In Eritrea, highly centralized mental health care services and lack of trained psychiatric personnel at primary health care units remain a challenge to the mental health care system. These problems can be minimized by introducing screening programs with a simple screening tool for mental disorders in the primary health care settings. Thus, this study aimed to assess the validity of the WHO self-reporting questionnaire 20 (SRQ-20) in Tigrigna version for use in Eritrean primary health care setting.The SRQ-20 was translated into a local language (Tigrinya) in a process of forward and backward translation. SRQ-20 data were collected in a primary health care setting on 266 respondents. Internal reliability was tested using Cronbach’s alpha. Factorial validity was done using principal component analysis with varimax rotation to investigate whether SRQ-20 items properly measure the underlying dimensions of mental illness. Criterion validity was analyzed by looking at the relationship between the SRQ-20 and Brief Psychiatric Rating Scale using Pearson’s correlation coefficient. Sensitivity, specificity and the predictive values of the screening instrument were used to assess how well the results of SRQ-20 correspond with the criterion instrument.The SRQ-20 had good internal reliability (α = 0.78). Factor analysis yielded two factors, explaining 31.2% of the total variance. The instrument performed well in detecting common mental disorders, with an area under the curve (AUC) of 0.879  to the overall sample and with optimal cut-off score at 5/6 with sensitivity 78.6% and specificity 81.5%. Cut-off scores were different for women (5/6) and men (4/5). For male participants, the AUC statistic was 0.877  and 0.871 (SE = 0.02 95% CI 0.81–0.92) for female participants.The Tigrinya version of the SRQ-20 can be used for screening probable common mental disorders in Eritrean primary health care setting, but cut-off scores need to be adjusted for men and women separately. Common mental disorders refer to two main diagnostic categories: depressive disorders and anxiety disorders. These disorders impact on the mood or feelings of affected persons; symptoms range in terms of their severity (from mild to severe) and duration (from months to years). These disorders are diagnosable health conditions, and are distinct from feelings of sadness, stress or fear that anyone can experience from time to time in their lives. Anxiety disorders involve generalized mood condition involving feelings of uneasiness, being fearful or feeling nervous whereas depressive disorders have emotions that involve feeling low, sad, fed up or miserable , 2.Untreated mental disorders result in poor outcomes for co-morbid physical illness commonly seen in the primary health care settings. Moreover, patients with mental disorders have a heightened risk of suffering from physical illness because of diminished immune function, poor health behavior, non-compliance with prescribed medical regimens and barriers to obtaining treatment for physical disorders.The fundamental mental health facts report has underscored the seriousness and increasing prevalence of mental health problems, highlighting that, every week, one in six adults experience symptoms of a mental health problem . MoreoveMental illness is considered a silent epidemic throughout most parts of Africa. Because of structural and systemic barriers such as inadequate health care infrastructure, insufficient number of mental health specialists, and lack of access to all levels of care, mental illness has been characterized as a neglected and increasingly burdensome problem affecting all segments of the population throughout Africa. Prioritizing mental health has also been difficult due to lack of resources, limited funding coupled with absent or ineffective mental health policies .A recent national mental health survey conducted in Eritrea reports a common mental disorder prevalence rate of 14.5% in the general population . The 201In Eritrea, inequitable distribution of psychotropic drugs, highly centralized mental health care services to urban centers and lack of trained psychiatric personnel at primary health care units are some of the challenges the mental health program is facing . AccordiThe problems of low financial expenditure and inequity in distribution of mental health facility can be minimized by introducing psychosocial interventions especially screening program for mental disorder in the primary health care settings which are accessible and affordable to the general population. Considering the understaffed and undertrained personnel in primary health care settings of the country, the SRQ would play an important role in improving community’s mental health. The WHO SRQ-20 is not functional and has never been used in Eritrea. The culturally sensitive nature of the questionnaire and the language difference of settings necessitate adaption of the instrument locally. The SRQ is expected to help because it is a simple instrument, poverty friendly, timely and does not need a professional to administer; which is feasible in our country.There are many psychiatric screening instruments developed by the World health Organization (WHO). Nevertheless, these instruments are time-consuming and require trained personnel for administration either through interview or through self-administered questionnaire, being infeasible for use in the primary health care, which, often, are the target settings for screening and early detection of CMDs. This gives rise to the need of the self-reporting questionnaire (SRQ-20), a 20-item mental disorder screening instrument developed by WHO to be applied in patients attending primary health care settings . Trudy HThe SRQ-20 is an instrument with twenty simple to understand items which question respondents about symptoms and problems likely to be present in those with neurotic disorder. It includes binary (yes/no) questions only, with codes “1” which represents the presence of a symptom, and “0” if the symptom is absent. The SRQ-20 item questions reflect depression, anxiety and psychosomatic complaints, which are all together, grouped under the common mental disorder (CMD) and have been found to detect probable cases of it with satisfactory accuracy . HoweverTherefore, this study aimed to assess the validity of the WHO self-reporting questionnaire 20 (SRQ-20) item in Tigrigna version in Eritrean setting. Specifically, this study evaluated the psychometric properties, optimal gender specific cut-off points for detecting CMDs using SRQ as a screening tool and assessed the SRQ-20 items’ capacity to screen for mental disorder relative to the gold standard (BPRS).This study was carried out using a cross-sectional study design.This study was conducted from September to December 2017 in two urban health facilities selected using purposive sampling. The selected health facilities were Semienawi Asmara Health Centre (SAHC) and Godaif Community Hospital (GCH). The health facilities were selected purposively because they serve large number of population and are relatively representative of PHCs in Asmara in terms their location and socio economic diversity. Both health facilities provide primary health care services to their local population and refer to higher health services for specialized care and services.2 × P × Q/E2. The study respondents were recruited using a simple random sampling. Eligible participants included both male and female who were in the age range of 18–65 years and who were attending the selected health facilities at the time of data collection. Individuals were excluded from the study if they were medically unstable, if they required referral to a higher level of care, or were not willing to participate in the study.Sample size determination was done on the basis of an estimated common mental disorder prevalence of 50%, as there was no local study done before. At a 95% confidence interval, a total sample of 266 participants were selected using the Daniel and Macfarlane single proportion formula for finite population, n = ZIn addition to the demographic characteristics of the respondents such as age, gender, ethnicity, educational level and marital status, the measures utilized in our study include the WHO self-reporting questionnaire and Brief Psychiatric Rating Scale.The self-reporting questionnaire is based on the original 20 yes/no questions translated to Tigrinya which consists of 20 items indicative of non-psychotic mental disorders. The questions are related to certain pains and problems that may have bothered the participant in the last 30 days. If the participant thinks the question applies to him/her, then will answer as yes and the other ways it will be no. The translation of these questions included language experts. It was translated in the standard back and forth translation format.The Brief Psychiatric Rating Scale is a 24-item questionnaire that provides a clinical assessment of the interviewee’s psychiatric status and leads to a psychiatric diagnosis. Although yet to be validated, the BPRS item is frequently used in primary health care settings of Eritrea. However, the instrument has been used in a number of countries with similar context to Eritrea and its factor structure remains to be similar across studies . BPRS reThe WHO SRQ-20 was not functional and has never been used in Eritrea in Tigrigna version. The culturally sensitive nature of the questionnaire and the language difference of settings necessitate adaption of the instrument locally. Prior application of the SRQ-20, cross-cultural adaption  and determination of optimal cut-off scores should be performed . For thiPrior to the interview, each participant was informed about the confidentiality of the data collection process. They were assured that participation was voluntary, and could withdraw from the interview at any time. After fully describing the study objectives in a private room, consented respondents were separately interviewed from other patients for health related questions. The interview was conducted during day time to the patients in the waiting room for outpatient treatment. During the interview, the data collector explained that they will be asked health related questions but not exactly about mental health in order to reduce misleading answers. If the participant was required by the medical personnel in the OPD then the interviewer would temporarily suspend the interview and continue after the patient completed OPD visit.All data were analysed using SPSS  version 20.Reliability  of the SRQ-20 questionnaire was calculated using a reliability coefficient .Face validity of the Tigrigna version of SRQ-20 in the pilot study through asking the respondents to guess the aim of the questionnaire at the end of each interview.In this study, content validity was done through mental health professionals, psychiatric nursing experts and language experts to judge the content and semantic validity of the instrument after its translation to the local language, Tigrigna.To assess factorial validity, we used principal component analysis technique with varimax rotation to investigate whether SRQ-20 items measure properly the underlying dimensions of mental illness. The Kaiser–Guttman criterion was employed to extract factors with Eigen values above one , 23. TheThe relationship between the testing instrument, the SRQ and the criterion (the BPRS) was assessed using Pearson’s correlation coefficient. Moreover, sensitivity, specificity and the predicative values of the screening instrument were used to assess how well the results of SRQ-20 correspond with the criterion instrument (BPRS).The optimum cut-off scores were chosen with maximum sensitivity and reasonable specificity at various cut off points. The Receiver Operating Characteristics (ROC) analysis was performed to evaluate the screening properties of the SRQ-20, using BPRS as the gold standard. The Area under Curve (AUC) statistic was calculated as a measure of accuracy of the SRQ-20.In this study, out of the 266 participants, more than half were women , and about 70% were in the age group of 18–35 years. The mean age and standard deviation of the participants was 32 (± 11.09). Most of the study participants reached high school  and  were married. Tigrigna ethnic group was dominant over other ethnic groups (89%); this is because the setting was in Asmara city in which majority of its population is Tigrigna. Detailed information about demographic characteristics of the study participants can be referred in Table The prevalence of common mental disorders (CMDs) was calculated using the gold standard questionnaire (BPRS). Out of the 266 total samples, 60 (23%) respondents were diagnosed of CMD. For male and female respondents, 17% and 27% were diagnosed with CMD respectively.Cronbach’s alpha of 0.784 indicated good internal consistency.The Tigrigna version SRQ-20 demonstrated good face validity when examined in the pilot study. The participants responded well throughout the study as there were no non-respondent from the approached individuals. This 100% item-completion rate also indicated strong face validity of the Tigrigna-version SRQ-20. Moreover, majority of the participants in the pilot study correctly guessed the aim of the questionnaire and understood that the questions were designed to assess mental status.When translated to Tigrigna all 20 items of the SRQ questionnaire were examined by mental health professionals and psychiatric nursing experts to judge the content validity whether it could be able to detect mental health disorder. The translated version was piloted in twenty respondents to check for conceptual equivalence, acceptability and feasibility. Because of being offensive and sensitive issue, the 17th item was placed to be at the end of the questionnaire. The translation did not change the ability of the questionnaire to detect the symptoms of CMDs. Moreover, some questions were modified to meet the cultural context, in which direct translation of word for word yielded meaningless and deviated understanding of the item. For example, item 7 says, “Is your digestion poor?” which the word “poor” indicates weak. Another question item19, “uncomfortable feeling in the stomach” cause misunderstanding for expecting other feelings rather than common bowel disorders like indigestion, constipation or epigastric pain Tables .Table 2TA principal components analysis (PCA) was conducted on the SRQ-20 data with varimax rotation. The tests of suitability for PCA indicated that this analysis was appropriate. The Kaiser–Meyers–Olkin (KMO) test result of 0.774 confirmed the sampling adequacy for the procedure. Bartlett’s test of sphericity was significant indicating that it was appropriate to perform a PCA.Using a combination of the Kaiser–Guttman criterion and the scree plot method we decided to extract two factors for the entire sample which explained 31.2% of the variance in the sample. We labeled these constructs factors into 1 and 2. Factor 1 included difficulty thinking clearly, tired easily, always tired, worthlessness, unhappy feeling, excessive crying, shaking hands, uncomfortable stomach, work suffering, difficulty in decision, stress simply, headache, fear easily, sleep badly, indigestion after eating, poor appetite and suicidal thought. Factor 2 included: difficulty in thinking, tired easily, always tired, worthlessness, stress simply, headache, loss of interest, difficulty in social interaction and suicidal thought. Other items were excluded from both factors as they had low factor loadings (see Table Both the gold standard questionnaire (BPRS) and the screening instrument Tigrigna version of the SRQ-20 were found to be moderately correlatedr = 0.537) but statistically highly significant with a p-value of < 0.001. As shown in Fig. 7 but staIf the SRQ-20 is to be effective in detection of CMDs, it should have a balanced high sensitivity and specificity with optimum cut-off point scores obtained through the ROC analysis. This balance was achieved at 5/6 optimal local cut-off point with sensitivity 78.6% and specificity 81.5% for the overall sample in our study. There exhibits a difference in the optimal cut-off between male 4/5) and female (5/6) respondents  and negative predictive values (NPV) of the Tigrigna version SRQ-20 were also calculated. The NPV, 92.8% is considered good indicating high ability of CMD non-cases detection and PPV was found to be 55.3%.These are the measures of determining the validity of the scale for screening of the PPD.This study aimed to validate the SRQ-20 item in Eritrean primary health care settings. In the overall sample, male to female ratio was almost proportional. Most of the respondents were in the age range of 18–25 years, married, Tigrigna ethnicity and middle-schooled. As can be inferred from the findings, the SRQ-20 item was found to have a substantial capacity for screening of common mental disorders in Eritrean primary health care settings. The cut-off scores for the SRQ-20 differed by gender.In the present study, the prevalence of CMDs in the overall sample was found to be 23%. Many epidemiological studies conducted in primary health settings identify mental disorder using screening instruments or clinical diagnosis . Since tMajority of the CMD cases in our study were females when compared to their male counterparts. This is similar to findings from other studies done in Ethiopia and Malawi –29. The In our study, we found good internal consistency of α = 0.78, almost similar with findings in China (α = 0.79) , but sliSimilar with other studies, the findings from the present study indicates that the SRQ-20 item is a useful tool in Eritrean primary health care settings. In this study, the area under the ROC curve statistic was 0.87. This result is consistent with findings from other countries’ primary health care settings where the area under the ROC curve ranged from 0.76 in Rwanda to 0.92 in Uganda , 32. In In this study, the balanced sensitivity and specificity was achieved at the higher cut-off score of 5/6 for women, as compared to the 4/5 cut-off score for men. For overall sample, an optimal local cut-off, 5/6 was found to balance the trade-off between sensitivity and specificity at 78.6% and 81.5% respectively. This is almost similar with a study conducted in the UAE were a cut-off score of 5/6 produced a balanced combination of sensitivity and specificity of 78.3% and 75.2%, respectively . StudiesAlthough the study has come up with important findings, due to some limitations, the findings should be interpreted with caution. As the translated version of SRQ-20 is in Tigrigna, other language speakers from different ethnic groups may not be beneficiaries of the instrument and limited diversity in the ethnicity of the participants may not represent and generalize the result of the current study to all Eritrean communities.The findings of the study have good implication for addressing the issue of screening for common mental disorders in primary health care settings. Here, the SRQ-20 item has been found to be suitable in primary a health care setting which is simple, easy to administer and with a yes/no questionnaire which is convenient for the interviewer and the respondents. Due to resource-poor conditions with ineffective means of detecting CMDs in Eritrea, the Tigrigna-version SRQ-20 item is expected to contribute in reducing the prevalence and burden of CMDs through its simplicity, acceptability and feasibility.The Tigrigna-version SRQ-20 is a valid and reliable instrument which has the capacity to detect cases of CMDs in cost-effective manner. The use of the SRQ-20 is recommended for use in the PHC settings for screening probable common mental disorders in Eritrea.


Type 2 diabetes mellitus (T2DM) is a disease associated with dysfunctional metabolic processes that lead to abnormally high levels of blood glucose. Preceding the development of T2DM is insulin resistance (IR), a disorder associated with suppressed or delayed responses to insulin. The effects of this response are predominately mediated through aberrant cell signalling processes and compromised glucose uptake into peripheral tissue including adipose, liver and skeletal muscle. Moreover, a major factor considered to be the cause of IR is endoplasmic reticulum (ER) stress. This subcellular organelle plays a pivotal role in protein folding and processes that increase ER stress, leads to maladaptive responses that result in cell death. Recently, zinc and the proteins that transport this metal ion have been implicated in the ER stress response. Specifically, the ER-specific zinc transporter ZIP7, coined the “gate-keeper” of zinc release from the ER into the cytosol, was shown to be essential for maintaining ER homeostasis in intestinal epithelium and myeloid leukaemia cells. Moreover, ZIP7 controls essential cell signalling pathways similar to insulin and activates glucose uptake in skeletal muscle. Accordingly, ZIP7 may be essential for the control of ER localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to IR. Accordingly, understanding the mechanisms of ZIP7 action in the context of IR may provide opportunities to develop novel therapeutic options to target this transporter in the treatment of IR and subsequent T2DM.  The prevalence of obesity has become pandemic due to an increasing obesogenic environment including poor nutrition and lack of exercise. The consequences of increased weight gain and obesity can result in the most devastating complications of type 2 diabetes mellitus (T2DM) . The aetIR is a systemic disorder that is broadly defined as the compromised ability of insulin to regulate glucose homeostasis in peripheral tissues. IR affects all cell types and is asymptomatic and therefore this makes it extremely difficult to treat and prevent . Long-teA major factor in the pathogenesis of IR is endoplasmic reticulum (ER) stress. This is a condition where the ER becomes dysfunctional due to an imbalance of influx of nascent unfolded polypeptides exceeding the normal processing capacity of the ER . This reWhile research to elucidate mechanisms implicated in ER-stress and IR are ongoing, recent studies have identified a role for zinc and the protein transporters of this metal ion in ER stress and apoptosis . Zinc isT2DM is a devastating disease characterized by IR and pancreatic beta cell failure ,19. IR iInsulin acts on multiple cellular processes that essentially provide an integrated molecular response to maintain glucose homeostasis between nutrient supply and demand . In normIn IR, target cells that have a high metabolic demand for glucose   fail to It is well established that ER stress is a major contributor to many disease states including obesity, IR and T2DM ,30  and 39A (SLC39A)  that plaThe SLC30A family of zinc transporters are part of the vertebrate cation diffusion facilitator proteins that are made up of three subgroups based on the cation they transport, namely Zn, Zn/Fe and Mn. In mammals, ten SLC30A are described (named ZnT1–ZnT10)  all of w2+, Mn2+ and Fe2+ and are involved in the transport of these ions across membranes [The solute carrier family 39A (SLC39A) of zinc transporters, increase cytosolic zinc by transport of this metal ion into the cell via the plasma membrane or from subcellular organelles . In mammembranes ,42.The importance of the zinc transporter family is highlighted by the numerous functions of these proteins in many disease states ,44,45,46Zinc is a vital trace element that is crucial for its role in supporting normal physiological function and cellular homoeostasis. As a divalent cation, zinc has numerous roles in catalytic , cell reIntracellular “free” zinc is sequestered within organelles such as the ER, Golgi and mitochondria with little “free” zinc found within the cytoplasmic , therebyWithin organelles and vesicles, the concentration of zinc is thought to range between tens and hundreds of micromolar ,57,58. UThe dysfunctional regulation of zinc homeostasis and associated pathophysiology has been studied extensively. While these have been covered succinctly in other reviews ,40,46,63Zinc plays a major role in embryonic, foetal and postnatal development in higher eukaryotes . Zinc-deA range of neurodegenerative conditions has also been observed in patients with altered expression of zinc transporters ,74. For Of the zinc transporters, perhaps the most well-studied is ZnT8. This transporter is predominately expressed in the endocrine pancreas and specifically enriched in the β-cells . ZnT8 coSimilarly, a Diabetes Prevention Program study that enlisted 3234 USA participants at high risk of developing T2DM were screened for the ZnT8 rs13266634 SNP. Of the 3007 participants that were genotyped, it was found that the C risk allele was significantly associated with elevated proinsulin levels . DespiteRecently, twelve rare ZNT8 truncated (loss-of-function) variant proteins were identified in a large population across five ethnicities that conferred a 65% reduced risk of T2DM . Of the ZnT8 is also a major autoantigen in the development of autoimmunity in type 1 diabetes (T1DM) . AutoantThe remainder of this review will address the importance of zinc, ZIP7, ER stress and insulin resistance. Where possible, extrapolation from other zinc transporters will be discussed where there is a direct link between ER stress and/or IR.C. elegans [The endoplasmic reticulum is of interest as it acts as a mobilizable zinc store with concentrations of this metal exceeding 5 nM . The ER  elegans  and from elegans . Alterna elegans , neurode elegans ,98 and c elegans . The overarching function of the UPR is to relay the protein-folding status in the ER  (and refRecently, zinc and the transporters of this metal ion were shown to be involved in the development of ER stress ,10,12,13Within the cytoplasm, zinc is managed by the transport and subsequent sequestering of zinc from the cytosol into subcellular stores or labile cytoplasmic zinc is bound up with special metal ion binding proteins called metallothioneins . AccordiAccordingly, dysfunctional regulation of the zinc transporter proteins and the decompartmentalization of intracellular zinc, through initial ER stress events or other factors that involve zinc transporter-mediated ER stress might exacerbate this condition leading to the UPR and apoptosis. For example, recent studies in mice suggest that dietary zinc is essential of ER stress-induced apoptosis . Mice chZIP7 has been extensively studied in a number of cell-based systems and animal studies. It is most documented for its role in cancer studies. For example, ZIP7 is upregulated in human cervical and colorectal cancer cells and silencing of ZIP7 suppressed cell proliferation, migration and invasion of these cells and induced apoptosis ,115. ZIPZIP7 like all SLC39A members, share many conserved regions predominantly within the TMDs and histidine-rich motifs found within the LIV-1 sub-group. The N-terminal region of many LIV-1 members harbours several histidine residues however, ZIP7 has a statistically significantly high proportion of histidine within the N-terminal region relative to the SLC39A family . The funZIP7 is unique in that it is localized to the early secretory pathway including the ER and Golgi apparatus and functions as a zinc “gatekeeper” that tightly controls the movement of zinc from these subcellular organelles into the cytosol in what is termed the zinc “wave” the . These sZIP7 was shown to be critical for maintaining ER homeostasis in MG-63 osteosarcoma cells . These sThese results for ZIP7 are further support by studies in intestinal epithelial cells where zinc transporter is implicated in ER homeostasis . These sWhile several recent studies have emerged linking ZIP7 to ER homeostasis and ER stress, other zinc transporters are now sharing some attention. For example, ZIP14 was shown to be critical for zinc uptake in liver and adaptation to ER stress . In thisUnderstanding the role of ZIP7 in glucose homeostasis and subsequent IR and T2DM is currently limited by existing studies and a lack of suitable animal models, although some extrapolation from cell-based studies and other related disease states may help elucidate a role for this zinc transporter in controlling glucose homeostasis. Previously it was identified that ZIP7 mRNA was elevated in response to glucose in mouse pancreatic islets . SimilarInsulin resistance is a condition in which an organism fails to respond to endogenous insulin. Consequently, glucose uptake is compromised in tissues such adipose and skeletal muscle. IR is associated with the development of type 2 diabetes mellitus which accompanies several pathological conditions including obesity, cancer and neurodegenerative disease. Despite years of research, there is still great uncertainty regarding the molecular mechanisms of IR. Human gene mutations in insulin signalling pathways trigger IR, however most IR people do not harbour these mutations, so attention has focused on other causes of IR, including endoplasmic reticulum stress.The ER plays a significant role in protein homeostasis through its functions related to the synthesis, folding and transport of proteins. Data supporting the contribution of defective insulin signalling in the development of ER stress-linked IR is strong, however the molecular mechanisms by which this effect occurs is lacking. ER stress triggers a signalling cascade known as the UPR, an acute mechanism that aims to re-establish cellular homeostasis through adaptive programmes that improve protein-folding processes. Recently, a supporting role for the zinc transporter ZIP7 has suggested that this protein ameliorates ER-stress in heart muscle cells through ER-mediated zinc flux and therefore has a protective role against oxidative stress and IR. The spatiotemporal regulation of ER-mediated zinc flux is tightly maintained by ZIP7 and studies that delineate the molecular mechanisms whereby ZIP7 protects the ER from oxidative stress and subsequently ameliorates IR will have enormous therapeutic utility for the development of novel drugs targeting this transporter.


Exercise intolerance is the first symptom of heart disease. Yet an objective and standardised method in canine cardiology to assess exercise capacity in a clinical setting is lacking. In contrast, exercise testing is a powerful diagnostic tool in humans, providing valuable information on prognosis and impact of therapeutic intervention. To investigate whether an exercise test reveals differences between dogs with early stage mitral regurgitation (MR) and dogs without cardiac disease, 12 healthy beagles  and 12 dogs with presymptomatic MR  underwent a six-stage submaximal exercise test (ET) on a motorised treadmill. They trotted in their individual comfort speed for three minutes per stage, first without incline, afterwards increasing it by 4% for every subsequent stage. Blood samples were taken at rest and during two 3-minute breaks in the course of the test. Further samples were taken after the completion of the exercise test and again after a 3-hour recovery period. Measured parameters included heart rate, lactate and the cardiac biomarkers N-terminal pro-B-Type natriuretic peptide and cardiac Troponin I. The test was performed again under the same conditions in the same dogs three weeks after the first trial to evaluate individual repeatability. Cardiac biomarkers increased significantly in both HG and PG in the course of the test. The increase was more pronounced in CHIEF B1 / B2 dogs than in the HG. N-terminal pro-B-Type natriuretic peptide increased from 435 ± 195 to 523 ± 239 pmol/L (HG) and from 690 to 815 pmol/L (PG). cTnI increased from 0.020 to 0.024 ng/mL (HG) and from 0.06 to 0.08 ng/ml (PG). The present study provides a method to assess exercise-induced changes in cardiac biomarkers under clinical conditions. The increase of NT-proBNP and cTnI is more pronounced in dogs with early-stage MR than in healthy dogs. Results indicate that measuring the parameters before and after exercise is adequate and taking blood samples between the different stages of the ET does not provide additional information. Also, stress echocardiography was inconclusive. It can be concluded that exercise testing, especially in combination with measuring cardiac biomarkers, could be a helpful diagnostic tool in canine cardiology. Exercise intolerance as the first symptom of mitral regurgitation (MR) in dogs evolves slowly and progressively and therefore often stays unnoticed until symptoms like coughing occur during exercise . In ordeAlthough potentially providing plenty of information, ET are not used routinely in clinical cardiology in dogs. The main reasons for this are the absence of a standardised objective testing method and the fact that dogs vary immensely in regard to size and breed. However, submaximal ET have been used in studies in dogs. Considerable limitations for clinical use have been the implementation of invasive measurement methods –10 or thHealthy dogs use their functional reserves in response to exercise by increasing sympathetic activity in combination with a vagotonic decrease. This leads to an increase in cardiac output, which is predominantly dependent on heart rate (HR) , 14. BeiThe cardiac biomarkers NT-proBNP and cardiac troponin I (cTnI) are promising parameters for canine cardiology, yet they are mostly used for research purposes, as solid characterisations for the use in a clinical setting are lacking , 20. ResNT-proBNP and its mature form B-type natriuretic Peptide (BNP) are markers of cardiac wall stress . They caUsually indicating myocardial damage , cTnI alAs patient classification in canine cardiology is based solely on results of clinical examinations at rest, it remains unknown whether ET in dogs with presymptomatic MR is suitable to detect early onset of exercise intolerance and might therefore provide additional information on the patient’s current status and the prognosis. Thus, the purpose of the present study is to investigate if results of a submaximal ET in dogs with presymptomatic MR differ from a healthy control group with particular focus on the exercise-induced changes in the cardiac biomarkers cTnI and NT-proBNP.This study was approved by an institutional ethics commission .All dogs underwent physical examination, blood count and serum biochemical analysis, urinalysis, electrocardiogram and echocardiography. The dogs were included if there was no evidence of a systemic or orthopaedic disease which could affect exercise performance on the treadmill or influence biomarker concentration . Further inclusion criteria were absence of any history of cardiac symptoms or medication.Twelve healthy beagle dogs aged 3 ± 2 (mean ± SD) years served as a healthy control group (HG). The dogs weighed 13 ± 3 kg and had a body condition score of 4–7. The group consisted of 3 neutered females, 5 intact and 4 neutered males. The Beagles were obtained from university institutes  or from a breeder for use in research . The dogs were raised in the clinic for small animals at the University of Veterinary Medicine, Hannover, foundation. They lived in pens in groups of a maximum of 6 dogs with daily access to a separate open-air area. They were fed commercial dry food for adult dogs twice daily according to the manufacturer’s instructions and had unlimited access to water.Twelve dogs of various breeds with a typical heart murmur of at least grade 1/6 over the mitral valve area  were also enrolled in this study . Owners Every dog was examined by an experienced cardiologic investigator using an ultrasound system .The HG and 3 dogs of the PG additionally underwent stress echocardiography. They were positioned in right lateral recumbency for image acquisition. Stroke volume was calculated according to Teichholz and the Simpson method of disks , 38. FurThe exercise test consisted of a 6-stage protocol on a motorised treadmill  with a duration of three minutes per stage, starting with 0% incline, increasing by 4% at each stage. The stages and measurements are summarised in Each dog trotted at its individual comfort speed, which was defined as the speed at which the dogs trotted freely in a steady and clear 2-beat movement without trying to brake or accelerate for at least 30 seconds. This speed was used in all treadmill examinations. To ensure a minimal workload, heart rate (HR) at stage 2 had to exceed 150 beats per minute (bpm) or be raised by 40% compared to values obtained at rest. To ensure that the exercise remained submaximal, the maximal HR was 240 bpm . In caseThe dogs were familiarised with the treadmill prior to the first trial. The duration of each session was less than 10 minutes including multiple breaks. All dogs rested for at least 15 minutes before venous blood samples for baseline measurements were taken.Room temperature was kept between 21 and 23 °C during all ETs to ensure the same ambient conditions. Each dog from the HG and 9 dogs from the PG underwent the ET with the same individual speed twice at an interval of 3 weeks to verify the repeatability of the measured parameters. Due to various outliers in the first trial, one dog of the HG was retested 8 weeks after the second trial and the first trial’s results were discarded. Another dog of the HG was playing intensively with other dogs in the pen shortly before samples were taken at recovery, so the data for that time point were also excluded from analysis for that day.® heart rate monitor with an electrode belt . It was obtained by averaging 5 consecutive values that were recorded during the last 30 seconds of each stage of exercise (during trotting) and at rest directly before the ET.Blood was collected from the vena saphena or vena cephalica antebrachii. RF was determined by counting the number of chest rises at rest, after stages 2, 4, after the end of the ET and at recovery. In case of panting, values were not recorded. HR was measured constantly by a Polar2 and PCO2) analysis and acid-base status (pH and bicarbonate) were taken anaerobically and stored on ice until analysis took place within a 10 minute timespan . Samples for lactate assessment were inserted into tubes containing fluorid heparine and measured immediately in a clinical chemistry analyser .Blood samples for oxygen and carbon dioxide partial pressure  were excluded from analysis for the time points after termination (except for cTnI and NT-proBNP). The data of the first trial are presented as mean ± standard deviation. The data or their residuals, respectively, were tested for normal distribution by a Shapiro-Wilk test.The values obtained on the first and second trial were compared using the intraclass correlation coefficient (ICC) with a 95% confidence interval . An ICC > 0.7 indicated repeatability of the data .Differences in the measured parameters were analysed using a one-way repeated measures analysis of variance (ANOVA) with Tukey’s honestly significant difference post hoc test. For parameters with only 2 time points (NT-proBNP and cTnI), a paired t-test was used. Values from the HG were compared with the values from the PG using a 2-sample t-test. Results were regarded as significant, if the P-value was ≤ 0.05.The submaximal ET was easy to perform and every dog was willing to run on the treadmill. All 24 dogs underwent the ET at a speed of 4.2 to 8 km/h and none of the ET had to be terminated due to an excessive increase of HR. Each dog showed increases of HR above 150 bpm or raised their resting HR by at least 40% at stage 2, indicating that the criteria for a minimum workload were met. One dog from the HG and 2 dogs from the PG refused to exercise further than stage 5 in both trials. With another dog from the HG, the test had to be stopped due to technical difficulties at stage 5 in the first trial.Significant differences between healthy and CHIEF B1 / B2 dogs were apparent in CB and in some other parameters (see below) but not at every level of exercise.In NT-proBNP increased by 124 pmol/l (P ≤ 0.01) after exercise in the PG , which wcTnI increased by 0.004 ng/ml  and 0.02 ng/ml . Values were higher in PG than HG at rest  and at recovery  and the increase of cTnI was more pronounced in the PG (P ≤ 0.05).Pre and post-exercise values of NT-proBNP showed excellent repeatability in both groups. cTnI in the PG also yielded a high ICC. Also the quotient of recovery to resting values of cTnI in the HG was 0.69 when all the data were analysed and 0.8 when data from the 2 dogs that did not undergo the whole ET were excluded.HR was significantly (p ≤ 0.001) higher at any level of exercise than at rest  and yielInitially lactate decreased but further workload led to an increase . After tValues for pH barely changed during the ET  but showBicarbonate showed an initial increase and then decresed with further workload. It was significantly higher in PG than in HG before (22.7 vs. 21.0 mmol/l) and after exercise (22.7 vs. 22.3 mmol/l).Due to panting in response to exercise, the respiratory frequency did not reveal any relevant information. Blood gases were measured from venous blood samples, therefore showed a great variation.The HG showed no evidence of heart disease in the sonographic examination.MR in the PG was confirmed by colour Doppler echocardiography, indicated by a regurgitant jet during systole at the mitral valve. Two of the 12 dogs in the PG were classified as CHIEF B2 and the remaining 10 dogs were staged CHIEF B1 based on the results of echocardiography [The submaximal ET investigated in the present study introduces a method for assessing the physiological reaction of selected cardiovascular parameters under predefined exercise conditions in healthy dogs and dogs with presymptomatic MR (CHIEF B1 / B2). It yielded workload-dependent alterations in the parameters lactate, bicarbonate, HR, pH, cTnI and NT-proBNP and can be performed in a clinical setting. The most promising results include assessment of cardiac biomarkers.Measuring the parameters at different stages of exercise revealed that significant changes occur predominantly between resting values and values after the last stage of the ET. They showed better repeatability than those values, which were measured during the exercise protocol. Therefore it can be concluded, that it is reasonable to abandon blood sample collection between stages and instead measure blood parameters before and after exercise only. However, it is important to observe HR continuously to register values above a submaximal level and ensure a minimal workload.Although CB concentration can be influenced by age, this can be due to decreased renal function  that migNT-proBNP concentrations vary immensely between breeds and also show a great intrabreed variation , 23. TheBlood sampling has to be performed twice for assessment of resting and exercise CB, but the results of this study indicate, that the diagnostic benefit of the procedure justifies the additional effort. The baseline measurement can also serve as a control value for future examinations. Testing resting values has become an important aspect of daily clinical cardiology in small animal patients and increased CB levels can indicate a variety of diseases of cardiac- or non-cardiac cause. Still, it has been shown, that resting values of NT-proBNP vary between different breeds and also within an individual . Also, bTo the best of our knowledge, this is the first study that demonstrates the impact of MR on differences in CB serum concentrations after submaximal exercise by directly comparing the post-exercise values of healthy dogs to patients with presymptomatic MR. Significant mild increases of cTnI have already been reported in healthy dogs after sled races –33, wherResults in the PG showed a better repeatability for every parameter than in the HG, which might be due to a decreased metabolic flexibility that has been shown for older men , becauseLactate accumulation tended to be increased in the PG compared to the HG, but a significant difference was only found 3 hours after exercise. A study showed that acute congestive heart failure leads to increased baseline lactate levels in dogs and cats . ClearlyPerforming stress echocardiography was not successful in our study. The main reason for this is most likely the delay between ET and image acquisition, which occurred while the dog was taken from the treadmill to the sonography table and prepared for sonography, because HR decreased rapidly in this time. Other studies implemented a dobutamine infusion for cardiac stress testing , 53, butDuring exercise, the cardiac output is increased predominantly by an increase in HR, which is the only parameter that can be easily monitored telemetrically and indicates the strain of the exercise on the dog . MeasureTherapeutic intervention using vasoactive medication in dogs with presymptomatic MR (stage CHIEF B1 / B2) is controversially discussed , 55. A rOwners see quality of life as an even more important factor than survival time, and therefore, improvement of quality of life is an important goal to be reached by therapeutic intervention . As qualMeasuring the parameters before and after exercise is adequate and blood sampling between the other stages did not provide any additional information in our study. However, continuous HR measurement is obligatory. Parameters, that provide the most promising results include CB. cTnI differentiated better between the HG and PG, but NT-proBNP has been shown to be helpful in human patients in long-term investigations , 7, therLimitations of the present study include differences of breed, housing and age between the groups, although the exercise-induced increase of CB might not have been affected by these factors, contrary to the baseline values.The present study is the first approach to assess several parameters of cardiac health in a submaximal ET on a treadmill comparing healthy and dogs with presymptomatic cardiac disease. It can be easily performed in a clinical setting and can also serve as a basis for further studies, especially for observations of therapeutic interventions. Results showed an exercise-induced, significant increase of CB NT-proBNP and cTnI in dogs with early-stage MR, which is more pronounced than in healthy dogs. Though further studies are necessary to assess the impact of age and breed on the results and also to determine corresponding reference values, the submaximal ET presented in this study seems suitable as a new tool in canine clinical cardiology. It could provide additional value regarding prognosis and therapy as exercise tests have shown to do in human patients –4.


Strategies to improve hypertension control are clearly warranted in light of the frequently expressed view that only 50% of treated hypertensive patients are able to meet their target blood pressure levels.While data from the USA has shown improved control over recent years , a study1In primary-care, public-sector facilities in South Africa, special efforts to improve hypertension management have shown that 68% of patients treated for their hypertension can achieve their targeted blood pressure levels.Reducing the cardiovascular and renal consequences of hypertension is dependent on sustained, long-term blood pressure control, implying that patient compliance is also a key factor for success. The physician’s choice of effective therapy will take this aspect fully into account and he/she will adopt approaches that will sustain patient compliance.Modern therapeutic agents that block the renin–angiotensin–aldosterone system (RAAS) and protect target organs without causing compliance-reducing symptoms should be the first choice in at-risk patients with hypertension.Once-a-day dosagePatients typically prefer to take their medication in the morning as part of their everyday routine. Compliance is improved by once-daily medication and physicians are keen to ensure that the prescribed antihypertensive medication meets the criteria of full 24-hour control and provides cover for the early morning rise in blood pressure. This rise in blood pressure is due to both orthostatic changes and the circadian rhythm of the RAAS system. It is also linked to an increased risk of cardiovascular events during the early morning hours.3Accurate assessment of blood pressure control is determined by self-measurement of blood pressure or by automated ambulatory 24-hour measuring devices. The MICARDIS Community Access Trial of Telmisartan in the primary-care setting (MICCAT-2)4 study showed that telmisartan alone or in combination with HCTZ produced significant reductions in blood pressure, which extended into both day and night time. Telmisartan reduced systolic and diastolic blood pressure (SBP/DBP) by 17.2/10.ARB efficacy versus ACE inhibitorsARBs are a good choice for hypertensive patients with the metabolic syndrome (associated obesity) and there are compelling indications for their use in postmyocardial infarction, left ventricular hypertrophy, chronic kidney disease, type 2 diabetes with microalbuminuria or albuminuria for ACE-intolerant patients and for the secondary prevention of stroke.Telmisartan provided more effective blood pressure lowering in this study and was particularly more efficient in the last six hours of the 24-hour dosing interval. Similar results were obtained by PRISM-2, which was conducted in the USA and Canada. A pooled analysis of both trials also showed a greater blood pressure lowering with telmisartan (–14.1/–9.6 vs –11.1/–7.2 mmHg).Telmisartan is the only ARB that has demonstrated therapeutic equivalence to the ACE inhibitor ramipril in hypertensive patients at increased vascular risk. The patient population in this study (ONTARGET) is of particular interest as it is representative of the majority of hypertensive patients seen in everyday clinical practice.The findings from this study showed that telmisartan 80 mg per day was as efficacious as the proven dosage of ramipril (10 mg/day) in reducing risk of cardiovascular death, myocardial infarction, stroke and hospitalisation for heart failure in a broad cross section of highrisk cardiovascular patients. It achieved these results with far fewer side effects, resulting in significantly fewer patients discontinuing therapy.Choosing telmisartan over other ARBs: the evidencePharmacological evidence of telmisartan’s efficacy in terms of blocking the angiotensin II type 1 receptor is accumulating. A recent Japanese study of constructed models of ARB molecules has found that the delta lock structure of telmisartan offers a superior fit to the receptor, compared to the other ARBs.10bChoosing the combination of telmisartan + HCTZBlood pressure control in some patients is ineffective with just monotherapy, and combinations of antihypertensive agents offer an opportunity to intensify treatment without adding to the pill load.In African patients where there may be evidence of less involvement of the RAAS system, the initial choice in the public sector is often a diuretic. A recent study in KwaZulu-Natal looked at prescribing habits in 54 public-sector hospitals in this region and compared this to supply data and to the SA Hypertension Guidelines.11It found that the most commonly used agents were diuretics (42%) and ACE inhibitors (27%) and that these prescriptions correlated well with supply data for these frequently used medications. Calcium channel blockers and beta-blocker usage was 6% each.Clearly, as ARBs become more available in the public sector, the opportunities offered by the combination of telmisartan and HCTZ should receive wider use. Publicity given to the lack of dialysis facilities for kidney failure in the public sector in South Africa should also add to the imperative to improve hypertension control.The blood pressure of patients who are at particular risk of cardiovascular disease, such as those who are obese or have type 2 diabetes, are often difficult to control. The SMOOTH study (Study of Micardis on Obese/Overweight Type 2 diabetes patients with HypErtension) showed the superior effect of telmisartan 80 mg plus HCTZ 12.5 mg, compared to valsartan 160 mg plus HCTZ 12.5 mg over 24 hours and especially in the early morning period.12The elderly patient also frequently falls into a difficult-to-treat category. A study in this patient group recruited 1 000 patients over the age of 60 years with isolated systolic hypertension and compared control between telmisartan plus HCTZ and amlodipine plus HCTZ. Referred to as the ACTOS study,A recent evaluation of more than 48 000 patients taking either a diuretic of a fixed-combination antihypertensive with a diuretic showed greatly improved compliance with the fixed combination . The fixed combination of the ARB/HCTZ achieved improved persistence and adherence to therapy even over the ACEI/HTCZ.The wider use of telmisartan in moderate hypertension as an early therapy can be substantiated at both a pharmacological and clinical level.


Link4Health, a cluster-RCT, demonstrated the effectiveness of a combination strategy targeting barriers at various HIV continuum steps on linkage to and retention in care; showing effectiveness in achieving linkage to HIV care within 1 month plus retention in care at 12 months after HIV testing for people living with HIV . In addition to standard of care, Link4Health included: 1) Point-of-care CD4+ count testing; 2) Accelerated ART initiation; 3) Mobile phone appointment reminders; 4) Care and prevention package including commodities and informational materials; and 5) Non-cash financial incentive. Our objective was to evaluate the cost-effectiveness of a scale-up of the Link4Health strategy in Swaziland.We incorporated the effects and costs of the Link4Health strategy into a computer simulation of the HIV epidemic in Swaziland, comparing a scenario where the strategy was scaled up to a scenario with no implementation. The simulation combined a deterministic compartmental model of HIV transmission with a stochastic microsimulation of HIV progression calibrated to Swaziland epidemiological data. It incorporated downstream health costs potentially saved and infections potentially prevented by improved linkage and treatment adherence. We assessed the incremental cost-effectiveness ratio of Link4Health compared to standard care from a health sector perspective reported in US$2015, a time horizon of 20 years, and a discount rate of 3% in accordance with WHO guidelines.[Using a threshold of <3 x per capita GDP, the Link4Health strategy is likely to be a cost-effective strategy for responding to the HIV epidemic in Swaziland. Swaziland has the highest prevalence of HIV in the world. With a population of 1.1 million persons, Swaziland has an estimated adult age 18–49 years) HIV prevalence of 31% and an estimated HIV incidence of 2.4%.9 years H However,In order to garner the individual and societal benefits from ART, HIV-positive individuals must achieve all steps of the HIV care continuum.–11 The cplus retention in care at 12 months after HIV testing for people living with HIV (PLWH) in Swaziland .).The largest portion of program costs was incurred through ART treatment costs, followed by outpatient care, and the cost of CD4+ count testing. Therefore, there is potential to reduce the cost of the HIV treatment program through reductions in the cost of outpatient care and CD4+ count testing as HIV programs shift to differentiated models of care in which stable HIV patients on ART may decrease the number and or frequency of clinic visits and universal ART initiation replacing the need for CD4+ count testing. For example, in some resource-limited settings, patients who achieve viral suppression and are clinically stable receive ongoing HIV care, including medications, in community adherence clubs, which decrease the number of clinic visits., 69 The Our analysis has a number of limitations. First, because of the compartmental nature of the transmission model, the effect on retention in care was represented through improvement of ART adherence and does not account for the other potential benefits gained such as access to other clinical assessments and health counselling. As a result, our analyses may underestimate the total health benefits generated by the Link4Health strategy. Second, the analysis included the same strategy costs for all individuals enrolled in the study, including those that did not ultimately receive the full intervention. This, however, likely overestimates the total cost of implementation as individuals not in HIV care would not incur the full strategy cost. Similarly, we assumed that HIV care visit costs would be the same for patients both on ART and those not on ART. In practice, however, these costs may differ due to factors such as the professional level of the healthcare worker. These differences in visit costs, however, are likely to be negligible when the cost ART treatment is considered. Third, not all model inputs were available for a Swazi-specific setting, which may impact cost-effectiveness. During model validation, the model was permitted to fit some indicators better than others in order to avoid overfitting to a particular data source. The robust cost-effectiveness results across sensitivity analyses, however, indicate that minor variations in these inputs are unlikely to substantially affect the results. Fourth, the Link4Health strategy was carried out in a population that has high prevalence of HIV compared to other countries in the world. Consequently, our results may not be applicable to other populations. Further testing is needed to investigate the Link4Health strategy’s effectiveness in populations outside of high HIV prevalence countries and contexts. Fifth, the nature of the Link4Health trial, which examined the implementation of a package of interventions together and did not isolate the impact of each component separately, made this analysis unable to estimate how each component individually affects the cost-effectiveness of the combined strategy. Similarly, due to the model structure it is not technically feasible to separate how annuals costs will accrue for each relevant budget holder. Finally, it is worth noting that the use of a cost-effectiveness threshold of <3 x per capita GDP, while transparent and easily applied, is insufficient to determine whether an intervention should be implemented. The more relevant cost-effectiveness threshold would be the incremental cost-effectiveness ratio of simultaneously resource constrained interventions, as the health gained from any additional funds allocated towards on Link4Health would likely exceed the health lost from removing funds from other interventions.The scale-up of the Link4Health strategy would substantially reduce HIV-related deaths and avert new HIV infections. With a favorable value over a 10 year timeframe or longer, using a threshold of <3 x per capita GDP, the Link4Health strategy could be a cost-effective strategy for confronting the HIV epidemic in Swaziland and other low-income countries with a generalized HIV epidemic. Efforts to strategically reduce strategy costs could lead to Link4Health being a highly cost-effective HIV intervention.S1 Technical Appendix(DOCX)Click here for additional data file.


This cross-sectional study examines time trends and sex differences in the suicide mortality rate among US youths adjusted for birth cohort and age. Does a measure of suicide mortality calculated by adjusting for chronological age and year of birth differ from unadjusted models?In this multiyear cross-sectional study using data from the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database, age and birth cohort–adjusted suicide mortality rates were estimated after controlling for a curved age effect and a V-shaped cohort effect that also differed by sex. The adjusted rates showed a more rapid increase and a smaller sex difference in the suicide mortality rates for US youths aged 10 to 19 years from 1999 to 2017.Age and birth cohort–adjusted suicide mortality rates may be an unbiased measure of the time trend and sex pattern in suicide among US youths and may be useful for informing evidence-based suicide prevention. Strategic planning to curb increasing suicide rate among US youths requires unbiased measures of suicide mortality, as the unadjusted suicide mortality rates conventionally used in describing time trends and sex patterns are confounded by the differences in chronological age and year of birth.To measure time trends and sex differences in suicide mortality among US youths using age and birth cohort (age-cohort)–adjusted rates.This population-based multiyear cross-sectional study of US youths aged 10 to 19 years was a secondary analysis of the suicide data for January 1, 1999, to December 31, 2017, derived from the Wide-Ranging Online Data for Epidemiologic Research, a database prepared by the US Centers for Disease Control and Prevention to promote research. Data analysis was conducted from May 24 to May 27, 2019.Age-cohort–adjusted suicide mortality rates by year and sex were used as the main outcomes. These adjusted rates were calculated based on the period effect estimated with the age-period-cohort (APC) modeling method. Participants’ age, year of birth, and the year when suicide occurred were used as time-related risk factors.Age-cohort–adjusted suicide mortality rates were estimated successfully by year and by sex. The adjusted rates were obtained after controlling for a V-shaped cohort effect and a curved age effect that also differed by sex. The unadjusted suicide mortality rate for male youths increased from 7.4 per 100 000 in 1999 to 10.7 per 100 000 in 2017, while the adjusted rate increased from 4.9 per 100 000 in 1999 to 8.7 per 100 000 in 2017. The unadjusted suicide mortality rates for female youths were 1.6 per 100 000 in 1999 and 3.5 per 100 000 in 2017, while the adjusted rates were 1.7 per 100 000 in 1999 and 4.2 per 100 000 in 2017.Findings of this study indicate a more rapid increase and smaller male-female difference in suicide rates among US youths since 1999 than those shown by the unadjusted suicide mortality rates. The adjusted rates provide unbiased data that are needed for evidence-based decision-making and strategies to curb the increasing suicide rates among US youths. Studies using the age-period-cohort (APC) modeling method have demonstrated the existence of the 3 components through empirical data.14 Methods to obtain an age-adjusted rate have been well established for bias correction9; however, an age-standardized rate remains confounded by potential differences in the mortality of people who were born in different years. In this study, we applied a new approach to obtain age and birth cohort (age-cohort)–adjusted suicide mortality rates, capitalizing on a classic epidemiologic method of APC modeling capable of controlling the impacts of both the age and cohort.Despite their wide acceptance and frequent use in research and practice, the reported suicide mortality rates are very likely to be biased if used to describe time trends and sex differences.age effect, which will contribute to the recorded suicide mortality in 2009; (2) suicide risk by birth cohort for youths born in 1994 (15 years ago) to 1999 (10 years ago), and variations in the suicide risk by birth cohort, also known as cohort effect, which will also contribute to the recorded suicide mortality in 2009; and (3) suicide risk in 2009 when the recorded suicide deaths occurred, also known as period effect.11To illustrate the new method, we used the suicide mortality rate for youths aged 10 to 15 years in 2009 as an example using hypothetical data . EpidemiIn 15 a public domain database prepared by the US Centers for Disease Control and Prevention to promote research. Total population and suicide deaths by single year of age from 10 to 19 years and by sex from 1999 to 2017 were included. Suicide deaths were those coded as U03, X60-X84, and Y87.0 in the Wide-Ranging Online Data for Epidemiologic Research database, following the definition of suicide in the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.16 This study was guided by Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies and was approved by the institutional review board at the University of Florida. Informed consent was waived because the data were deidentified.Deidentified suicide data were extracted from the Wide-Ranging Online Data for Epidemiologic Research database,The 3 examined time-related risk factors were age in years, year of birth, and year when a suicide occurred. The registered age of suicide death was used as the variable age, and it ranged from 10 to 19 years. The year when the reported suicide death occurred was used as the variable period, and it ranged from 1999 to 2017. The year of birth was computed by subtracting the age from the period and was used as the variable cohort; it ranged from 1980 to 2007. These 3 time-related variables were used for APC modeling analysis.11Annual suicide mortality rates per 100 000 individuals by single year of age and sex were computed as the number of suicide deaths divided by population estimates for 1999 through 2017. These computed suicide mortality rates were analyzed using the APC modeling approach, assuming that the occurrence of suicide deaths follows a Poisson distribution.ijkr as the estimated suicide mortality rate for youth in age group i, time period j, and birth cohort k, the following log-linear regression was used for APC modeling in Equation 1: u was the intercept or grand mean, iα was the effect for age group i , jβ was the effect for period j , and kγ was the effect for birth cohort k .Using 11 The modeling analysis was implemented using Stata statistical software version 15.0 with a special software package apc_ie (StataCorp). Thus, the estimated age, period, and cohort effects were manually plotted by sex to visualize changes in the risk pattern of suicide along with the 3 time-related risk variables.7The model parameters in Equation 1 were estimated using the intrinsic estimator.u was the intercept, jβ was the effect for period j , αmedian was the median of age effects, and γmedian was the median of cohort effects, all estimated through the APC modeling analysis as described by Equation 1. Computation of the age-cohort–adjusted rates was completed using an Excel spreadsheet (Microsoft Corp). The adjusted rates by year were plotted together with the unadjusted rates for male youths and female youths to reveal the differences for efficient result interpretation.Finally, the age-cohort–adjusted suicide mortality rate was estimated based on the period effect that was independent of the chronological age and birth cohort using Equation 2: Unlike most reported studies to our knowledge, data for the total population of US youths were analyzed in this study. Consequently, no type I error due to sampling was involved; therefore no significance test was conducted for statistical analyses.The The age effect derived from APC modeling analysis indicated a curve-linear association of chronological age with suicide risk, with the effect for female youths increasing more rapidly than for male youths from ages 10 to 16 years A. LikewiThe estimated period effect C reflectAge-cohort–adjusted suicide mortality rates were calculated based on the estimated period effect C. The adFor male youths, the adjusted rates were lower than the unadjusted rates across the period, with a larger difference before 2008 corresponding with the 1981 through 1998 birth cohorts, when these youths were born, and with a higher cohort effect for male youths than for female youths B. FurtheIn contrast to male youths, the adjusted suicide mortality rates for female youths were higher than the unadjusted rates, with a larger difference in more recent years and a more rapid increase over time compared with the unadjusted rates. According to the adjusted rates, the unadjusted rates underestimated the level and time trend in suicide mortality for US female youths, since the unadjusted rates were confounded by the curved age effect A and V-sIn this study, we calculated the age-cohort–adjusted suicide mortality rates to describe the time trends and sex difference in suicide mortality among US youths aged 10 to 19 years from 1999 to 2017. The adjusted rates were calculated based on the period effect estimated using the classic epidemiologic method of APC modeling to control for the effect of chronological age and birth year. The adjusted rates provided unbiased data for evidence-based planning and decision-making for suicide prevention among US youths.5 findings from the adjusted rates indicate that even more urgent action is needed to control the increasing trend.The age-cohort–adjusted suicide mortality rates indicated that suicide mortality among US youths increased continuously and more rapidly than the unadjusted rates had suggested. The unadjusted rates for male youths showed a declining trend before 2007, but this trend disappeared when measured by adjusted rates. The adjusted suicide mortality rate increased more rapidly than the unadjusted rate among female youths. We found that the differences between the adjusted and the unadjusted rates were primarily due to the effect of chronological age and birth year. Although the increasing trend in suicide among youths has been reported in the literature,17 The progressive increases in the adjusted suicide mortality rates for both sexes during the period was associated with the increases in social media exposure18 and substance abuse.19 Additional studies with new data are needed to examine factors associated with the increasing trends in suicide.Although a systematic examination of factors associated with the increasing trends is beyond the scope of this study, a short-term increase in adjusted suicide risk during 2003 to 2005 could be due to reductions in the prescribed antidepressants in response to the regulation issued by the US Food and Drug Administration in 2004.20The sex difference measured by adjusted rates was smaller than that of the unadjusted rate for US youths during the period. Measured by the unadjusted rates, the male-female differences in the rate of suicide deaths youths was 5.8 per 100 000 in 1999 and 7.2 per 100 000 in 2017; however, the sex differences in the 2 years were reduced to 3.2 per 100 000 in 1999 and 4.5 per 100 000 in 2017 when the adjusted rates were used. This finding suggests that we cannot ignore the risk of suicide among female youths, as their risk of suicide was higher than the unadjusted rates shown in this study and those of others in the literature.13 there was a curve-linear association between age and the risk of suicide, with the risk increasing with age from 10 to 19 years old. This finding suggests the importance of early prevention to reduce the suicide risk among youths in the United States. Furthermore, the risk started at a lower level and increased more rapidly for female youths than for male youths up to age 16 years. This sex difference could be associated with the earlier emotional and cognitive maturation of female youths compared with male youths.22 Further studies are needed to investigate the difference in risk associated with age. Suicide prevention guidelines and strategies should also consider this sex difference.In addition to the adjusted rates, this study generated 2 by-products: age effect and cohort effect. First, consistent with published data,24This study revealed a V-shaped cohort effect with a decline in suicide mortality risk for those born from 1980 to 1995 and an increase in suicide mortality risk for those born after 1995. The increased cohort effect of suicide mortality risk after 1995 corresponded with the later Millennial Generation and Generation Z, characterized by long-term internet use and intense social media exposure, both of which have previously been associated with increased risk of suicide.International Statistical Classification of Diseases and Related Health Problems, Tenth Revision16 codes to classify suicide death; misclassification cannot be completely ruled out. Despite the limitations, findings of this study provide new data to measure time trends and sex differences in suicide mortality among US youths. These data are needed for evidence-based planning and precision intervention to reduce the suicide rate.This study has limitations. First, APC modeling uses aggregated data to separate the period effect from the other 2 time-related variables of chronological age and birth year. Therefore, it cannot examine factors associated with the time trend using individual-level data. Second, this study used To our knowledge, this is the first study to apply the age-cohort–adjusted rates in describing the occurrence of suicide among US youths. Compared with unadjusted suicide mortality rates, the age-cohort–adjusted rates indicate a more rapid increase in suicide mortality among US youths during 1999 to 2017. Compared with the unadjusted suicide mortality rates, the adjusted suicide mortality rates were lower for male youths and higher for female youths, and the sex differences were smaller. This study suggests that there is a need for greater efforts to control the rapidly increasing suicide mortality trend, with extra attention given to female youths.


To investigate whether the introduction of a named general practitioner  improved patients’ healthcare for patients aged 75 and over in England.Random sample of 27 500 patients aged 65 to 84 in 2012 within 139 English practices from the Clinical Practice Research Datalink linked with Hospital Episode Statistics.Prospective cohort approach, measuring patients’ GP consultations and emergency hospital admissions 2 years before/after the intervention. Patients were grouped in (i) aged over 74 and (ii) younger than 75 in both periods in order to compare who were or were not subject to the intervention. Adjusted associations between the named GP scheme, continuity of care and emergency hospital admission were examined using multilevel modelling.National Health Service policy to introduce a named accountable GP for patients aged over 74 in April 2014.(A) Continuity of care index-score, (B) risk of emergency hospital admissions, (C) number of emergency hospital admissions.The intervention was associated with a decrease in continuity index-scores of −0.024 ; there were no differences in the decrease between the two age groups . In the pre-intervention and post-intervention periods, respectively, 15.4% and 19.4% patients had an emergency admission. The probability of an emergency hospital admission increased after the intervention ; this increase was bigger for patients over 74 . The average number of emergency hospital admissions increased after the intervention (rate ratio (RR) 1.178, 95% CI 1.103 to 1.259, p<0.001); this increase was greater for patients over 74 .The introduction of the named GP scheme was not associated with improvements in either continuity of care or rates of unplanned hospitalisation. This study was the first to investigate the relationship between the introduction of a named general practitioner (GP) scheme and continuity of primary care and unplanned hospitalisation.This study took a 4 year observational period into account, namely 2 year periods before and after the implementation of the named GP policy.This cohort study used individual electronic healthcare records data from the Clinical Practice Research Datalink linked with Hospital Episode Statistics.Our data set did not make it possible to specify the named GP assigned to a patient.As all older patients included in the sample survived the 4 year observational period, this might reduce the generalisability of our findings.Nearly every country in the world is experiencing growth in the number and proportion of older persons.In the UK, patients are registered at one general (family) practice but might see different physicians within that practice. The introduction of a named GP scheme was intended to facilitate older patients consulting the same doctor, thus improving continuity of primary care . As there is some evidence that continuity of primary care is declining in England,A key objective of the introduction of the named GP scheme was to avoid or decrease hospital admission. Previous systematic reviews based on international literature concluded that better clinician continuity of care reduces hospitalisation.This study used data from the Clinical Practice Research Datalink (CPRD) which contains anonymised electronic healthcare records on 4.4 million patients (6.9% of the UK population) and is nationally representative in terms of age, sex and ethnicity.Based on our previous work, we expected 13.5% to undergo an emergency admission over a single year, therefore over 2 years, we estimate 22% will experience an admission.After the introduction of the named GP scheme in April 2014, all patients aged 75 and over had to be notified by letter or during a consultation by 30 June 2014 of their named and accountable GP, or within 21 days after a patient became 75 or was newly registered if their practice was not already operating a personal list.10.1136/bmjopen-2019-029103.supp1Supplementary dataet alThree outcome measures were assessed, the first being change in continuity of primary care. We used a combination of CPRD staff codes to identify GP staff  within the practice and dates of consultations to identify whether these occurred during the pre-intervention or post-intervention period. Consultations included clinic and surgery consultations, home visits, out-of-hours’ visits, telephone consultations and third-party consultations. Following Hobbs The second outcome assessed was change in probability of experiencing at least one emergency hospital admission after the second GP consultation in both the pre-intervention and post-intervention periods. We made no distinction between admissions by specific routes . A patient’s probability of at least one emergency hospital admission may not necessarily reflect the number of admissions a patient experienced. The probability might have decreased while the average number of emergency hospital admissions might have increased and vice versa. The third outcome, therefore, was the number of emergency hospital admissions after the second GP consultation in both the pre-intervention and post-intervention periods, categorised as zero, one, two and three or more.Our choice of covariates was guided by the QAdmission score,To adjust for continuity of care (BB index-score) for the second outcome, we determined the continuity of care until an emergency hospital admission or to the end of each period (whichever came first) when not having experienced such an emergency admission, excluding from the analysis patients who experienced an emergency admission before their first or second GP consultation (as these patients would not have a continuity score). This resulted in a reduction in the of number of observations from 38 500 to 37 207. The BB index-scores were divided into quintiles.A patient’s BB index and a patient’s emergency hospital admission were measured for both the pre-intervention and the post-intervention periods. To account for repeated measurements by time, by patient and by practice, this study used multilevel modelling. Because continuity of care was a continuous variable, a normal response regression model was used to associate the named GP scheme with continuity of care (BB index-score). Because experiencing at least one emergency hospital admission was a binary variable, a binomial logit regression model to associate the named GP scheme with risk of emergency hospital admissions was used. A Poisson regression model was used to associate the named GP scheme with the number of emergency hospital admissions as this outcome was a count.To represent whether the effect of the intervention operated differently for patients aged over 75 (exposed) from those aged under 75 (unexposed), we included the age × period interaction. This could be interpreted as difference in change of the BB index score, the relative OR of emergency hospital admission or the relative rate ratio of number of emergency hospital admissions. We used Stata 15.1 to perform our analyses.The distribution of the BB index varied widely, with similarity between the pre-intervention and post-intervention distributions . RespectThe BB index-score decreased over time by 0.028 (from 0.428 in the pre-intervention period to 0.399 in the post-intervention); this equates to a drop in the mean continuity of care by about 6.5%. The BB index-score for patients aged 75 and over decreased from 0.434 pre-intervention to 0.403 post-intervention (a mean decrease of 0.031). This decrease was slightly bigger than for patients younger than 75, from 0.422 pre-intervention to 0.397 post-intervention (a drop of 0.025). An unadjusted multilevel  model for continuity of care (BB index-score) showed there was no evidence that this decrease in continuity of care following the intervention differed between the two age groups , we inclWe also calculated for each practice the average practice-level continuity of care score over 2012 to 2014, having divided practices into tertiles: low, middle, high continuity of care. This allowed us to determine whether patients in practices with different levels of continuity of care show differing trends in continuity of care post-intervention. The result of an interaction between period, age and practice-level continuity of care is illustrated in In the pre-intervention and the post-intervention periods, respectively, 2966 (15.4%) and 3745 (19.4%) patients had one or more emergency admissions. The probability of an emergency hospital admission for patients aged 75 and over showed an absolute increase of 6.3% points over time (from 19.9% pre-intervention to 26.2% post-intervention). There was evidence from the unadjusted model that the relative increase in odds of admission was 17.9% (95% CI 5.9% to 31.4%) greater in those aged over 75 years than those aged under 75 years after the introduction of the named GP scheme . This reIn the pre-intervention period 16 269 (84.6%), 2070 (10.7%), 557 (2.9%) and 339 (1.76%) experienced respectively no, one, two or three or more emergency hospital admissions. In the post-intervention period 15 520 (80.6%), 2368 (12.3%), 750 (3.9%) and 627 (3.3%) experienced respectively no, one, two or three or more emergency hospital admissions. The mean number of emergency hospital admissions for patients aged 75 and over showed an absolute increase of 0.154 over time (from 0.313 pre-intervention to 0.467 post-intervention). There was evidence from the unadjusted model that the relative increase in mean number of emergency hospital admissions after the introduction of the named GP scheme was 14.6% (95% CI 5.5% to 24.5%) greater in those aged over 75 years than those aged under 75 years .To adjust for continuity of care (BB index-score) and for number of GP consultations we determined the continuity of care at the end of each period for all patients included in the analysis, in contrast to the other outcome where continuity of care was estimated only until the event date. In this model the relative difference between the two age groups was slightly lower than in the unadjusted model  (Continuity of care decreased between the pre-intervention and post-intervention periods and this decrease was similar for patients aged between 65 and 74 (who were not eligible for the named GP scheme over the period of study) and patients aged 75 and over (who were eligible). Over time, continuity of care for patients aged 75 years or over declined less in practices which had lowest continuity of care at baseline. The average decrease in continuity of care was small, about 6.5% from baseline, although there was considerable variation across patients and practices. The probability of an emergency hospital admission increased between the pre-intervention and post-intervention periods and this increase was greater for patients 75 and over. The average number of emergency hospital admissions also increased, and this increase was greater for patients aged 75 and over. In general, the introduction of a named GP scheme was not associated with improvements in either continuity of care or rates of emergency hospital admissions.Emergency hospital admission showed a stronger increase among patients aged 75 and over, contrary to what we expected, but we don’t think that this is associated to the measured decrease in continuity of care as patients 75 and over and those younger than 75 experienced a similar drop in continuity. It is unclear whether the increase is due to the named GP system mediated through some other mechanism than continuity of care, or whether it’s due to other factors not captured by our study.This study used longitudinal individual-level data from older patients in the CPRD to assess continuity of care and its relationship with the incidence of unplanned hospital admission before and after the introduction of a named GP scheme, by comparing patients assigned a named GP with slightly younger patients not assigned a named GP. This allowed us to determine and compare continuity of care and unplanned hospital admission over time and between the affected and unaffected group. The observation period was a 2-year period before and after the introduction of a named GP scheme, allowing us to calculate robust continuity of care scores for each period using the BB index-scores. The data set allowed us also to control for practice-level, clinical and demographic covariates.The study had some limitations. First, all the patients included in the sample survived the 4-year observational period. This may indicate that we had a particularly ‘healthy’ group of older patients and might, therefore, reduce the generalisability of the study’s findings. Our data set did not make it possible to specify the named GP assigned to a patient, therefore we could not use other measures of continuity of care such as the provider identification index.Lloyd and Steventon published a protocol for a regression discontinuity study to investigate the effect of the introduction of the named GP scheme on the number of GP contacts per patients, the number of GP referrals to specialists and the number of common diagnostic tests.et al showed that the proportion of patients seeing their preferred GP dropped between 2012 and 2017, especially in practices with higher percentages of those aged 75 and older.Using aggregated practice-level data from the GP patient survey, Levene The named GP scheme for older patients was introduced by the NHS, with each individual general practice having to assign doctors to older patients on their list. The General Medical Services Contract did not advise practices to consult patients about their preferred GP as part of this assignment process, nor did it guarantee that patients would see the same clinician at each consultation. However, where patients expressed a preference as to which GP they have been assigned, the practice had to make reasonable effort to accommodate these requests.Allocating a GP does not imply that patients are able to see or speak to that GP whenever they require advice or care since this depends on GP workload, practice opening hours, salaried and part-time working contracts.A policy of allocating a named GP in itself is not effective and more sophisticated interventions would be needed to improve continuity of care in the UK or countries with similar healthcare systems. However, it is not possible to tell from our study whether applying an assigned named GP scheme in a country where continuity of care is not common, might actually lead to improvements in continuity of care and, consequently, hospital use.Future research might focus on differences between practices concerning the implementation of the named GP scheme. As this research showed a difference between patients in general practices with on average low versus high continuity of care, a number of other differences could impact implementation, such as practice size and proportion of part-time GPs. Our study focused on continuity of care and unplanned hospital admission. Future research using a 2year or even longer observational period might focus on other healthcare use such as number of GP referrals or diagnostic tests,This study does not investigate the views and experiences of patients or practice staff. Evidence suggests that older patients value continuity of care,