Tuberculosis in Children with Rheumatic Diseases Treated with Biologic Disease-Modifying Anti-Rheumatic Drugs.

Chronic rheumatic diseases entail the use of biologics in children. Immunosuppressive effects of drug therapy put children at risk of various infections including tuberculosis (TB). Even though TB is a major concern among individuals on biological DMARDs, the incidence and distribution among children on these drugs is not known. Hence, we performed a literature search to ascertain the prevalence of tuberculosis amongst children with rheumatic disorders treated with biological agents. Articles available on MEDLINE and SCOPUS published on or after January 1, 2010 to 1 October 2019 were reviewed and collated. We found that published data on TB infections in children with rheumatic disorders on biologics is scant even from regions with highest TB burden. Tuberculosis was reported on occasion (0-5 cases per country) in the developed world with most reports being from Turkey. While most of the retrospective studies suggest that TB risk is minimal in the paediatric rheumatology patients, prospective studies suffer from a short observation period. Most registries focus on response to therapy rather than complications. In this review we have then discussed about the variation in screening strategies for latent TB and the role of bacille Calmette-Guerin (BCG) vaccination. Based on the dearth of data and inconsistency in data collection, we propose a way forward in the form of establishing well-designed long-term prospective national registries from countries with high background prevalence of TB with focus not only on treatment efficacy but also on adverse events and infections.

[OUR EXPERIENCE WITH THE USE OF BIPORTAL ENDOSCOPIC SURGERY IN THE TREATMENT OF HERNIATED DISCS OF THE LUMBAR SPINE].

Open microdiscectomy is the standard surgical treatment for herniated discs at the lumbar level. However, with open operations on the spine, the risk of developing postoperative instability of the spine and the occurrence of chronic back pain is quite high. Biportal endoscopic spinal surgery is a new method in minimally invasive spinal surgery, which has several advantages over open surgery. The aim of the study was to analyze the results of treatment of patients with hernias of the intervertebral discs who underwent biportal endoscopic discectomy and compare them with the results of treatment with open microdiscectomy. The analysis of the results of treatment of 155 patients who underwent a diskectomy operation from March 2019 to October 2019 was performed: 67 patients were operated by biportal endoscopy in the spine surgery clinic of the Institute of Traumatology and Orthopedics of the National Academy of Medical Sciences of Ukraine, while 88 - The first patient was operated on by open microdiscectomy in the Ivano-Frankivsk Regional Clinical Hospital. Pain intensity was assessed using a visual analogue pain scale (VAS), patient satisfaction and quality of life were assessed using a modified MacNab scale and the Oswestry Disability Index (ODI), respectively, 1 week, 3 months and 6 months after surgery. Perioperative data were also evaluated (duration of surgery and length of stay in the hospital, blood loss and complications). X-ray results were evaluated using pre- and postoperative MRI (6-8 weeks after surgery). One week after surgery, the level of VAS back pain in the biportaldiskectomy group showed more significant improvements than in the group after open microdiscectomy. However, the comparative results after a 3-month and 6-month period for VAS (back and leg), ODI questionnaires, a modified MacNab scale, did not significantly differ between the two groups. In the biportaldiskectomy group, the level of blood loss (32.82±15.9) was lower, and the length of hospital stay (2.8±1.6) was shorter than in the group of patients after open microdisectomy (141.1±56.5) and (6.6±1.3), respectively. However, the duration of the operation (71.3±21.9) was longer in the biportal discectomy group than in the group after open microdisectomy (62.2±14.6), the difference was statistically significant. Biportal endoscopic spinal surgery is an effective method for the treatment of hernias of the intervertebral intervertebral discs of the lumbar region, which has several advantages over open surgery, namely: less tissue trauma, less blood loss, faster back pain regression after surgery, higher patient satisfaction with the result of treatment, and reduced hospital stay.

[COMPARATIVE CHARACTERISTICS OF OPEN AND TRANSFORAMINAL ENDOSCOPIC DISCECTOMY IN THE TREATMENT OF HERNIATED DISCS].

Open lumbar discectomy was considered the gold standard among surgical methods for the treatment of hernias, however, due to technological progress in endoscopy and improved surgical approaches, a transforaminal discectomy technique has been developed that can reduce tissue trauma and reduce the risk of postoperative complications. The aim of the study was to evaluate the results of surgical treatment of hernias of the intervertebral discs with transforaminal endoscopic discectomy, and compare them with the results of a conventional open microdisectomy. From 2014 to 2019, out of 298 examined, 146 patients underwent transforaminal endoscopic discectomy and 152 patients underwent open microdiscectomy. Clinical results were evaluated using the Visual Analogue Pain Scale and the Oswestry Disability Index. Long-term results were evaluated based on the modified Macnab criteria. Patients who underwent transforaminal endoscopic discectomy showed shorter periods of return to working capacity and a hospital stay, which is associated with a shorter operation time and less tissue trauma compared to the group in which open microdiscectomy was performed. Our data showed that transforaminal endoscopic discectomy can provide the typical benefits of minimally invasive surgery, including: reducing the time of surgery, the time spent in the hospital, restoring disability, as well as reducing the use of painkillers.

Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes.

The risk of schizophrenia is increased in offspring whose mothers experience malnutrition during pregnancy. Polyunsaturated fatty acids (PUFAs) are dietary components that are crucial for the structural and functional integrity of neural cells, and PUFA deficiency has been shown to be a risk factor for schizophrenia. Here, we show that gestational and early postnatal dietary deprivation of two PUFAs-arachidonic acid (AA) and docosahexaenoic acid (DHA)-elicited schizophrenia-like phenotypes in mouse offspring at adulthood. In the PUFA-deprived mouse group, we observed lower motivation and higher sensitivity to a hallucinogenic drug resembling the prodromal symptoms in schizophrenia. Furthermore, a working-memory task-evoked hyper-neuronal activity in the medial prefrontal cortex was also observed, along with the downregulation of genes in the prefrontal cortex involved in oligodendrocyte integrity and the gamma-aminobutyric acid (GABA)-ergic system. Regulation of these genes was mediated by the nuclear receptor genes Rxr and Ppar, whose promoters were hyper-methylated by the deprivation of dietary AA and DHA. In addition, the RXR agonist bexarotene upregulated oligodendrocyte- and GABA-related gene expression and suppressed the sensitivity of mice to the hallucinogenic drug. Notably, the expression of these nuclear receptor genes were also downregulated in hair-follicle cells from schizophrenia patients. These results suggest that PUFA deficiency during the early neurodevelopmental period in mice could model the prodromal state of schizophrenia through changes in the epigenetic regulation of nuclear receptor genes.

Challenges in pediatric drug use: A pharmacist point of view.

The pediatric population is an enormously diverse segment of population varying both in size and age. The diversity caused pharmacists face various challenges primarily related to procuring, provision as well as use of drugs in this group of patients. Pediatric dose calculation is particularly a concern for pharmacists. Another challenge faced by pharmacists is unavailability of suitable formulations for pediatric use. This has also led many pharmacists to prepare extemporaneous liquid preparations, even though stability data on such preparations are scarce. Some extemporaneous preparations contain excipients which are potentially harmful in children. Besides that, inadequate labeling and drug information for pediatric drug use had not only challenged pharmacists in recommending and optimizing drug use in children, but also inadvertently caused many drugs used outside the approved terms of the product license (off-label use). Pharmacists are striving to stay connected to overcome the common and comparable challenges faced in their day to day duties and strive to maximize the safe and effective use of medicines for children.

Analysis of induced pluripotent stem cells carrying 22q11.2 deletion.

Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each subject, total of four cell lines) and three controls (total of four cell lines). Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. As an underlying mechanism, we focused on the role of DGCR8, a key gene for microRNA (miRNA) processing and mapped in the deleted region. In mice, Dgcr8 hetero-knockout is known to show a similar phenotype of reduced neurosphere size (Ouchi et al., 2013). The miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38α, and conformingly the levels of p38α were upregulated in the patient-derived cells. p38α is known to drive gliogenic differentiation. The inhibition of p38 activity by SB203580 in patient-derived neurospheres partially restored neurogenic competence. Furthermore, we detected elevated expression of GFAP, a gliogenic (astrocyte) marker, in postmortem brains from schizophrenia patients without the 22q11.2 deletion, whereas inflammation markers (IL1B and IL6) remained unchanged. In contrast, a neuronal marker, MAP2 expressions were decreased in schizophrenia brains. These results suggest that a dysregulated balance of neurogenic-to-gliogenic competence may underlie neurodevelopmental disorders such as schizophrenia.

Large-Scale Distribution of Total Mass versus Luminous Matter from Baryon Acoustic Oscillations: First Search in the Sloan Digital Sky Survey III Baryon Oscillation Spectroscopic Survey Data Release 10.

Baryon acoustic oscillations in the early Universe are predicted to leave an as yet undetected signature on the relative clustering of total mass versus luminous matter. A detection of this effect would provide an important confirmation of the standard cosmological paradigm and constrain alternatives to dark matter as well as nonstandard fluctuations such as compensated isocurvature perturbations (CIPs). We conduct the first observational search for this effect, by comparing the number-weighted and luminosity-weighted correlation functions, using the SDSS-III BOSS Data Release 10 CMASS sample. When including CIPs in our model, we formally obtain evidence at 3.2σ of the relative clustering signature and a limit that matches the existing upper limits on the amplitude of CIPs. However, various tests suggest that these results are not yet robust, perhaps due to systematic biases in the data. The method developed in this Letter used with more accurate future data such as that from DESI, is likely to confirm or disprove our preliminary evidence.

Antimicrobial activities of a promising glycolipid biosurfactant from a novel marine Staphylococcus saprophyticus SBPS 15.

Biosurfactants have gained a renewed interest in the recent years for their commercial application in diverse research areas. Recent evidences suggest that the antimicrobial activities exhibited by biosurfactants make them promising molecules for the application in the field of therapeutics. Marine microbes are well known for their unique metabolic and functional properties; however, few reports are available till date regarding their biosurfactant production and antimicrobial potential. In an ongoing survey for bioactive microbial metabolites from microbes isolated from diverse ecological niches, a marine Staphylococcus saprophyticus SBPS 15 isolated from the petroleum hydrocarbon contaminated coastal site, Puducherry, India, was identified as a promising biosurfactant producer based on multiple screening methods. This bacterium exhibited growth-dependent biosurfactant production and the recorded yield was 1.345 ± 0.056 g/L (on dry weight basis). The biosurfactant was purified and chemically characterized as a glycolipid with a molecular mass of 606.7 Da, based on TLC, biochemical estimation methods, FT-IR spectrum and MALDI-TOF-MS analysis. Further, the estimated molecular mass was different from the earlier reports on biosurfactants. This new glycolipid biosurfactant exhibited a board range of pH and temperature stability. Furthermore, it revealed a promising antimicrobial activity against many tested human pathogenic bacterial and fungal clinical isolates. Based on these observations, the isolated biosurfactant from the marine S. saprophyticus revealed board physicochemical stabilities and possess excellent antimicrobial activities which proves its significance for possible use in various therapeutic and biomedical applications. To the best of our knowledge, this is the first report of a biosurfactant from the bacterium, S. saprophyticus.

Awareness, knowledge and views of off-label prescribing in children: a systematic review.

AIM: The aim of this review was to provide an updated overview of awareness, knowledge and views of off-label prescribing in children. METHOD: A literature search using electronic databases including PubMed, Medline, Scopus, Science Direct, Springer Link, Proquest, Ebsco Host and Google Scholar was conducted. Additional articles were identified by reviewing the bibliography of retrieved articles. The articles were searched with any of the following medical subject headings (MeSH) terms in the title: attitude, awareness, knowledge, experience, view, off-label, pediatric, paediatric and children. The inclusion criteria were full text articles published in English between January 2004 and February 2015 and reported outcome related to awareness, knowledge and views regarding off-label prescribing in children. Editorials, reviews, notes, conference proceedings, letters and studies reporting prevalence of off-label prescribing were excluded. The articles were scrutinized using thematic analysis. RESULTS: Eleven studies conducted among doctors, community pharmacists, paediatric nurses, parents and children met the inclusion criteria. Nine themes were developed through document analysis which included main domains such as knowledge, awareness and views on off-label drug use in children, choice of information sources, reasons and suggestions to reduce off-label prescribing, concern regarding obtaining consent and participation in clinical trials. CONCLUSION: The studies reviewed reported that the majority of doctors and community pharmacists were familiar with the term off-label prescribing but knowledge among parents was low. Awareness on off-label prescribing in children remains low among all study participants. There is a mismatch between views on off-label prescribing in children of study participants and the finding of previous studies.

22q11.2 deletion carriers and schizophrenia-associated novel variants.

The penetrance of schizophrenia risk in carriers of the 22q11.2 deletion is high but incomplete, suggesting the possibility of additional genetic defects. We performed whole exome sequencing on two individuals with 22q11.2 deletion, one with schizophrenia and the other who was psychosis-free. The results revealed novel genetic variants related to neuronal function exclusively in the person with schizophrenia (frameshift: KAT8, APOH and SNX31; nonsense: EFCAB11 and CLVS2). This study paves the way towards a more complete understanding of variant dose and genetic architecture in schizophrenia.

Serum hepcidin-25 may replace the ferritin index in the Thomas plot in assessing iron status in anemic patients.

INTRODUCTION: Biochemical markers of iron deficiency do not distinguish iron-deficient anemia (IDA) from the anemia of chronic disease (ACD) and the combined state of ACD/IDA. Serum hepcidin-25 might be a marker resolving this problem. We investigated the extent to which serum hepcidin-25 enables the differentiation of the states above in comparison with the ferritin index plot, the so-called Thomas plot [soluble transferrin receptor (sTfR)/log ferritin and the reticulocyte hemoglobin content (CHr)]. METHODS: Serum hepcidin-25 was determined in 155 anemic patients who were classified as having latent iron deficiency (latent ID), IDA, ACD, or ACD/IDA using the ferritin index plot (Thomas plot). Hepcidin-25 was determined using an isotope-dilution micro-HPLC-tandem mass spectrometry method. The ability to discriminate among these states based on serum hepcidin-25 alone or in combination with the CHr was evaluated in a receiver operating characteristic curve analysis and a comparison with the recently established ferritin index plot. RESULTS: Serum hepcidin-25 correlated with ferritin and the ferritin index. Use of a hepcidin-25 cutoff level of ≤4 nmol/l allowed the differentiation of IDA from ACD and ACD/IDA. Furthermore, the discrimination of ACD/IDA from ACD required combination with CHr in a new plot (hepcidin-25 and the CHr). The hepcidin-25 plot and the ferritin index plot showed a good correspondence in the differentiation of iron states in patients with anemia. CONCLUSION: Patients with IDA can be differentiated from ACD and ACD/IDA but not ACD from ACD/IDA based on hepcidin-25 alone. The combination of hepcidin-25 with CHr in the hepcidin-25 plot was useful for the differentiation of the states above.

Fentanyl pre-treatment alleviates pain during injection of propofol-lipuro premixed with lignocaine.

We studied the effect of fentanyl pretreatment on alleviating pain during the injection of Propofol-Lipuro. One hundred and seventy patients were randomly allocated to receive either 100 mcg of intravenous fentanyl or normal saline (placebo) followed by intravenous Propofol-Lipuro premixed with 20 mg lignocaine. The incidence of injection pain was 32% and 13% in the placebo and fentanyl groups, respectively. We found a statistically significant reduction in incidence of injection pain in the fentanyl group when compared with the placebo group (p<0.003). The number needed to treat was 6 (3.2< 95% CI <15.1). In conclusion, fentanyl pretreatment is effective in alleviating pain during injection of Propofol-Lipuro.

Malaysian Cardiothoracic Surgery Registry--a patient registry to evaluate the health outcomes of patients undergoing surgery for cardiothoracic diseases in Malaysia.

The formulation of the Cardiothoracic Registry. Cardiothoracic surgery is the field of medicine involved in surgical treatment of diseases affecting organs inside the thorax (the chest). It is a general treatment of conditions of the heart (heart disease) and lungs (lung disease). In Malaysia, due to lack of data collection we do not have estimates of number and outcome of such procedure in the country. Western figures are often used as our reference values and this may not accurately reflect our Malaysian population. The Malaysian Cardiothoracic Surgery Registry (MyCARE) by the Ministry of Health will be a valuable tool to provide timely and robust data of cardiology practice, its safety and cost effectiveness and most importantly the outcome of these patients in the Malaysian setting.

The current practice of sedation and analgesia in intensive care units in Malaysian public hospitals.

We sought to review the current practice of sedation and analgesia in intensive care units (ICUs) in Malaysian public hospitals. A questionnaire survey was designed and sent by mail to 40 public hospitals with ICU facility in Malaysia. The anaesthesiologists in charge of ICU were asked to complete the questionnaire. Thirty seven questionnaires were returned (92.5% response rate). Only 35% respondents routinely assess the degree of sedation. The Ramsay scale was used prevalently. A written protocol for sedation was available in only 14 centers (38%). Although 36 centers (95%) routinely adjust the degree of sedation according to patient's clinical progress, only 10 centers (14%) interrupt sedation on a daily basis. Most respondents agreed that the selection of agents for sedation depends on familiarity (97%), pharmacology (97%), the expected duration for sedation (92%), patient's clinical diagnosis (89%) and cost (73%). Midazolam (89%) and morphine (86%) were the most commonly used agents for sedation and analgesia, respectively. Only 14% respondents still frequently use neuromuscular blocking agents, mostly in head injury patients. Our survey showed similarity in the choice of sedative and analgesic agents in ICUs in Malaysian public hospitals comparable to international practice. Nevertheless, the standard of practice could still be improved by implementing the practice of sedation score assessment and daily interruption of sedative infusion as well as having a written protocol for sedation and analgesia.

Central venous catheter-related blood stream infections: incidence and an analysis of risk factors.

Six hundred and fifty-five central venous catheters (CVC) in 496 patients in the intensive care unit of Hospital Sultanah Aminah were studied to determine the incidence and risk factors for central venous catheter-related blood stream infection (CR-BSI). CR-BSI was diagnosed in 38 catheters, giving an incidence of 9.43 CR-BSI per 1000 catheter days. The mean duration in situ was 8.4 +/- 4.9 days for infected CVCs and 6.0 +/- 3.8 days for non infected CVCs (p = 0.001). CVCs inserted in ICU had the highest infection rate (9.4%) compared to those inserted in the operating theatre (1.4%) and ward (2.8%) (p = 0.001). The highest rate of CR-BSI occurred with 4-lumen catheters (usually inserted when patients needed total parenteral nutrition) with a percentage of 15.8%. The majority of the CVCs (97.9%) were inserted via the subclavian or the internal jugular routes and there was no statistical difference in CR-BSI between them (p = 0.83). Number of attempts more than one had a higher rate of CR-BSI compared to single attempt with percentage of 7.0% vs 4.8% (p = 0.22). The top two organisms were Klebseilla pneumoniae and Pseudomonas aeruginosa. In conclusion, the incidence of CR-BSI in our ICU was 9.43 CR-BSI per 1000 catheter days. The risk factors were duration of CVC in situ, venue of insertion and use of 4 lumen catheter for total parenteral nutrition. The site of insertion, number of lumen up to 3 lumens and the number of attempts were not risk factors.

Comparison of BACTEC MGIT 960 system and BACTEC 460 TB system for growth and detection of Mycobacteria from clinical specimens.

This study was carried out to compare the performance of BACTEC MGIT 960 with the BACTEC 460 TB for growth and detection of Mycobacteria from human clinical specimens. The BACTEC MGIT 960 instrument is a fully automated system that utilizes MGIT tubes containing an oxygen sensor embedded in silicon at the bottom and filled with 7 mL of modified Middlebrook 7H9 broth. Identical samples were inoculated into the two automated systems and incubated for six weeks. Over a period of three months, 279 specimens were decontaminated and processed according to the standard CDC NALC/NaOH method, using the commercial MycoPrep kit. Forty-two specimens (15%) yielded Mycobacterium tuberculosis; 37 (88%) were detected by the fluorescent BACTEC MGIT 960 and 35 (83%) detected by the radiometric BACTEC 460 TB. Fifteen specimens (5%) yielded Mycobacterium Other Than Tuberculosis (MOTT); 10 (66%) were detected by BACTEC MGIT 960 and 11 (73%) detected by BACTEC 460 TB. The average time to detection and contamination rates and the average time to obtain results of antimicrobial susceptibility tests between the two systems were compared. The performance of the BACTEC MGIT 960 was comparable to the BACTEC 460 TB system which has been the "Gold Standard" for automated detection of TB. The former was more rapid, as sensitive and less labour intensive than the BACTEC 460. Our data demonstrates that the BACTEC MGIT 960 system is an accurate, automated and a non-radioactive alternative to the BACTEC 460 TB for the culture and susceptibility testing of M. tuberculosis.

Percutaneous dilational tracheostomy--a 3 year experience in a general hospital in Malaysia.

All percutaneous tracheostomies performed in the general intensive care unit (ICU), Hospital Sultanah Aminah, Johor Bahru, Malaysia, from July 1999 to June 2002 were studied. The tracheostomies were performed as an elective bedside technique in the ICU. A total of 352 percutaneous tracheostomies were performed. Eighty-eight percent of the tracheostomies were completed within 15 minutes. The most common complication was bleeding which occurred in 52 patients (14.7%). The rest of the complications encountered were:- transient hypoxia twelve (3.4%), inability/ difficulty to insert tracheostomy tube eight (2.3%), false passage four (1.1%), transient hypotension two (0.6%), pneumothorax two (0.6%), peristomal infection two (0.6%), subcutaneous emphysema one (0.3%), cuff rupture one (0.3%), oesophageal cannulation one (0.3%), and granuloma formation one (0.3%). Conversion to conventional tracheostomies were performed on 7 patients (2%). There was one unfortunate death related to percutaneous tracheostomy. In conclusion, percutaneous dilational tracheostomy can be used safely to manage the airway of critically ill patients.