac Contraction during Drug Discovery.

Cardiotoxicity is a common cause of attrition in preclinical and clinical drug development. Current in vitro approaches have two main limitations, they either are limited to low throughput methods not amendable to drug discovery or lack the physiological responses to allow an integrated risk assessment. A human 3D cardiac microtissue containing human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), cardiac endothelial cells and cardiac fibroblast were used to assess their suitability to detect drug induced changes in cardiomyocyte contraction. These cardiac microtissues, have a uniform size, spontaneously beat, lack a hypoxic core, and contain key markers of each cell type. Application of field stimulation and measurement of cardiac contraction confirm cardiac microtissues to be a suitable model to investigate drug-induced changes in cardiomyocyte contractility. Using a bespoke image acquisition work flow and optical flow analysis method to test 29 inotroptic and 13 non-inotroptic compounds in vivo We report that cardiac microtissues provide a high-throughput experimental model that is both able to detect changes in cardiac contraction with a sensitivity and specificity of 80 and 91%, respectively, and provide insight into the direction of the inotropic response. Allowing improved in vitro cardiac contractility risk assessment. Moreover, our data provide evidence of the detection of this liability at therapeutically relevant concentrations with a throughput amenable to drug discovery.

Attrition Due to Orthopedic Reasons During Combat Training: Rates, Types of Injuries, and Comparison Between Infantry and Noninfantry Units.

PURPOSE: The purpose of this study is to identify the prevalence and types of orthopedic injuries in infantry and noninfantry units responsible for attrition from combat training. METHODS: 18,651 soldiers consecutively recruited to combat units (5 infantry and 4 noninfantry units) were included in this study. All recruited soldiers underwent and successfully passed a meticulous medical selection process. In all units, the soldiers participated in a suited fitness program that included marching, running, and strength training. Data were collected directly from attrite soldiers' files and detailed lists provided by the units' medical clinics. RESULTS: Out of 18,651 recruits, 641 (3.44%) attrite because of medical reasons. The leading cause of attrition was orthopedic diagnoses, and their overall rate was 43% (274 out of 641). Overuse injuries accounted for 90% of all orthopedic injuries. Low-back and lower extremity injuries accounted for 71.5% of all orthopedic injuries. There was high similarity in orthopedic injuries types and rates between infantry and noninfantry units. CONCLUSION: On the basis of our results, we recommend a multidisciplinary intense effort including physicians, physical training officers, physiotherapists, and commanders to significantly reduce overuse injuries, especially in the low-back and lower extremity regions. Language: en

Attrition Due to Orthopedic Reasons During Combat Training: Rates, Types of Injuries, and Comparison Between Infantry and Noninfantry Units.

ABSTRACT Purpose: The purpose of this study is to identify the prevalence and types of orthopedic injuries in infantry and noninfantry units responsible for attrition from combat training. Methods: 18,651 soldiers consecutively recruited to combat units (5 infantry and 4 noninfantry units) were included in this study. All recruited soldiers underwent and successfully passed a meticulous medical selection process. In all units, the soldiers participated in a suited fitness program that included marching, running, and strength training. Data were collected directly from attrite soldiers' files and detailed lists provided by the units' medical clinics. Results: Out of 18,651 recruits, 641 (3.44%) attrite because of medical reasons. The leading cause of attrition was orthopedic diagnoses, and their overall rate was 43% (274 out of 641). Overuse injuries accounted for 90% of all orthopedic injuries. Low-back and lower extremity injuries accounted for 71.5% of all orthopedic injuries. There was high similarity ...

Prevention and Management of Tooth Wear: The Role of Dental Technology.

Tooth wear is a multifactorial condition and the term is used to describe all types of non-carious tooth substance loss: abrasion (produced by interaction between the teeth and other substances), attrition (produced during tooth-to-tooth contact), erosion (produced by a chemical process) and abfraction (produced through abnormal occlusal loading that predisposes tooth substance to mechanical and chemical wear). Dental technology has an important role in preventing, managing and monitoring tooth wear in a variety of ways. Hard poly(methyl methacrylate) or soft ethylene-vinyl acetate splints can be prescribed to alleviate bruxism, the most common cause of attrition. Thermoformed appliances can be used for the application of products that reduce dental erosion such as fluoride gel. Patients with significant tooth surface loss may require laboratory-made restorations, as well as removable appliances with bite planes that generate inter-occlusal space to facilitate restorations, or surgical templates to provide guidance in preparing restorations for those requiring surgical crown lengthening. Dental study models and digitised models can also prove valuable in terms of monitoring the condition. This paper presents a review of the role that dental technology plays in tooth wear prevention, management and monitoring.

Attrition in Italian Ranger trainees during special forces training program: a preliminary investigation

Purpose This pilot observational study aimed at determining the causes of attrition during the Italian Army-Rangers training program identifying possible predictor characteristics.

Mimicking the Kidney: A Key Role in Organ-on-Chip Development.

Pharmaceutical drug screening and research into diseases call for significant improvement in the effectiveness of current in vitro models. Better models would reduce the likelihood of costly failures at later drug development stages, while limiting or possibly even avoiding the use of animal models. In this regard, promising advances have recently been made by the so-called “organ-on-chip” (OOC) technology. By combining cell culture with microfluidics, biomedical researchers have started to develop microengineered models of the functional units of human organs. With the capacity to mimic physiological microenvironments and vascular perfusion, OOC devices allow the reproduction of tissue- and organ-level functions. When considering drug testing, nephrotoxicity is a major cause of attrition during pre-clinical, clinical, and post-approval stages. Renal toxicity accounts for 19% of total dropouts during phase III drug evaluation—more than half the drugs abandoned because of safety concerns. Mimicking the functional unit of the kidney, namely the nephron, is therefore a crucial objective. Here we provide an extensive review of the studies focused on the development of a nephron-on-chip device.

Editor's Highlight: Plasma miR-183/96/182 Cluster and miR-124 are Promising Biomarkers of Rat Retinal Toxicity.

Retinal toxicity is one of the leading causes of attrition in drug development, and drug-induced retinal toxicity remains an issue in both drug discovery and postmarketed drugs. Derisking strategies to help with early identification of retinal injury utilizing a predictive retinal miRNA biomarker would greatly benefit decision-making in drug discovery programs, ultimately reducing attrition due to retinal toxicity. Our previous work demonstrated elevation of circulating retina-enriched miRNAs in a retinal toxicity model. To further validate our previous observation, 2 additional rat retinal injury models were utilized in this study: NaIO3-induced retinal injury and laser-induced choroidal neovascularization (CNV) injury model. Following induction of retina tissue injuries, circulating miR-183/96/182 cluster (miR-183 cluster), and miR-124 was investigated, as well as evaluations using an electroretinogram (ERG) and histopathology analysis. Data revealed that circulating miR-183/96/182 cluster was significantly increased (2- to 15-fold) compared with baseline/control in both laser-induced CNV and NaIO3-induced retinal injury models. Moreover, the severity of the retinal injury evaluated by ERG and histopathology correlated highly with elevation of these retina-enriched miRNAs in plasma. MiR-124 was also significantly increased in comparison with baseline/control by ∼25-fold postrepeat-doses of 30 mg/kg NaIO3 treatment. Increased level of these plasma miRNA biomarkers appeared to be dose- and time-dependent upon NaIO3 or laser treatment. The results suggest that the retina-enriched miRNAs (miR-183/96/182 cluster and miR-124) could serve as convenient and predictive biomarkers of retinal toxicity in drug development.

The genetics of drug efficacy: opportunities and challenges.

Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.

Attrition of undergraduate nursing students at selected South African universities.

BackgroundThe nursing profession forms the backbone of many healthcare systems. It therefore needs a consistent supply of registered nurses to deliver continuous and safe quality healthcare, and to replace the nurses leaving or retiring from the profession. Attrition actively occurs among nursing students in South Africa and threatens the future supply of registered nurses.AimThe aim of the study was to describe the attrition rate at selected South African universities and the factors influencing undergraduate nursing students to discontinue their nursing studies at these universities.MethodA quantitative descriptive design was followed. Heads of the nursing departments at the selected universities captured data with a specifically designed questionnaire. Thereafter their former nursing students provided information via a structured telephonic interview on the reasons why they discontinued the nursing programme.ResultsThe study revealed that attrition of undergraduate nursing students for three intake years (2007, 2008 and 2009) at the participating universities was between 39.3% and 58.7%. Academic and financial reasons as well as poor wellness and health were the main causes for attrition. Another factor was failure to cope with the demands of the clinical environment.ConclusionAttrition might not occur immediately when a nursing student is challenged, as the student might exploit the various types of support offered. Although some nursing students do benefit from the offered support, a large number of nursing students still discontinue the undergraduate nursing programme.

Examining the Relationship Between Mental, Physical, and Organizational Factors Associated With Attrition During Maritime Forces Training.

For infantry units of the Dutch Ministry of Defence, high attrition rates (varying from 42 to 68%) during initial training are a persisting problem. The reasons for this attrition are diverse. Having better insight into the causes of attrition is a prerequisite for implementing preventive measures. To achieve this, a monitoring assessment system was developed that integrated the effects of physical, mental, and organizational determinants on operational readiness. The aim of this study was to implement the monitoring tools and to establish the set of determinants that best predicted attrition during infantry training of new recruits. Eighty-five recruits were monitored over a 24-week infantry training course. Before the training, recruits were screened for medical, psychological, and physical wellness. During the monitoring phase, mental, physiological, and organizational indicants were obtained using an array of tools such as questionnaires, chest belt monitors (for heart rate, acceleration, and skin temperature measurements), and computerized tests (e.g., vigilance, long-term memory). Survival analyses were used to tease out the determinants of individual and grouped predictors of attrition. Nearly half the recruits (47%) failed the training. Attrition was predicted by both physiological and mental determinants. However, the organizational determinant "trainers' judgment" on the "recruits' military quality" dominated the physiological and mental determinants. It was concluded that the monitoring system was successfully implemented during infantry training, and that the survival analysis method emphasized on single effects and interactions between the different determinants. Based on the current findings, we recommend several steps to successfully implement a monitoring method in settings with high demands.

Engineering Student Retention and Attrition Literature Review

The University of Saskatchewan, similar tomany engineering colleges, would like to improve studentretention. With that in mind, a literature review wasundertaken to summarize current peer reviewed literaturerelated to engineering student retention and attrition inan attempt to better understand the potential structuralcauses, processes, and student characteristics that maycontribute to student success or attrition. Through asystematic search of several major databases using thekeywords “engineering and attrition or retention,” andafter narrowing the scope to peer reviewed articleswritten between 2005 and the present, each article’sabstract was read and evaluated. Forty-five papers weredeemed to be highly relevant, and were thus included inthe literature review. Preliminary trends that haveemerged in this review are: the potential causes of highattrition rates in engineering schools, various methodsthat have been used to determine the causes of attrition,interventions that have been implemented and stories oftheir success/failure, and attributes that have been foundto correlate with student attrition or success. This paperis an attempt to organize this body of research into asingular source that can be referenced by engineeringeducators or researchers who wish to increase studentretention and improve the educational experience of theirstudents.

Establishment of animal models of drug-induced liver injury and analysis of possible mechanisms

Drug-induced liver injury (DILI) is one of leading causes of attrition during both early and late stages of drug development and postmarketing. DILI is generally classified into the intrinsic and idiosyncratic types. Intrinsic DILI is dose dependent and predictable as exemplified by acetaminophen toxicity. However, the occurrence of idiosyncratic DILI with very low incidence and severe liver damage is difficult to predict because of the complex nature of DILI and poor understanding of its mechanism. In this review, we summarize current knowledge and our accumulated experimental findings on the pathogenic mechanisms of DILI focusing on the reactive metabolites of drugs formed by drug-metabolizing enzymes and immune- and inflammation-related responses. Considering drug metabolism and pharmacokinetics, we have established nonclinical animal models of DILI for 10 types of clinical drug known to cause idiosyncratic DILI in humans. Using animal models, it has been shown that the formation of reactive metabolites and both innate and adaptive immunity are involved in the pathogenesis of drug hepatotoxicity. Based on information on biomarkers obtained from animal models, we developed a cell-based system that predicts the potential DILI risks of drugs. The results of these studies increased our understanding of the mechanisms of DILI and help to predict and prevent idiosyncratic DILI caused by drug candidates.

Malawi Primary School Teacher attrition from 1996 to 2011

The purpose of this analysis was to examine the causes of primary school teacher attrition between 1996 and 2011 in Malawi. Data collected by the Ministry of Education was used to extract the number of teachers leaving the profession along with the reasons for leaving by reasons and overall annual teacher attrition was calculated. Overall teacher attrition declined from 4.9% in 2004 to 4.0% in 2007. Mortality was the main cause of attrition since 1996, and it increased from 0.5% in 1996 to 1.8% in 2001 but declined to 1.2% by 2004 The finding of the analysis shows that primary Teacher attrition was highest (5.2 %) in 2004 for male teachers compared to females (4.5 %) and declined to 3.2% and 1.9% in 2007, respectively. Considering all the reasons for teacher attrition in percentage terms, about 33% of teacher attrition was caused by death in males and 40% in females from 2004 to 2007. The paper concludes that instead of seeing teachers leaving the system due to retirement and resignation, as has been the case many years, a number of teachers died in service and many also left due to dismissal and other reasons that are not known. This pattern needs to be checked and attended to if Malawi is to attain the Education for All Goals.

Physical fitness and depressive symptoms during army basic combat training.

Mental health-related problems are a significant cause of attrition during basic combat training (BCT). Evidence in civilian populations suggests that physical fitness is associated with psychological benefits in civilians, but little is known about the association between physical fitness and psychological adjustment during BCT. This study prospectively examined the association between physical fitness and depressive symptoms in 300 BCT soldiers from May to July 2012 at Fort Jackson, Columbia, SC. Soldiers completed a baseline Army Physical Fitness Test (APFT) and survey within 1 wk of arriving at BCT and an end-of-cycle survey after 8 wk of BCT. Soldiers were assigned to the "high" fitness category if they had a passing score on the standard APFT of greater than or equal to 180 out of 300 points. Soldiers scoring less than 180 points on the APFT were assigned to the "low" fitness category. Depressive symptoms were measured using the 20-item Center for Epidemiologic Studies Depression scale. In multivariate analyses, adjusting for baseline demographics, self-reported sleep before BCT, BCT confidence, Army identification, and depressive symptoms, the odds of reporting depressive symptoms were 60% lower for soldiers in the high fitness category (odds ratio, 0.40; 95% confidence interval, 0.19-0.84) compared with soldiers in the low fitness category. Analogous to other positive outcomes of soldier fitness, improvement of soldier physical fitness before BCT might improve soldiers' psychological health outcomes.

Assessment of cardiomyocyte contraction in human-induced pluripotent stem cell-derived cardiomyocytes.

Functional changes to cardiomyocytes are a common cause of attrition in preclinical and clinical drug development. Current approaches to assess cardiomyocyte contractility in vitro are limited to low-throughput methods not amenable to early drug discovery. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) were used to assess their suitability to detect drug-induced changes in cardiomyocyte contraction. Application of field stimulation and measurement of cardiac contraction (IonOptix edge detection) and Ca(2+) transients confirmed hiPS-CMs to be a suitable model to investigate drug-induced changes in cardiomyocyte contractility. Using a live cell, fast kinetic fluorescent assay with a Ca(2+) sensitive dye to test 31 inotropic and 20 non-inotropic compounds in vivo, we report that hiPS-CMs provide a high-throughput experimental model to detect changes in cardiomyocyte contraction that is applicable to early drug discovery with a sensitivity and specificity of 87% and 70%, respectively. Moreover, our data provide evidence of the detection of this liability at therapeutically relevant concentrations with throughput amenable to influencing chemical design in drug discovery. Measurement of multiple parameters of the Ca(2+) transient in addition to the number of Ca(2+) transients offered no insight into the mechanism of cardiomyocyte contraction.

Physical durability of two types of long-lasting insecticidal nets (LLINs) three years after a mass LLIN distribution campaign in Mozambique, 2008-2011.

We conducted a prospective evaluation to measure the physical durability of two brands of long-lasting insecticidal nets (LLINs) distributed during a campaign in 2008 in Nampula Province, Mozambique. Households with LLINs tagged during the campaign (6,000) were geo-located (34%) and a random sample was selected for each of 3 years of follow-up. The LLINs were evaluated in the field and a laboratory for presence of holes and a proportional hole index (pHI) was calculated following the World Health Organization guidelines. We performed 567 interviews (79.0%) and found 75.3% (72.1-78.4%) of households retained at least one LLIN after 3 years; the most common cause of attrition was damage beyond repair (51.0%). Hole damage was evident after 1 year, and increased by year. Olyset had a significantly greater mean number of holes and pHI compared with PermaNet 2.0 brand (all P values ≤ 0.001). Additional information about LLIN durability is recommended to improve malaria control efforts.

Experimentally validated HERG pharmacophore models as cardiotoxicity prediction tools.

The goal of this study was to design, experimentally validate, and apply a virtual screening workflow to identify novel hERG channel blockers. The hERG channel is an important antitarget in drug development since cardiotoxic risks remain as a major cause of attrition. A ligand-based pharmacophore model collection was developed and theoretically validated. The seven most complementary and suitable models were used for virtual screening of in-house and commercially available compound libraries. From the hit lists, 50 compounds were selected for experimental validation through bioactivity assessment using patch clamp techniques. Twenty compounds inhibited hERG channels expressed in HEK 293 cells with IC50 values ranging from 0.13 to 2.77 μM, attesting to the suitability of the models as cardiotoxicity prediction tools in a preclinical stage.

Drug-induced liver injury and drug development: industry perspective.

Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.

Patients who return to care after tracking remain at high risk of attrition: experience from a large HIV clinic, Uganda

We determined the retention rate of patients infected with HIV who resumed care after being tracked at the Infectious Diseases Clinic (IDC) in Kampala, Uganda. Between April 2011 and September 2013, patients who missed their clinic appointment for 8-90 days were tracked, and those who returned to the clinic within 120 days were followed up. The proportion of patients retained among tracked patients, and those who resumed care before tracking started was compared. At 18 months of follow up, 33 (39%) of the tracked patients and 72 (61%) of those who had resumed care before tracking started were retained in care. The most important cause of attrition among the traceable was self-transfer to another clinic (38 [73%] patients), whereas among those who resumed care before tracking was loss to follow up (LTFU) (32 [71%] patients). Tracked patients who resume care following a missed appointment are at high risk of attrition. To increase retention, antiretroviral therapy clinics need to adopt a chronic care model which takes into consideration patients' changing needs and their preference for self-management.

Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans

Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies. Unfortunately, dog in vitro models allowing long term cultures are not available. The objective of the present manuscript is to describe the development of a co-culture dog model for predicting hepatotoxic drugs in humans and to compare the predictivity of the canine model along with primary human hepatocytes and HepG2 cells. After rigorous optimization, the dog co-culture model displayed metabolic capacities that were maintained up to 2weeks which indicates that such model could be also used for long term metabolism studies. Most of the human hepatotoxic drugs were detected with a sensitivity of approximately 80% (n=40) for the three cellular models. Nevertheless, the specificity was low approximately 40% for the HepG2 cells and hepatocytes compared to 72.7% for the canine model (n=11). Furthermore, the dog co-culture model showed a higher superiority for the classification of 5 pairs of close structural analogs with different DILI concerns in comparison to both human cellular models. Finally, the reproducibility of the canine system was also satisfactory with a coefficient of correlation of 75.2% (n=14). Overall, the present manuscript indicates that the dog co-culture model may represent a relevant tool to perform chronic hepatotoxicity and metabolism studies.