Cryptococcal meningitis (CCM) is the leading cause of meningitis in people living with HIV (PLWH) in sub-Saharan Africa (SSA). The mortality and morbidity associated with CCM remain high. Combination of antifungal therapy, diligent management of intracranial pressure (IP) and the correct timing of the introduction of antiretroviral therapy (ART) minimise the risk of mortality and morbidity. The absence of spinal manometers in many healthcare centres in SSA challenges the accurate measurement of cerebrospinal fluid (CSF) pressure and its control.We hypothesised that four lumbar punctures (LPs) in the first week of the diagnosis and treatment of CCM would reduce IP such that in-hospital mortality and morbidity of HIV-associated CCM (HIV/CCM) would be significantly reduced.We conducted a retrospective study to assess whether receipt of four or more LPs in the first week of the diagnosis and treatment with combination antifungal therapy of HIV/CCM would be associated with the reduction of in-hospital mortality in adult PLWH.n = 5/43) compared with 62 patients who received less than four LPs (mean = 2.18 [± 0.80]) with an in-hospital mortality of 29% (n = 18/62) and a relative risk of 0.80 , p = 0.034.From 01 January 2016 to 31 December 2016, 116 adult patients were admitted to the Dora Nginza District Hospital in Zwide, Port Elizabeth, South Africa. After exclusion of 11 , 105 patients were included in the analysis. The mean age was 39.4 (standard deviation [s.d.] ± 9.7) years, 64.8% were male. All were PLWH. A total of 52.4% had defaulted ART and 25.7% were ART naïve. Forty-three patients received four or more LPs (mean = 4.58 [± 0.96]) in the first week of hospitalisation with an associated in-hospital mortality of 11.6% (In the current study of adult PLWH presenting to hospital with HIV/CCM, four or more LPs in the first 7 days following admission and the initiation of treatment were associated with a 17.4% reduction in absolute risk of in-hospital mortality and a 20% reduction in relative risk of in-hospital mortality. This mortality difference was noted in patients who survived and were in hospital at the time of the 7-day study census and persisted until the time of hospital discharge. We, therefore, conducted a single centre retrospective cohort study to determine the impact on in-hospital mortality of four or more LPs in the first 7 days of antifungal therapy compared with PLWH/CCM who received fewer than four LPs.15 The internal medicine department consists of a 120-bed unit without access to intensive or high care services and with limited access to radiological imaging apart from plain chest radiography.The study was designed as a retrospective cohort review of PLWH/CCM admitted to the department of medicine at the Dora Nginza Hospital from 01 January 2016 to 31 December 2016. The Dora Nginza Hospital is a district hospital located in the Zwide township of the Nelson Mandela Bay Municipality (Port Elizabeth), SA. The Nelson Mandela Bay region has a population of 1 152 115 and an unemployment rate of 36.6%.Clinical notes, discharge summaries and death notification registries were reviewed to identify patients who received a primary or secondary diagnosis of CCM.A standardised data collection form was prepared. This included patient demographic details, comorbidities, history of previous CCM, data of concurrent tuberculosis (TB) and details of the index admission. Patients’ folders were checked for the results of therapeutic LPs and to document the indications for the procedure. The National Health Laboratory Services (NHLS) computer records were accessed for admission bloods, CD4 count, HIV viral load (VL) and CSF results. Identifying patient material was anonymised at the time of the collection and storage of data.p-value of < 0.05 defined significance. Patients who died or left hospital within the first 7 days were excluded from the mortality analysis. Statistical analyses were performed by using IBM SPSS Statistics for Macintosh version 24.0.Continuous variables are reported as mean  when normally distributed and as median  when not normally distributed. Discrete data are presented as number and percentages. Pearson’s chi-square test and corresponding 95% Confidence Intervals (CI) were used to calculate the mortality difference between the study and comparator groups. A Approval to conduct the study was obtained from Walter Sisulu University Human Research Committee. Ethical clearance number: 027/2018.From 01 January 2016 to 31 December 2016, a total of 116 patients received a diagnosis of CCM. After exclusion of 11 , 105 patients were available for study analysis .The mean age of patients was 39.4 (s.d. ± 9.7) years. A total of 65.2% were male. All the patients were PLWH and had a median CD4 count = 37  cells/µL. Human immunodeficiency virus infection was newly diagnosed on the index admission in 25.7%. Default from previous ART was recorded in 52.4% of patients .Cryptococcus neoformans in 94.3%. One hundred and three (n = 103) patients received local guideline-based therapy consisting of a combination of amphotericin B and fluconazole. Two patients did not receive fluconazole: one had acute hepatitis B and the other, a drug-induced liver injury (DILI) resulting from TB therapy.A total of 17.1% of patients gave a history of previous CCM. Headache was the most prevalent presenting symptom (91.4%) followed by a low Glasgow Coma Scale (32.4%) . A totaln = 23/105 (21.9%) patients died during the index hospitalisation.A total of 496 LPs were performed. Each patient received a mean of 4.62 (s.d. ± 2.30) therapeutic LPs . The mean duration of hospitalisation of the entire group was 19.4 (s.d. ± 8.3) days. A total of n = 5/43), whereas those with < 4 LPs in the first 7 days had in-hospital mortality of 29% (n = 18/62). This represents a 17.4% absolute risk reduction of in-hospital mortality and a relative risk of 0.80 , namely a 20% relative risk reduction of in-hospital mortality  cm H2O versus 22.7 (s.d ± 10) cm H2O, p < 0.001.22 A schedule of at least four LPs with CSF drainage of 20 mL – 30 mL12 in the first week of diagnosis and treatment could be life-saving in settings with no access to spinal manometers.Spinal manometers are recommended for the measurement of rIP. In resource limited settings spinal manometers are seldom available. Instead, guidelines recommend using tubing from intravenous giving-sets.12 This study provides evidence that rIP in HIV/CCM can be managed without recourse to spinal manometers.The optimal management of CCM consists of a triad of (1) combination antifungal therapy, (2) intracranial pressure (IP) management with CSF drainage and (3) immune reconstitution with ART after completion of 4 to 6 weeks of combination antifungal therapy to avoid CCM-IRIS.The limitations of this study include it’s retrospective and single centres design. Also, we do not have data on the volume of CSF removed and survival beyond the index hospitalisation.In conclusion, this study shows that PLWH/CCM can be effectively managed in centres with limited access to spinal manometers. We have shown that ≥ four LPs with CSF drainage in the first 7 days of hospitalisation improves early survival.


Onchocerca volvulus, Loa loa and Mansonella perstans infections, respectively, in humans and vectors under experimental and natural field conditions. Surveys were conducted in four health districts of Cameroon using skin snip and thick blood film methods to detect skin (O. volvulus) and blood (L. loa and M. perstans) dwelling microfilaria in humans. Engorged vectors  were evaluated by LAMP. Dissected, wild-caught vectors were also analyzed. LAMP showed a prevalence of 40.4% (O. volvulus), 17.8% (L. loa) and 36.6% (M. perstans) versus 20.6% (O. volvulus), 17.4% (L. loa) and 33.8% (M. perstans) with microscopy. Simulium spp. were dissected for microscopy and pooled for LAMP. The O-150 LAMP assay infection rate was 4.3% versus 4.1% by microscopy. Chrysops spp. were dissected and analyzed individually in the LAMP assay. The RF4 LAMP assay infection rate was 23.5% versus 3.3% with microscopy. The RF4 LAMP assay also detected parasites in Chrysops spp. fed on low microfilaremic volunteers. The Mp419 LAMP assay infection rate was 0.2% for C. milnei and 0.04% for C. grahamii, while three other species were LAMP-negative. The sensitivity, species specificity, rapidity and ease of its use of these filarial LAMP assays, and validation of their performance in the field support use as alternatives to microscopy as diagnostic and surveillance tools in global health programs aimed to eliminate onchocerciasis.Conventional diagnosis of filarial infections is based on morphological identification of microfilariae using light microscopy and requires considerable expertise, is time-consuming, and can be subjective. Loop-mediated isothermal amplification (LAMP) has advantages over microscopy or PCR because of its operational simplicity, rapidity and versatility of readout options. LAMP assays represent a major step forward in improved filarial diagnostic tools suitable for low resource settings and field applicability. The study goal was to retrospectively evaluate the performance and suitability of the O-150, RF4, and Mp419 LAMP assays for diagnosing  To achiL. Loa (African eye worm) causes loiasis and can be co-endemic with onchocerciasis in Cameroon, Central African Republic, Democratic Republic of Congo, Gabon, Nigeria, and the Republic of Congo, , may experience severe adverse events   –11. Henclopathy) –14.M. perstans, Mansonella. sp. DEUX, M. ozzardi, M. streptocerca and M. rodhaini. M. perstans has the widest geographic distribution; 33 countries in sub-Saharan Africa and in South America -based methods have been developed to detect lla spp. –30, but amplicon , L. loa   is a simple to perform alternative to PCR that does not require expensive equipment and offers a colorimetric readout particularly suitable for low resource settings –37. In aL. loa , O. volvvolvulus , and M. perstans . The pre22.1O. volvulus infections, a total of 670 skin snips samples were collected from four health districts (HD) in the Littoral region of Cameroon that were subjected to microscopy and the O-150 LAMP , negative predictive value (NPV) and the Kappa index) of all three LAMP assays using microscopy as reference diagnostic method were calculated . The O-1All three LAMP assays had higher sensitivity and specificity than microscopy. The RF4 and Mp419 LAMP assays had high PPV, while O-150 was intermediate; however, these findings need to be discussed against the fact that mf microscopy in onchocerciasis has a low sensitivity, in particular in hypoendemic settings (see discussion), and a latent class analysis would be helpful to determine the “true” (=higher) prevalence values (2.3O. volvulus DNA) and negative (or molecular biology grade H2O) control samples were included. Of the 16 pools, which consisted of 32 engorged flies, all 16 (100%) were positive by the LAMP assay.A total of 16 pools (2 flies/pool) of flies that had fed on a volunteer (mf load 50 mf/mL) were analyzed using the colorimetric O-150 LAMP assay. Positive (2.4Chrysops flies that had fed on volunteers with low (<10 mf/mL) or high  mf load were evaluated with the colorimetric RF4 LAMP assay. Positive (L. loa DNA) and negative (molecular biology grade H2O) control samples were included. Of the 18 fliesthathadfedonthevolunteerwithlow parasitemia, 88.9% were positive, while 94.4% of the 18 flies that had fed on the volunteer with high parasitemia were positive , while 11 of 12 pools (91.7%) scored positive after feeding on a volunteer with 80,000 mf/mL.2.6S. damnosum) collected, 9,134 were dissected to compute the entomological indices and the remaining flies were stored in 80% ethanol  were analyzed with the LAMP assay. As per the World Health Organization , we assu2.7Chrysops dissected and examined by microscopy   and C. grahamii (0.04%) flies (Wild-caught %) flies .3O. volvulus  while the Melong HD recorded the lowest prevalence of 28.1%. The greater number of positives using LAMP is consistent with the greater sensitivity of LAMP previously reported in populations that have received MDA in which the low sensitivity of microscopy was exacerbated (M. streptocerca) as demonstrated in other studies  pools from the 32 flies engorged on the volunteer were positive by the LAMP. When the assay was further used to analyze pools of wild-caught black flies LAMP detected a similar number of positives compared with dissection and microscopy. It is important to note that the infection and infective rates from pool screening were calculated with an assumed parity of 50% as recommended , while substantially lower in Manjo (5.9%).The Chrysops was clearly demonstrated using experimentally infected Chrysops which had fed on individuals with either high  or low parasitemia . After ingestion by the vector, L. loa microfilariae require 7-14 days to develop into infective stage larvae  parasitaemia suggests the suitability of this method for identification of Chrysops with extremely low levels of infection that may be missed using microscopy. Significantly higher rates of infection were detected using LAMP, with the East MDA, East non-MDA, South West 1, and North West sites having the highest infection rates with LAMP (16.4%-31.6%) while the South West 2 CDTI project site recorded the lowest infection rate of 0.5%.The suitability and sensitivity of LAMP to detect infection in infected e larvae , 50. In Despite more than a decade of onchocerciasis CDTI in the South West 1 CDTI project, infection rates have remained high. This may be due to the persistence of a permanent parasite reservoir. Alternatively, a study by Wanji et al. has identified increased apathy towards ivermectin intake in the study area . Low adhCulicoides vectors, providing a new tool for entomological screening for M. perstans.The Mp419 LAMP had excellent sensitivity (96.7%), specificity (94.2%) and Kappa index (89%), when using blood samples, indicating that the LAMP assay is equivalent to microscopy. The utility of the Mp419 LAMP assay was also demonstrated in the O. volvulus, L. loa and M. perstans in humans and different vector species under experimental and field conditions. These new tools should facilitate surveillance and control efforts for important filarial diseases.In summary, we demonstrate the suitability and usefulness of the panel of simple LAMP tests to detect 44.1The parasitological survey of the study was conducted from the month of May 2020 to January 2021 in the Littoral region of Cameroon, in the Loum , Melong , Yabassi , Nkondjock  and Manjo health districts (HDs), belonging to the Littoral 2 Community-Directed Treatment with Ivermectin (CDTI) project . For theSimulium), South West, North West and East region (Chrysops) and the Littoral region (Culicoides) in Cameroon. Blackflies were collected in the village of Biatsotsa located on the River Mbam in the Bafia HD, part of the Mbam drainage basin. The Bafia HD belongs to the Centre 1 CDTI project area that, despite over 20 rounds of annual CDTI, is still meso-endemic for onchocerciasis  and South West 2 (Mamfe HD) are situated in areas of mild he study . The Eashe study , 56.4.2The study was comprised of two main parts: parasitological survey and an entomological survey. The parasitological survey involved the use of skin/blood samples to detect skin-dwelling and blood-dwelling mf infection and the entomological survey involved the use of experimentally-infected flies to determine sensitivity and a field phase using wild-caught insects.4.34.3.14.3.1.1The examination for the presence or absence of nodules was done following the WHO standard protocol as previously conducted . Consent4.3.1.2Skin snipping was done as previously described . Prior t4.3.1.3DNA from skin biopsies was extracted using the QIAGEN DNeasy Blood and Tissue Kit , following the manufacturer’s instruction. Using sterilized forceps, skin biopsies were placed into 2 mL Eppendorf tubes (Eppendorf AG) containing 160 mL of 1X Phosphate Buffered Saline  and 18–20 (1.0–1.3 mm) glass beads . The skin snips were homogenized at 7000 rpm for 180s using a MagNA Lyser Instrument . After homogenization, the Qiagen protocol was followed and DNA was eluted in 200 μL of elution buffer and stored at -20°C until use for LAMP assays.4.3.24.3.2.1Diurnal blood collections were performed between 8am-4pm. The thick blood film (TBF) was prepared by spreading 50 mL non-heparinized finger-prick blood on clean, labeled and dry slides covering an area of 1.5×2.5 cm. The smears were allowed to air-dry and then packaged for transport back to the base for staining with 10% Giemsa using standard procedures .4.3.2.2L. loa and M. perstans) were identified using microfilarial identification keys , following the manufacturers’ instructions. Blood samples were homogenized with the use of a pipette prior to dispensing 200 μL of the blood samples into the respective labelled 1.5 mL tubes containing 20 μL of Protease. To these tubes, 200 μL of Buffer AL was added and thoroughly homogenized by pulse vortexing for 15 seconds and incubated at 56°C for 10min. Following incubation, 200 μL of 96% ethanol was added and vortexed thoroughly before pipetting into a QIAmp DNA Mini spin column which was placed in a 2 mL collection tube. The remaining steps were performed as described above for skin snip DNA extraction.4.44.4.14.4.1.1S. damnosum flies allowed to take blood on a consented microfilaridermic volunteer (50 mf/mL) were captured using Simulium rearing tubes. and transported to the laboratory . During this period, flies were fed with sterile 15% sucrose solution and maintained at a temperature of 23–28°C and 79–80% relative humidity   . To prodng, USA) ) for up 4.4.1.3M. perstans microfilaremic volunteers were seated with their legs exposed to the knee level under a rectangular netting cage trap. The cage was raised for 10-15 minutes to allow contact between host and midges and then lowered to trap the attracted midges. After 15 minutes, the Culicoides spp. within the cage were aspirated and blown into labeled 50 mL Falcon tubes filled 3/4 with plaster of Paris (POP) which served as an absorbent layer at the bottom of the tubes to retain moisture. Once transported to the insectarium , they w4.4.24.4.2.1Simulium flies coming for a blood meal were caught just as they landed using an aspirator as described in other studies . Undissected flies were pooled in batches of 100 into 80% ethanol for DNA extraction and LAMP pool screening.Captured female blackflies were anaesthetized with chloroform and identified for species and counted. Then the flies were dissected in physiological saline under a dissecting microscope by entomology experts who distinguished parous  from nulliparous  flies as described . The abd4.4.2.1.2Each pool of whole flies, fly heads or bodies was weighed  and placed in a 1.5 mL Eppendorf tube. Total DNA was extracted using the Zymo Research Genomic DNA Tissue MiniPrep Kit  following manufacturer’s protocol; for pools of bodies (tissue mass >25 mg), the volumes of digestion buffer and proteinase K were doubled. All samples were eluted with 200 μL and the DNA stored at -20°C until use.4.4.2.2Insect collections were performed between 7:00 and 18:00 from the August to October 2014 for a period of 5 days/ community . Trained4.4.2.2.1Chrysops were dissected in 0.9% NaCl under a dissecting microscope. The head, thorax and abdomen of each fly were separated and the abdomens were teased gently to pull out the ovarioles to determine parous status of the flies. Parous flies were further dissected to find L. loa larvae, counted and the infection rates calculated as described  and 10 μL Proteinase K, incubated at 55°C for 1-3 hours followed by DNA extraction according to manufacturer’s protocol. DNA was eluted with 200 μL of elution buffer and stored at -20°C until use.Individual 4.4.2.3Culicoides identification.Collections of midges were carried out using Centers for Disease Control miniature black UV-light traps . UV-light traps set at strategic positions around human dwellings at each of the seven sites. Midges were collected hourly between 6:00 and 18:00. The contents of each trap were emptied hourly using aspirators into labelled plastic cups containing 80% alcohol and then transported to the laboratory for 4.4.2.3.1Culicoides species was done based on keys through the examination of the wing pigmentation pattern under a dissecting microscope , following the manufacturer’s instruction. Flies were placed into 2 mL Eppendorf tubes containing 80 μL of 1X Phosphate Buffered Saline  and 18–20 (1.0–1.3 mm), glass beads  and homogenized at 4000 rpm for 90 seconds using a MagNA Lyser Instrument (Roche Diagnostics GmbH). After homogenization, 180 μL of ATL buffer and 20 μL of proteinase K were added into the homogenate and incubated at 56°C overnight. Following the overnight incubation, samples were processed per the protocol and the DNA was eluted with 200 μL of elution buffer. The eluted DNA was stored at -20°C until use for LAMP assays.4.5O. volvulus tandem repeat region O-150 was targeted in the study, the colorimetric O-150 LAMP assay was performed with some modifications . Samples were considered positive for the indicated filarial nematode if a color change from pink to yellow was observed (2O) remained pink.To prevent cross-contamination, all sufaces were cleaned with 10% bleach solution and filter tips were used. All tubes are tightly closed and never opened after amplification to avoid contaminating the work area. The ications . The L. ublished . The M. ublished , with soobserved , while n4.6Data collected and compiled on paper record sheets were entered into Microsoft Excel 2010 and then exported to GraphPad Prism version 9.0 for subsequent analyses. Contingency tables were used to express the relationship between variables. Fischer’s Exact test was used to compare proportions with P ≤ 0.05 considered significant.LAMP assay performance characteristic values , negative predictive value (NPV) and Kappa index) standard methods employing 2x2 contingency tables for evaluation of diagnostic tests were used. Microscopy was used as the “gold standard”. The 95% confidence intervals for all values were calculated as previously described .Simulium flies using microscopy were computed as previously described (Simulium and Culicoides flies were computed using the algorithm described by Katholi and colleagues (Infection and infective rates for escribed . The inflleagues .m = number of pools, n = size of pool, k = number of negative pools and P = prevalence of infection.Where Chrysops was determined as the proportion of infected flies to the total number of flies dissected as previously described (The infection rate for escribed .Supplementary MaterialSupplementary Table S1Supplementary Table S2


Many patients with hypertension require more than one drug to achieve blood pressure control. They are prescribed with fixed-dose combination (FDC) antihypertensive therapy rather than monotherapies. Although it is commonly admitted that the use of FDC may improve compliance to treatment, adherence rates in patients receiving FDCs have not been documented. Therefore, the aim of this study was to assess the adherence to treatment in patients receiving FDCs of antihypertensive medications in a real-world setting in Egypt.We conducted a multi-center cross-sectional study over a period of 1 year from Jan 2017 to Jan 2018. We included patients above 21 years old with essential hypertension who were already prescribed with an FDC of antihypertensive treatment for at least 3-month duration. We assessed the adherence to treatment by patient self-assessment using the Morisky 8-Item Medication Adherence Scale (MMAS 8).This study enrolled 2000 hypertensive Egyptian patients. The mean age of enrolled patients was 55.8 ± 10.9 years. Male to female ratio was 1.08. The mean MMAS score was 6.5 ± 1.9. Our analysis showed that 825 (41.3%) patients reached high adherence score, 523 (26.2%) medium adherence, and 652 (32.6%) low adherence.p < 0.001). Out of 746 patients with controlled blood pressure (< 140/90), 387 (51.9%) patients were highly adherent to treatment. Higher level of education was significantly associated with high adherence rate; 559 (67.8%) patients were university graduates, 232 (28.1%) had primary/secondary school education, and 34 (4.1%) were illiterate (p < 0.001).Furthermore, Male patients showed higher adherence rate than females  fixed-dose combination was associated with higher adherence rate than twice regimen daily (0.8%), Higher adherence to medication is associated with high level of education and employment, and it can lead to better blood pressure control. Thus, patient education programs may increase patients’ adherence to their medication. Hypertension (HTN) is a major global public health concern and is the leading cause of global death or disability . About 3Target BP control in hypertensive patients cannot be achieved without “good” adherence to prescribed medications according to healthcare providers’ instructions . AccordiWe followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement guidelines when reporting this manuscript. This study was approved by the Egyptian Ministry of Health.This was a multi-center, cross-sectional, observational study that was conducted over a period of 1 year from Jan 2017 to Jan 2018. We included 2000 Egyptian hypertensive patients from 100 centers spanning the Mediterranean coast, Nile Delta region, and southern Egypt.We included patients meeting the following criteria: (1) males or females aged > 21 years; (2) patients with essential hypertension who were prescribed antihypertensive treatment with FDC for at least 3-month duration. All patients signed informed consent; and (3) patients willing to give written informed consent. We excluded all patients with severe renal impairment (GFR < 30 ml/min) or have any one of the following conditions: pregnancy, lactation, secondary hypertension, hypersensitivity to the used medications, or participating in other clinical studies.For each eligible patient, we reported the following data; during the recruitment process, the following data were collected for each patient eligible for the study: socio-demographic characteristics , educational status, marital status, and occupation. Furthermore, we collected the data regarding the duration of hypertension, number of previous antihypertensive medications, duration, and type of treatment with FDC of anti-hypertension medications. Moreover, data regarding blood pressure measurements, medical history/comorbidity , family history of hypertension and cardiovascular disease, and self-administrated MMAS 8 questionnaire were obtained. Highly adherent patients were identified with the score of 8 on the scale, medium adherers with a score of 6 to < 8, and low adherers with a score of < 6.All investigators received a formal, standardized training for blood pressure measurements. The blood pressure was assessed in the sitting position following a 5-min rest using a standardized automated sphygmomanometer (Omron T9P). A total of three readings were obtained, in which the first reading was discarded and the average of the second and third readings was obtained. Data were collected in the form of case report form (CRF). The CRFs were computerized with the data validation process, in which any raised inconsistencies led to appropriate queries to investigator resolution who is obliged to respond by confirming or modifying the inconsistent data. All of the key data were checked for each CRF (absence of missing data and consistency control).The primary objective was to measure the percentage of patients highly adherent to the treatment with FDC of anti-hypertension medications. The secondary objectives were to identify different patients’ profiles by comparing the characteristics of patients with a high, medium, and low adherence to the medication and to determine the causes of poor adherence to medication.Assuming that high adherence to treatment would be achieved in 50% of patients, with ≤ 10% of patients non-evaluable, enrollment of 2000 patients would provide a precision of 2.3% in the calculation of the 95% CI. If the rate of 0adherence were to be either higher or lower than 50%, precision would be better.t test, Wilcoxon signed-rank, and McNamara test for continuous variables. Chi-square test was used in case of categorical variables. For all statistical tests, P value ≤ 0.05 was considered statistically significant and the 95% CI for the percentage of highly adherent patients has been calculated. Univariate and multivariate logistic regression analyses were applied to identify the predictive factors for achieving high adherence to antihypertensive treatment. Univariate logistic regression considered each factor individually and multivariate considered all factors simultaneously. Multivariate model selection was carried out using stepwise and forward method by removing variables from the model that were not significant. The Hosmer–Lemershow test was used to measure the goodness-of-fit of the logistic regression model with p value ≤ 0.05 indicating poor fitness of model. Odds ratios (OR) with 95% confidence intervals (95% CI) were provided. All statistical tests were performed using SPSS program version 25.All categorical variables were presented in frequency and percentage, whereas numerical variables were presented with mean and SD. Categorical data were described by frequency and percentage. Comparative analysis and inferential statistics were performed using paired The mean age of enrolled patients was 55.8± 10.9 years old. The majority of participants were males 1040 (52.0%). Regarding the physical activity, 451 (22.6%) were inactive, 676 (33.8%) with low activity, 667 (33.4%) with moderate activity, and 206 (10.3%) with high activity. About two thirds of patients 1503 (75.1%) never smoke, 299 (15.0%) smokers, and 198 (9.9%) quit smoking. All demographics data are presented in Table The mean systolic blood pressure (SBP) was 140.5 ± 16.8 mmHg, and the diastolic blood pressure (DBP) was 86.1 ± 10.0 mmHg. Controlled SBP (< 140 mmHg) was presented in 847 (42.4%) patients. In addition, the mean heart rate (HR) was 79 ± 8.8 beat/min. The mean duration since diagnosis of hypertension was 9.1 ± 7.3 years. Interestingly, 1181 (59.1%) patients have a family history of hypertension, and 461 (23.1%) have no family history of hypertension.Concerning antihypertensive medication, 602 (30.1%) patients received monotherapy, 606 (30.3%) patients received two types of antihypertensive drugs, 326 (16.3%) patients received triple combination therapy, and 145 (7.2%) patients received four types of antihypertensive drugs. The mean duration of treatment with FDC of anti-hypertension medications was 39.2 ± 36.9 months. The most frequent combination used was ARBs/HCTZ 846 (42.3%), then 337 (16.9%) ACE-I/HCTZ, 251 (12.6%) ARBs/CCB, and 227 (11.4%) triple combinations (ARBs/CCB/HCTZ). More than 98% of patients received FDC once time per day.Supplementary file .The most frequent comorbidities were dyslipidemia 987 (49.35%), diabetes mellitus 885 44.25%), obesity 566 (28.3%), and coronary artery disease 309 15.45%). We summarized the medical and surgical history of patients according to the Medical Dictionary for Regulatory Activities (MedDRA) and the concomitant medications in 5.45%. We5%, obesiThe mean value of adherence to medication by MMAS was 6.5 ± 1.9. Our analysis showed that 41.3% (95% CI [39.1 to 43.4%]) patients reached the high adherence, 26.2% (95% CI [24.3 to 28.1%]) of patients were medium adherent, and 32.6% (95% CI [30.6 to 34.7%]) of the patients were low adherent to the treatment. The correlation between the medication adherence and patient’s demographics is shown in Table p < 0.001). Higher level of education was significantly associated with high adherence rate: 559 (67.8%) university level, 232 (28.1%) primary/secondary school, and 34 (4.1%) illiterate, (p < 0.001). In addition, once daily (99.2%) fixed-dose combination was associated with high adherence rate than twice daily (0.8%), p = 0.03. More than 82% of the high adherent patients were married, and 11.2% were widowed. There is no significant difference between the smokers or non-smokers regarding to the adherence to medication (p = 0.066).Male patients showed higher adherence rate than females , high adherence was found in 387 (51.9%) patients, medium adherence in 232 (27.4%) patients, and low adherence in 187 (22.1%) patients as presented in Fig. 40 mmHg, p < 0.001). Also, patients with long history of hypertension showed lower adherence with medications (p = 0.795). In terms of patients with family history, 71.5% of high adherent patients are presented with a family history of hypertension. There is no significant difference between the scale degrees regarding the duration of treatment with FDC of anti-hypertension medications (p = 0.429). The majority of high adherent patients were receiving the combination of ARBs/HCTZ (47.0%) and ACE-I/HCTZ  effects of age on treatment adherence [p = 0.001). They explained this by the heavy alcohol consumption, lower education level, and lower knowledge of hypertension control in young patients [Daniel and his colleagues found that adherence to therapy was better in the age group of 40–59 years and those > 80 years of age, and that the most highly adherent participants were 61–70 years old (31.4%). Moreover, 32 of these patients in the age group of 51–60 years (30.5%) had a moderate adherence, and half of their hypertensive patients who had low adherence rates (< 20%) to treatment were in the age group of 51–60 years, and, demonstrating significant (dherence . Similarpatients .p < 0.001). In contrast, Ambaw et al. reported that men were found to be less adherent when compared to women. They added that men are loaded by the outdoor activities which make them busy and make them forget their medications [Regarding the adherence difference in gender classification, we found that males showed highly significant adherence to treatment compared to females . This finding is similar to those of Mallat et al. [We found a significant difference between the MMAS degrees according to the number of previous antihypertensive medications; increased numbers of antihypertensive drugs are associated with intermediate and poor adherence , remembering to renew the prescriptions, and then affording the price of the medication are important elements that affect the adherence to the treatment plan , 29, 30.In an Egyptian hypertensive population treated with FDCs, higher medication adherence rates were associated with higher education level, middle eastern ethnicity, employed patients, and lower BP levels. Patients with high adherence had lower BP levels and lower BMI as compared with patients with medium and low adherence. Developing awareness through patient education programs could increase patients’ adherence to their medication.Additional file 1:. Medical History / Co-morbidityAdditional file 2:. Concomitant Medication


Ninety-nine patients with CR after induction therapy were examined, and their 5-year OS and EFS were 66.4 ± 4.9% and 56.3 ± 5.1%, respectively. The 5-year OS rates according to treatment were 59.9 ± 7.4% in the chemotherapy group and 72.3 ± 6.3% in the hematopoietic stem cell transplantation (HSCT) group (p = 0.089). The EFS was 50.1 ± 7.4% in the chemotherapy group and 61.7 ± 6.9% in the HSCT group (p = 0.098). OS and EFS according to cytogenetics were insignificant. Our findings confirmed that the response to induction treatment was important for survival and HSCT had no significant survival benefits compared with those of chemotherapy. Moreover, many early induction deaths under the age of 2 years were observed.Acute myeloid leukemia (AML) is the second most common pediatric leukemia, with a survival rate of 70%. In this retrospective study, we evaluated the treatment outcomes of pediatric AML among 144 patients diagnosed between 2000 and 2013. After induction, 80.6% of patients achieved complete remission (CR). The 5-year overall survival (OS) and event-free survival (EFS) rates were 58.8 ± 4.2% and 49.8 ± 4.2%, respectively. Based on the response to induction therapy, the 5-year OS was 66.9 ± 5.7% in patients with CR ( Pediatric acute myeloid leukemia (AML) accounts for approximately 25% of all childhood leukemias in Korea and is the second most common leukemia type after acute lymphocytic leukemia in the country. The age-standardized rate of childhood acute myeloid leukemia in Korea for the period 1999–2011 is 28.3 per million ,5. The iTherefore, in the present study, we reviewed the treatment experience of pediatric patients with AML across 10 tertiary medical institutions in South Korea to identify the characteristics and outcomes of the disease and use the results as the basis for risk stratification and future prospective studies.We performed a retrospective study among patients with AML diagnosed between 2000 and 2013. In all, 236 patients aged <20 years at the time of diagnosis were enrolled from 10 tertiary medical centers in the Yeungnam region in Korea. Among them, 26 patients with acute promyelocytic leukemia were excluded, 36 were transferred to medical centers outside the region before initiation of treatment, 2 died before the commencement of treatment, 3 had insufficient data in their medical records, and 25 were transferred during treatment. Therefore, 144 patients were included in the final analysis of treatment outcomes .AML diagnosis was confirmed when the number of leukemia cells in the bone marrow (BM) aspirate was ≥20%, and relapse was defined as a blast count >5% in the BM. Cytogenetic analyses were performed on metaphases from BM aspirates obtained at diagnosis at the regional laboratories as part of routine care. Specific groups according to the World Health Organization (WHO) classification, based on the presence of abnormalities, such as core-binding factor leukemias t and inv(16)(p13.1q22) or t; t; mixed lineage leukemia (MLL) translocations with other partner genes, inv(3)(q21q26.2), or t; and monosomy seven, were defined irrespective of the presence of other aberrations. A normal karyotype was defined as a karyotype with the absence of clonal cytogenetic aberrations and FISH negativity for t, inv(16), and MLL aberrations. A complex karyotype was defined as a karyotype with the presence of three or more chromosomal abnormalities in the absence of one of the WHO-designated recurring translocations or inversions . Other c3; and CNS3, overt CNS leukemia as per the Rome Workshop criteria . Traumatic lumbar puncture was defined as the presence of >10 erythrocytes/mm3 in the CSF or macroscopically contaminated CSF.The cytogenetic risk status of the patients was stratified according to the AML committee of the international BFM study group criteria . The cenThe definitions of response after induction were as follows: CR, BM with a blast count <5%, absence of peripheral (PB) leukemia cells, absence of extramedullary disease; partial response (PR), BM with 5–15% blast cells, absence of PB leukemia cells, and evidence of normal hematopoietic cell regeneration. No response (NR) was confirmed when a patient did not achieve CR or PR and survived beyond the first 6 weeks of treatment. Early induction death was defined as death occurring within the first 6 weeks of treatment. OS was defined as the time from diagnosis to death or with living patients censored at last follow-up. EFS was calculated from the date of diagnosis to the last follow-up or first event .After being diagnosed with AML, the patients received induction and consolidation chemotherapy according to each institution’s policy. AML 2000, AML-BFM 2004, DCTER, 7 + 3, and 5 + 3 regimens were used for induction chemotherapy, whereas consolidation chemotherapy was performed using different regimens. Maintenance chemotherapy or HSCT was performed depending on the associated risk, donor availability, and institutional policy.p-values were two-sided, and p < 0.05 was considered significant.The patients’ demographic, clinical, and pathological data were compared among the three response groups using the Kruskal-Wallis test for continuous variables and chi-square test for categorical variables. EFS and OS values, along with their standard errors, were estimated using the Kaplan-Meier method. The log-rank test was used to compare the survival rates. When comparing the survival outcomes between chemotherapy and HSCT, patients with secondary AML and unknown cytogenetic data were excluded while patients with CR response to induction treatment were included in the study. SPSS ver. 25.0  was used for all statistical analyses. All This multicenter, retrospective study was approved by the Daegu Joint Institutional Review Board  and performed according to the Declaration of Helsinki 1975.The characteristics of the patients are summarized in n = 43, 30%). MLL rearrangements  were found in 12 (8.3%) patients. Thirty-four (23%) patients were cytogenetically normal. (Cytogenetic data were available for 127 (88.1%) patients. The most frequently observed chromosomal abnormality in this study was the RUNX1-RUNX1T1 fusion . According to cytogenetics, 90.2% showed CR with favorable cytogenetics, 76.1% showed CR with intermediate cytogenetics, and 73.3% showed CR with adverse cytogenetics (p = 0.911).The regimen used for induction was 84 (58.3%) DCTER, 12 7 + 3 regimen, and 48 (33.3%) other. The median number of cycles of induction and consolidation was two (range 1–4) and three (range 1–8), respectively. After induction chemotherapy, 116 (80.6%) patients achieved CR, 9 (6.3%) achieved PR, and 6 (4.2%) showed NR. Eleven (7.6%) early induction deaths were observed. Treatment response after induction chemotherapy according to the age group was as follows: in the 0–1.99-year group, 13 patients (59.1%) showed CR, 4 (18.2%) showed PR, and 4 (18.2%) had early deaths. The CR rates in the 2–9.99-year and ≥10-year groups were 46 (83.6%) and 57 (85.1%), respectively, and early induction deaths were observed in five (9.1%) and two (3.0%) patients, respectively . The 0–1p = 0.146) (p = 0.112)   C. The 5-= 0.112) D. The 5-= 0.044) E,F. In sp = 0.041)  .p = 0.089). The EFS rates according to treatment were 50.1 ± 7.4% in the chemotherapy group and 61.7 ± 6.9% in the transplantation group (p = 0.098). OS and EFS rates according to cytogenetic data were insignificant.Excluding patients with secondary AML and unknown cytogenetic data, 99 patients with CR1 after induction were examined, and the 5-year OS and EFS rates were 66.4 ± 4.9% and 56.3 ± 5.1%, respectively . The 5-yp = 0.089). The EFS was 50.1 ± 7.4% in the chemotherapy group and 61.7 ± 6.9% in the HSCT group (p = 0.098). OS and EFS according to cytogenetics were insignificant.The present study evaluated the survival outcomes of patients diagnosed with pediatric AML in the Yeungnam region of Korea. In this retrospective study, we evaluated the treatment outcomes of pediatric AML among 144 patients diagnosed between 2000 and 2013. Of all patients, 80.6% achieved CR after induction. The 5-year OS and EFS rates were 58.8 ± 4.2% and 49.8 ± 4.2%, respectively. Ninety-nine patients with CR after induction therapy were examined, and the 5-year OS rates according to treatment were 59.9 ± 7.4% in the chemotherapy group and 72.3 ± 6.3% in the HSCT group , patients achieving CR after two induction courses continued with three consolidation courses without HSCT in CR1. The 3-year EFS and OS rates were 52.6% and 74%, respectively. It was concluded that DB AML-01 response-guided therapy showed favorable OS without HSCT . In the Application of HSCT must be carefully considered for potential benefits. Our study demonstrated that there were no differences in the OS and EFS between patients who received chemotherapy and patients who underwent HSCT as post-remission consolidation therapy. According to the cytogenetics data, the survival outcome of chemotherapy and HSCT did not show any significant difference. In addition, in a previous study, we had reported that there is no difference in the survival outcome based on donor type and stem cell source after allogenic HSCT . In a recent study of pediatric AML patients in China, unmanipulated haploidentical HSCT may overcome the poor prognostic significance of resistant to the first course of induction chemotherapy in children with AML . Anotherp = 0.074). Although it is not statistically significant, this seems to be due to the small number of patients involved with adverse cytogenetics. In adverse cytogenetics, transplantation may help improve survival, and if there is no suitable donor, haploidentical HSCT should also be considered. In addition, HSCT should be considered in secondary AML and AML with chloroma, which showed relatively poor survival.In this study, among adverse cytogenetics, OS and EFS in the transplantation group showed a tendency that the treatment outcome was better than that of chemotherapy , is a malignant extramedullary tumor that involves immature cells of myeloid origin. The reported incidence of MS in pediatric AML is 10–20% ,18. It mOne study on COG reported that the prognosis was worse in patients with extramedullary leukemia with skin involvement than in patients with non-skin involvement, and CNS positivity was more common in this group. Patients with non-skin involvement reported a high incidence of t abnormalities and a good prognosis. Local radiotherapy did not improve the survival outcome in these patients . A singlIn the UK Medical Research Council Acute Myeloid Leukemia 12 (UK MCR AML 12) trial, patients with AML were randomized to receive mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy, and 270 patients entered the second randomization phase, receiving four or five treatment courses in total. There was no difference in the CR rate between the induction regimens, but there was a benefit associated with mitoxantrone with regard to the relapse rate. However, this did not translate to better EFS or OS rates. The results of the second randomization did not show a survival benefit in association with the fifth course of treatment, suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. In that study, the EFS was superior to that observed in the preceding AML10 trial, partly owing to fewer deaths in remission, highlighting the importance of supportive care .In our study, the 5-year OS and EFS rates were 58.8 ± 4.2% and 49.8 ± 4.2%, respectively. However, when the treatment period was analyzed, it was confirmed that the EFS associated with AML had shown improvement since 2006 (5-year EFS 57.1 ± 5.7% vs. 41.0 ± 6.2%), without major changes in the protocol. This may be because the level of supportive care has improved in recent years, as noted in the UK MRC AML12 trial. Owing to the retrospective nature of this study, an accurate treatment-related mortality analysis was not possible; hence, this study has limitations in establishing the role of supportive care in improved EFS.In a Nordic study, cytogenetics and the presented WBC count were the only independent prognostic factors associated with overall survival; age was not an independent prognostic factor . In our According to our findings, four (18.2%) of the 22 children aged <2 years died. The rate of early death during induction was higher than that in other age groups. Therefore, it is necessary to develop a treatment protocol to increase the rate of CR while reducing the levels of toxicity in this patient group.The results of the present multicenter study conducted in the Yeungnam region, Korea, are very meaningful as they reflect the therapeutic results of pediatric AML, when patients are treated with various protocols in a real-world setting. However, owing to the limitations associated with retrospective studies, the protocols were not uniform across the institutions. Some data about the cause of death were not available. Additionally, the results of genetic tests were not available for some patients.Our findings confirmed that the response to induction treatment was important for survival, HSCT had no significant survival benefits compared with those of chemotherapy, and there were many early induction deaths under the age of 2 years.Further prospective studies must focus on the development of new treatments aimed at reducing the rate of toxicity and improving the remission rate in patients aged <2 years. Additionally, it is crucial to develop novel therapies with improved long-term outcomes; moreover, careful identification of high-risk patients who can benefit from HSCT is required.


This study describes the use of thigh-worn accelerometers to collect high-quality data on sedentary time and physical activity in the Maastricht Study, a prospective cohort study in the Netherlands. Data have been collected in 9000 participants, aged 40-75 years, 49% women, and 25% has type 2 diabetes by design. All participants were asked to wear an activPAL accelerometer for 7 days. Percentage sedentary, standing and stepping time of waking time were calculated. Participants had on average 6.4 valid days (≥14h of monitoring) and 90% wore the device >4 days. Men spent significantly more time sedentary than women (63.3±10.3% versus 57.0±10.1%); standing and stepping time were significantly higher in women  than in men . Sedentary time significantly increased with increasing age while standing time decreased; no clear age-gradient in stepping time was found.


ALK fusion gene-positive non-small cell lung cancer (NSCLC). As per the approval condition in Japan, this post-marketing surveillance (PMS) study evaluated the clinical safety  and efficacy (including ORR and PFS) of ceritinib in Japanese patients. Interim analysis was conducted ~ 2 years after the start of this non-interventional, multicentre, uncontrolled, open-label, special drug-use investigation and results are reported from March 28, 2016 to April 28, 2018. Each patient was followed up for 1 year. Most patients started treatment with 750 mg ceritinib. Safety profile was similar to that observed at the time of approval. No new AEs or ADRs with incidences higher than that at approval were identified. The rate of gastrointestinal ADRs  was 73.64%. Meaningful efficacy was observed in both post-crizotinib and post-alectinib settings, with ORR of 29.55% (95% CI 20.29–40.22) and disease control rate of 53.41% (95% CI 42.46–64.12). No concerns regarding the safety and efficacy of ceritinib were identified. No new measures, including modification of the PMS study protocol, are considered necessary.Ceritinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with unresectable advanced and/or recurrent  ALK+ non-small cell lung cancer (NSCLC) in the United States1 and the European Union2. In Japan, ceritinib was initially approved for crizotinib-resistant or intolerant ALK+ unresectable advanced/recurrent NSCLC (March 2016), and later received supplemental approval for ALK+ unresectable advanced/recurrent NSCLC (September 2017)3. Considering the limited number of Japanese patients enrolled in the clinical trials assessing the safety and efficacy of ceritinib, one of the conditions for approval of ceritinib in Japan was to conduct a post-marketing surveillance (PMS) study as part of the risk management plan in all patients treated with ceritinib.Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK+ unresectable advanced/recurrent NSCLC and also to identify any safety and efficacy issues in paediatric, elderly and pregnant patients and in patients with renal/hepatic impairment, interstitial lung disease or heart disease, if they were enrolled in the study.The objective of this study was to evaluate the clinical safety and efficacy of ceritinib in Japanese patients with During the period from March 28, 2016 to April 28, 2018 (data cutoff date), 112 case report forms (CRFs) from 80 sites were collected, and 110 patients were included in the safety analysis population. Of these 110 patients, 88 were included in the efficacy analysis population  had received ≥ 4 prior lines of therapy and 38 patients (34.55%) had received 3 prior lines of therapy before starting treatment with ceritinib. Overall, 104 patients (94.55%) had received crizotinib as prior therapy, 105 patients (95.45%) had received alectinib and 88 patients (80.00%) had received combination chemotherapy including a platinum-based drug.The initial dose of ceritinib was 750 mg in 87 patients (79.09%), 600 mg in 15 patients (13.64%), 450 mg in 5 patients (4.55%), 300 mg in 1 patient (0.91%) and 150 mg in 2 patients (1.82%); administration was started from 750 mg (as the approved dosage of ceritinib at the data cutoff date) in most patients. The median value for the mean daily dose of ceritinib (Table The median duration of ceritinib use was 60.5 days (range: 1–364); duration of ceritinib use was calculated as day of the last dose − day of the initial dose + 1 (not considering the interruption period). The median value for the actual treatment duration of ceritinib use was 51.5 days (range: 1–364), where actual treatment duration with ceritinib was calculated as day of the last dose − day of the initial dose + 1 (excluding the interruption period).Of the 110 patients included in the safety analysis population, 6 patients (5.45%) completed the 52-week observation period, 95 patients (86.36%) discontinued or dropped out and 59 patients (53.64%) discontinued the treatment due to worsening of underlying disease.Of the 110 patients in the safety analysis population, adverse events were noted in 107 patients (97.27%). A causal relationship with ceritinib was not ruled out in 99 patients, and these events were assessed as adverse drug reactions. The adverse drug reactions noted in ≥ 10% of patients (any grade) were diarrhoea (51.82%), nausea (36.36%), vomiting (28.18%), decreased appetite (15.45%), abnormal hepatic function (14.55%) and renal impairment (10%).The most common grade ≥ 3 adverse drug reactions reported in at least 2 patients were diarrhoea (6.36%), nausea (5.45%), decreased appetite (3.64%), vomiting, abnormal hepatic function, liver disorder (each 2.73%), interstitial lung disease, drug-induced liver injury, increased alanine aminotransferase (ALT) and decreased platelet count (each 1.82%). The most common serious adverse drug reactions in at least 2 patients  were nausea (2.73%), decreased appetite (1.82%) and interstitial lung disease (1.82%).Adverse events leading to discontinuation of ceritinib were noted in 70 of 110 patients (63.64%). Adverse reactions leading to ceritinib discontinuation were seen in 33 patients (30%).The most common adverse drug reactions leading to discontinuation of ceritinib in at least 3 patients  were nausea, vomiting, liver dysfunction (each 4.55%) and renal impairment (2.73%).Tables Of the 110 patients in the safety analysis population, nausea/vomiting/diarrhoea (73.64%) were the most common adverse drug reactions in the priority investigation items.Adverse drug reactions were noted in 43 of 46 patients aged ≥ 65 years (93.48%), which included diarrhoea in 23 patients (50.00%), vomiting in 14 patients (30.43%), nausea in 13 patients (28.26%), decreased appetite and hepatic function abnormal in 10 patients each (21.74%) and increased blood creatinine in 9 patients (19.57%); gastrointestinal disorders were frequently noted. Serious adverse drug reactions were noted in 7 patients (15.22%), which included decreased appetite, dehydration, cerebral infarction, myocardial infarction, pneumonia aspiration, nausea, cholecystitis acute, liver disorder, pyrexia, increased ALT, increased gamma-glutamyltransferase and increased blood alkaline phosphatase in 1 patient each (2.17%).Of the 11 patients aged ≥ 75 years, 10 patients (90.91%) experienced adverse drug reactions, including diarrhoea in 6 patients (54.55%) and increased blood creatinine in 3 patients (27.27%). Serious adverse drug reactions were noted in 2 patients (18.18%) and included aspiration pneumonia, acute cholecystitis, pyrexia, increased gamma-glutamyltransferase and increased blood alkaline phosphatase, each in 1 patient (9.09%).Adverse drug reactions were noted in all 6 patients who had renal impairment while starting the treatment with ceritinib. These included renal impairment in 5 patients (83.33%), diarrhoea in 4 patients (66.67%) and vomiting in 2 patients (33.33%). Serious adverse drug reactions were interstitial lung disease, pneumonia and pulmonary alveolar haemorrhage that occurred in the same patient.Of the 5 patients who had hepatic impairment while starting treatment with ceritinib, 3 experienced adverse drug reactions, which included each of interstitial lung disease, nausea, constipation, abnormal hepatic function and increased blood bilirubin in 1 patient (20.00%). A serious adverse drug reaction of grade 4 interstitial lung disease was noted in 1 patient.Renal impairment, nausea, diarrhoea, interstitial lung disease, pneumonia and pulmonary alveolar haemorrhage were the adverse drug reactions noted in 1 patient who had interstitial lung disease while starting treatment with ceritinib; interstitial lung disease, pneumonia and pulmonary alveolar haemorrhage were of grade 3 or higher severity.Adverse drug reactions were noted in 2 of 3 patients who had heart disease while starting treatment with ceritinib. Adverse drug reactions were diarrhoea and nausea in 2 patients (66.67%), and each of pneumonia, interstitial lung disease, pulmonary alveolar haemorrhage, vomiting and renal impairment in 1 patient (33.33%). Serious adverse drug reactions  were noted in 1 patient.Of the 110 patients in the safety analysis population, 29 patients (26.36%) died. Adverse drug reactions were noted in 4 patients. The primary causes of death were malignant neoplasm progression in 27 patients (24.55%), stage IV NSCLC in 21 patients (19.09%), NSCLC in 4 patients (3.64%), metastasis to the central nervous system in 3 patients (2.73%) and metastasis to the meninges in 2 patients (1.82%). Adverse drug reactions that led to death  were pneumonia and pulmonary alveolar haemorrhage in the same patient .In the efficacy analysis population (88 patients), the best overall response rate  was 29.55% , and the disease control rate (CR + PR + stable disease [SD]) was 53.41% (95% CI 42.46–64.12)  was 91.0 days (95% CI 66.00–112.00). Figure Evaluation of the factors that may affect efficacy revealed that ECOG PS was the sole factor for which the 95% CI of the odds ratio within category did not include 1. While the response rate was 52.00% (13/25 patients) in ECOG PS “0” patients, it was 22.92% (11/48) in ECOG PS “1” patients; the 95% CI of the odds ratio did not include 1 , and a significant difference was observed in the response rate. No significant difference was observed in other factors. Additional details regarding tumour response are included in Table ALK+ unresectable advanced/recurrent NSCLC. The safety results reported in this PMS study are consistent with those reported in previous clinical studies5. Gastrointestinal disorders and hepatobiliary disorders were frequently noted, similar to the safety profile observed at approval.This PMS study reported the results of the clinical use of ceritinib in patients with For the priority investigation items, no issues requiring special attention were observed in this PMS study compared with the results of a pooled analysis of 6 clinical trials of ceritinib . QT prolongation was reported in 0.91% of patients in the PMS study versus 9.1% of patients in the pooled analysis. Interstitial lung disease was reported in 1.82% of patients in the PMS study versus 0.4% of patients in the pooled analysis. Hyperglycaemia was reported in 3% of patients and diabetes mellitus in 0.2% of patients in the pooled analysis, while no patient reported hyperglycaemia/diabetes mellitus in the PMS study. The incidence of nausea, vomiting and diarrhoea was lower in the PMS study compared with the pooled analysis: nausea, 36.36% versus 73.2%; vomiting, 28.18% versus 59.0%; diarrhoea, 51.82% versus 79.4%. This could be due to better management of gastrointestinal events with dose reductions at the appropriate time and administration of antiemetics or antidiarrhoeals. Pancreatitis was reported in 1.82% of patients in the PMS study (as a priority investigation item), while the pooled analysis reported pancreatitis in 0.1%, increased amylase in 5.8% and increased lipase in 4.6% of patients. Bradycardia was reported in 0.91% of patients in the PMS study versus 0.7% of patients in the pooled analysis. Pericarditis was reported in 0.91% of patients in the PMS study (as a priority investigation item), while the pooled analysis reported 1.7% of patients with pericarditis, along with 1.1% of patients with pericardial effusion. Infection was reported in only 1.82% of patients in the PMS study (pneumonia and otitis externa in 0.91% each), while the pooled analysis reported pneumonia in 1.3%, lung infection in 0.7%, oral candidiasis in 0.7%, gastroenteritis in 0.6% and pharyngitis in 0.5% of patients. Hepatic impairment was reported in 33.64% of patients in the PMS study (as a priority investigation item), while the pooled analysis reported up to 60% of patients with liver laboratory test abnormalities, 0.7% of patients with hepatotoxicity, 48.3% of patients with increased ALT and 39.5% of patients with increased aspartate aminotransferase (AST).ALK+ NSCLC previously treated with chemotherapy and crizotinib)6. No new adverse events or adverse drug reactions with incidences higher than that at approval were identified in this study.The safety profile reported in this PMS study is also in line with the safety profile observed in the Japanese subgroup of patients (N = 24) from the ASCEND-2 study , and in the ASCEND-2 study, the response rate was 37.1% (95% CI 29.1–45.7) for the overall population and 45.8% (95% CI 25.6–67.2) for the Japanese subgroup . It is important to note that the PMS study was less restrictive compared with clinical trials and did not set any patient inclusion/exclusion criteria in terms of performance status and previous therapy. The PMS study included a greater number of patients with a poor condition at baseline compared with the ASCEND-2 study, including patients who had an ECOG PS of 3 or higher, had brain metastasis at baseline or had received ≥ 4 prior lines of therapy. A direct comparison of the efficacy results was not feasible due to the difference in patient characteristics and also the limited tumour assessments in the PMS study.There were no safety or efficacy issues in elderly patients and no safety issues among patients with renal/hepatic impairment or interstitial lung diseases/heart diseases.7, ceritinib is recommended as the first-line therapy (PS 0–1) for patients with ALK+ NSCLC (recommendation grade 2B). Ceritinib as second- or later-line therapy is recommended for ALK+ NSCLC patients with resistance to or progression after treatment with first-line ALK-tyrosine kinase inhibitors .As per the Clinical Practice Guideline for Lung Cancer in Japan (published on November 2019)No new adverse events or adverse drug reactions whose incidences were especially higher than that at approval were identified and no new measures, including modification of the PMS study protocol, are considered necessary. The occurrences of adverse events and adverse drug reactions will continue to be monitored carefully, and efforts will be made to raise awareness among physicians and medical institutions by using the package inserts and other materials.As per the approval condition, this investigation aimed to include all Japanese patients treated with ceritinib for a specified post-marketing period. Patients starting ceritinib before the conclusion of the contract with the medical institution/municipality were allowed to enrol in the investigation and register after the conclusion of the contract.ALK+ unresectable advanced/recurrent NSCLC, and 500 patients were to be included in the safety analysis population. The target sample size for registration was set at 520 patients to make up for patients who might be excluded from the safety analysis population. A central registration system was adopted for patient registration. The data recorded by the investigator/sub-investigator in CRFs were collected for this investigation.This multicentre, uncontrolled, observational study  was conducted in accordance with the Good Post-marketing Study Practice (GPSP) ordinance in Japan. The study protocol and the implementation guideline (summary of the study protocol) were approved by a scientific/ethical review committee of Novartis. Then the implementation guideline was presented to and was approved at all participating sites/institutions by institutional review boards (IRBs) or approved according to each institutional rule. Informed consent was not obtained from the patients for this survey, because obtaining informed consent is not necessary in GPSP ordinance. However, as approved by all IRBs, before the survey was conducted, the following were explained to the patients by investigational doctors; "Objective and procedure of the survey", "Personal Information Protection Law" and "Publication of the survey information". Furthermore, none of the authors had access to identifying patient information when analysing the data because of Personal Information Protection Law. The names of the participating institutions are not listed in the manuscript due to restrictions on disclosure. The target sample size for registration was 520 patients with As this is a non-interventional investigation, visit schedule was as per routine medical practice. The investigator/sub-investigator recorded data in the CRFs at every patient visit, if possible.Each patient was followed up for 1 year (52 weeks). Patients discontinuing or completing treatment with ceritinib in less than a year from the start of treatment were followed up to 30 days after the final dose, and the follow-up information was entered in the CRFs.This study collected information including patient characteristics, data on ceritinib use (duration and dose), use of any concomitant drugs or therapies, laboratory parameters, pregnancy information in women, safety and efficacy.Safety assessments included adverse events, adverse drug reactions (defined as an adverse event related to ceritinib), seriousness, priority investigation items  and laboratory parameters . Each priority investigation item included a specific group of preferred terms of standardised Medical Dictionary for Regulatory Activities (MedDRA) as per protocol. The severity of adverse events was evaluated as per the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.The safety analysis population included all patients whose CRFs were collected except those who met the following safety analysis exclusion criteria: patients whose CRFs were lacking the signature or name/seal of the investigator/sub-investigator, patients who received treatment out of the contract period, patients whose adverse events were not recorded, patients whose registration was not fixed, patients with duplicate registration, patients with prior ceritinib use, patients who had participated in a study for unapproved drugs, patients with off-label use and patients who had not visited the site after the initial dose.Efficacy was assessed with ORR and PFS. ORR was evaluated as per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (using the best response at 6 months from the start of treatment or at the end of the observation period). Patients with confirmed CR or PR in the assessment were regarded as responders. ORR was assessed in the efficacy analysis population, which consisted of all patients included in the safety analysis population excluding those for whom an efficacy assessment was not feasible. PFS was evaluated from the start of treatment of ceritinib to the first onset of exacerbation or death and was assessed in the safety analysis population.The number and proportion of patients with onset of adverse drug reactions of priority investigation items were summarized by events. Odds ratio and its 95% confidence interval were estimated for categories in the analysis by patient characteristics. The data of "Unknown" and "Not described" were not included in the data for the odds ratio calculation. PFS was summarised using the Kaplan–Meier method. Statistical analysis were performed with SAS software, version 9.3, and adverse drug reactions were encoded using the MedDRA version 21.0 and classified according to their preferred terms.


To find out the frequency of ZAP-70, CD38 and CD49d in patients diagnosed with CLL in our population.st January 2018 to 30th November 2018. Permission from Institutional Ethical Committee was obtained. Blood samples were collected by non-probability consecutive sampling technique and analyzed for blood counts and flow cytometry was done for ZAP-70, CD38 and CD49d. Manufacturer’s instructions for the kits were strictly followed.This is a cross sectional study conducted in Army Medical College in collaboration with Armed Forces Institute of Pathology and Military Hospital Rawalpindi from 1Fifty-one newly diagnosed patients with CLL were studied for the prognostic markers in CLL. CD 38 was expressed in 25(49%) and CD49d in 21(41.2%). ZAP-70 expression was not detected in our series of patients.We conclude that CD38 and CD49d expression was detected in almost half of the patients of CLL in our series. CD49d showed statistically positive correlation with CD38, showing that it is a more pragmatic choice for reliable prognostication of CLL along with CD38. Chronic Lymphocytic Leukemia (CLL) is characterized by accumulation of small mature looking, ineffectual, CD5+ B-cells in the peripheral blood, bone marrow and secondary lymphoid tissues.2The peak incidence of CLL is between 60 to 80 years, and only 10% of patients are younger than 55 years of age. In Pakistan it accounts for 20.1% of all leukemias.49/L, which may reach to 300 x 109/L. The peripheral smear shows small mature looking lymphocytes with numerous smudge cells. A bone marrow biopsy, if done, shows predominance of mature lymphocytes, replacing 95% of normal hemopoietic tissue. Immunophenotyping is done to confirm the diagnosis.6Its diagnosis is based upon clinical presentation and laboratory features.The Rai and Binet staging systems are well recognized systems which serve as standard for assessing treatment requirements and overall survival in the patients diagnosed with CLL. However, both these systems are unable to categorize the patients into groups requiring treatment from those in whom the disease remains indolent.8ZAP-70 and CD38 are well-established immunophenotypic markers indicating poor prognosis in CLL. ZAP-70 is a protein rarely present on normal B-lymphocytes whereas CD38 is expressed on them. Patients who are positive for ZAP-70 and CD38 have a poor prognosis with aggressive disease course and a shorter overall survival. On the other hand those who are negative for ZAP-70 and CD38 have much better results.9CD49d is a recently added prognostic marker. It belongs to the integrin family with an important function in leukocyte activation, trafficking and survival.This study helps us to evaluate the prognosis of CLL at the time of diagnosis in our population. ZAP-70, CD38 and CD49d are prognostic markers of CLL. They help in segregating those patients of CLL which will need treatment from those that can be placed in the “Wait and watch” group. Globally, studies show that CD49d is gaining acceptance as an independent prognostic marker and may replace the combination of ZAP-70 and CD38. Foregoing in view, we planned a study to find out the frequency of ZAP-70, CD38 and CD49d in CLL patients our setup.st January, 2018 to 31st October, 2018 after the approval of Institutional Review Board dated on January 24, 2019.This cross sectional study was conducted in Department of Hematology, Army Medical College in collaboration with Armed Forces Institute of Pathology Rawalpindi from 1Total 51 newly diagnosed cases of CLL were included in our study. Sample size (n=44) was calculated by WHO calculator . Sample collection was done by non-probability purposive sampling.Three (3) ml of venous blood was drawn under aseptic conditions. It was transferred to Ethylenediaminetetraacetic acid (EDTA) tube. Complete blood counts were generated through Sysmex KX-21TM automated hematology analyzer after adequate quality control. Immunophenotyping was performed by flow cytometry to analyze for ZAP-70, CD38 and CD49d by BD FACS caliber and BD FACS CANTO. Known negative samples were used as normal controls. Manufacturer’s instructions for the kits used were strictly followed.Data was analyzed by statistical package for social sciences (SPSS 23). For qualitative variables frequency and percentages were calculated and quantitative variables Mean and Standard Deviation (SD) were calculated. Correlation between CD38 and CD49d was calculated by applying the Pearson Chi-Square. P-value <0.05 was considered statistically significant.9/L (range 11.7 – 538x109/L) and 169 ± 67 x 109/L(range 08 – 383x109/L) respectively. The mean absolute lymphocyte count was 68.2 ± 71.6 x 109 / L (range 7.9 – 505.7 x 109/L)  were male and 11 (21.5%) were females. The mean age of the patients was 65 years± 10.64 (mean ± SD) years with a range of 39 – 86 years. The mean hemoglobin, white cell and platelets counts were 11.1 ± 2.7 g/dl (range 3.6 – 16.1); 80.8 ± 74.2 x 10x 109/L) .CD38 expression was detected in 25 (49%) cases with the mean value of 34.4% (range 0-96) while CD49d was expressed in 21 (41.2%) cases with a mean of 35.4 (range 0-99). ZAP-70 expression was not detected in any case . The meaWe calculated the correlation between CD38 and CD49d by applying the Pearson Chi-Square. The p-value was <0.05 showing that the two variables are statistically significant . We diviChronic lymphocytic leukemia is the most frequently occurring chronic leukemia in the Western world.14We studied 51 newly diagnosed patients of CLL. Among these, 25 (49%) were positive for CD38.Our study is consistent with other studies conducted in China, India and Iraq showing almost similar results i.e. CD38 positivity was found in 56.7%,44% and 30.6% of patients.19CD49d was positive in 21 (41.2%) cases which is comparable to results by Bulian P et al. in Italy, Uzay A et al in Turkey and Gattei V et al. in Italy who reported CD49d positivity in 52%, 47% and 39% of cases respectively.The expression of ZAP-70 was not recorded in our cases. A study conducted by Zeeshan R et al. showed ZAP-70 expression in only 13% cases.22There was a significant correlation between CD38 and CD49d . No correlation was found between ZAP-70 and either of the other two markers (CD38 & CD49d). We divided our data into two groups i.e. Group-1 (below 60 years of age) and Group-2 (60 and above). No association was found between the immunophenotypic markers and age.In an analysis of 3000 patients done in Italy for flow cytometric based prediction of overall survival (OS) in CLL, CD49d+ had a significantly high risk of death and lower poor survival rate as compared to CD49d- patients. By a Cox analysis for OS, they showed that CD49d+ patients have a two-fold increase risk of death and it was the only flow cytometry based marker with independent prognostic relevance for OS. They also compared models for prognostic markers with and without CD49d by several prediction performance measures indicating that excluding CD49d significantly reduced the prognostic power of the model.11In 2017, a study conducted by Ahmed S et al.The limitation in our study was that only a small number of patients were studied. It is strongly recommended that all the three prognostic markers i.e. CD38, ZAP-70 and CD49d are studied in all the newly diagnosed patients of CLL. As the study was single centered, that’s why it’s difficult to extrapolate it to whole Pakistani population. Therefore, it is highly recommended that these immunophenotypic markers should be studied on a large cohort of patients in centers which extend diagnostic and therapeutic facilities to patients of Chronic Lymphocytic Leukemia in Pakistan. Thus, this pilot study can form a foundation for larger studies on the subject.We conclude that assessing prognosis of CLL at the time of diagnosis is essential for all patients to segregate patients into groups who need urgent treatment because of presence of adverse prognostic markers from those who can be placed in watch and wait group. CD38 and CD49d expression was detected in almost half of the patients and were significantly correlated. CD49 is gaining acceptance internationally as an independent prognostic marker and is more reliable for prognostication of CLL along with CD38.We recommend that along with the conventionally used biomarkers i.e. ZAP-70 and CD38, CD49d should also be added to the immunophenotyping panel for stratification of prognostic groups in CLL. Further studies should also be done on larger groups of patients to evaluate the frequency of these biomarkers in our population and re-evaluation should be done for the inclusion of ZAP-70 in the immunophenotyping panel.HH conceived, designed and did statistical analysis & manuscript writing.NUD did overall supervision, proof reading and final drafting.SAK did the conceptualization of the study and critical revision of article.HH, SG did data collection and statistical analysis.HH takes the responsibility and is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


Lactobacillus iners is a common member of the human vaginal microbiota, with a genome size smaller than that of other lactobacilli. Here, we report the complete genome sequences of six L. iners strains isolated from different vaginal swab specimens. Three strains were found to harbor ∼100-kbp plasmids, which were not known previously. Lactobacillus iners is a common member of the human vaginal microbiota, with a genome size smaller than that of other lactobacilli. Here, we report the complete genome sequences of six L. iners strains isolated from different vaginal swab specimens. Three strains were found to harbor ∼100-kbp plasmids, which were not known previously. Lactobacillus iners is a Gram-positive, facultative anaerobic bacterium that is a member of the human vaginal microbiota  or Caucasian women (n = 3). The swab specimens were originally collected after obtaining informed consent from all participants, who also provided consent for storage of the samples and their use in future research studies related to women's health. The original studies were approved by the University of Maryland School of Medicine institutional review board. The swab specimens were resuspended in 1 ml of brucella broth supplemented with hemin and vitamin K, and then 25 μl of the suspension was plated onto human blood bilayer agar with Tween 80. After 48 to 72 hours of aerobic or anaerobic (5%:10%:85% H2/CO2/N2 gas mixture) incubation at 37°C, the strains were isolated. Large genomic DNA fragments were extracted using the MasterPure complete DNA purification kit . Sequencing libraries were prepared using the SMRTbell express template prep kit 2.0 , size selected on a BluePippin instrument , and sequenced on a PacBio Sequel II instrument (Pacific Biosciences) with a single-molecule real-time (SMRT) cell 8M.The six https://github.com/Kzra/Simple-Circularise; v1 default settings), and then oriented using Circlator v1.5.5 with default settings , providing an average genome coverage of 2,258× . Long read assembly was performed using the Canu assembler v1.8 on the raw PacBio reads with a target genome size of 1.3 Mbp and a minimum read length of 1 kbp . For thrsettings , such thL. iners was 1.36 Mbp and ranged from 1.32 Mbp to 1.40 Mbp, with an average GC content of 33.3%  of 98.7% and overlap of 91.6%, as estimated by pyani v0.2.10 with the -ANIm setting (L. iners genomes were found to encode 6 rRNA operons, while the genome of strain C0254C1 encoded one fewer. All of the genomes encoded 71 tRNA genes, except the genome of strain C0059G1, which encoded 73. The plasmid was found to encode between 97 and 100 genes, including several related to conjugal transfer.The average genome size of the six of 33.3% . Despite setting . The thr setting . The aveCP049223 to CP049231. Raw sequencing reads were submitted to the NCBI Sequence Read Archive under the BioProject PRJNA608123.The six genome sequences and three plasmid sequences have been deposited in the NCBI GenBank with accession numbers


Due to an error during production, Section 3.2 in the results section was inadvertently omitted in the published paper . The cor3.2. Cancer and Employment StatusIn Model 2, we estimated the effects of time since cancer diagnosis on employment status. Compared with women without cancer, ≤2 year cancer survivors had a 2.8 times greater likelihood of being employed at baseline (95% CI = 1.02–7.85) and a 3.3 times greater likelihood of working overtime (95% CI =1.65–6.61). Occupation type did not modify the association between cancer and employment status (Model 3). Women who were 6–10 year cancer survivors had a 2.3 times higher likelihood of being employed at baseline (95% CI = 1.04–5.20) and overtime (95% CI = 1.44–3.85) than women without a history of cancer; however, if these women had professional jobs, they were less likely to work overtime than women with unskilled or manual jobs  (Model 4). Health status indicators, such as fatigue and depression, were not associated with employment and had minimal impact on multivariable model estimates.These changes do not affect the scientific results. We apologize for any inconvenience caused to readers or authors by this error. The article will be updated and the original will remain on the webpage.


Truncus arteriosus (TA) is a complex congenital heart disease that carries morbidities in the first year of life. Previous authors have reported an operative mortality of 50%. In this report, we aim to report on the survival of patients with TA in our medical center in the recent era.A retrospective review of all patients diagnosed with TA in Siriraj Hospital, Thailand from August 1995 to March 2018 was performed. Patients with single ventricle, hemiTA were excluded. The characteristics and outcomes of repaired and unrepaired TA patients with a known recent functional status in 2018 were reviewed. Operative mortality risks were analyzed using a multivariate model.p-value 0.041). Of the 31 operation survivors, 17 required re-intervention within 0.4–11.4 years. Eight patients had reoperation at 8.7 years (range: 2.7–14.6 years) post-repair. Freedom from reoperation was 93%, 70.4%, and 31%, at 5, 10, and 15 years, respectively. All late survivors were in functional class I–II. Of the 22 unrepaired TA patients, 11 patients (50%) died . Survival of unrepaired TA patients was 68.2%, 68.2%, and 56.8, at 5, 10, and 15 years of age, respectively. At the end of study, 11 survivors of TA with palliative treatment had a recent mean oxygen saturation value of 84.1 ± 4.8% and a mean weight for height of 81.4 ± 12.7%, which were significantly lower than those of 31 late-survivors who had undergone anatomical repair.A total of 74 patients  were included in the cohort. One-third of the patients had associated anomalies including DiGeorge syndrome (13.5%). Anatomical repair was not performed in 22 patients (29.7%). The median age at time of repair for the 52 patients was 133 days (range: 22 days to 16.7 years). Complex TA was 10%. Early mortality occurred in 16 patients (30.8%). Five patients (9.6%) had late deaths at 0.3–1.2 years. Significant mortality risk was weight at time of operation <4 kg (HR 3.05, 95% CI [1.05–8.74], Contemporary survival rates of patients with TA following operation in the center has been gradually improved over time. Most of the operative mortality occurs in the early postoperative period. Compared to patients with TA who had palliative treatment, operative survivors have a better functional status even though they carry a risk for re-intervention. Truncus arteriosus (TA) is a rare, complex congenital heart disease characterized by a single great artery supplying both systemic and pulmonary circulations, as the so called common arterial trunk . Based oAnatomical repair of TA was reported in 1967 by Siriraj Hospital is one of referral cardiac centers that performs surgical corrections and provides postoperative care for children with TA in Thailand. In a report of early cases prior to 2004, Loahaprasitiporn and colleagues found an operative mortality of 50% following corrective surgery, within 6 weeks to 6 months of age . MedicalThis study was a single-centered, observational study using a hospital database from a large referral cardiac center in Thailand. Following approval from the Siriraj Institutional Review Board Faculty of Medicine, Siriraj Hospital, Mahidol University (COA no. Si 379/2017), all consecutive patients who had a confirmed diagnosis of TA type I–III (Collett and Edward)  by echocp-value < 0.05 was considered to be statistically significant. Statistical analyses were performed with SPSS 20.0 for Windows .The patients’ baseline characteristics and outcomes were summarized using descriptive statistics. Normally distributed data was presented as mean  ± SD, while the median (with range) was used where the distribution of data was not normal. Categorical data was represented as a number and a percentage (%).The comparison of continuous variables between groups was assessed using an unpaired T test for normally distributed data and a Wilcoxon rank-sum test for non-normally distributed data. Differences between the categorical data were assessed with a Chi-square or Fisher’s exact test. Patients were classified into two groups; those who underwent anatomical repair for TA and those who had palliative treatment. Cumulative survival, from date of birth and date of operation to the endpoint, was calculated using the Kaplan-Meire analysis with log-rank test. The association between baseline characteristics and postoperative mortality was evaluated with multivariate analysis. A A total of 74 patients with TA  was included in the study cohort. Median age of referral and diagnosis at the center was 70 days of age (range: 0–25.9 years). The patients’ demographics are summarized in n = 2), aged 1–6 months old (n = 31), aged 6 months–1 year old (n = 13), age more than 1 year old (n = 6). Three patients underwent PAB prior to a total correction. The right ventricular to pulmonary artery valve conduit diameter varied from 12–25 mm, depending on the patient’s size, with z-score of 2.3 ± 0.9. The types of conduit are shown in n = 36) were complete in a follow up with a median duration of 5.7 years (range: 0.46–19.8 years). Late mortality was reported in five patients (9.6%) at a median duration of seven months after operation (range: 5.5 months–1.2 years), related to infection and possible persistent pulmonary hypertension postoperatively (n = 52) was 63.5% at 1-year and steady at 59.5% after 2 years following the operation. Consequently, survival rates of early survivors (n = 36) at 1, 5, 10, and 15 years following repair were 91.7%, 85.9%, 85.9%, and 85.9%, respectively. A univariate analysis of 17 variables revealed 2 potential risk factors of mortality following repaired TA: weight at operation <4 kg and preoperative major infection within 1 month  . In patients with late mortality, preoperative major infection within one month and pulmonary hypertensive crisis in the operating room requiring inhaled nitric oxide were shown to be mortality risks by the univariate analysis. Nevertheless, only pulmonary hypertensive crisis in the operating room requiring inhaled nitric oxide was found to be an independent risk factor for late death by the multivariate analysis .ratively . The pos 1 month . The inde 0.039) . With reThirty-one late survivors following total correction were reported surviving until the end of 2018 and were having regular follow-ups at the medical center. The median postoperative follow-up was 6.4 years (range: 1.0–19.8 years). Seventeen patients (54.8%) required either catheter intervention or reoperation for conduit change at a median time of 3.1 years post-operation (range: 0.4–11.4 years). The range in number of catheter interventions was 0–4 times per patient. Freedom from re-intervention was reported to be 93.3%, 48.3%, 43.9%, and 35% at 1, 5, 10, and 15 years post-repair, respectively. Reoperation for conduit replacement had been performed in 8 patients (25.8%) at the median time of 8.7 years (range: 2.7–14.6 years) after their corrective surgery. Freedom from reoperation in survivors with repaired TA was 100%, 93%, 70.4%, and 31% at 1, 5, 10, and 15 years postoperation, respectively.2 and post-pulmonary vasodilator testing pulmonary vascular resistance index of 6.9 ± 4.9 WU m2. Some patients who were deemed to be receiving a conservative treatment were referred back to the primary hospital. All 22 patients in this study had been in recent contact and had a known clinical status in 2018. Since their most recent visit , 11 patients (50%) had died. Seven patients had died in infancy (less than 1.5 years of age), and the primary cause of death was heart failure, precipitated by infections such as sepsis or pneumonia. Four patients who died (13–32.8 years of age) had late referral and diagnoses of ES. Of the four patients, two died from pneumonia and two patients had sudden death, which was likely related to adverse cardiac events. The survival rates of the TA with palliative treatment were 72.7%, 68.2%, 68.2%, and 56.8, at 1, 5, 10, and 15 years of age, respectively. In comparing the survival ages of 52 patients with TA repair, 63.5% were surviving at 1-year and 59.6% were steady at 5-years of age, with no statistical differences. The survival of 36 early-survivors following TA repair was significantly higher than that of 22 patients with palliative treatment (Log rank p 0.03). At the end of study cohort in 2018, 11 survivors of TA with palliative treatment had a recent mean oxygen saturation value of 84.1 ± 4.8% and a mean weight for height of 81.4 ± 12.7%, which were significantly lower than those of 31 late-survivors who had undergone anatomical repair.Twenty-two patients in the cohort had not undergone anatomical repair for TA. Cardiac catheterization, which was performed in 6 patients showed mean pulmonary arterial pressure of 70.8 ± 14.0 mmHg, baseline pulmonary vascular resistance index of 20.1 ± 14.11 WU mOf the 52 patients who underwent surgical correction, 47 patients (90.3%) received postoperative pulmonary vasodilators including inhaled nitric oxide, iloprost, or oral forms such as sildenafil, bosentan or beraprost sodium. In five patients who had not been given pulmonary vasodilators, four underwent total correction prior to 2000, when inhaled nitric oxide was unavailable in the theatre and intensive care unit. Sixteen early deaths (30.8%) occurred with a median postoperative time of three days (range: 0–40 days), related to pulmonary hypertensive crisis or myocardial ischemia, followed by sepsis and multi-organ dysfunction. Twenty-eight patients were prescribed oral pulmonary vasodilators when they were discharged home after their operation. Monotherapy was given: beraprost in 3 patients and sildenafil in 25 patients. The median time of post-operative pulmonary arterial hypertension therapy was 6.9 months (range 1–109 months). Pre-treatment targeted therapy was used in two patients who underwent total correction at age 14 and 16 years, because of late referrals and the decision of parents. They were placed on sildenafil  prior to the cardiac catheterization in the referral center. Interestingly, both patients had baseline oxygen saturation in room air of 90–94%. Cardiac catheterization preoperatively showed elevated pulmonary artery pressure (PAP) in both patients. The first patient had a mean PAP (mPAP) of 80 mmHg, Qp:Qs of 1.36, and pulmonary vascular resistance (PVR) index of 13.6 WU m2 in room air and mPAP 72 mmHg; the PVR index declined to 0.9 WU m2 after inhaled nitric oxide 20 PPM testing. The second patient had a mPAP of 63 mmHg, Qp:Qs of 6, PVR of 3.4 WU, and PVR index of 3.9 WU m2 in room air. Following surgical repair, these two patients continued with the pulmonary vasodilator . Repeat cardiac catheterizations at two years post repair were performed, with a decreased mean PAP to 30 mmHg in the first patient and 28 mmHg in the second patient.Of the 22 patients who received palliative treatment, 11 were mortality cases; 7 patients died in infancy (less than 1.5 years of age) due to heart failure. These 7 patients had no indication for receiving PAH therapy. Four of the patients who died (13–32.8 years of age) had late referrals and were diagnosed with ES. Of these four patients, two received oral pulmonary vasodilator (one beraprost and one sildenafil). Of the 11 surviving patients, 6 received oral pulmonary vasodilator (3 beraprost and 3 sildenafil).n = 36) was 91.7% at 1-year and 85.9% at 2-years postoperatively. The independent risk factor for overall mortality was weight at operation <4 kg . At the median postoperative time of 6.4 years (range: 1.0–19.8 years), more than half of the late-survivors required either catheter intervention or reoperation for conduit change. Freedom from reoperation in repaired TA survivors was 100%, 93%, 70.4%, and 31%, at 1, 5, 10, and 15 years, respectively. All survivors were in the WHO functional class I-II. Of the 22 patients who had palliative treatment , 11 patients (50%) died, with survival rates of 72.7%, 68.2%, 68.2%, and 56.8, at 1, 5, 10, and 15 years of age. This cohort was first to be used in a report of long-term outcomes of patients with TA in Thailand, following the report of Loahaprasittiporn and colleagues who reported early outcomes using the 1995-2004 database from our medical center . Repair of complex TA, which required truncal valve repair or aortic arch interruption repair was performed in 10% of the cases. Early and late mortality was 30.8% and 9.6%, respectively. Mean survival rate of early repaired TA survivors . These findings suggest that repair of TA in patients who are older than one year of age is feasible, though physicians need to deliberately select the cases . Complex TA, coronary abnormality, and extracardiac associated anomalies were not found to be strong predictors of death in our study. The number of truncal valve and interrupted arch repairs in our study was only five, which may have been too small a sample size to demonstrate a statistic difference in the multivariate analysis. The reports of late death (9.6%) were consistent with several other previous studies  died within 1.5 years of age due to intractable heart failure and infection. The second group (n = 4) died at 10-years and older due to ES and progressive truncal valve regurgitation, precipitated by infection. In previous publications, almost 80% of the patients with unrepaired TA died before 1 year of age and few survived until adulthood (p = 0.03). Therefore, complete repair of TA likely improves the survival of patients with TA. To improve public health outcomes for patients with this lesion, early detection and referral can help manage and repair the lesion in patients who are neonates or at least younger than three months of age. The optimal surgical and postoperative care in neonates and infants in the center is the main focus.Of 22 patients who had TA with palliative treatment, 12 patients were definitely late diagnosed and then referred, which led to a progression of the disease to severe pulmonary arterial hypertension or Eisenmenger syndrome, where total repair should not be performed. Four patients were referred in infancy, and were on the list for TA repair, but they died while waiting for surgery due to infection and multi-organ failure at their local hospital. Three patients were diagnosed and then referred as neonates, but they died from neonatal sepsis/NEC/pneumonia in the center. The parents of two patients denied surgery for their children. One patient had Jacobsen syndrome with severe thrombocytopenia, which has a high risk for major surgery. The parents agreed to have palliative pulmonary artery banding to alleviate heart failure symptoms. The economic burden may play a role in late diagnoses and referrals and in the decision to deny surgery in the earlier era. The fate of patients with palliative treatment for TA was also a focus of this study. Mortality can be classified into 2 groups: the first group . The small number of patients in the study affected the multivariate analysis. In addition, the age of referral and diagnosis of TA at the center is mainly known for patients who were older than neonate, because of the limited resources available in the developing country. Management and surgical strategies also tend to be inconsistent, as they often depend on the preferences of individual surgeons and pediatric cardiologists.Contemporary survival rates of patients with TA following operation in the center has been gradually improved over time. Most of the operative mortality occurs in the early postoperative period. Compared to patients with TA who had palliative treatment, operative survivors have a better functional status even though they carry a risk for re-intervention. Weight at operation under 4 kg is identified as a significant early and all-mortality risk factor. The survival rate of patients with repaired TA, who can be discharged from hospital after their operation is better than patients with unrepaired TA. We encourage primary physicians to detect this lesion as early as possible for the optimal repair and management.10.7717/peerj.9148/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.9148/supp-2Supplemental Information 2Click here for additional data file.