The present study aimed to evaluate psychological impact of COVID-19 outbreak on postgraduate trainees in Pakistan by quantifying the symptoms of depression, anxiety and acute stress disorder and by analysing potential risk factors associated with these symptoms.2 test and logistic regression analysis were performed. The significance level was set at α=0.05.Following Institutional Review Board approval, a cross-sectional study was conducted among 10,178 postgraduate trainees following COVID-19 outbreak through e-log system of College of Physicians and Surgeons of Pakistan. The nine-item Patient Health Questionnaire, seven-item Generalised Anxiety Disorder scale and Stanford Acute Stress Reaction Questionnaire were used to collect data. Statistical analyses were conducted using SPSS.26. Descriptive statistics, Mann-Whitney U test, the χThe prevalence of depressive symptoms, generalised anxiety disorder and acute stress disorder were 26.4%, 22.6% and 4.4%, respectively. Female postgraduate trainees, senior trainees and front-line workers reported experiencing more anxiety, depression and acute stress symptoms . Logistic regression showed that being a front-line and senior staff member and female was associated with higher risk of experiencing symptoms of depression, anxiety and acute stress.Our study findings raise concerns about the psychological well-being of postgraduate trainees during the acute COVID-19 outbreak in Pakistan. It is necessary to employ strategies to minimise the psychological distress and provide adequate psychosocial support for postgraduate trainees during crisis situation such as COVID-19 pandemic. Recent literature also suggests that HCWs are very vulnerable to emotional distress during COVID-19.3–5 Insufficient data are currently available from low- and middle-income countries (LMICs) regarding changes in prevalence of depression during the pandemic. However, a recent study conducted in India found 32.6% of HCWs having depression during COVID-19 pandemic, which is much higher than the 10% prevalence for common mental disorders reported in its general population.6The World Health Organization (WHO) identifies viral disease outbreaks like COVID-19 pandemic as a serious threat to public health.7 Previous studies report that junior doctors feel pressured and resentful that the primary care in acute situations is often left to them.8 During COVID-19 pandemic, postgraduate trainees are likely to be the main workforce to deal with the impending influx of patients with COVID-19. Mobilisation of postgraduate trainees to high demand departments, high likelihood of contacting suspected or confirmed cases with COVID-19, making difficult ethical decisions, cancellation of teaching programmes, and study leaves, uncertainty regarding jobs and rotations are some of the concerns identified by junior doctors during COVID-19 pandemic and are likely to adversely impact their mental and physical well-being.9 Similar views have been reported from Pakistan.10 A recent rapid review shows that presence on front lines, being younger and being more junior is associated with increased risk of psychological distress in HCWs during viral outbreaks.2 The psychological distress is associated with medical errors and lapses in professionalism as well as high risk of serious psychiatric problems including suicidal ideation.11 12Postgraduate trainees are among the most vulnerable HCWs even in usual times with high prevalence of burnout and psychological morbidity.Although psychological distress is to be expected during COVID-19 in LMICs like Pakistan, where postgraduate trainees in particular are under pressure to look after a large number of potentially infectious patients, institutions, supervisors and employers can help to mitigate this by implementation of several effective interventions. However, their psychological well-being has not been formally evaluated so far. To address this gap, the present study aimed to evaluate psychological impact of COVID-19 outbreak on postgraduate trainees in Pakistan by quantifying the symptoms of depression, anxiety and acute stress, and by analysing potential risk factors associated with these symptoms.13 It has nine items, score of each item ranges from 0 to 3 with total score range being 0–27. The scores are interpreted as normal (0–4), mild (5–9), moderate (10–14) and severe (15–21) depression. As recommended, PHQ-9-total score of 8 points or greater was defined as the presence of depressive symptoms for the current study.14 The seven-item Generalised Anxiety Disorder  was used to assess the severity of symptoms of anxiety.15 The scores are interpreted as normal (0–4), mild (5–9), moderate (10–14) and severe (15–21) anxiety. Stanford Acute Stress Reaction Questionnaire  questionnaire was used to measure residents acute stress in accordance with Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for acute stress disorder.16 The SASRQ is a six-point Likert scale consisting of 30 items assessing dissociation, re-experiencing, avoidance, anxiety and hyperarousal. Each item has a score of between 0 and 5, with a combined score ranging from 0 to 150, and a higher score indicating higher levels of self-reported stress. To meet acute stress disorder criteria, respondent had to indicate having at least three of five possible dissociation symptoms, and at least one symptom each of hyperarousal, anxiety, avoidance and re-experiencing of stressful event. Information to access confidential psychological support was also provided during the study. Data were analysed using SPSS version 26.0 . A descriptive analysis was conducted using numbers and percentages for categorical data and mean±SD for continuous data. Medians with IQRs were reported for the skewed data values, Mann-Whitney U test was performed for comparison between the groups. Data for each level for symptoms of depression, anxiety, and stress were presented as numbers and percentages. The significance level was set at α=0.05. Qualitative variables were compared using χ2 test. Logistic regression analysis was performed to observe the potential risk factors for symptoms of depression, anxiety and acute stress in participants. Factors with significant association (p<0.05) with the outcome variables at univariate analysis level were further included in the final multivariate analysis model. The associations between risk factors and outcomes are presented as ORs and 95% CIs, after adjustment for confounder variables.This was a cross-sectional study conducted following COVID-19 outbreak, through e-log system of College of Physicians and Surgeons (CPSP) from 15 April 2020 to May 2020. CPSP is the largest internationally recognised Postgraduate Medical Institute in Pakistan established in 1962 and is responsible for postgraduate medical training and research. It awards fellowships in 73 specialities/subspecialities and membership in 22 disciplines. All postgraduate trainees inducted from 2011 onwards in CPSP residency programmes have to make entries of all academic activities and work performed in mandatory e-logbook using their registration numbers and passwords. Trainees are unable to enter activities that are more than 3 months old. Supervisors verify the entries on a regular basis helping in monitoring the progress of trainees. Currently, there are 24, 477 postgraduate trainees enrolled with CPSP. Our study target population was postgraduate trainees who would access their e-logbook during the study duration from 15 April 2020 to May 2020. All trainees accessing e-portal were able to see the survey and answer the questionnaire by clicking on the relevant link. Among the 11, 489 trainees, who accessed e-log portal during the study period, 10, 178 participated with a response rate of 88.6%. Institutional Review Board approved the study. Participation was voluntary; all study participants provided informed consent, and confidentiality of information was assured. Demographic data collected from the participants included age, gender, marital status, speciality, year of residency, and medical and psychiatric history. Residents who were directly involved in diagnosing, treating or providing care to patients with diagnosed or suspected patients with COVID-19 on self-report were classified as front-line workers, while others were considered as second-line workers. Furthermore, postgraduate trainees in the first 2 years of residency were classified as junior trainees and those in year 3 and year 4 were considered as senior residents. The questionnaire included three validated questionnaires in English language focusing on depression, anxiety and acute stress disorder. The nine-item Patient Health Questionnaire (PHQ-9) was used to screen and measure the severity of symptoms of depression.A total of 10, 178 postgraduate residents completed the survey with majority (56%) being female and belonging to surgery and allied speciality (55%). A total of 3767 (37%) were directly involved in diagnosing, treating or providing care to patients with diagnosed or suspected patients with COVID-19 (front-line workers). The prevalence of depressive symptoms, GAD and acute stress disorder was 26.4%, 22.6% and 4.4%, respectively . The valThe associations of potential risk factors with depressive symptoms, GAD and acute stress disorder during COVID-19 outbreak are presented in COVID-19 pandemic had a considerable impact on healthcare systems worldwide, and threaten not only the physical health but also psychological and social health of HCWs including junior doctors. To our knowledge, this study is the first large-scale national survey in Pakistan to investigate the psychological impact of COVID-19 pandemic on postgraduate trainees. This cross-sectional survey enrolled 10, 178 respondents, and overall, our findings raise concerns about the psychological well-being of postgraduate trainees involved in the acute COVID-19 outbreak.17 18 People in LMICs, including Pakistan, are exposed to more stressors, which alongside greater stigma and social inequalities leads to less likelihood of accessing timely treatment. In the absence of any large population-based studies from Pakistan looking at the relative change or increase in anxiety and depression during the COVID-19 pandemic, we are unable to comment that symptoms observed in postgraduate trainees in our study differ from those of the general population.Even prior to pandemic, LMICs have reported higher prevalence of depressive disorders and anxiety than the aggregate prevalence for very high human development index countries in the world.et al reported prevalence of anxiety symptoms as 24.1%, while in another web-based survey of HCWs in China, 19.8% of HCWs appeared to have depressive symptoms.4 19 However, these results are in contrast with extremely high prevalence (35%–50%) of psychological morbidity in some reports from China, particularly in Wuhan province and in neighbouring India.3 4 6 Similarly, prevalence of acute stress disorder as 4.4% in our sample, although closer to 5% observed in a study following SARS outbreak in Taiwan in 2004, is very low compared to 29.8% reported by Zhu et al during current COVID-19 outbreak.19 20 This comparatively low psychological morbidity in our sample may partially be explained due to relatively lower (2.1%) COVID-19 case fatality of Pakistan as compared to USA (5.9%), Italy (14.3%), UK (14.0%), Iran (5.3%) and China (5.5%).21 Another reason may be the timings of the study, as it was conducted prior to the peak of the CoV outbreak in Pakistan, when healthcare system was coping well comparatively. The differences in the results between various studies in the literature can also be contributed to variability in study settings, methodologies, instruments used to assess the psychological morbidity and participants’ backgrounds such as age and culture.Our study contributes to literature on prevalence of psychological symptoms in postgraduate trainees. Prevalence of GAD and depression as 22.6% and 26.4%, respectively, in our sample are in line with few recent studies of HCWs during COVID-19. Zhu 22 23 Thus, although many other factors may have contributed, our results indicate that COVID-19 outbreak perhaps led to increase in prevalence of depression and anxiety among postgraduate trainees in Pakistan. Increase workload, sleep deprivation, being junior resident and pay disparity were observed to be associated with depression in junior doctors in Pakistan in literature.22 These stressors are likely to be compounded by high risk of infection, inadequate safety equipment, social isolation— especially from family—and physical exhaustion leading to high psychological morbidity during these challenging times.10 Female postgraduate trainees in our sample had higher prevalence of psychological morbidity as well as more severe symptoms on all psychological measures. Previous studies have also demonstrated that female gender is associated with increased vulnerability to psychological distress.2 3 24 Similar to recent literature, front-line workers and those directly exposed to patients with COVID-19 in our sample had high risk of developing psychological symptoms.2 3 24 This is understandable given that not only front-line postgraduate trainees are more exposed to the risk of COVID-19 infection themselves but also have to deal with the sickest patients.Previous small-scale studies done to assess psychological morbidity among postgraduate trainees in Pakistan found that 14% had depression symptoms and 8% had moderate anxiety.2 3 This could be explained by observed practice in hospitals in Pakistan of senior postgraduate trainees being given more responsibility of looking after COVID-19 units, intensive care units and high dependency units, thus perhaps being more exposed to patients at greatest risk of dying from the COVID-19 illness. However, this finding warrants further research.Our results of senior postgraduate trainees having significantly high psychological morbidity than year 1 and year 2 trainees are different from existing literature, in which less clinical experience has been linked with high adverse psychological outcome.25 Psychological first aid for front-line workers has also been recommended by WHO and includes the assessment of needs and concerns; practical care and support; basic needs provision; empathic listening; and access to information, services and social supports. These steps can allow postgraduate trainees to function at their best during this global health emergency.Although all the health resources of the country are currently deployed towards service provision for increasing number of patients with COVID-19, the policy makers in teaching and training institutions need to make special efforts to promote the psychological well-being of post-graduate trainees. Self-care, need to maintain healthy balance lifestyle during residency training and in future careers and building skills in resilience should be emphasised in the training curriculum. Adequate training around infectious diseases and provision of adequate personal protective equipment should be recommended to all institutions. The postgraduate trainees should have appropriate work shifts, regular breaks and guaranteed supplies. Encouragement among peers, adequate supervision and access to psychological interventions should be guaranteed in order to deal with the psychological problems.The study has some limitations. Although all scales showed very good reliability  in our sample, only PHQ-9 and GAD-7 has been previously validated in Pakistani population. As the study was cross sectional, we cannot evaluate the temporality and causality of the observed factors. Psychological assessment in our study was based on self-report tools. The use of clinical interviews may help in a more comprehensive assessment. We also cannot exclude the possibility of a response bias. Almost 47% of total enrolled residents in e-log portal (11 489/24 477) accessed it during the study period. It may be possible that many medical residents, who were directly participating in the care of patients with COVID-19 and thus having increase likelihood of psychological morbidity, were too busy to log in during the study duration. Also, residents who saw but did not responded to survey may have been too stressed out and overwhelmed to respond, thus skewing the results. Alternatively, those who received the survey but did not reply may have had no distress and therefore were not interested in responding. Furthermore, our study was conducted during a critical period of the COVID-19 pandemic in Pakistan when cases were still rising but prior to mid-June 2020 (the days that Pakistan saw the peak of COVID-19 cases and most likely high stressful time for HCWs). Longitudinal approach might help verifying whether long-term overload and distress develops as cases with COVID-19 reach their peak in the country and whether psychiatric disorders, especially posttraumatic stress disorder, might occur with the COVID-19 progression.Despite the limitations, this study has significant strengths. To the best of our knowledge, this is the first national study to report the psychological symptoms among postgraduate trainees during the COVID-19 pandemic. The data represented all four provinces and included trainees from multiple specialities. Thus, the results of the study can be considered representative of postgraduate trainee doctors’ psychological well-being during this outbreak.To conclude, the present study provides insight into the potential immediate psychological sequelae of COVID-19 pandemic on postgraduate trainees in the resource-constrained setting of a LMIC. Our results show high levels of depression and anxiety experienced by trainees caring for patients with COVID-19 in Pakistan. Female residents, those in the third and fourth year of residency and front-line workers experience more psychological distress. It is necessary to employ strategies to minimise the psychological distress and provide adequate psychosocial support for postgraduate trainees during a crisis situation such as COVID-19. Further research is needed to assess the long-term impact of this outbreak on trainee mental health as well as effectiveness of interventions to improve their psychological well-being.High psychological distress among postgraduate trainees during COVID-19 pandemic is reported in Pakistan.Female postgraduate trainees and those working as front-line healthcare workers reported experiencing more anxiety, depression and acute stress symptoms.Senior postgraduate trainees reported more anxiety and depression symptoms.Provision of adequate psychosocial support for postgraduate trainees during a crisis situation such as COVID-19 outbreak is essential.Studies outside Pakistan, with larger sample size and similar/uniform scales and cut-off points are needed for comparison.Further research is needed to explore the reasons for senior residents having high prevalence of anxiety and depression.Longitudinal studies with larger sample sizes are needed to understand the long-term mental health consequences of this devastating global pandemic on postgraduate trainees.Qualitative research will also be helpful to gain insight into the impact of COVID-19 pandemic on postgraduate trainees’ psychological well-being.The unprecedented nature of the COVID-19 pandemic challenges is likely to cause extreme psychological stress among the healthcare workers.Front-line healthcare workers, women, junior staff and nurses are more likely to suffer anxiety and depression.postgradmedj-97-632-DC1-inline-supplementary-material-1Table S1: Mean Scores & Standard deviation of Depression, Anxiety & Stanford Acute Stress Questionnaire and its subscales during COVID-19 outbreak in total cohort and subgroups.Click here for additional data file.


Regrettably, no pharmaceutical products (vaccine or medicine) have fully approved by regulatory authorities for the prevention or treatment of COVID-19 disease so far. By June 2020, the U.S. Food and Drug Administration (FDA) issued emergency authorization for the investigational remdesivir in COVID-19 hospitalized patients.5In November 2002, severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in china, and several months later caused over 8000 cases in 26 countries. 17 years later in December 2019, a novel coronavirus, known as SARS-CoV-2, which causes COVID-19 disease in humans reported in Wuhan China and considered global pandemic as its high contagious properties. In January 2020, World Health Organization (WHO) declared COVID-19 as an international public health emergency. As of June 2020, COVID-19 is responsible for more than 6 million confirmed cases and more than 377 000 deaths in 215 countries. There are many interesting similarities between SARS-CoV and SARS-CoV-2, not only in name.6In light of the inadequate impact that alternative non-pharmacological strategies on disease mitigation various available antiviral therapies are being tested against this emerging disease yet. For decades, Chloroquine/ Hydroxychloroquine (CQ/HCQ) have been used as anti-malaria medications and also for their immunomodulatory effects in conditions including rheumatoid arthritis disease and systemic lupus erythematosus.7 While HCQ has a half-life of 30 days and takes about 6 months to fully eliminate the body. These medications are excreted in the milk.8 The safety margin of chloroquine is low. Recent experiments reported that CQ/ HCQ efficiently inhibited COVID-19 infection.10 Some guidelines suggested prophylactic strategies for those accidentally exposed to SARS-CoV-2 to prevent viral transmission. CQ and HCQ may interfere with virus replication at the early stages of infection or increasing endosome-mediated pH at the viral entry/cell fusion, as well as post-translational modification of the glycosylation of cellular receptors of SARS-CoV-2.6 Along with this, Savarino et al suggested that CQ may reduce the level of inflammatory cytokines and could ameliorate acute respiratory distress syndrome.11 Recent preliminary clinical studies suggested that CQ and HCQ may be able to lower the COVID-19 viral load and reduce the duration of viremia.CQ and its β-hydroxylated analog, HCQ have a large distribution volume and demonstrate similar pharmacokinetic patterns in body organs. CQ is rapidly absorbed in the gastrointestinal tract. The CQ has an approximate half-life of 50 days and a high renal clearance, making the bioavailability of CQ an important clinical factor for kidney failure patients.12 Previous studies showed that SARS-CoV-2 binds to an enzyme called angiotensin-converting enzyme 2 (ACE2) receptor on the surface of human tissues.14 ACE2 Receptors distributed in body organs such as lung, heart, and renal tubular cells and upregulated by COVID-19 infection.14 Therefore, the virus could specifically invade positive ACE2 cells and lesion target tissues. After respiratory infection, the virus infiltrates the blood circulation and could persist in the kidney and trigger renal tissue injury. The rate of kidney dysfunction in hospitalized COVID-19 patients is high.16 This devastating synergism between SARS-CoV-2 and CQ/HCQ could be a lethal combination for patients in critical care units and would affect patients even after discharge from the hospital. Based on these investigations, we believe that the renal damage should be considered in COVID-19 patients during clinical work, because of the kidney impairment caused by both viral infection and CQ/HCQ treatment with certain renal toxicity.12 Physicians should increase their attention to renal failure in aged COVID-19 patients who received CQ/HCQ to reduce deaths. Furthermore, due to the potential pathogenicity of the virus to the kidney as well as the respiratory system, clinicians should pay attention to the risk of renal lesions in patients during the bedridden period and later clinical follow-up.Drug-induced renal failure is a common pharmacological reaction, while the precise mechanism of drug-induced renal failure remains unclear yet. However, some reports suggest that between 5 and 20% of cases of acute renal failure can be directly attributed to drugs and chemicals, although minor damage may pass undetected. It is important to be aware of the types of drugs that can induce renal impairment because, if suspected and acted on early, the damage to the kidney may be reversible. The renal system provides the ultimate solution for the excretion and eliminations of many xenobiotics and metabolites, often subject to high levels of potentially toxic substances. As a result, the renal tubular cell and the renal papillae typically experience direct toxic damages. This form of nephrotoxicity is typically dose-dependent. Many groups of medicines that cause renal injuries, and in patients who have pre-existing renal injury these effects are distinct. Wang et al showed that chronic CQ consumption has a devastating effect on glomerulus as well as acute distal tubular cell apoptosis in rats.Not applicable.Authors of this paper declare no financial competing interests.


Parkinson’s disease (PD) is a complex multisystem disorder with motor and non-motor symptoms (NMS). NMS may have an even greater impact on quality of life than motor symptoms. Subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to improve motor fluctuations and quality of life, whereas the effects on different NMS have been less examined. Sleep disturbances and autonomic dysfunction are among the most prevalent NMS. We here report the efficacy of STN-DBS on sleep disturbances and autonomic dysfunction. In the parent trial, 60 patients were included in a single-center randomized prospective study, with MDS-UPDRS III and PDQ-39 as primary endpoints at 12 months of STN-DBS. Preplanned assessments at baseline and postoperatively at 3 and 12 months also included Parkinson’s Disease Sleep Scale (PDSS); Scopa-Aut; and MDS-UPDRS I, II, and IV. We found that STN-DBS had a significant and lasting positive effect on overall sleep quality, nocturnal motor symptoms and restlessness, and daytime dozing. Several aspects of autonomic dysfunction were also improved at 3 months postoperatively, although at 12 months only thermoregulation (sudomotor symptoms) remained significantly improved. We could not identify preoperative factors that predicted improvement in PDSS or Scopa-Aut. There was a close relationship between improved autonomic symptoms and improved quality of life after 1 year. NMS and especially sleep and autonomic dysfunction deserve more focus to improve patient outcomes further. However, it has been increasingly recognized that PD is a complex multisystem disorder with motor and non-motor symptoms (NMS)3. NMS can be divided into four domains: autonomic, sleep, neuropsychiatric, and sensory symptoms, including pain5. NMS have a significant impact on quality of life6, often even to a greater extent than motor symptoms10.Parkinson’s disease (PD) is a common neurodegenerative disease diagnosed by the classical motor signs of bradykinesia, tremor, and/or rigidity13. The significance of NMS in the DBS-treated cohorts and the effect of DBS on these symptoms are reflected by several publications on this topic during the past years16.Treatment of PD aims at reducing symptoms, as no treatment that can modify disease progression has been established. Symptom reduction through treatment with levodopa and other dopaminergic agents is highly effective, but in later disease stages the management of motor and non-motor fluctuations can be challenging. When oral medical treatment proves to be insufficient in reducing tremor or motor fluctuations, deep brain stimulation (DBS) is an effective and well-established symptomatic treatment option17. The patients eligible for subthalamic nucleus (STN)-DBS typically are in an advanced stage of the disease when the NMS burden is high, but the reported effects of STN-DBS on NMS are somewhat conflicting in the literature. Some studies have shown that DBS is better than dopamine replacement therapy in reducing NMS18, others have shown only minor effects of STN-DBS compared to levodopa and that the pattern of NMS was similar in a non-operated PD reference population20. Improvements in NMS have, however, been shown in several studies23. The literature thus presents variable findings in this research field, which is impeded by the use of many different methods and questionnaires, including non-validated scales or questionnaires25.NMS burden has been shown to increase by disease duration, age, and with more severe motor impairment27, but autonomic NMS are also common 28. Despite the high frequency, such symptoms have been less investigated than the total NMS burden. To our knowledge, few long-term studies have investigated the effect of STN-DBS on sleep and dysautonomia.Sleep problems have been reported in 60–98% of PD patientsIn this study, we have evaluated the impact of bilateral STN-DBS on sleep problems and dysautonomia during the first year of chronic stimulation and explored their relationship to motor and quality-of-life outcomes.29. There were no significant differences in Parkinson’s Disease Sleep Scale (PDSS) or Scopa-Aut  between the two randomization groups of the parent study (see “Methods” section), neither regarding improvement from baseline to the 12-month follow-up nor in the scores at the different time points. Thus, for the purpose of this paper, we analyzed the two groups as one sample. Median age at surgery was 62 (44–71) years, disease duration 11 (4–23) years, and median preoperative Movement Disorder Society revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III scores in the medication-off/-on states were 47/13 (range 23–78/1–45). Complete baseline characteristics are presented in Table In this study, 60 patients were included, operated, and examined preoperatively, with planned follow-up after 3 and 12 months of continuous STN-DBS30 at both the 3- and 12-month evaluations, as presented in our previous publication29 , and two patients were lost to 1-year follow-up. Significant improvements were found for MDS-UPDRS I–IV, Parkinson’s Disease Questionnaire-39 (PDQ-39), and levodopa equivalent daily dosage (LEDD)Mean PDSS total score improved significantly from 93.8 ±21.3) at baseline to 110.0 (±21.7) at 3 months and 107.3 (±21.3) at 12 months of STN-DBS. Changes for each domain are shown in Table 1.3 at ba31 were reduced from 31% preoperatively to 14% at 3 months  and to 12% at 12 months (p = 0.005), see Fig. The proportion of patients with severe sleep abnormalities (PDSS score ≤ 83 points)p < 0.001). At 12 months, it was 15.2 (±8.4) (p = 0.073). Analyses of each Scopa-Aut domain showed significant improvement at 12 months only for the thermoregulatory domain. Interestingly, from that domain, only excessive sweating during day and night improved significantly  and question 18 (p = 0.044).Scopa-Aut total score improved significantly overall over the three time points ), see Table p = 0.468) and the model of covariance showed goodness of fit of 8% (p = 0.135). For Scopa-Aut difference, the predictive model showed goodness of fit of 3% (p = 0.590), whereas the covariance model showed goodness of fit of 31% (p < 0.001), with improvement in PDQ-39 as the only significant contributor. There is no violation of the assumption of normality, linearity, or multiple collinearity in the models. There are some overlapping questions in the questionnaires that might explain at least parts of the prediction of the variance, but Scopa-Aut and PDQ-39 only share the questions of feeling unpleasantly hot or cold.Multivariable linear regression analyses were performed to identify predictive factors and covariables of the changes observed in PDSS and Scopa-Aut scores from baseline to 12 months of STN-DBS. Variables entered into the regression models were chosen based on clinical experience and exploratory correlation analyses. The results are shown in Table In this prospective study of 60 PD patients treated with STN-DBS, our main finding was improvement of sleep disturbances at 12 months, as evaluated by PDSS. The domains overall sleep quality, nocturnal restlessness, nocturnal motor symptoms, and daytime dozing all improved. Statistically significant improvement in autonomic symptoms was also found at 3 months but was no longer evident at 12 months, except for sudomotor function.34, but there are conflicting results in the literature. Polysomnography cannot detect excessive daytime sleepiness and it is not feasible to study all PD patients with this modality. Therefore, several self-rating questionnaires that solely evaluate sleep have been developed, such as Epworth sleepiness scale, Pittsburgh Sleep Quality Index, and PDSS. Compound scales used to evaluate NMS also include sleep items . However, varying use of these scales has resulted in no uniform presentation of sleep symptoms. We have used the PDSS recommended by the MDS Task Force because it includes most of the potential sleep disturbances that PD patients may encounter35.Objective improvement in sleep quality following STN-DBS has been shown by polysomnography in small numbers of patients16. However, many previous studies have included small numbers of patients followed for a short time period. In 10 patients with 3 months of follow-up, PDSS showed improved sleep quality but, unlike our findings, without improvement of excessive daytime sleepiness36. In two other studies using PDSS, one showed improved scores for daytime sleepiness, sleep quality, and restless legs syndrome (n = 17) at 6 months postoperatively37, and the other showed significant improvements in PDSS after 6 months (n = 40) but not after 12 months (n = 26)38.Overall, previous reports indicate that STN-DBS may improve nocturnal sleep in PD patients, particularly sleep quality40. However, findings in a study that compared untreated PD patients, advanced PD patients (Hoehn & Yahr (H&Y) 4–5), and healthy controls indicated that sleep disruption occurs even before pharmacologic therapy and is likely a symptom of the underlying disease as well41. In a study comparing globus pallidus interna- and STN-DBS, there was no difference in PDSS improvements, despite a more pronounced LEDD reduction in the STN group. This may imply that the DBS effect on sleep surpasses the effect of dopaminergic medication reduction42.Reduction of LEDD is hypothesized to play a role in the improvement of sleep symptoms, as studies have shown poorer sleep quality and less rapid eye movement (REM) sleep on higher doses of dopaminergic medication taken prior to sleep34. A polysomnography study found that motor symptoms and medication explained only 10–30% of the variation of sleep efficiency, percentage of different sleep stages (including REM sleep), and total sleep time. These authors also suggest that other factors, related to changes in the disease process itself, are impacting sleep quality in PD43.Improvement in nocturnal mobility has also been suggested to be a significant contributor to improved sleep. However, Monaca et al. found only a mild motor improvement, but a significant improvement in sleep. They suggested that motor improvement alone could not fully explain sleep improvement, indicating that a possible direct effect on sleep/wakefulness regulatory centers might be involved44 and of basal ganglia circuits that also affect sleep physiology45. Furthermore, the pedunculopontine nucleus and globus pallidus externa are both connected to STN48 and are important in sleep regulation. Studies have shown that DBS in these areas increases REM sleep49.The fact that PD is perceived as a network disorder is contributing to the complexity of this field. The clinical effects of STN-DBS has been suggested to result from modulations of the connectivity within the cortico-striato-thalamo-cortical loop52. Therefore, the improvement of sleep quality probably also can be attributed to several mechanisms.The causes of sleep disturbances thus seem complex and likely multi-factorial. Motor and non-motor PD symptoms, medication, dysregulation of sleep–wake function, and co-morbidities such as sleep-related breathing disorders can probably all play a roleIn this study, it was evident that both overall sleep quality and motor-associated sleep symptoms improved significantly. Sleep onset and maintenance insomnia improved less convincingly. Regression analyses did not reveal preoperative variables that predicted the PDSS reduction at 1 year or covariates to the PDSS improvement. Together, this may indicate that STN-DBS causes improvement in sleep disturbances through several mechanisms such as improvement in both nocturnal motor and NMS. There might also be a more direct effect on sleep–wake regulation centers.53, and our results further confirm this.Regarding autonomic symptoms, the significant improvement of Scopa-Aut total score at 3 months was no longer evident after 12 months of STN-DBS. However, thermoregulatory function remained significantly improved, due to reduced excessive sweating both during the day and night. This improvement of sudomotor function has been described in several previous publications17. In a study of 131 patients, Scopa-Aut scores worsened by 20% after 12 months of follow-up, and the worsening of autonomic symptoms correlated with reduced performance of daily activities of living and health-related quality of life54. Thus our findings of lower Scopa-Aut score at 12 months compared to the preoperative score  could still imply some degree of long-term improvement when accounting for the expected gradual worsening over time. Few previous reports have used Scopa-Aut to evaluate the effect of STN-DBS on autonomic symptoms. However, one study of 24 patients reported similar results as presented here, where Scopa-Aut initially improved but with subsequent deterioration55. Many studies focusing on NMS have used NMSS or NMSQ57, but these scales reflect total NMS burden and fluctuations and not autonomic dysfunction specifically. However, many of these studies show the same pattern of initial improvement of NMS with later worsening over time25.Scopa-Aut total score has been reported to increase by age and disease durationWe could not identify any preoperative factors that predicted the change in Scopa-Aut from preoperative to 12 months, but the parallel improvement of PDQ-39 was identified as a significant covariate. This might imply that improvements in autonomic symptoms contribute importantly to improved quality of life.To our knowledge, this is the only long-term study that combines a relatively high number of patients, with specific evaluations of autonomic and sleep symptoms in PD patients after STN-DBS. The strengths of our study are the prospective design with systematic follow-up, the larger number of patients, and the longer follow-up time compared to previous studies. One limitation of our study is that the presented data were not planned as secondary outcomes but as preplanned investigations in a randomized study with motor symptoms and quality of life as primary endpoints. Thus, for the main variables presented in this article (PDSS and Scopa-Aut), the power to detect statistical differences between the two randomization groups of the parent study was not calculated. No such differences were found, and therefore we studied longitudinal changes of these variables in the whole study population. Multiple testing has been performed, but we have tried to correct for this using Bonferroni correction. No control group was included.In summary, our study confirms a significant and lasting benefit of STN-DBS on sleep quality in PD patients with motor fluctuations. Some aspects of autonomic dysfunction also improved, although only thermoregulatory (sudomotor) function remained significantly improved at 12 months. We could not identify preoperative factors that predicted improvement in PDSS or Scopa-Aut. We did, however, find a close relationship between improved Scopa-Aut and improved quality of life at 1 year. Quality of sleep and autonomic symptoms deserve more focus both in the preoperative and postoperative evaluation of PD patients for STN-DBS. Future studies should consider including these factors among the main outcomes, especially in studies focusing on optimal electrode location, closed-loop DBS, and when exploring new targets.29. The primary endpoints of the parent trial were the differences in motor outcome (scores of MDS-UPDRS III medication-off) and quality of life (PDQ-39), from baseline to 1 year of STN-DBS. The multiple simultaneous MER group had a significantly greater improvement both in MDS-UPDRS III off score and in two PDQ-39 domains (activities of daily living and bodily discomfort)29.From 2009 to 2013, 60 patients referred for STN-DBS to the Department of Neurology, Oslo University Hospital were included in a single-center, prospective, randomized, double-blind study. We compared two methods of using up to five trajectories of preoperative microelectrode recordings (MER): single sequential versus multiple simultaneous introduction of MER to guide the placement of the permanent electrode. The detailed description of the study design  and the main results of this study on motor and quality of life outcomes have been published previouslyInclusion criteria for surgery were levodopa-responsive PD, with motor fluctuations including dyskinesia or medication-resistant tremor and/or intolerable side effects of dopaminergic drugs. Before inclusion, a neurologist, a psychiatrist, and a neuropsychologist evaluated all patients. Exclusion criteria included previous surgery for PD, marked axial motor symptoms, unresponsiveness to levodopa, significant cognitive impairment, major psychiatric disorders, or significant abnormalities on neuroimaging. All patients signed written informed consent. We have complied with all relevant ethical regulations, and the regional ethics committee (REK) approved the study.58. The MDS-UPDRS III (range 0–132) was scored after overnight withdrawal of dopaminergic drugs (medication-off) and after a levodopa dose approximately 1.5 times the patient’s usual morning dose (medication-on). Postoperative evaluations were always made in the stimulation-on state. The H&Y score (0–5) was performed according to the recommendations of the MDS task force59. LEDD were calculated as advised by Tomlinson et al.30. Disease-specific health-related quality of life was assessed with PDQ-3961.Patients were investigated with the MDS-UPDRS to assess non-motor experiences of daily living (Part I), motor experiences of daily living (Part II), motor examination (Part III), and the severity and impact of motor fluctuations (Part IV)62. It consists of 15 items to be scored from 0  to 10 (symptom-free), and maximum score is 150 . Cutoff values of ≤83 for severe sleep abnormalities and ≤120 to detect sleep disturbances have been proposed63. The Scopa-Aut is a self-administered questionnaire, consisting of 26 items. It assesses the following domains: gastrointestinal symptoms (7 items), urinary symptoms (6 items), cardiovascular symptoms (3 items), thermoregulation (4 items), pupillomotor function (1 item), and sexual function (2 separate items for each gender)64. Each item is scored from 0 (never) to 3 (often), except for question 26, which is a yes/no question, and consequently not included in our statistical analysis. Total score ranges from 0 to 69 (for both genders), with higher scores expressing more severe symptoms.As part of the preplanned investigations performed at baseline, and after 3 and 12 months of STN-DBS, sleep disturbances were assessed with the PDSS and autonomic symptoms with the Scopa-Aut questionnaire. PDSS is a self-rated scale designed to measure common nocturnal problems, sleep disturbances, and excessive daytime sleepiness over the previous weekt tests), we analyzed the two groups as one sample for the purpose of this paper.Because there were no significant differences in the changes of PDSS or Scopa-Aut from preoperative to 3 months and 12 months between the two randomization groups (independent sample p < 0.006) and for Scopa-Aut denominator 7 (significance level p < 0.007). Where significant p values were found, pairwise comparisons were also performed to see if the significant change was for both time points. In SPSS, this is done in the same model and based on estimated marginal means. These p values are also Bonferroni corrected by multiplying for the three tests (p < 0.02).The sample was assessed with tests for normality. Except for MDS-UPDRS IV at 3 and 12 months, variables were normally distributed. One-way repeated-measures ANOVA were performed to determine the difference between the preoperative and postoperative scores. For MDS-UPDRS IV, the Friedman Test was performed. Bonferroni corrections were made for PDSS with denominator 9 , PDSS 84–120 (detecting sleep disturbances), and PDSS ≥121 (no sleep disturbance detected) according to proposed cutoff values. McNemar’s test was performed to compare whether the proportion of patients in these subgroups changed from preoperative to 3 months and from preoperative to 12 months.We defined three subgroups of PDSS severity p levels.Pearson’s rank order correlation was performed to compare scores of PDSS, Scopa-Aut, PDQ-39, MDS-UPDRS , H&Y, LEDD, age at surgery, and duration of PD for both preoperative and 12-month follow-up scores and for the changes of scores between these time points. For correlation with MDS-UPDRS IV, we also used Spearman’s rank correlation, which showed similar correlation coefficients and preoperative factors might predict the changes in PDSS and Scopa-Aut from preoperative to 12 months of STN-DBS (prediction models) and (2) whether changes in other selected variables during this treatment period were associated with the changes observed in PDSS and Scopa-Aut scores (covariance models). The variables entered in the models were chosen based on clinical experience and knowledge, hypotheses presented in the literature on variables that can affect improvement in sleep and autonomic symptoms, and through exploratory correlation analyses. We included all variables that showed significant correlation . We used tolerance (>0.10) and variance inflation factor (<10) to assess for multicollinearity and checked that correlation was <0.7. We used a forced entry method, which means that all predictor variables are tested in one block to assess their predictive ability while controlling for the effects of other predictors in the model. The model fit is presented by adjusted R square.We performed multivariable linear regression analysis to assess (1) which Missing single-item data points for PDSS, Scopa-Aut, and PDQ-39  were imputed using the last-observation carried-forward method. If the entire questionnaire was missing, these patients were excluded from the analysis. All statistical analyses were performed using IBM SPSS.22.Further information on research design is available in the Reporting Summary


The role of specific blood tests to predict poor prognosis in patients admitted with infection from SARS-CoV-2 remains uncertain. During the first wave of the global pandemic, an extended laboratory testing panel was integrated into the local pathway to guide triage and healthcare resource utilisation for emergency admissions. We conducted a retrospective service evaluation to determine the utility of extended tests  compared with the core panel .Clinical outcomes for adult patients with laboratory-confirmed COVID-19 admitted between 17 March and 30 June 2020 were extracted, alongside costs estimates for individual tests. Prognostic performance was assessed using multivariable logistic regression analysis with 28-day mortality used as the primary endpoint and a composite of 28-day intensive care escalation or mortality for secondary analysis.From 13 500 emergency attendances, we identified 391 unique adults admitted with COVID-19. Of these, 113 died (29%) and 151 (39%) reached the composite endpoint. ‘Core’ test variables adjusted for age, gender and index of deprivation had a prognostic area under the curve of 0.79 (95% CI 0.67 to 0.91) for mortality and 0.70 (95% CI 0.56 to 0.84) for the composite endpoint. Addition of ‘extended’ test components did not improve on this.Our findings suggest use of the extended laboratory testing panel to risk stratify community-acquired COVID-19 positive patients on admission adds limited prognostic value. We suggest laboratory requesting should be targeted to patients with specific clinical indications. In December 2019, COVID-19 was reported in China, caused by SARS-CoV-2.The ability to identify patients at greatest risk of developing life-threatening complications from SARS-CoV-2 infection based on haematological and biochemical laboratory markers was suggested early in the pandemic. A range of admission tests including D-dimer, ferritin, high-sensitivity troponin I (hs-Trop) and lactate dehydrogenase (LDH) have been linked with disease severity and risk of death.A joint National Health Service (NHS)–University collaboration supporting the rapid creation of an electronic healthcare registry (see online supplementary: extended methods) provided a timely opportunity to retrospectively assess the value and cost of implementing this extended laboratory panel. This is particularly relevant given a recent systematic review of methodological and reporting standards highlighting caution before extrapolating models and decision thresholds derived from prognostic biomarker studies into local clinical practice.https://tinyurl.com/all-wales-COVID-19-guidelines), with hypoxia  the primary triage criteria for admission. Patients transferred in from other hospitals were excluded. The primary dataset was extracted as part of a service evaluation to assist local care planning. A fully anonymised dataset was created by a member of the Health Board NHS IT team. Prior to anonymisation, the postcode was used to extract the Welsh Index of Multiple Deprivation (WIMD) for each patient, as obtained from https://wimd.gov.wales/. As such, ethical approval was not required for this study.We identified patients aged ≥18 years admitted between 17 March 2020 and 30 June 2020 via the ED of the University Hospital of Wales . This 1000-bed hospital is a tertiary referral centre within the region with the greatest recorded total of COVID-19 case positives in Wales.Data fields including admission date, clinical outcomes and laboratory measurements were integrated into an electronic healthcare registry ‘Cardiff Hospital Records Database - CHoRD’ using a bespoke software package: CHoRDBuilder see . Laborat10.1136/jclinpath-2020-207157.supp1Supplementary dataTwenty-eight-day mortality was chosen as the primary endpoint in accordance with UK COVID-19 mortality reporting. To support generalisability between studies,All testing was performed in the United Kingdom Accreditation Service-accredited Biochemistry, Immunology, and Haematology Laboratories at the University Hospital of Wales. Cost estimates were obtained from the Health Board Laboratory Medicine Directorate, reflecting consumables, reagent, analyser running and maintenance costs, and staff time chargeable to NHS test requestors.2 testing was performed. For continuous data, Welch’s t-tests were used if the assumptions of normality were met; otherwise, non-parametric Mann-Whitney U tests were employed. In edge cases, permutation testing was performed. Two-sided statistical significance was set at p<0.05, with Bonferroni correction for multiple testing.Statistical significance testing was performed according to the data encountered: for categorical data, such as gender, Fisher’s exact or χCandidate laboratory variables were triaged for inclusion based on their membership of core or extended laboratory test panels, before a data-driven approach was applied. This included assessment of variability, individual p values corrected for multiple comparisons and multicollinearity with generation of a Spearman’s rank correlation matrix.Logistic regression, support vector machines, random forest and gradient boosted trees were all considered for multivariate predictive models. Models with complexity greater than logistic regression were found to offer little improvement (data not shown). Multivariate logistic regression was implemented in Python (V.3.7) using the Scikit-Learn package V.0.23)23 and Sthttps://github.com/burtonrj/CardiffCovidBiomarkersTo minimise bias, models were evaluated using cross-validation with fivefolds, with stratification to account for class imbalance. Performance statistics are reported as the average across all folds with binomial proportion 95% CIs. Model discrimination was assessed by area under receiver operating characteristic curve (ROC AUC), accuracy  and weighted F1 score . In addition to these performance metrics, threshold-performance curves were generated to assess the effect of the decision threshold on model sensitivity and specificity.Our evaluation is reported using the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidance for Prediction Model development and validation see .These data were generated as part of a rapid service improvement and as such patients were not involved in the setting of the research question or interpretation of the study.We focused on admissions occurring after the operational roll-out of the first extended laboratory test panel components into standard clinical practice. During this 105-day period, over 13 500 ED attendances were recorded. Of these, 391 adults were admitted via ED with a laboratory-confirmed diagnosis of COVID-19 meeting our definition of likely community-acquired COVID-19 . The medWe next analysed the association between individual candidate variables and patient outcomes to identify important predictors of adverse outcome. Admission clinical variables are presented in In univariate analysis of the core laboratory panel components, increased CRP, neutrophil:lymphocyte ratio, urea, creatinine or decrease in serum albumin were all strongly associated with risk of death. Within the extended panel, D-dimer, hs-Trop and PCT differed between survivors and non-survivors on univariate analysis . No exteWe therefore used multivariate logistic regression to adjust for the role of age, while controlling for gender and WIMD, based on consistent identification of their contribution to outcomes in COVID-19 cohorts.We next assessed the discriminative value associated with inclusion of extended panel components within our multivariate model, relative to this core test set . AdditioLocal cost estimates for NHS requesting the core laboratory panel totalled £16.44 per patient, with an additional £55.48 incurred for the extended set . In ordeTo support the effective and efficient use of resources through evidence-based clinical practice, we conducted a service evaluation determining the prognostic value associated with routinely performed laboratory investigation in 130 adults admitted with community acquired SARS-CoV-2 infection. By leveraging a bespoke electronic healthcare registry, we reveal an extended panel  provided only limited additional prognostic information beyond that provided by components of the core panel . Together, this directs refinement of the clinical testing panel employed before and during future potential waves, underlining the relevance of this registry approach to support cost-utility of investigation pathways.et alWe identified five studies within the peer-reviewed and preprint literature concerning laboratory biomarker risk stratification of adult COVID-19 admissions in the UK population.Consistent with the emerging COVID-19 literature, we observed an association between laboratory markers of acute phase inflammatory response , cardiac injury, activation of thrombosis and renal impairment with subsequent adverse outcome.Our service evaluation has several strengths, notably assessment of the performance of an extended panel of laboratory tests not widely considered in UK prognostic studies to date within a clinical cohort identified based on commonly used clinical and virological criteria.Our evaluation also has a number of limitations, reflecting the challenges of clinical data collection during an epidemic. It represents retrospective experience from a single tertiary referral centre, limiting sample size. However, the study cohort inclusion criteria reflected national admission criteria for COVID-19 that remain active as the UK enters the next wave of COVID-19, highlighting the likely wider relevance of these findings. Second, availability of extended test panel results during the early admission period was mixed. Admission D-dimer and hs-Trop results were available for 70%–80% of patients, comparing favourably to a similar UK registry-based study where D-dimer results were only available at time of admission in 37.2%.Laboratory markers supporting early risk stratification of patients are often used in the ED setting and have been shown to benefit patient triage.In conclusion, we report our real-world experience from the use of an extended laboratory prognostic testing panel in patients hospitalised with community-acquired COVID-19. These findings directly inform clinical practice, guiding cost-efficient use of resources in potential future waves.During the first wave of the pandemic, the literature and guidance from the UK Royal College of Pathologists supported the use of extended biochemistry and haematology testing on admission to support risk stratification of patients with COVID-19 infection; however, the prognostic performance of these markers remains unclear.Our service evaluation suggests that systematic testing of COVID-19 positive patients with likely community-acquired disease on admission with an ‘extended’ laboratory panel  provides limited additional prognostic information for 28-day mortality or intensive care admission, relative to conventional ‘core’ tests such as a full blood count, renal function and C reactive protein combined with simple demographics.Few clinicians know the cost of the tests they request for their patients. With individual ‘extended’ panel members costing over £20 per test, and thousands of tests requested per month within a single hospital, these costs quickly escalate.Besides the financial impact, over-requesting of laboratory tests are likely to increase the number of false-positive results, with the potential to lead to further potentially harmful investigations . We suggest that the use of these laboratory markers be targeted to patients with specific clinical indications for these, such as procalcitonin to guide antibiotic stewardship or hs-Troponin I in patients with suspected myocardial injury.


Introduction: mTOR inhibitors are anticancer agents affecting mTOR/AKT/PI3K pathway that is one of the most important in human cancer cells. Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma.in vitro models.Present study is aimed to assess the activity of the two mTOR inhibitors (rapamycin - RAP and sapanisertib - MLN) as a single agent and combined with gemcitabine  in uterine sarcoma and carcinosarcoma Material and methods: SK-UT-1 and SK-UT1-B (uterine carcinosarcoma), MES-SA (leiomyosarcoma) and ESS-1  cell lines were used. An MTT assay was performed to examine the cytotoxicity of RAP, MLN and mixtures: RAP+MLN, RAP+GEM, MLN+GEM against these cells. The interactions between tested compounds were assessed in isobolographic analysis.Results and conclusions: Carcinosarcoma cell lines (both SK-UT-1 and SK-UT-1B) do not respond to RAP and respond relatively weakly to MLN treatment. Additive and supraadditive effects were noted for combined treatment with GEM and MLN. Endometrial stromal sarcoma cell line (ESS-1) occured to be sensitive to both RAP and MLN, but the response was stronger for MLN. Additive effect of all tested drug combinations was observed for ESS-1. Leiomyosarcoma cell line (MES-SA) was found sensitive to both mTOR inhibitors. Additive effects in combinations of GEM, RAP and MLN were observed, what makes them promising for future preclinical and clinical trials. Additivity with slight tendency towards antagonism between GEM and MLN observed in MES-SA cell line is unexpected finding and might prompt the mechanistic research aimed to explain this phenomenon. It integrates many cell functions including growth, proliferation, translation and transcription Such properties made it one of the most actively investigated molecular target in oncology. Many substances affecting mTOR have been identified so far.The mTOR protein executes its metabolic function by composing complexes with raptor and mLST8/GβLTORC1) and with rictor and mSIN,GβL TORC2)  and with  and witTORC1 regulates mostly protein synthesis by phosphorylation of translation factors, TORC2 controls cell survival and cytoskeleton functions, both complexes are linked by AKT Streptomyces hygroscopicus bacteria. It is widely used as immunosupresant in prevention of transplanted organ rejection and restenosis of coronary vessels (stents coated with rapamycin). Rapamycin binds and deactivates mTOR molecule. It was proved to efficiently inhibit activity of TORC1 complex The most 'classic' mTOR inhibitor is rapamycin (sirolimus), from which the names of protein and pathway were created, it is natural compound isolated from culture of MLN  is novel allosteric and ATP-competitive mTOR inhibitor. Unlike rapamycin, this compound inhibits both TORC1 and TORC2 complexes. The mechanism of overcoming rapamycin resistance by MLN was revealed by Rodik-Outmezguine et al. Gemcitabine is commonly using chemotherapeutic, according to recent recommendations is one of agents to be used in standard systemic treatment of uterine sarcomas Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma The majority of studies that investigated the effectiveness of various mTOR inhibitors , in sarcomas, were designed to assess single agent activity There is limited number of studies already finished and ongoing assessing the performance of MLN added to conventional chemotherapy but these do not recruit patients with neither uterine sarcomas nor carcinosarcomas Presently, there is a gap in knowledge about interactions between tested compounds in uterine sarcoma models. In present study we propose to evaluate the activity of both mentioned mTOR inhibitors in combination with gemcitabine as a standard therapeutic agent, that may indicate the directions for future therapeutic regimens.The study is aimed to assess the activity of RAP and MLN as a single agent, in combination and combined with gemcitabine in uterine sarcomas and carcinosarcomas in vitro models.Four cell lines were selected to experiments:- SK-UT-1 and SK-UT1-B- derived from uterine carcinosarcoma - MES-SA- derived from leiomyosarcoma- ESS-1- derived from low grade endometrial stromal sarcoma.Cell lines were obtained from the Laboratorio de Investigación Traslacional, MD Anderson Cancer Centre in Madrid, Spain. The SK-UT-1, SK-UT-1B and MES-SA cells were cultured according to ATCC recommendations 20The methodology of cell cultures and detailed description of used cell lines was described in details previously Cell viability was assessed by performing MTT test. Cells were plated in microplates and incubated in presence of various concentrations of RAP , MLN , GEM  and following 1:1 mixtures: RAP+MLN, RAP+GEM, MLN+GEM for 96 h. Afterwards MTT  -2,5-diphenyltetrazolium bromide) solution was added for 3 h of incubation. Living cells metabolize MTT into purple formazan crystals that are solubilised. The solution was examined optically in light 570 nm length with ELX-800 plate reader  and analyzed with Gen5 software . All experiments were repeated three times and the median value was used for calculations.The IC50 values were calculated by computer-assisted log-probit analysis. Differences in cells viability between control and particular concentrations of tested compounds were evaluated with one-way ANOVA Tukey's post-hoc testing. P<0.05 was considered to indicate a statistically significant difference. The analysis was performed using GraphPad Prism 5.0 .In order to analyze pharmacodynamic interactions between tested substances isoblography was used. The methodology of this analysis was described in our previous paper Detailed results of single agent activity of RAP and MLN measured in MTT test in SK-UT-1, SK-UT-1B, ESS-1 and MES-SA cell lines are presented on Figures 50 values obtained for each agent in monotherapy in all tested cell lines are summarized in table 50 values were not determined.ICThe results of MTT test performed to assess the activity of combinations of tested drugs in SK-UT-1, SK-UT-1B, ESS-1 and MES-SA were presented in Figure The results of isobolographic analysis indicating type of interactions between examined substances are presented in Figures Resistance of carcinosarcoma cell lines  to rapamycin and relatively weaker response to MLN than observed in other investigated cell lines was noticed. Such observation were not reported yet in available literature. The resistance to rapamycin might be explained by feedback activation of AKT and as consequence activation of mTOR pathway. The results of genetic analysis by Jones et al. revealed that the activity of mTOR pathway in carcinosarcomas is less altered, comparing to type I endometrial cancer 50 cell viability was decreased to about 50% in SK-UT-1 and about 30% in SK-UT-1B such results have to be considered as promising and this combination might occur to be useful in clinical practice. No data regarding activity of mTOR inhibitors in combination with chemotherapy in uterine carcinosacoma models or in clinical practice are available in literature up to date. Bae‐Jump et al. revealed synergistic effect of rapamycin and cisplatin combination in endometrial cancer cells, however the cells that were used were derived from type I endometrial cancer Interestingly, we noticed additive and supra-additive effects of combined GEM and MLN in SK-UT-1 and SK-UT-1B. Taking into consideration that we achieved relatively deep inhibition of cell viability in presence of relatively low concentrations of tested compounds. When both substances were mixed in 1/10 of their ICAdditive effect of all tested combinations was observed in endometrial stromal sarcoma cell line (ESS-1), though it responded to treatment with rapamycin moderately. Endometrial stromal sarcoma tumours are, in most cases, hormone-sensitive. In systemic treatment of these tumours anti-oestrogen agents are widely using in combinations with cytostatics and radiotherapy - DNA synthesis alteration by GEM- mTOR pathway inhibition- Oestrogen receptor deactivation.The importance of mTOR signalling in leiomyosarcoma tumours biology is known in vitro as well as in vivo in patients suffering from such conditions as i.a. breast cancers, gliomas There are two main limitations of mTOR inhibitors usefulness in clinical practice. One is acquisition of resistance by cancer cells, second one is toxicity to patients. Acquiring the resistance to mTOR inhibitors (most commonly rapamycin and its derivates) was detected in various tumours' models Multidrug regimens have a chance to overcome both of them. Obviously, these may allow decreased dosing by exploiting additivity and synergy in drugs combinations. Hence, lead to reduce dose-depending toxicity, but targeting multiple cellular pathways at the same time gives, also a chance to avoid formation of cells resistance to anti-neoplastic agent. When many pathways are altered simultaneously then single mutation resulting with resistance to one of agents is not associated with survival handicap and risk of resistance is much lower comparing to monotherapy.The mTOR pathway is considered as one of regulating mechanisms responsible for cell sensitivity to GEM. Such relation was already proved in various cancers including breast and pancreatic Interestingly, the combination of GEM and mTOR inhibitors is already in early phases clinical trials. So far results of the studies are inconsistent. Combination of temsirolimus  and GEM showed promising activity in pancreatic cancer in vivo. Secondly, the reported project do not include any mechanistic research, partially the activity mechanisms of used compounds were previously described The present study is not free of limitations. The most important is using only 2D models of uterine sarcomas and carcinosarcoma, such models are easily reproducible and allow to perform isobolographic analysis of relations between tested substances, but on the other hand do not fully reflect behaviour of tumours 1. Carcinosarcoma cell lines (both SK-UT-1 and SK-UT-1B) do not respond to RAP and respond relatively weak to MLN treatment. Although, additive and supraadditive effects were noted in combined treatment with GEM and MLN.2. Additive effect in all tested combinations was observed in endometrial stromal sarcoma cell line (ESS-1). This suggests that combinations of mTOR inhibitors and GEM might be effective combination in treatment of such tumours, especially in cases of hormone-insensivity.3. Leiomyosarcoma cell line (MES-SA) appeared as the most sensitive to both mTOR inhibitors among all of tested cell lines. Additive effects observed in combinations of GEM, RAP and MLN make them promising for future preclinical and clinical trials.4. Tendency to antagonism between GEM and MLN observed in MES-SA cell line is unexpected finding and might prompt mechanistic research aimed to explain this phenomenon


P = 0.0009). Furthermore, a significant improvement was observed regarding short-term Constant score , and short-term visual analogue scale score . This systematic review indicates the efficacy of PRP when applied to the bone–tendon interface during arthroscopic rotator cuff repair.Because of its healing properties, platelet-rich plasma (PRP) has been applied to the bone–tendon interface during arthroscopic rotator cuff repair to improve surgical outcomes. However, its effects remain ambiguous. Therefore, we conducted this systematic review and meta-analysis to assess the effects of PRP on retear rate and functional outcomes. Randomised control trials were identified and extracted. Data collection was completed on 15 February 2020. The results are expressed as the risk ratio (RR) for the categorical variables and weighted mean difference for the continuous variables, with 95% confidence intervals (CIs). Analyses were performed using RevMan 5.3 software. Seven randomised controlled trials published from 2013 to 2018, with 541 patients in total, were included. The results revealed a significant decrease in retear rate [RR 0.38, 95% CI ,  The gold standard for treatment is arthroscopic repair when conventional treatment fails4. Even though the surgical technique has been continually improved, the retear rate remains high at 34%–94%, as revealed by several studies8. Notably, poor tendon-bone healing is considered a cause of retear10. The original fibrocartilage tissue is replaced by fibrovascular scar tissue after surgery, which has lower mechanical flexibility than does the original tissue14. Besides, pain and weakness are also an issue of rotator cuff tear which may have a great influence on the patients’ daily activity. It is worth mentioning that several studies have demonstrated the benefits of platelet-rich plasma (PRP) therapy as an adjuvant to rotator cuff repair to improve surgical outcomes20.Rotator cuff tear causes pain and limited motor function of shoulder21. It contains an abundance of growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF)23. Recent studies have reported that PRP can potentially aid wound repair22. Nevertheless, the effects of PRP on rotator cuff repair remain controversial17. Delve into the previous studies17, some of these16 stated that PRP application is effective in reducing retear rate and improving clinical outcome while the other17 showed no improvement in both. Furthermore, some studies included different type of rotator cuff tear, some included PRP application both intra-operative and post-operative, and some included patients with rotator cuff tear that were not diagnosed by MRI or sonography pre-operative. Hence, we conducted this systematic review and meta-analysis of randomised controlled trials (RCTs) to evaluate the outcome of PRP application on the bone–tendon interface during arthroscopic rotator cuff repair.PRP is a concentration of platelets prepared through centrifugation of autologous whole blood24 as type IV or V for MRI findings and following Barth et al.25 as grade IV or V for sonography findings), Constant score, the University of California at Los Angeles (UCLA) activity score, Disabilities of the Arm, Shoulder, and Hand (DASH) score, or visual analogue scale (VAS) score.The inclusion criteria of this study were as follows: (1) full-thickness rotator cuff tear; (2) diagnosis based on MRI or sonography; (3) application of arthroscopic rotator cuff repair; (4) application of PRP on the bone–tendon interface during arthroscopic repair in the intervention group; and (5) reported outcomes, including retear rate  application of a plasma-rich fibrin or matrix; (2) diagnosis not based on MRI or sonography findings; (3) partial-thickness tear of the rotator cuff; and (4) sonography-guided injection of PRP postoperatively.26. We searched electronic databases, such as PubMed, EMBASE, Cochrane, and Google Scholar. Medical subject heading (MeSH) terms were used for searching these electronic databases, and ‘Platelet-Rich Plasma’ (MeSH) AND ‘Rotator Cuff’ (MeSH) were used as the keywords. RCTs were identified using the refined search function in the databases, if available. In addition, articles were identified through a manual search of the reference lists of the relevant articles. The literature search spanned the date of database inception to 15 February 2020. Two reviewers independently reviewed the full texts of all potentially relevant articles to identify articles meeting the eligibility criteria. The individually recorded decisions of the two reviewers were then compared, and dissimilarities in the decisions were resolved by a third reviewer.The authors independently screened the literature, extracted data, and performed crosschecks in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelinesThe following information was obtained from each RCT identified: type of rotator cuff tear, image used for diagnosis, surgical procedure, number and mean age of the participants of PRP and control groups, follow-up duration, follow-up images, and outcome measurements.27. The following domains were assessed: (1) randomisation process, (2) deviations from intended interventions, (3) missing outcome data, (4) outcome measurement, (5) selection of the reported result, and (6) overall bias. Risk-of-bias assessment was conducted by two independent reviewers according to Cochrane Handbook for Systematic Reviews of Interventions28. Differences of opinion between reviewers were resolved by discussion and consultation with a third author.Risk-of-bias assessment was performed using the RoB 2 tool, a revised Cochrane risk-of-bias tool for randomised trials, which is a widely used quality assessment tool for evaluating RCTshttps://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman/revman-5-download). A P value of < 0.05 was considered statistically significant. We used the I2 test to provide an objective measurement of statistical heterogeneity. According to the Cochrane Handbook for Systematic Reviews of Interventions28, heterogeneity was quantified using the I2 statistic with a rough guide for interpretation as follows: 0–40%—might not be important, 30–60%—may represent moderate heterogeneity, 50–90%—may represent substantial heterogeneity, and 75–100%—considerable heterogeneity. A random-effects model was used in this meta-analysis. As for the result with I2 > 50% even though a random-effects model was used, we will remove the study that result in the heterogeneity. The results were expressed as the risk ratio (RR) for the categorical variables and as the weighted mean difference for the continuous variables, with 95% confidence intervals (CIs). Because of differences in surgical patterns, a subgroup analysis was performed on the basis of surgical pattern (single-row and double-row repair). Furthermore, we used a cut-off point of 12 months for determining whether differences existed between short-term (≤ 12 months) and long-term (> 12 months) follow-ups.Statistical analysis was performed using RevMan 5.3 software, which was provided by the Cochrane Collaboration  of studies included in each analysis.29. Eight citations that were noncompliant with the inclusion criteria were excluded after their title and abstract were screened. The full text of the remaining 14 citations was screened, which revealed three articles that dealt with the use of plasma-rich fibrin, one that involved diagnosis not based on MRI or sonography findings, one that dealt with partial-thickness tear, and two that involved PRP application through sonography-guided injection postoperatively. Finally, seven articles were selected for this systematic review and meta-analysis36 . Only one study27. The risk of bias in each study is illustrated in Fig. The quality of the RCTs included was assessed by two reviewers independently by using the RoB 2 tool, a revised Cochrane RoB tool for randomised trials36 were identified as having low risk in the randomisation process, and one was identified as having uncertain risk35. The risk of deviations from intended interventions was low in four studies36 and uncertain in three studies35. Two studies were identified as having uncertain risk36 and was identified as having high risk32 related to missing outcome data. Furthermore, one study was high risk in terms of outcome measurement35. All studies had a low risk for selection of the reported result36. Finally, the risk of overall bias was noted as low in one study30, uncertain in four studies36, and high in two studies35.Six studies36, which included 233 patients in the PRP group and 231 in the control group. The homogeneity across the studies was good . The retear rate was significantly lower in the PRP group than in the control group  but not for single-row repair  . The short-term Constant score was significantly higher in the PRP group than in the control group . Moreover, subgroup analysis revealed a statistically significant intergroup difference related to the short-term Constant score for single-row repair  but not for double-row repair   and thus the study by Pandey et al.31 was removed, which reduced the value of I2 to 0%, indicating good homogeneity (P = 0.91). No statistically significant intergroup differences were observed with respect to the long-term Constant score  . The short-term UCLA score was significantly higher in the PRP group than in the control group . Subgroup analysis revealed a statistically significant intergroup difference in terms of short-term UCLA score for single-row repair  but not for double-row repair   and thus the study by Pandey et al.31 was removed, which reduced the value of I2 to 0%, indicating good homogeneity (P = 0.93). No statistically significant intergroup differences were noted regarding the long-term UCLA score  . No statistically significant intergroup differences were noted regarding the short-term DASH score  . The short-term VAS score was significantly lower in the PRP group than in the control group . Subgroup analysis revealed statistically significant intergroup difference with respect to the short-term VAS score for both the single-row , P = 0.006] and double-row  repair patterns . No statistically significant intergroup differences were noted with respect to the long-term VAS score  (Fig. Three studies reported the long-term VAS scoreTable Retear rate, for overall and double-row repair in subgroup analysis.Short-term Constant score, for overall and single-row repair in subgroup analysis.Short-term UCLA score, for overall and single-row repair in subgroup analysis.Short-term VAS score, for overall and both single-row and double-row repair in subgroup analysis.We conducted this systematic review and meta-analysis to determine the effects of applying PRP to the bone–tendon interface during arthroscopic rotator cuff repair. The results of our analysis revealed statistically significant differences in the following aspects:37. Notably, different growth factors are required to achieve this goal. PRP has been widely used to improve the healing of bones, cartilage, and tendons41. PRP contains an abundance of growth factors, such as PDGF, TGF-beta, FGF, VEGF, and EGF23. These growth factors can trigger tissue regeneration44 and improve the vascularity of the repaired tendon48, thereby reducing the retear rate. Our analysis revealed a statistically significant decrease in the retear rate of the PRP group, namely in the double-row repair subgroup.The primary goal of PRP use is to reduce the retear rate. The tendon healing process can be divided into three stages, namely inflammation, proliferation, and remodeling49 stated that the single application of PRP is effective in increasing the local level of growth factors for up to 28 days, and that could trigger healing process of the repaired area. The injured tendon is stated to recover to its maximum strength in 12 months50. As a result, when added on PRP application, it shows significant better outcomes in short-term follow up, while the effect of PRP application is not obvious in long-term follow up.According to our finding, there are significant differences in terms of short-term outcomes but not in that of long-term ones. Zumstein et al.52, and thus, provides a better environment for tendon healing. As a result, the effect of PRP administration is not obvious. In contrast, single-row repair provides a lower biomechanical strength, and thus the effect of PRP administration is significant. It corresponds to our result which demonstrates better clinical outcomes in single-row repair group in the subgroup analysis for a short-term follow up. However, there is no adequate data to analysis the difference in each group of a long-term follow up. Thus, further studies comparing single-row and double-row repair for a long-term follow up are warranted.Previous studies had demonstrated that double-row repair has better clinical outcomes when compared with single-row repair due to it provides a better biomechanical property 17. First, the previous reviews included studies that involved intraoperative administration and sonography-guided postoperative administration of PRP. Furthermore, each study has different times of administration sonography-guided postoperatively. We thought that it will result in different outcome when compared with intraoperative administration. As a result, our review included studies that dealt with PRP application on the bone–tendon interface during arthroscopic repair since it is stated by Zumstein et al.49 that the single application of PRP is effective in increasing the local level of growth factors for up to 28 days. Second, our review included studies that administrated only PRP and not any other platelet-rich matrix in order to lower the bias caused by different material applied. Third, all the RCTs included in this review were conducted on patients with full-thickness rotator cuff tear who received diagnoses based on preoperative MRI or sonography findings since other studies included participants of partial tear and those diagnosed intraoperatively.Nevertheless, our review had several differences compared with previous systematic reviews and meta-analysesNonetheless, our review has some limitations. First, the absence of a standard preparation of PRP and the use of varying concentrations and amounts of PRP in the studies may have caused different outcomes in individual studies. Second, the tear size differed among studies. Third, the sample size of the included studies was relatively small and the data is not adequate for further analysis for long-term follow up in different surgical type. Thus, further reviews involving high-quality, large-scale RCTs are needed to overcome the limitations of this review.This systematic review and meta-analysis revealed that application of PRP to the bone–tendon interface during arthroscopic rotator cuff repair is beneficial. PRP was observed to reduce the retear rate and improve functional outcomes, namely during the short-term follow-up of single-row repair. In other words, we recommend the application of PRP on bone-tendon interface during arthroscopic rotator cuff repair for the improvement of patients’ early functional outcomes, especially in single-row repair. Last but not the least, further high-quality and large-scale RCTs are needed to provide more information of the benefit of PRP.


BackgroundDepression is a fairly common finding among end-stage renal disease (ESRD) patients and is an independent risk factor for morbidity and mortality. The psychiatric manifestations of the disease may affect their compliance to medications and alter sleep quality that is often overlooked. This translates into poor quality of life and poorer disease prognosis. Our study aims to assess the prevalence of depression and its association with compliance to medical therapy and sleep quality among ESRD patients on hemodialysis.MethodologyIn this cross-sectional study, a total of 288 hemodialysis patients with a confirmed diagnosis of ESRD were evaluated for depression using Patient Health Questionnaire-9 (PHQ-9) scale. Only patients with moderate-to-severe depressive symptoms on PHQ-9 were further evaluated for sleep quality and compliance to medications using Pittsburgh Sleep Quality Index (PSQI) and Drug Attitude Inventory-10 (DAI-10), respectively. The characteristics of ESRD patients with depression were also assessed. Median PHQ-9, DAI-10, and PSQI scores were calculated, and the correlation between study variables was assessed using Spearman’s correlation.ResultsOf the 288 included participants, 188 (65.27%) had depression as evaluated via PHQ-9. Of these 188 patients, 114 were males while 74 were females. A total of 113 (60.01%) of depressed patients had poor compliance to medication while 137 (72.87%) patients had poor sleep quality. Higher PHQ-9 scores were positively correlated with disease duration, dialysis years, and time between diagnosis and therapy  and negatively with marital and employment status . Spearman’s correlation showed a significant negative correlation of PHQ-9 scores with DAI-10 scores but a significant positive correlation with PSQI scores. The correlation between DAI-10 and PSQI was a significant negative correlation.ConclusionsThis study indicated a high prevalence of moderate-to-severe depression among ESRD patients on hemodialysis. Poor sleep quality and non-adherence to medications are frequent among ESRD patients with depression. These psychiatric components must be considered to optimize medical treatment and improve the quality of life in this subset of patients. More studies should be conducted to assess the risk factors of depression in patients with ESRD. End-stage renal disease (ESRD) is a condition in which kidneys gradually and progressively fail to perform their metabolic, endocrine, and other regulatory functions . GloballFrequent hemodialysis, fear of severe complications, financial burden, and limitations in daily life lead to severe mental effects such as depression . DepressThe dilemma is the underdiagnosis of the psychiatric components of ESRD. Lack of sufficient physician-patient interaction and medical management without necessary psychiatric consultation contributes to increased prevalence of depression in ESRD patients, which ultimately leads to dismal disease outcomes . The litSleep disturbance has been reported in up to 80% of patients undergoing hemodialysis due to kidney failure by many studies ,14. It iThis study aims to report the prevalence of moderate-to-severe depression among ESRD patients. We also aim to assess the correlation of sleep quality and compliance to medications with depression among patients with moderate-to-severe depression. Furthermore, we aim to identify their possible associations with various patient-related parameters. Because compliance with medical therapy affects disease prognosis, the results of this study may help to identify a patient population that is at a higher risk for non-compliance and hence poor outcomes among hemodialysis patients. This will aid healthcare professionals to timely manage these high-risk patients so that the medical care provided to them can be optimized.This cross-sectional study involved a total of 288 hemodialysis patients with a confirmed diagnosis of ESRD (glomerular filtration rate ≤15 mL/min). Patients with a history of recurrent psychotic episodes, prior psychiatric illness , substance abuse, and a family history of psychiatric ailment were excluded from the study. The exclusion criteria were applied after appropriate history taking. All patients underwent evaluation for depression using the Patient Health Questionnaire-9 (PHQ-9) scale. Only patients with moderate-to-severe depressive symptoms on PHQ-9 were further evaluated for sleep quality and compliance to medications using the Pittsburgh Sleep Quality Index (PSQI) and Drug Attitude Inventory-10 (DAI-10), respectively. Patients with positive scores (from 0-10) on DAI-10 were labeled as compliant while negative scores were labeled as non-compliant. All patients were categorized into their relevant categories based on their PHQ-9, DAI-10, and PSQI scores. Patients with depression and poor sleep quality were referred to the psychiatry department for proper psychiatric consultation.The normality of data was ascertained using the Kolmogorov-Smirnov test. The median scores of PHQ-9, DAI-10, and PSQI were calculated and baseline demographic variables were identified. Pertinently, the correlation of these study variables with PHQ-9 scores was calculated using Spearman’s rank-order correlation. Mann-Whitney U-test was used to identify the differences in PHQ-9 and PSQI scores among compliant and non-compliant patients. Next, we observed how PHQ-9, DAI-10, and PSQI scores were correlated using Spearman’s correlation matrix. A p-value of less than 0.05 was considered statistically significant. All statistical analysis was performed using Statistical Package for Social Sciences  version 25.0.Out of the 288 patients, 188 (65.27%) had moderate-to-severe depressive illness, as identified using PHQ-9. A total of 114 patients were males while 74 were females. The baseline characteristics of the 188 study participants are shown in Table The normality analysis revealed that the data were not normally distributed (p < 0.05). The median age of the study participants was 55 years ranging from 24 to 83 years. The details of study participants along with median PHQ-9, DAI-10, and PSQI scores are elucidated in Table A total of 113 (60.01%) of the depressed patients had poor compliance to medications while 137 (72.87%) patients had poor sleep quality. The breakdown of study participants with various PHQ-9, DAI-10, and PSQI categories are delineated in Table PHQ-9 scores were positively correlated with disease duration, dialysis years, and time between diagnosis and dialysis  and negatively with marital and employment status . The Spearman’s correlation values of demographic variables with PHQ-9 and DAI-10 are shown in Table Non-compliant patients had significantly higher median PHQ-9 scores than compliant patients (p = 0.002). Furthermore, patients with poor sleep quality had higher PHQ-9 scores than those with good sleep quality (p = 0.017). This comparison is shown in Table Spearman’s correlation matrix showed that PHQ-9 scores were negatively correlated with DAI-10 but positively correlated with PSQI scores Table .The results of our study indicate that longer duration of disease, unemployment, not being married, and a shorter time between diagnosis and hemodialysis are significantly correlated with depression (p < 0.05). These associations are also supported in studies that identify similar factors ,15. A meOur study also indicates a positive correlation between PHQ-9 and PSQI scores and a negative correlation with DAI-10 scores. The higher scores on PSQI indicate poor sleep quality , indicatA study highlighting the factors leading to depression in ESRD reported that social stigmatization and disability due to the chronic disease are important factors that contribute to the development of depression among ESRD patients . FinanciUnfortunately, the psychiatric components of the disease are not given adequate importance and are overlooked. Moreover, the lack of psychiatric consultation further deteriorates the mental health status of patients and along with the burden of ESRD, predisposes them to a depressive mental state. The results of our study necessitate proper attention to these psychiatric illnesses by clinicians so that these patients do not develop non-compliance or poor sleep quality. Furthermore, the use of non-pharmacologic interventions with cognitive behavioral therapy can also be helpful in treating such patients. Thus, the study highlights potential target areas that can be used to optimize medical therapy and improve the quality of life of hemodialysis patients. We recommend further case-control or cohort studies to evaluate the risk factors for depression so that the high-risk population can be identified and promptly treated using pharmacologic or non-pharmacologic interventions.The inclusion of only a single public sector dialysis center as the study setting constitutes one of the limitations of our study. A multi-centered study including multiple public sector hospitals would enable the researchers to describe the prevalence of depression and trends of compliance in hemodialysis patients in a more precise manner. Other public health hospitals should be used to corroborate our study findings. Assessing the causes of depressive illness among the patients would have made our results more comprehensive. Moreover, the cultural aspects of the patients were not considered which accounts for another limitation in our study. Nonetheless, the results of our study necessitate the need for curation of specific guidelines that consider the psychiatric components of the disease for optimal multidisciplinary management.This study indicated an overall high prevalence of depression among hemodialysis patients. Non-compliance to medications and poor sleep quality are immensely common entities among hemodialysis patients with concomitant depression. Prolonged disease duration, more years of dialysis, and being unmarried or unemployed predisposed patients to develop more severe depression and poorer compliance to medications. The severity of depression is also associated with poor sleep quality and non-compliance among patients. The interplay of psychiatric components is complex in ESRD, and the interaction must be kept in mind so that optimal medical therapy can be offered to this subset of patients. Further cohort or case-control studies will help to evaluate the significant risk factors for depression in hemodialysis patients.