Efficacy and Safety of Pectoral Nerve Block (Pecs) Compared With Control, Paravertebral Block, Erector Spinae Plane Block, and Local Anesthesia in Patients Undergoing Breast Cancer Surgeries: A Systematic Review and Meta-analysis.
We aimed to compare the safety and efficacy of pectoral nerve block (Pecs) I and II with control or other techniques used during breast cancer surgeries such as local anesthesia, paravertebral block, and erector spinae plane block (ESPB). We searched 4 search engines (PubMed, Cochrane Library, Scopus, and Web of Science) for relevant trials, then extracted the data and combined them under random-effect model using Review Manager Software. We found 47 studies, 37 of them were included in our meta-analysis. Regarding intraoperative opioid consumption, compared with control, a significant reduction was detected in Pecs II (standardized mean difference [SMD]=-1.75, 95% confidence interval [CI] [-2.66, -0.85], P=0.0001) and Pecs I combined with serratus plane block (SMD=-0.90, 95% CI [-1.37, -0.44], P=0.0002). Postoperative opioid consumption was significantly lowered in Pecs II (SMD=-2.28, 95% CI [-3.10, -1.46], P<0.00001) compared with control and Pecs II compared with ESPB (SMD=-1.75, 95% CI [-2.53, -0.98], P<0.00001). Furthermore, addition of dexmedetomidine to Pecs II significantly reduced postoperative opioid consumption compared with Pecs II alone (SMD=-1.33, 95% CI [-2.28, -0.38], P=0.006). Pecs block is a safe and effective analgesic procedure during breast cancer surgeries. It shows lower intra and postoperative opioid consumption than ESPB, and reduces pain compared with control, paravertebral block, and local anesthesia, with better effect when combined with dexmedetomidine.


Histidinol dehydrogenase from salmonella typhimurium and Escherichia coli. Purification, some characteristics and the amino acid sequence around a reactive thiol group.
The purification and some physical properties of histidinol dehydrogenase, L-histidinol-nicotinamide adenine dinucleotide oxido-reductase (EC 18.104.22.168) from either Salmonella typhimurium or Escherichia coli are reported in this paper. Modification of histidinol dehydrogenase with one equivalent of N-(4-dimethylamino-3,5-dinitrophenyl)maleimide at pH 6.8 yields an enzyme that is inactive toward the oxidation of L-histidinol. The modified cysteine residue was located in an acid insoluble tryptic core. The amino acid sequence around the reactive thiol group in S. typhimurium is: Leu-Cys-Gly-Val-Glu-Glu-Ile-Phe, and in E. coli is: Leu-Cys-Gly-Val-Glu-Asp-Val-Phe. These unique sequences show no homology to the reactive thiol groups from some other dehydrogenases.


Current evidence for transurethral laser therapy of non-muscle invasive bladder cancer.
Bladder cancer is the second most common malignancy of urologic tumors. Back in 1976, lasers were added to the endourological armetarium for bladder tumor treatment. Despite nowadays' standard procedure for staging and treating non-muscle invasive bladder tumor by transurethral resection of bladder tumors (TURB) via a wire loop, laser resection techniques for bladder tumor came back in focus with the introduction of Ho:YAG and not to mention recently Tm:YAG lasers. This review aims to display the current evidence for these techniques. Throughout April 2010, MEDLINE and the Cochrane central register of controlled trials were searched previously for the following terms: "Laser, resection, ablation, coagulation, Nd:YAG Neodym, HoYAG: Holmium, Tm:YAG Thulium and transitional carcinoma, bladder, intravesical." Eleven articles on Ho:YAG and 7 on Tm:YAG were identified. Searches by Cochrane online library resulted in no available manuscripts. Today, Nd:YAG does not play any role in treatment of lower urinary tract transitional cell carcinoma. Ho:YAG and Tm:YAG seem to offer alternatives in the treatment of bladder cancer, but still to prove their potential in larger prospective randomized controlled studies with long-term follow-up. Future expectations will show whether en bloc resection of tumors are preferable to the traditional "incise and scatter" resection technique, in which is contrary to all oncological surgical principles. For the primary targets, here are within first-time clearance of disease, in addition to low in-fields and out-of-fields recurrence rates.


Effect of electronic prescription on attainment of cholesterol goals.
Although recent federal mandate provides incentives for physicians to use electronic prescribing (e-prescribing), clinical end points to support its use are lacking. E-prescribing should improve low-density lipoprotein (LDL) goal attainment. In this retrospective cohort study, we queried the electronic medical records (Allscripts Electronic Health Record [EHR]) of a multispecialty outpatient academic medical practice to identify patient encounters during which consecutive lipid panels were drawn in 2007 (n = 2218). The EHR did not include a clinical decision tool for guideline adherence but did include formulary decision support (FDS), which informs physicians about drug costs specific to each patient. Logistic regression was used to examine whether the odds of reaching LDL goal were influenced by e-prescribing and adjusted for characteristics known to affect prescribing patterns and goal attainment. Of 796 patients not at LDL goal at baseline, 49% (n = 393) were at goal at follow-up. Patients receiving an e-prescription with FDS were 59% more likely to achieve LDL goal than those with a manual prescription (95% confidence interval [CI]: 1.12-2.25). Superior LDL goal attainment may be from lower cost of medications; patients with an e-prescription were significantly more likely to receive a generic statin than patients with a manual prescription (38% vs 22.9%; P = 0.0004), and for each $10 increase in prescription price, the likelihood of being at goal decreased by 5% (odds ratio = 0.95; 95% CI: 0.93-0.98). Our study is the first to demonstrate that e-prescribing with FDS is associated with improved LDL goal attainment. Therefore, e-prescribing can deliver tangible clinical gains to patients, likely from improved adherence to more affordable treatment.


Dentin stresses in post-reconstructed teeth with diminishing bone support.
Dentin stresses from simulated functional loads to post-reinforced tooth models with four levels of periodontal support were calculated using finite element analysis. As bone levels diminished, stresses were found to increase dramatically and to concentrate in the small amount of dentin remaining near the post apex.


Determination of T1- and T2-relaxation times in the spleen of patients with splenomegaly.
Twenty-nine patients with known splenomegaly and seven healthy volunteers were examined. The T1 and T2 relaxation times were read out from a region of interest centrally in the spleen. Even though different mean T1 and T2 relaxation times were found between the groups, the great scatter and the considerable overlap between the groups makes the contribution of relaxation time measurements to the differential diagnosis of splenomegaly of limited value.


Cardiac rehabilitation of Baduanjin exercise in coronary heart disease after PCI: A protocol for systematic review and meta-analysis of randomized controlled trials.
Percutaneous coronary intervention (PCI) is an effective revascularization strategy in patients with coronary heart disease (CHD). However, recent studies had indicated that postPCI patients usually suffer from a low-quality life. Cardiac rehabilitation (CR) has been recommended by numerous guidelines in the clinic for these patients. And Baduanjin exercise can significantly benefit patients with CHD. Regrettably, the effect of Baduanjin exercise on postPCI patients is still not clear. Therefore, this systematic review and meta-analysis protocol is planned to explore the effect of Baduanjin exercise in patients with CHD who have undergone PCI. PubMed, Excerpta Medica Database, Cochrane Library, Web of Science, Wanfang Database, SINOMED, China Science and Technology Journal Database, and China National Knowledge Infrastructure will be searched for appropriate articles from respective inceptions until December 1th, 2020. Two reviewers will independently conduct article selection, data collection, and risk of bias evaluation. Disagreements will be resolved first by discussion and then by consulting a third author for arbitration. The primary outcome will include left ventricular ejection fraction. And the change in the scores on the Seattle Angina Questionnaire, SF-36 health survey scale, Zung Self-rating Anxiety scale and self-rating depression scale will be used as the secondary outcomes. RevMan 5.3 will be used for meta-analysis. This systematic review and meta-analysis will explore whether Baduanjin exercise is an effective intervention in postPCI patients. This systematic review and meta-analysis will provide convincing evidence of Baduanjin exercise that specifically focuses on CR of Baduanjin exercise on CHD after PCI. INPLASY202130065.


The Role of Plasma Transfusion in Pre-Hospital Haemostatic Resuscitation.
Traumatic haemorrhage remains a major cause of preventable death and early haemostatic resuscitation is now a mainstay of treatment internationally. Recently, 2 randomized control trials (RCTs) - PAMPer (Prehospital Air Medical Plasma) and COMBAT (Control of Major Bleeding After Trauma), evaluating the effect of pre-hospital use of plasma on mortality provided conflicting results, raising important questions on the role of plasma resuscitation in pre-hospital environment. Both PAMPer (n = 501 patients) and COMBAT (n = 144 patients) trials were pragmatic RCTs that evaluated the effect of pre-hospital plasma transfusion (two units) versus standard of care on 28/30 days mortality in trauma patients who presented with clinical signs of haemorrhagic shock (defined as hypotension or tachycardia). The PAMPer trial showed that plasma transfusion reduced 30-day mortality compared with standard of care (23% vs 33%, 95% confidence interval -18.6; -1.0%; P = 0.03), while COMBAT trial showed no difference in 28-day survival. The post-hoc analyses of the 2 trials have suggested that the benefit of pre-hospital plasma transfusion may be greater for patients who are coagulopathic, have blunt injury and have a transport time from the scene of injury to the hospital of >20 minutes. In this review we evaluate strengths and limitations of the two trials and their differences and similarities, which may explain the conflicting results, as well as provide directions for future trials to better define the target population that would most benefit from pre-hospital plasma resuscitation. Further, considering the logistical challenges of carrying any blood components on an aircraft, cost/safety of plasma, and the scarcity of universal blood group donors, there is a need for a health economic evaluation of pre-hospital plasma transfusion in trauma patients, prior to this intervention becoming universal.


The ongoing debate over Medicare: understanding the philosophical and policy divides.
This Article examines the evolution and status of Medicare, as well as the myriad current efforts to reform this longstanding entitlement. The author analyzes why healthcare financing for the elderly follows an administered pricing, fee-for-service model, while the working population generally obtains its insurance under a competitive market model. As a non-means-tested program modeled after Social Security, Medicare embraces both a universal entitlement philosophy of government-provided basic health services, and a need-based entitlement philosophy of caring for the Medicare-eligible elderly.


Building a flagellum outside the bacterial cell.
Flagella, the helical propellers that extend from the bacterial surface, are a paradigm for how complex molecular machines can be built outside the living cell. Their assembly requires ordered export of thousands of structural subunits across the cell membrane and this is achieved by a type III export machinery located at the flagellum base, after which subunits transit through a narrow channel at the core of the flagellum to reach the assembly site at the tip of the nascent structure, up to 20μm from the cell surface. Here we review recent findings that provide new insights into flagellar export and assembly, and a new and unanticipated mechanism for constant rate flagellum growth.


Emergency care in post-conflict settings: a systematic literature review.
Emergency care systems (ECS) organize and provide access to life-saving care both during transport and at health facilities. Not enough is known about ECS in uncertain contexts such as post-conflict settings. This review aims to systematically identify and summarize the published evidence on the delivery of emergency care in post-conflict settings and to guide health sector planning. We searched five databases (PubMed MEDLINE, Web of Science, Embase, Scopus, and Cochrane) in September 2021 to identify relevant articles on ECS in post-conflict settings. Included studies (1) described a context that is post-conflict, conflict-affected, or was impacted by war or crisis; (2) examined the delivery of an emergency care system function; (3) were available in English, Spanish, or French; and (4) were published between 1 and 2000 and 9 September 2021. Data were extracted and mapped using the essential system functions identified in the World Health Organization (WHO) ECS Framework to capture findings on essential emergency care functions at the scene of injury or illness, during transport, and through to the emergency unit and early inpatient care. We identified studies that describe the unique burden of disease and challenges in delivering to the populations in these states, pointing to particular gaps in prehospital care delivery (both during scene response and during transport). Common barriers include poor infrastructure, lingering social distrust, scarce formal emergency care training, and lack of resources and supplies. To our knowledge, this is the first study to systematically identify the evidence on ECS in fragile and conflict-affected settings. Aligning ECS with existing global health priorities would ensure access to these critical life-saving interventions, yet there is concern over the lack of investments in frontline emergency care. An understanding of the state of ECS in post-conflict settings is emerging, although current evidence related to best practices and interventions is extremely limited. Careful attention should be paid to addressing the common barriers and context-relevant priorities in ECS, such as strengthening prehospital care delivery, triage, and referral systems and training the health workforce in emergency care principles.


Dual-isotope-based source apportionment of nitrate in 30 rivers draining into the Bohai Sea, north China.
Excessive nitrate (NO3-) in rivers can lead to water quality deterioration, and can also be directly input into estuaries and oceans, thus posing a serious threat to the stability of their ecosystems. In this study, the concentration, isotopes and sources of NO3- in 30 rivers discharging into the Bohai Sea were comprehensively investigated. The mean concentration of NO3--N was 2.24 ± 2.11 mg L-1, with obvious seasonal and spatial variations. In total, 104.24 kt of NO3--N was discharged into the Bohai Sea annually, to which the Yellow River Basin and Liao River Basin made the largest contributions. The range of δ15N-NO3- was -1.1‰ to +33.2‰ (mean value, +11.4 ± 5.0‰), with no significant seasonal or spatial differences; the mean value of δ18O-NO3- was +9.4 ± 7.2‰, with much higher values seen in June. Based on the MixSIAR model, manure (24.3 ± 7.5%) and sewage (19.1 ± 14.5%) were the primary sources of NO3- in the 30 rivers, followed by NO3- fertilizers (16.3 ± 12.5%), soil N (15.5 ± 11.9%), atmospheric deposition of NO3- (13.5 ± 5.7%) and NH4+ fertilizers (11.4 ± 8.9%). This finding highlights the vital roles of sewage and manure management in riverine NO3-. Using a mathematical method, the contributions of various sources to each river were simulated. The results indicated that management of the Yellow River, Daliao River, Liao River, and Xiaoqing River is more urgently needed than that of other rivers to control Bohai NO3- pollution. We believe that this finding will provide guidance for scientific management of NO3- pollution in these 30 rivers and the Bohai Sea.


Brainstem serotonin deficiency in the neonatal period: autonomic dysregulation during mild cold stress.
Based on previous studies in adult animals, devoid of 5-HT neurones, showing altered thermoregulation in cold stress (4°C) and a reduced ventilatory response to CO₂, we hypothesized that neonatal mice lacking 60-70% of their 5-HT neurones (Pet-1(-/-)) would have: (1) a reduced thermogenic response to a mild drop in ambient temperature (TA), (2) reduced V(E) and heart rate (HR) responses to mild cooling that reflect this reduced thermogenic response, and (3) a reduced ventilatory response to CO₂ after postnatal day 12 (P12), when 5-HT neurones become chemosensitive in vitro. We first determined that a 60-70% loss of 5-HT-positive neurones results in a ~90% loss of 5-HT from the brainstems of Pet-1(-/-) animals. We then subjected Pet-1(-/-) and wild-type (WT) mice (N = 5) to mild environmental cooling (T(A) = 29°C) at ~P12. T(A) was initially held at 34°C for ~20 min, reduced to 29°C over 15 min and held for an additional 10 min at steady state, and then returned to 34°C. From 34°C to 29°C, there was a robust increase in V(O₂) in P12WT, but not Pet-1(-/-) animals (68±19.9% versus -16±8%, respectively; P = 0.002). On average, body temperature (T(B)) dropped 1.1°C more in Pet-1(-/-) compared to WT animals (P = 0.03). HR remained unchanged in WT but dropped 22±2.3% in Pet-1(-/-) animals (P = 0.01). Genotype had no effect on tail temperature (T(T)), either at 34°C or 29°C. After cooling, values for V(O₂) and HR of Pet-1(-/-) animals were no different to values predicted by Q₁₀ effects alone, while values of WT animals were greater than predicted. V(E) increased in WT with cooling, while it decreased in Pet-1(-/-) animals (P = 0.002). Still, Pet-1(-/-) animals hyperventilated relative to WT (increased V(E)/V(O₂)) irrespective of T(A) (P = 0.002). As tested in a separate group of pups, there was no difference in the ventilatory response to CO₂ between WT and Pet-1(-/-) animals, either at P5 or P15. We conclude that during neonatal life in mouse pups: (1) brainstem 5-HT is critical for the thermogenic response to a mild drop in environmental temperature probably via a sympathetically-mediated increase in brown fat metabolism; (2) reduced thermogenesis probably contributes to the reduced HR and V(O₂) observed with 5-HT deficiency; and (3) the presence of some brainstem 5-HT is sufficient for an appropriate ventilatory response to hypercapnia up until P15. Infants with reduced brainstem 5-HT could be prone to cardiovascular and respiratory abnormalities resulting from compromised thermogenesis.


Changes in Medicare Part B Spending for Biologic Drugs After Biosimilar Entry Into the Market.
This cross-sectional study describes changes in annual Medicare Part B spending for biologic drugs after biosimilar entry, focusing on the first 4 products to experience biosimilar competition: filgrastim, infliximab, epoetin alpha, and pegfilgrastim.


Pulmonary injury after radioactive iodine therapy in pediatric papillary thyroid cancer: a case report.
Radiation-induced lung injury is a rare complication of radioactive iodine therapy (RAIT) in pediatric thyroid cancer treatment. In this case report, we describe a pediatric patient with an ERC1::RET-positive classic papillary thyroid carcinoma who developed progressive respiratory symptoms and chest imaging abnormalities following RAIT for lymph node and pulmonary disease. A pediatric patient with ERC1::RET-positive classic papillary thyroid carcinoma was hospitalized for pulmonary decompensation three months following one empiric dose of RAIT. Testing revealed no evidence of infection or progression of pulmonary metastases, and there was no improvement with empiric antibiotic therapy for pneumonia. Despite empiric anti-inflammatory therapies, the patient remains symptomatic from a respiratory standpoint with requirement for supplemental oxygen and evidence of fibrotic changes on chest imaging. This patient's pulmonary condition is consistent with radiation-induced pulmonary injury including development of pulmonary fibrosis. With the availability of RET fusion targeted inhibitors, this case highlights a rare pulmonary side effect of radioactive iodine for clinicians to recognize. Upfront targeted therapy protocols may help avoid radioactive iodine-associated adverse reactions.


Detection of Circulating Tumor Cells in Cerebrospinal Fluid of Patients with Suspected Breast Cancer Leptomeningeal Metastases: A Prospective Study.
The diagnosis of breast cancer (BC)-related leptomeningeal metastases (LM) relies on the detection of tumor cells in cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, the sensitivity of this technique is low. Our goal was to evaluate whether circulating tumor cell (CTC) detection in CSF using the CellSearch® system could be used for LM diagnosis. This prospective, monocentric study included adult patients with suspected BC-related LM. The clinical sensitivity and specificity of CTC detection in CSF for LM diagnosis were calculated relative to conventional CSF cytology. Forty-nine eligible patients were included and 40 were evaluable (CTC detection technical failure: n = 8, eligibility criteria failure: n = 1). Cytology was positive in 18/40 patients. CTCs were detected in these 18 patients (median: 5824 CTC, range: 93 to 45052) and in 5/22 patients with negative cytology (median: 2 CTC, range: 1 to 44). The detection of ≥1 CSF CTC was associated with a clinical sensitivity of 100% (95% CI, 82.4-100) and a specificity of 77.3% (95% CI, 64.3-90.3) for LM diagnosis. HER2+ CTCs were detected in the CSF of 40.6% of patients with HER2- BC (median: 500 CTC, range: 13 to 28 320). The clinical sensitivity of CTC detection in CSF with the CellSearch® system for LM diagnosis is higher than that of CSF cytology. CTC detection in patients with negative cytology, however, must be further investigated. The finding of HER2+ CTCs in patients with HER2- BC suggests that the HER2 status of LM should be evaluated to increase the treatment opportunities for these patients.


Molecular genetic aspects of attention-deficit/hyperactivity disorder.
Two genome wide scans, one of which was subsequently extended, have led to the identification of different chromosomal regions assumed to harbour genes underlying attention-deficit/hyperactivity disorder (ADHD). Some of these regions were also identified in patients with autism and/or dyslexia. The only region for which both studies detected a LOD score >1 was on chr 5p13 which is in the vicinity of the location of the candidate gene DAT1. The candidate gene approach has revealed the most robust and replicated findings for DRD4, DRD5, and DAT1 polymorphisms. Meanwhile interesting endophenotype studies have also been conducted suggesting a genetic basis for different diagnostic and therapeutic criteria. Animal studies for ADHD have investigated especially hyperactivity and have focused mainly on knockout and QTL designs. In knockout mice models the most promising results were obtained for genes of the dopaminergic pathway. QTL results in rodents suggest multiple loci underlying different forms of natural and induced hyperactivity. The molecular results mentioned above are presented and discussed in detail, thus providing both clinicians and geneticists with an overview of the current research status of this important child and adolescent psychiatric disorder.


Edible films and coatings - Not just packaging materials.
Edible films and coatings (EFC) are macromolecular-based structures forming thin layers that are usually studied as tools to improve food stability, sometimes being considered as parts of both the packaging system and the food itself. However, EFC are not mere packaging materials, and sometimes they do not even play roles related to those of packaging. This graphical review summarizes possible roles of EFC, including primary packaging, keeping water activity gradients between food components, controlling mass transfer on food processing, carrying active components, or serving as sources of sensory appeal. EFC may even be designed in a way that two or more of those roles may be played simultaneously.


Prescribing of menopausal hormone therapy in Germany: Current status and changes between 2004 and 2016.
Prescribing of menopausal hormone therapy (MHT) declined drastically after publication of the Women's Health Initiative's (WHI) findings in 2002, but studies on longer-term trends and details of use are scarce. We used the German Pharmacoepidemiological Research Database (GePaRD) containing health insurance claims data from ~25 million persons. Using data from 2004-2016, we conducted cross-sectional analyses to determine the prevalence of MHT use overall and by type and route of administration in women aged 45-75. In longitudinal analyses, we assessed MHT use over 5 years and compared the patterns between different time periods. From 2004 to 2016, prevalence of systemic MHT prescriptions decreased by >60% in women aged 55-65 and by >50% in women aged 50 and 70 years old. Prevalence declined for most types and routes of administration at all ages (-16% to -79%) with some exceptions, for example, local MHT (vaginal estrogen). Among 50-year-old women in 2012, 6% were already prescribed systemic MHT at age 49 and of the remaining women, 16% were newly prescribed systemic MHT before age 55. At all ages, the cumulative dose of systemic MHT prescribed over 5 years was lower in the period 2012-2016 compared to 2005-2009 (-6% to -46%). For most types of MHT and all age groups, prevalence declined considerably between 2004 and 2016 in Germany. The cumulative dose per MHT user also decreased, suggesting a trend towards a shorter duration of use.


Pubertal immune stress transiently alters spatial memory processes in adulthood.
Pubertal immune challenge can permanently alter hippocampus-dependent memory processes in a sex-specific manner. Although gonadal hormones can influence various cognitive processes, their role in regulating the cognitive sequelae to pubertal immune challenge has not been thoroughly assessed. We examined whether a pubertal immune challenge could affect hippocampus-dependent memory functions in adulthood and whether these effects are regulated by gonadal steroid hormones. We hypothesized that exposure to an immune challenge during puberty would induce sex-specific deficits in the behavioral and cellular correlates of hippocampus-dependent memory during adulthood. At six weeks of age, during the stress-vulnerable pubertal period, male and female CD-1 mice were injected with either saline or the bacterial endotoxin lipopolysaccharide (LPS). Three weeks later, mice underwent either gonadectomy or sham-surgery. At ten weeks of age (i.e., in adulthood), mice began behavioral testing in an open field, Barnes maze, and Morris water maze. Brain tissue was collected at 17 weeks of age and stained for doublecortin and Ki67 to examine migrating neuronal progenitor cells and cellular proliferation in the neurogenic subgranular zone (SGZ) and the cornus ammonis (CA)1 and CA3 regions of the hippocampus. Pubertal LPS treatment impaired learning during adulthood in both sexes and increased cellular proliferation in the CA1 region in castrated males only. Although adult sex hormones did not reliably modulate these changes, gonadectomy impaired learning during the Morris water maze in both sexes. Learning deficits were more prominent during the Barnes maze, which suggests a stress-dependent expression of LPS-induced cognitive deficits. Neurogenesis in the SGZ and cellular proliferation in the CA3 were not affected by pubertal LPS treatment or gonadectomy. These novel findings emphasize the sensitivity of developing cognitive processes during puberty to immune challenges and suggest a possible mechanism for learning-based difficulties in adulthood.


Study subnetwork developing pattern of autism children by non-negative matrix factorization.
As a developmental disorder, the brain networks of autism children show abnormal patterns compared with that of typically developing. The differences between them are not stable due to the developing progress of children. It has become a choice to study the differences of developing trajectories between autistic and typically developing children by investigating the change of each group respectively. Related researches studied the developing of brain network by analyzing the relationship between network indices of the entire or sub brain networks and the cognitive developing scores. As a matrix decomposition algorithm, non-negative matrix factorization (NMF) was applied to decompose the association matrices of brain networks. By NMF, we can obtain subnetworks in an unsupervised way. The association matrices of autism and control children were estimated by their magnetoencephalography data. NMF was applied to decompose the matrices to obtain common subnetworks of both groups. Then we calculated the expression of each subnetwork in each child's brain network by two indices, energy and entropy. The relationship between the expression and the cognitive and development indices were investigated. We found a subnetwork with left lateralization pattern in α band showed different expression tendency in two groups. The expression indices of two groups were correlated with cognitive indices in autism and control group in an opposite way. In γ band, a subnetwork with strong connections on right hemisphere of brain showed a negative correlation between the expression indices and development indices in autism group. NMF algorithm can effectively decompose brain network to meaningful subnetworks. The finding of α band subnetworks confirms the results of abnormal lateralization of autistic children mentioned in relevant studies. We assume the results of decrease of expression of the subnetwork may relate to the dysfunction of mirror neuron. The decrease expression of γ subnetwork of autism may be related to the weaken process of high-frequency neurons in the neurotrophic competition.


Clinical multicenter evaluation of a new FXa-based Antithrombin assay.
The determination of functional Antithrombin is a central part of thrombophilia screening. In this multicenter study, a new FXa-based method (INNOVANCE® Antithrombin) was evaluated on four different analyzers. The INNOVANCE Antithrombin method was evaluated by precision and reference interval studies and by comparing the new method with established methods through parallel measurement of samples from 249 patients and 151 apparently healthy individuals. The INNOVANCE Antithrombin assay demonstrated on all analyzers repeatability coefficients of variation (CVs) ≤ 3.2% and within-device and between-run CVs ≤ 6.9%. The reference intervals of all analyzers are comparable with 2.5th percentiles between 80% and 85% of normal. The INNOVANCE Antithrombin and the FIIa-based Berichrom® AT III (A) methods demonstrated good concordance with correlation coefficients of r = 0.908 or higher. The INNOVANCE Antithrombin method demonstrated furthermore an excellent comparability with the STA® Antithrombin III assay and an acceptable comparability with the Coamatic® LR Antithrombin assay. The patients with congenital deficiency (n = 31) were identified with all assays except for the patients carrying the P41L heparin-binding site mutation, which was only identified with the INNOVANCE Antithrombin and the STA Antithrombin III methods. The INNOVANCE Antithrombin assay has high sensitivity for Antithrombin deficiencies and is reliable, precise and suitable for routine clinical use.


Anti-Epileptic Medication Exposure Influences Functional Status in New Zealand Stroke Patients: A Retrospective Population-Level Study.
Patients who develop seizures after stroke have disproportionately poorer outcomes and increased mortality. Our objective was to investigate whether exposure to anti-epileptic medications influenced long-term functional status after stroke. We used linked health administrative data from a cohort of adult stroke patients in New Zealand. Demographics and prescription information were obtained from the National Minimum Dataset and Pharmaceutical Collection, respectively. Activities of daily living (ADL) scores for the same patients were obtained using the International Resident Assessment Instrument. Beta regression was used to investigate the relationship between anti-epileptic drug (AED) exposure and functional status. The study included 3606 patients with a single ischaemic stroke between 2012 and 2017. In total, 15% were dispensed an AED in the 3 months before or after stroke. The adjusted odds ratio (OR) for AED exposure was 1.29 (95% confidence interval [CI] 1.15-1.45). Overall AED exposure, categorical body mass index (BMI), ethnicity, length of hospital stay, and exposure to paracetamol, opioids, anti-psychotics, and anti-nausea medications were significantly associated with changes in the mean ADL score percentages. Considering the exposure timeframe, the ORs for AED exposure only after stroke and for exposure both before and after stroke were 1.52 (95% CI 1.31-1.78) and 1.09 (95% CI 0.93-1.27), respectively. Stroke patients with AED exposure had greater odds of a higher ADL score, indicating a poorer long-term functional status than those unexposed to AEDs. The timeframe of exposure impacted on functional status, with patients exposed only after stroke having increased odds of higher ADL scores than those exposed both before and after stroke.


Potentiation of the immobility response elicited by bandaging and clamping in mesencephalic rats.
In earlier work, we showed that adult rats exhibit immobility response (IR) if a clamp is fastened to the skin of the nape of the neck, but not at other areas of the body, and not by bandaging. The present study characterizes IR in adult rats with complete mesencephalic transections. In the mesencephalic rats, the duration of the IR not only increased, but the stimuli capable of eliciting it were more diverse. All head and body areas clamped or bandaged were capable of inducing a profound IR. In contrast, the IR in intact rats was of shorter duration, and was only induced by clamping the neck, or by bandaging the upper or the lower torso. Furthermore, unlike the mesencephalic rats the ability of the bandaging to induce IR is reduced after the first trial and finally disappears. Only clamping the neck was able to persistently induce IR in intact rats. These data support the hypothesis that the IR control system is in the midbrain, hindbrain or spinal cord, and that systems above the mesencephalon modulate the IR. Such modulation appears to involve the ability to discriminate amongst tactile stimuli, and to integrate previous experience.


Osteoradionecrosis of the thoracic wall and its surgical management.
Four patients with disabling radiation defects of the chest involving skeletal and soft tissues were successfully treated with a one stage breast flap. Closure of the defect resulted after an uncomplicated and safe operation. Safety and reduced morbidity are hallmarks of the breast flap repair for this difficult problem. Although alternative methods can be used, the preparation of staged flaps and postoperative problems in major myocutaneous flaps increase the risk of such therapy and the hospital stay for these elderly, debilitated patients. The low morbidity of this one stage flap with a minimal hospital stay make this treatment a very viable and appealing alternative for patients whose long-term prognosis is exceedingly poor.


Age modulates Fe3O4 nanoparticles liver toxicity: dose-dependent decrease in mitochondrial respiratory chain complexes activities and coupling in middle-aged as compared to young rats.
We examined the effects of iron oxide nanoparticles (IONPs) on mitochondrial respiratory chain complexes activities and mitochondrial coupling in young (3 months) and middle-aged (18 months) rat liver, organ largely involved in body iron detoxification. Isolated liver mitochondria were extracted using differential centrifugations. Maximal oxidative capacities (V(max), complexes I, III, and IV activities), V(succ) (complexes II, III, and IV activities), and V tmpd, (complex IV activity), together with mitochondrial coupling (V(max)/V0) were determined in controls conditions and after exposure to 250, 300, and 350 μ g/ml Fe3O4 in young and middle-aged rats. In young liver mitochondria, exposure to IONPs did not alter mitochondrial function. In contrast, IONPs dose-dependently impaired all complexes of the mitochondrial respiratory chain in middle-aged rat liver: V(max) (from 30 ± 1.6 to 17.9 ± 1.5; P < 0.001), V(succ) (from 33.9 ± 1.7 to 24.3 ± 1.0; P < 0.01), V(tmpd) (from 43.0 ± 1.6 to 26.3 ± 2.2 µmol O2/min/g protein; P < 0.001) using Fe3O4 350 µg/ml. Mitochondrial coupling also decreased. Interestingly, 350 μ g/ml Fe3O4 in the form of Fe(3+) solution did not impair liver mitochondrial function in middle-aged rats. Thus, IONPs showed a specific toxicity in middle-aged rats suggesting caution when using it in old age.


An Upgraded "Two-in-One" Strategy toward Highly Crystalline Covalent Organic Frameworks.
A highly crystalline bicarbazole-based covalent organic framework (BCzP-COF) was synthesized via an upgraded "two-in-one" strategy by the self-polycondensation of A2 B2 monomer with two neopentyl acetal and two amine groups. Such a strategy is propitious to afford higher crystallinity, larger special surface areas and better morphology than that of using unprotected monomer with free aldehydes and amines. Additionally, the off-white powder of BCzP-COF could serve as acidichromism sensor with a significant color change. Intriguingly, the conductivity of the protonated BCzP-COF can improve by six orders of magnitude compared to that of the pristine samples. This work has the potential to lead to bicarbazole-functional materials for chemosensors and electronic devices.


gamma-Carboxyglutamic acid, a component in human pediatric bladder stones containing calcium salts.
The amino acid gamma-carboxyglutamic acid (Gla) has been previously detected in the vitamin K-requiring blood clotting factors, proteins of calcified vertebrate tissue, renal tissue, plasma protein C, ectopic calcifications, and calcium-containing renal calculi. This paper reports the presence of Gla in the EDTA-soluble, non-dialyzable material recovered from human pediatric bladder stones containing calcium salts. In bladder stones composed of calcium oxalate, uric acid and ammonium acid urate, 73 Gla residues per 1,000 amino acid residues were detected. Bladder stones composed of calcium oxalate, uric acid, ammonium acid urate, and hydroxyapatite contained 48 Gla residues per 1,000 amino acid residues present. No Gla was detected in the predominantly magnesium ammonium phosphate (struvite) bladder stones. These results with human bladder stones from children under 10 years of age are consistent with the observations from adult patients in which Gla was detected in the calcium-containing renal calculi but not in the non-calcium-containing renal calculi. The present study adds to the growing body of information concerning the possible role of Gla in normal and abnormal calcium metabolism.


Incidence, determinants and clinical impact of definite stent thrombosis on mortality in women: From the WIN-DES collaborative patient-level pooled analysis.
Predictors and clinical outcomes of stent thrombosis (ST) in women have not been well investigated. Present study aimed to identify predictors of definite ST and its impact on mortality in women undergoing percutaneous coronary intervention (PCI). Patient-level data of women enrolled in 26 randomized trials of DES was pooled. The study population was stratified based on the presence or absence of definite ST. Cox proportional hazards models were used to determine the predictors of definite ST. To analyze the temporal impact of definite ST on mortality Cox regression with ST entered as time-updated covariate was used. Of 11,557 patients undergoing PCI with stent implantation, definite ST occurred in 105 patients (0.9%) over median follow-up of 3years. Independent predictors of ST were age (HR 1.03 per year decrease, 95% CI 1.00-1.05; p=0.041), diabetes mellitus (HR 2.25, 95% CI 1.27-3.99; p=0.005), non-ST-segment elevation myocardial infarction (NSTEMI) at presentation (HR 1.97, 95% CI 1.04-3.75; p=0.037) and stent diameter (HR 3.76 per mm decrease, 95% CI 1.66-8.53; p=0.002). Compared to women without ST, the adjusted hazard ratios for mortality in the first 7days, 8-30days, and beyond 30days from ST were 115.81 (95% CI 68.96-194.47); 37.44 (95% CI 17.31-80.98); 3.54 (95% CI 2.20-5.69), respectively. In this large-scale pooled analysis of women, definite ST was uncommon yet associated with substantial mortality risk, which peaked early and rapidly attenuated over time. Younger age, diabetes, NSTEMI and stent diameter were found to be predictors of ST.


Antagonistic activity of selenium-enriched Bifidobacterium breve against Clostridioides difficile.
Probiotics have the potential to be used in the prevention of Clostridioides difficile infection (CDI). In this study, selenium (Se)-enriched Bifidobacterium breve YH68-Se was obtained under optimal culture conditions with single-factor and response surface optimization. The overall environmental resistance of YH68-Se was superior to that of the parental strain YH68, mainly reflected in the substantial improvement of antioxidant activity and gastrointestinal tolerance. YH68-Se dramatically inhibited C. difficile growth, spore, biofilm, toxin production, and virulence gene expression, rapidly disrupted C. difficile cell membrane permeability and integrity, and altered the membrane proton motive force (PMF), induced a large outflow of intracellular substances and eventually caused bacterial death. The main factor inducing this process originated from the lactic acid (LD) in YH68-Se. In addition, the LD production of YH68 increased with increasing selenite concentration and was accompanied by enhanced activities of thioredoxin reductase (TrxR), glutathione peroxidase (GSH-Px), and increased concentration of autoinducer-2 (AI-2), which may be the crucial factors contributing to the outstanding probiotic properties of YH68-Se and their potent antagonism of C. difficile. KEY POINTS: • Compared with the parental strain B. breve YH68, the environmental resistance of YH68-Se was improved. • YH68-Se was able to produce more lactic acid, which suppressed the important physiological activities of C. difficile and rapidly disrupted their cell membrane structures. • Sodium selenite in the suitable concentration range gradually increases the yield of lactic acid and phenylacetic acid, increased the concentration of autoinducer-2, and enhanced the activities of antioxidant enzymes TrxR and GSH-Px in YH68.


Mechanism of the interaction of propranolol and a potent vasodilator antihypertensive agent - minoxidil.
A study, using non-invasive techniques, was carried out in ten patients with essential hypertension to examine the mechanism of the hypotensive effect of propranolol when used in combination with a potent vasodilator antihypertensive - minoxidil. The hypotensive effect of minoxidil, a mean (+/- SEM) decrease of 42.4 +/- 4.3 mm Hg, was accompanied by a marked increase in heart rate, cardiac index and plasma renin activity and a significant decrease in total peripheral resistance, limb vascular resistance and pre-ejection period. Addition of propranolol further reduced mean arterial pressure by an average of 12.9 +/- 2.0 mm Hg. Propranolol returned cardiac index to control values and total peripheral resistance index rose but not to control levels. Plasma renin activity was significantly reduced by propranolol. By multiple regression analysis no correlation was found between propranolol-induced decrease in mean arterial pressure and changes in cardiac index, total peripheral resistance index or plasma renin activity. Quantitatively, the reduction in cardiac index observed probably accounted for the hypotensive effect of propranolol. The role of plasma renin activity reduction in the hypotensive effect of propranolol in this situation remains to be clarified. The findings in the present study were consonant with the known actions of vasodilator antihypertensive agents and propranolol and indicate the applicability of non-invasive methodology to the investigation of cardiovascular drugs in man.


A shared decision-making communication training program for physicians treating fibromyalgia patients: effects of a randomized controlled trial.
Fibromyalgia syndrome (FMS) is a condition of chronic widespread pain that is difficult to control and is associated with strains in physician-patient interaction. Shared decision making (SDM) can be a potential solution to improve interaction. We evaluated the effects of an SDM intervention, including an SDM communication training program for physicians, in a randomized controlled trial with FMS patients. The main objective was to assess whether SDM improves the quality of physician-patient interaction from patients' perspective. Patients were randomized to either an SDM group or an information-only group. The SDM group was treated by physicians trained in SDM communication and had access to a computer-based information package; the information-only group received only the information package and was treated by standard physicians. All patients were offered the same evidence-based treatment options for FMS. Patients were assessed with questionnaires on physician-patient interaction (main outcome criteria) and decisional processes. Physicians filled out a questionnaire on interaction difficulties. Assessment took place immediately after the initial consultation. Data from 85 FMS patients (44 in the SDM group and 41 in the information-only group) were analyzed. The mean age was 49.9 years (S.D.=10.2), and 91.8% of patients were female. The quality of physician-patient interaction was significantly higher in the SDM group than in the information-only group (P<.001). We found no differences in secondary outcome measures. SDM with FMS patients might be a possible means to achieve a positive quality of physician-patient interaction. A specific SDM communication training program teaches physicians to perform SDM and reduces frustration in patients.


Well-defined alkylpalladium complexes with pyridine-carboxylate ligands as catalysts for the aerobic oxidation of alcohols.
Neophylpalladium complexes of the type [Pd(CH(2)CMe(2)Ph)(N-O)(L)], where N-O is picolinate or a related bidentate, monoanionic ligand (6-methylpyridine-2-carboxylate, quinoline-2-carboxylate, 2-pyridylacetate or pyridine-2-sulfonate) and L is pyridine or a pyridine derivative, efficiently catalyze the oxidation of a range of aliphatic, benzylic and allylic alcohols with oxygen, without requiring any additives. A versatile method is described which allows the synthesis of the above-mentioned complexes with a minimum synthetic effort from readily available materials. Comparison of the rates of oxidation of 1-phenylethanol with different catalysts reveals the influence of the structure of the bidentate N-O chelate and the monodentate ligand L on the catalytic performance of these complexes.


Early surgical site infections in adult spinal trauma: a prospective, multicentre study of infection rates and risk factors.
Spine surgery is known to have a high risk of surgical site infection (SSI). Multiple studies have looked into the risk factors and incidence of SSI during elective surgery, but only two retrospective studies have specifically evaluated SSI during surgery following spine trauma. This work was based on a prospective cohort study that included all the patients operated on for spinal trauma at 13 French hospitals over a three-month period. The main endpoint was the occurrence of a SSI during the three-month period. Patients with multiple trauma or open fractures were excluded from the study. Of the 169 patients re-examined after a minimum of three months, six had had an acute SSI (3.55%). The following factors were significantly related to a SSI: age, ASA score, diabetes, procedure duration, delay elapsed between accident and procedure, number of levels fused, bleeding and prolonged presence of urinary catheter. Our results were consistent with the published infection rates of 2 to 10%. The risk factors identified have all been described in previous studies on elective spine surgery. Level IV, prospective cohort study.


Thyroid hormone therapy in cardiovascular disease.
The relationship between thyroid disease states and cardiovascular hemodynamics is well recognized. Although the long-term effects of thyroid hormone are thought to result from changes in myocardial gene expression, attention has recently focused on acute, non-nuclear-mediated actions of L-triidothyronine (T3), the biologically active form of the hormone. Various lines of evidence have documented that T3 can act as a vasodilator and inotrope. With this recognition have come novel treatment strategies targeted at specific clinical conditions including heart failure and cardiac surgery that are associated with impaired cardiovascular performance and low serum T3 levels. An understanding of the mechanisms of action of thyroid hormone on the heart and peripheral vasculature is essential for the rational implementation of thyroid hormone as a therapeutic agent. As outlined in this review, initial clinical experience suggests that the ability of thyroid hormone to increase cardiac output and to lower systemic vascular resistance may provide a novel treatment option for physicians caring for patients with cardiovascular illness.


Dataset of enhanced UV-C emitting properties of Pr3+-activated rare earth phosphates driven by structural lattice distortion through a substitutional doping strategy.
Ongoing global pandemic crisis of coronavirus (COVID-19) and its fast- and wide-spreading into entire worlds, critically intimidating our current and future lives, put more emphasis on the development of efficient UV-C emitting phosphors for the germicidal and medical applications due to the intense UV-C emission, which can effectively deactivate such viruses. In this regard, UV-C emitting Pr3+-activated three presentative rare earth phosphate such as YPO4, LaPO4, and La (x mol.%, x =0-0.21)-doped YPO4 have been systematically investigated in terms of crystallographic evolution and their impact on the UV-C emitting properties. Scanning electron microscopy (SEM) images along with X-ray diffraction (XRD) patterns attested the substitutional doping of La into YPO4 host matrices. Optical properties mainly investigated using the photoluminescence (PL) emission spectroscopy in the spectral range from 220-300 nm corresponding to UV-C energy region clearly demonstrated that the substitutional doping of La into YPO4:Pr3+ leads to the increase in transition probability of UV-C emission, resulted from the electronic transition of activator corresponding to [Xe]4f15d1→[Xe]4f2. The data presented here are related to the research article entitled "Structural distortion induced enhancement in UV-C emitting properties of Pr3+-activated La-substituted yttrium phosphates (Y1- x La x PO4:Pr3+)".


Salivary clearance of sugar before and after insertion of fixed orthodontic appliances.
This study was conducted for the purpose of establishing the possible influence of orthodontic therapy with fixed appliances on salivary clearance of sugar. Fifteen consecutive patients between the ages 12 and 17 years took part in the investigation. Unstimulated salivary flow rate, residual volume of saliva in the mouth after swallowing (RESID), and salivary clearance of sugar was determined on two occasions, before treatment commenced and after a minimum of 3 weeks of appliance wear. Analysis of the data showed that both RESID and salivary flow rate exhibited significantly increased levels during orthodontic therapy. The insertion of fixed appliances did not seem to have any effect on the rate of salivary clearance of sugar. It was assumed that this finding could be a consequence of the combined effects of the changes in salivary flow rate and RESID.


[Neuroendocrine tumor associated with an intestinal cyst: a case report].
Intestinal (tailgut) cysts or retrorectal cystic hamartomas are rare benign lesions that are included in the category of developmental cystic lesions. Their origin is still uncertain, although several hypotheses have been proposed to explain their development. They are located mainly in the presacral (retrorectal) space and predominately affect middle-aged women (40-60 years). Taking into account location and histological characteristics, the main differential diagnoses include epidermoid cysts, duplication cysts and teratomas. Malignant transformation of these lesions is rare and preferentially into adenocarcinoma and neuroendocrine tumors. We present a case of an intestinal cyst associated with a well-differentiated neuroendocrine tumor (G1) in a 63-year-old woman.


Unprecedent aminophysalin from Physalis angulata.
The 95% ethanol extract of the whole plant of Physalis angulata Linn. afforded one new skeletal physalin named aminophysalin A (1) and one new naturally occurring 5β-hydroxy-6a-chloro-5,6-dihydrophysalin B (2), together with five known physalins (3-7). Their structures were elucidated through MS, IR, NMR spectroscopy analyses and X-ray crystallography. Aminophysalin A (1) had an absolutely unusual structural feature in the chemistry of physalins with a nitrogen atom. Compounds 1-7 were evaluated for quinone reductase activities in hepa 1c1c7 cells. Physalin H (6) showed strong quinone reductase induction activity with IR (Induction ratio, QR induction activity) value of 3.74±0.02, using 4-bromoflavone as a positive control substance (2.17±0.01, 10 μg/mL), while compounds 1, 2, 3, 5 showed weak quinone reductase induction activity.


Synthesis of pyrroles through coupling of enyne-hydrazones with Fischer carbene complexes.
[reaction: see text] The coupling of enyne-imines with Fischer carbene complexes leads to the formation of alkenylpyrrole derivatives. Maximum yields of pyrrole adducts were obtained using N,N-dimethylhydrazones. A mechanism involving alkyne insertion followed by nucleophilic attack of the imine nitrogen at the intermediate alkenylcarbene complex was proposed.


Nonradioactive in situ hybridization. A rapid approach for the identification of marker chromosomes: study of a case of acute leukemia with a Yq specific DNA probe.
Nonradioactive in situ hybridization provides a rapid method for detecting specific nucleic acid sequences. In this study of a patient with acute leukemia, we applied in situ hybridization for identification of a marker chromosome and determination of the number of copies of this marker in interphase nuclei using a biotinylated Yq-specific DNA probe (pY3.4). We show that nonradioactive interphase in situ hybridization can be a useful method for karyotypic analysis in addition to routine cytogenetic techniques in neoplastic disorders.


[Secondary Data for Pharmacoepidemiological Research - Making the Best of It!]
Studies using secondary data such as health care claims data are often faced with methodological challenges due to the time-dependence of key quantities or unmeasured confounding. In the present paper, we discuss approaches to avoid or suitably address various sources of potential bias. In particular, we illustrate the target trial principle, marginal structural models, and instrumental variables with examples from the "GePaRD" database. Finally, we discuss the strengths and limitations of record linkage which can sometimes be used to supply missing information.


Depigmented extramammary Paget's disease.
Depigmented extramammary Paget's disease (EMPD) has been reported in a few cases. Depigmented macules or patches may be the only presenting sign or may coexist with the classical erythematous lesions. To investigate the occurrence rate and clinical presentation of depigmentation in EMPD. All pathology-proven cases of EMPD diagnosed in our department during 1990-2003 were retrieved. The clinical photographs were reviewed for evidence of local depigmentation. The pathological diagnosis of EMPD in the whitish lesions was confirmed by positive expression of cytokeratin 7 or carcinoembryonic antigen, and/or the presence of intracytoplasmic mucin. Of 19 cases of EMPD, six (30%) manifested depigmented lesions which were confirmed to be EMPD pathologically. In two patients, the hypopigmentation was associated with erythematous lesions at the initial presentation. In four others, the depigmentation developed later as local recurrence after excision, cryotherapy, photodynamic therapy or radiotherapy. The progressive enlargement of the depigmentation and the appearance of separate new white lesions in these four cases suggested that the localized depigmentation was unlikely to be simple postinflammatory hypopigmentation. Our study suggests that depigmented EMPD may not be rare. Localized depigmentation in the genital area can be an early sign of EMPD and its local recurrence. In patients with an established diagnosis of EMPD, appearance of new white lesions and continuous enlargement of depigmented patches should not be dismissed as simple treatment-induced postinflammatory hypopigmentation or another type of hypopigmented lesion without biopsy confirmation.


A fully automated method for clot based coagulation panels using an MCA Multistat Centrifugal Analyzer.
Small modifications of the commercially available software of the I.L. Multistat Centrifugal Analyzer (MCA) enabled us to evaluate clot based prothrombin times (PT), activated partial thromboplastin times (APTT) and thrombin times (TT) simultaneously within one run. This imparted a great deal of flexibility to this procedure in that batches and/or panels of clot based and other types of turbidimetric tests can be performed concurrently in any combination. The PT and TT by this turbidimetric procedure correlated very well with those of the Fibrometer in normal specimens as well as in a wide variety of coagulation defects. The turbidimetric APTT procedure, however, often produced clotting times longer than those achieved with the Fibrometer. The discrepancy between the Fibrometer and turbidimetric APTT procedures was shown to be the consequence of greater sensitivity of the latter to detect low concentrations of heparin, elevated fibrinogen split products and mild factor deficiencies. The available clot based procedures are suitable for use in detecting specific factor deficiencies and the presence of coagulation inhibitors.


Jugular--dural sinuses--jugular reflux in dynamic brain-flow imaging as a sign of unilateral innominate vein obstruction: case report.
Unilateral innominate vein obstruction with patency of the superior vena cava was suspected when early jugular--sinuses--jugular reflux of tracer occurred during brain-flow imaging. Radiographic venography confirmed this pattern of venous obstruction.


Differential determinants and reasons for the non- and partial vaccination of children among Nigerian caregivers.
Vaccination has saved millions of lives. However, the vaccination rate in Nigeria remains low. We differentiate reasons for incomplete vaccination by status: not- and partially- vaccinated, and examine the association between sociodemographic characteristics of caregivers and reasons for incomplete vaccination. Data from the Multiple Indicator Cluster Survey (MICS) conducted in Nigeria in 2016 and 2017 was analyzed. The logistic regression was used to evaluate associations between sociodemographic characteristics of caregivers and incomplete vaccination according to different reasons. The most common reason for non-vaccination is that caregivers have no faith in immunization (27.0%), followed by lack of awareness of the need for immunization (26.0%) and the perception that the place where immunization is given is too far/inconvenient (24.3%). The most common reason for partial vaccination is that caregivers thought the children had already been fully immunized (44.8%), followed by the inconvenient location for immunization (15.3%) and supply-side issues such as shortage of vaccine stock and absence of vaccinators (14.4%). Among caregivers whose children are never vaccinated, a lower level of education is correlated with more likelihood of having no faith in immunization and poorer households are more likely to state a lack of awareness of the need for immunization need and an inconvenient place as the reasons for non-vaccination. Among caregivers whose children are only partially vaccinated, educated and wealthier caregivers are more likely to state that they thought their children were fully vaccinated, while poorer caregivers tend to give an inconvenient immunization place as the reason for incomplete vaccination. Supply-side barriers are not systematically correlated with educational attainment or wealth level of caregivers. Barriers to vaccination are different according to vaccination status: not- and partially- vaccinated, as is the association between sociodemographic characteristics of caregivers and reasons for incomplete vaccination. The policy to increase vaccination take-up should take these differentials into consideration.


Dietary patterns are associated with central adiposity and carotid intima-media thickness in children and adolescents with congenital heart disease.
Unhealthy dietary patterns (DP) in childhood are associated with cardiovascular disease in adulthood. DP in children and adolescents with congenital heart disease (CHD) are unknown. The aims of this study were to describe DPs of children and adolescents with CHD and to evaluate their associations with central adiposity, high-sensitivity C-reactive protein (hs-CRP) and carotid intima-media thickness (cIMT). A cross-sectional study including 232 children and adolescents with CHD. Dietary data were based on three 24-h dietary recalls. Central adiposity was evaluated by waist circumference. hs-CRPs were determined by nephelometry. The cIMT was measured using ultrasound. DPs were identified using principal component analysis. Data were examined using logistic and linear regressions. Six DPs were identified. In multivariable-adjusted analysis, unhealthy DP (high intake of poultry, red meat, cold cuts and processed meats, soft drinks and sweetened beverages) and healthy DP (high intake of fish, eggs, bread, beans, tubers and roots, fruit and fruit juice) were associated with increased and decreased odds of central adiposity, respectively (Odds ratio (OR): 2.10; 95% confidence interval (95% CI) 1.09; 4.02; OR: 0.48 95% CI 0.24; 0.93). Besides, low-fat dairy DP (high intake of low-fat milk and dairy, mixed dishes, ultra-processed breads, candy and chocolate) was inversely associated with cIMT (β: - 0.024; 95% CI - 0.04; - 0.01). Unhealthy DP seems to increase the risk of central adiposity, while the healthy DP seems to decrease the risk of central adiposity. Still, low-fat dairy DP was inversely associated with cIMT. These findings may be helpful to develop nutrition recommendations for early cardiovascular disease prevention in children and adolescents with CHD.


Long-term Mortality in Pediatric Firearm Assault Survivors: A Multicenter, Retrospective, Comparative Cohort Study.
The objective was to determine whether children surviving to hospital discharge after firearm assault (FA) and nonfirearm assault (NFA) are at increased risk of mortality relative to survivors of unintentional trauma (UT). Secondarily, the objective was to elucidate the factors associated with long-term mortality after pediatric trauma. This was a multicenter, retrospective cohort study of pediatric patients aged 0 to 16 years who presented to the three trauma centers in San Francisco and Alameda counties, California, between January 2000 and December 2009 after 1) FA, 2) NFA, and 3) UT. The Social Security Death Master File and the California Department of Public Health Vital Statistics (2000-2014) were queried through December 31, 2014, to identify those who died after surviving their initial hospitalization and to delineate cause of death. Multivariate Cox proportional hazards regression was performed to determine associations between exposure to assault and long-term mortality. We analyzed 413 FA, 405 NFA, and 7,062 UT patients who survived their index hospital visit. A total of 75 deaths occurred, including 3.9, 3.2, and 0.7% of each cohort, respectively. Two-thirds of all long-term deaths were due to homicide. After multivariate adjustment, adolescent age, male sex, black race/ethnicity, and public insurance were independent risk factors for long-term mortality. FA (adjusted hazard ratio [AHR] = 1.8, 95% confidence interval [CI] = 0.82-4.0) and NFA (AHR = 1.9, 95% CI = 0.93-3.9) did not convey a statistically significant difference in risk of long-term mortality compared to UT. Being assaulted by any means (with or without a firearm), however, was an independent risk factor for long-term mortality in the full study population (AHR = 1.9, 95% CI = 1.01-3.4) and among adolescents (AHR = 1.9, 95% CI = 1.01-3.6). Children and adolescents who survive assault, including by firearm, have increased long-term mortality compared to those who survive unintentional, nonviolent trauma.


Dexamethasone decreases membrane fluidity of leukemia cells.
Lipid fluidity in the plasma membrane of leukemia cells was determined by measuring steady-state fluorescence polarization (P) of 1,6-diphenyl-1,3,5-hexatriene. In vitro dexamethasone treatment induced a dose-, time- and temperature-dependent and reversible increase in P values of primary leukemia cells and glucocorticoid-sensitive leukemia cell lines having specific glucocorticoid receptors. Membrane fluidity of glucocorticoid-resistant subclones with impaired specific dexamethasone binding capacity was not influenced by the drug. The results of this study suggest that dexamethasone modulates leukemia cell membrane fluidity via a classical glucocorticoid receptor dependent pathway.


Management of germ cell tumors with somatic type malignancy: pathological features, prognostic factors and survival outcomes.
Germ cell tumors with somatic type malignancy are rare, occurring in approximately 2.7% to 8.6% of germ cell tumor cases. Prognostic factors and optimal management remain poorly defined. The Indiana University testis cancer database was queried from 1979 to 2011 for patients demonstrating germ cell tumor with somatic type malignancy at orchiectomy or subsequent resection. Patients with transformation to primitive neuroectodermal tumor only were excluded from study due to distinct management. Chart review, pathological review and survival analysis were performed. A total of 121 patients met the study inclusion criteria. The most common somatic type malignancy histologies were sarcoma (59), carcinoma (31) and sarcomatoid yolk sac tumor (17). Of these patients 32 demonstrated somatic type malignancy at germ cell tumor diagnosis. For those with delayed identification, median time from germ cell tumor to somatic type malignancy diagnosis was 33 months. This interval was longest for carcinomas (108 months). At a median followup of 71 months, 5-year cancer specific survival was 64%. Predictors of poorer cancer specific survival included somatic type malignancy diagnosed at late relapse (p = 0.017), referral to Indiana University for reoperative retroperitoneal lymph node dissection (p = 0.026) and grade (p = 0.026). None of these factors maintained prognostic significance on multivariate analysis. Somatic type malignancy histology subtype, stage, risk category and number of resections were not predictive of cancer specific survival. Germ cell tumor with somatic type malignancy is associated with poorer cancer specific survival than traditional germ cell tumor. Established prognostic factors for germ cell tumor lose predictive value in the setting of somatic type malignancy. Aggressive and serial resections are often necessary to optimize cancer specific survival. Tumor grade is an important prognostic factor in sarcomas and sarcomatoid yolk sac tumors.


Regional and spatial impacts of external and internal conflicts on ecological footprint: the case of Middle East and Africa.
The economic and environmental structures of countries are greatly impacted by domestic and foreign conflicts. To promote sustainable development, it is crucial to understand the spatial impact of these conflicts on the ecological footprint of a region. With a focus on Middle Eastern and African countries, this paper investigates the impact of such conflicts on their environments, taking into consideration the unique spatial features of their ecological footprints. Using a spatial econometric model, the study assesses the contributions of ecological footprint determinants, particularly internal and external conflict indicators, across 46 Middle Eastern and African countries from 2001 to 2019. The results indicate that internal conflict can lead to increased pressure on natural resources and ecological systems in neighboring countries, while energy use and economic growth impose a significant ecological burden both domestically and abroad. While urbanization and resource rents were found to reduce the ecological footprint, trade openness was found to be nonsignificant. Conflicts such as war, foreign pressure, civil war, and civil disorder were found to have a significant negative impact on the environment, suggesting that reducing these conflicts would improve environmental circumstances. The findings highlight the need for conflict resolution measures to achieve a sustainable environment in the Middle Eastern and African regions and have implications for other countries facing similar issues.


Effects of Colonization of Gnotobiotic Swiss Webster Mice with Helicobacter bilis.
Helicobacter bilis (Hb) causes hepatitis in some strains of inbred mice. The current study confirmed that Hb directly causes portal hepatitis in outbred gnotobiotic Swiss Webster (SW) mice, as we previously reported for conventional SW mice. Hbmonoassociated SW mice also developed mild enterocolitis, expanded gut-associated lymphoid tissue (GALT), and tertiary lymphoid tissue in the lower bowel. At 1 and 10 mo after infection, Hb-induced GALT hyperplasia exhibited well-organized, ectopic germinal centers with increased mononuclear cell apoptosis, MHC class II antigen presentation, and pronounced endothelial venule formation, consistent with features of tertiary lymphoid tissue. In the lower bowel, Hb induced mainly B220+ cells as well as CD4+ IL17+, CD4+ IFNγ+, and CD4+ FoxP3+ regulatory T cells and significantly increased IL10 mRNA expression. This gnotobiotic model confirmed that Hb causes portal hepatitis in outbred SW mice but stimulated GALT with an antiinflammatory bias. Because Hb had both anti- and proinflammatory effects on GALT, it should be considered a 'pathosymbiont provocateur' and merits further evaluation in mouse models of human disease.


Tandem mass spectrometry of modified and platinated oligoribonucleotides.
Therapeutic approaches for treatment of various diseases aim at the interruption of transcription or translation. Modified oligonucleotides, such as 2'-O-methyl- and methylphosphonate-derivatives, exhibit high resistance against cellular nucleases, thus rendering application for, e.g., antigene or antisense purposes possible. Other approaches are based on administration of cross-linking agents, such as cis-diamminedichloroplatinum(II) (cisplatin, DDP), which is still the most widely used anticancer drug worldwide. Due to the formation of 1,2-intrastrand cross links at adjacent guanines, replication of the double-strand is disturbed, thus resulting in significant cytotoxicity. Evidence for the gas-phase dissociation mechanism of platinated RNA is given, based on nano-electrospray ionization high-resolution multistage tandem mass spectrometry (MS(n)). Confirmation was found by investigating the fragmentation pattern of platinated and unplatinated 2'-methoxy oligoribonucleotide hexamers and their corresponding methylphosphonate derivatives. Platinated 2'-methoxy oligoribonucleotides exhibit a similar gas-phase dissociation behavior as the corresponding DNA and RNA sequences, with the 3'-C-O bond adjacent to the vicinal guanines being cleaved preferentially, leading to w(x)-ion formation. By examination of the corresponding platinated methylphosphonate derivatives of the 2'-methoxy oligoribonucleotides, the key role of the negatively charged phosphate oxygen atoms in direct proximity to the guanines was proven. The significant alteration of fragmentation due to platination is demonstrated by comparison of the fragment ion patterns of unplatinated and platinated 2'-O-methyl- and 2'-O-methyl methylphosphonate oligoribonucleotides, and the results obtained by H/D exchange experiments.


Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products.
FDA limited N-nitrosodimethylamine (NDMA) - a carcinogenic impurity formed during metformin (MET) tablets manufacturing - level to 96 ng/day; a step which led to recall of MET products. This work aims to investigate the root cause of NDMA formation during MET tablets manufacturing. We focused on three main contributing causes: use of water and heat during intra-granulation, and the nitrite/nitrate quantities in excipients. Thirteen MET tablet formulations (immediate or sustained-release) were manufactured, on batch level. Each batch was manufactured using one excipient and excluding one cause at a time and NDMA level was assayed. NDMA traces were undetectable in MET tablets manufactured using polyvinyl pyrrolidone or hydroxypropyl cellulose SSL, even when water and/or heat were employed during intra-granulation. Levels of NDMA in MET tablets with hydroxypropyl methyl cellulose (HPMC) E5 or carboxymethyl cellulose sodium 4000 were 67.08 ± 2.3 and 66.21 ± 2.5 ng/day, in the presence of water and/or heat. No impact of employing extra-granular PolyoxTM, HPMC E5 or HPMC K15 on NDMA formation, despite the high nitrite and nitrate content in these excipients. Water, heat, and excipients' nitrite and nitrate levels are the key players, which should collectively exist, to cause NDMA formation during MET tablets manufacturing.


Enteroviral disease in early infancy.
To discover the nature of enteroviral infections in early infancy (infants less than two months of age) in the United States, data were examined of 338 such infants with nonpolio enterovirus isolates reported to the Center for Disease Control in 1972-1975. Interpretation of such data is limited by reporting bias and difficulty in documenting disease causality. Enteroviral disease was severe in 74% of the infants. The most common clinical manifestations were meningitis, severe systemic disease, nonspecific febrile illness, and gastrointestinal symptoms. Fifty-one percent of all enteroviral disease was associated with echoviruses; 45% with Coxsackie B viruses; and only 4% with Coxsackie A viruses. Disease was more prevalent in the summer months, was recognized throughout the country, and occurred more frequently in males.


Caffeine consumption and schizophrenia: A highlight on adenosine receptor-independent mechanisms.
Schizophrenia is a common psychiatric disorder which affects approximately 1% of the population worldwide. However, the complexity of etiology, treatment resistance and side effects induced by current antipsychotics, relapse prevention, and psychosocial rehabilitation are still to be uncovered. Caffeine, as the world's most widely consumed psychoactive drug, plays a crucial role in daily life. Plenty of preclinical and clinical evidence has illustrated that caffeine consumption could have a beneficial effect on schizophrenia. In this review, we firstly summarize the factors associated with the caffeine-induced beneficial effect. Then, a variety of mechanism of actions independent of adenosine receptor signaling will be discussed with an emphasis on the potential contribution of the microbiome-gut-brain axis to provide more possibilities for future therapeutic, prognosis, and social rehabilitation strategy.


Psilocin, LSD, mescaline, and DOB all induce broadband desynchronization of EEG and disconnection in rats with robust translational validity.
Serotonergic psychedelics are recently gaining a lot of attention as a potential treatment of several neuropsychiatric disorders. Broadband desynchronization of EEG activity and disconnection in humans have been repeatedly shown; however, translational data from animals are completely lacking. Therefore, the main aim of our study was to assess the effects of tryptamine and phenethylamine psychedelics (psilocin 4 mg/kg, LSD 0.2 mg/kg, mescaline 100 mg/kg, and DOB 5 mg/kg) on EEG in freely moving rats. A system consisting of 14 cortical EEG electrodes, co-registration of behavioral activity of animals with subsequent analysis only in segments corresponding to behavioral inactivity (resting-state-like EEG) was used in order to reach a high level of translational validity. Analyses of the mean power, topographic brain-mapping, and functional connectivity revealed that all of the psychedelics irrespective of the structural family induced overall and time-dependent global decrease/desynchronization of EEG activity and disconnection within 1-40 Hz. Major changes in activity were localized on the large areas of the frontal and sensorimotor cortex showing some subtle spatial patterns characterizing each substance. A rebound of occipital theta (4-8 Hz) activity was detected at later stages after treatment with mescaline and LSD. Connectivity analyses showed an overall decrease in global connectivity for both the components of cross-spectral and phase-lagged coherence. Since our results show almost identical effects to those known from human EEG/MEG studies, we conclude that our method has robust translational validity.


Managing Resident Mental Health: Prevention is Better than Cure.
There is a high prevalance of burnout and mental health illness among trainees. Through structured meetings, Program Directors (PDs) have an opportunity to screen and aid residents that may be affected by mental health concerns. However, barriers to this process exist. This study sought to evaluate the perspectives of PDs regarding mental health screening for trainees. A 13-item survey-based study. Electronic distribution of the survey was performed via three individualized requests sent via e-mail to PDs. PDs of 5 ACGME specialties, including Internal Medicine, Pediatrics, Emergency Medicine, General Surgery, and Psychiatry were invited to participate. In total, 595 PDs responded to the survey (response rate = 40.0%) In general, PDs expressed dissatisfaction with the management of burnout and mental health. Most PDs supported periodic screening of residents for burnout (87.0%) and mental health (73.9%). For a resident that could screen positive for mental illness, most PDs were concerned about the possibility of harm to a patient (70.7%) and implications for future licensing (65.7%). Only 30.2% of PDs currently use some form of standardized screening to identify residents struggling with mental health and burnout concerns. The majority of PDs across 5 ACGME specialties support the use of periodic screening of residents for burnout and mental health. However, concerns exist regarding such screening such as the implications for future licensing. Additional work needs to be done to address PD concerns and destigmatizate mental health wellbeing and care among trainees.


Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study.
Previous studies have demonstrated that androgen receptor is expressed in many breast cancers, but its expression in relation to the various breast cancer subtypes as defined by molecular profiling has not been studied in detail. We constructed tissue microarrays from 3093 breast cancers that developed in women enrolled in the Nurses' Health Study. Tissue microarray sections were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6, epidermal growth factor receptor (EGFR) and androgen receptor (ER). Immunostain results were used to categorize each cancer as luminal A or B, HER2 and basal like. The relationships between androgen receptor expression and molecular subtype were analyzed. Overall, 77% of the invasive breast carcinomas were androgen receptor positive. Among 2171 invasive cancers, 64% were luminal A, 15% luminal B, 6% HER2 and 11% basal like. The frequency of androgen receptor expression varied significantly across the molecular phenotypes (P<0.0001). In particular, androgen receptor expression was commonly observed in luminal A (91%) and B (68%) cancers, but was less frequently seen in HER2 cancers (59%). Despite being defined by the absence of ER and PR expression and being considered hormonally unresponsive, 32% of basal-like cancers expressed androgen receptor. Among 246 cases of ductal carcinoma in situ, 86% were androgen receptor positive, but the frequency of androgen receptor expression differed significantly across the molecular phenotypes (P=0.001), and high nuclear grade lesions were less likely to be androgen receptor positive compared with lower-grade lesions. Androgen receptor expression is most commonly seen in luminal A and B invasive breast cancers. However, expression of androgen receptor is also seen in approximately one-third of basal-like cancers, providing further evidence that basal-like cancers represent a heterogeneous group. Our findings raise the possibility that targeting the androgen receptor pathway may represent a novel therapeutic approach to the management of patients with basal-like cancers.


Beneficial effect of retigabine on memory in rats receiving ethanol.
Retigabine belongs to the novel generation of antiepileptic drugs but its complex mechanism of action causes that the drug might be effective in other diseases, for instance, alcohol dependence. It is known that ethanol abuse impaired the function of brain structures associated with memory and learning such as the hippocampus. In our previous study, retigabine reduced hippocampal changes induced by ethanol in the EEG rhythms in rabbits. This study is focused on the impact of retigabine on memory processes in male rats receiving alcohol. Memory was evaluated in various experimental models: Morris water maze, Contextual, and Cued Fear Conditioning tests. Retigabine was administered for 3 weeks directly to the stomach via oral gavage at a dose of 10 mg/kg. Rats received also 20% ethanol (5 g/kg/day in two doses) via oral gavage for 3 weeks and had free access to 5% ethanol in the afternoon and at night. Morris water maze was performed after 1 and 3 weeks of ethanol administration and after 1 week from the discontinuation of ethanol administration. Contextual and Cued Fear Conditioning tests were carried out after 24 h and 72 h of alcohol discontinuation. The drug significantly decreased ethanol-induced memory disturbances during alcohol administration as well as slightly improved learning processes after the discontinuation of ethanol administration. This beneficial effect of retigabine-ethanol interaction on memory may be a relevant element of the drug's impact on the development of addiction.


COVID-19 deaths in the USA: Benford's law and under-reporting.
I use Benford's law to assess whether there is misreporting of coronavirus disease of 2019 (COVID-19) deaths in the USA. I use three statistics to determine whether the reported deaths for US states are consistent with Benford's law, where the probability of smaller digits is greater than the probability of larger digits. My findings indicate that there is under-reporting of COVID-19 deaths in the USA, although the evidence for and the extent of under-reporting does depend on the statistic one uses to assess conformity with Benford's law. Benford's law is a useful diagnostic tool for verifying data and can be used before a more detailed audit or resource intensive investigation.


ChatGPT and Publication Ethics.
Academic publishing is crucial for scientific communication, is governed by accepted ethical norms, and underpins the collective literature on basic science, and technological and medical principles and advances. In November 2022, the public and professional global communities, including the scientific community, witnessed the release of ChatGPT by OpenAI in San Francisco, California, USA. Excluding its public appeal and entertaining aspects but considering its diverse potential applications, some ethical concerns must be considered before establishing guidelines on using and including ChatGPT or similar platforms in scientific publishing. Some academic publishers and preprints have accepted manuscripts with ChatGPT listed as a "co-author". Though excluding such platforms from scientific publishing may not be practicable with time, establishing ethical principles is essential before ChatGPT could become a "co-author" in any scientific, published manuscript.


Lactulose vs polyethylene glycol 3350--electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial.
Hepatic encephalopathy (HE) is a common cause of hospitalization in patients with cirrhosis. Pharmacologic treatment for acute (overt) HE has remained the same for decades. To compare polyethylene glycol 3350-electrolyte solution (PEG) and lactulose treatments in patients with cirrhosis admitted to the hospital for HE. We hypothesized that rapid catharsis of the gut using PEG may resolve HE more effectively than lactulose. The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE. Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization. The primary end point was an improvement of 1 or more in HE grade at 24 hours, determined using the hepatic encephalopathy scoring algorithm (HESA), ranging from 0 (normal clinical and neuropsychological assessments) to 4 (coma). Secondary outcomes included time to HE resolution and overall length of stay. A total of 25 patients were randomized to each treatment arm. Baseline clinical features at admission were similar in the groups. Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P < .01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related. PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE. clinicaltrials.gov Identifier: NCT01283152.


Role of amino acids at positions 34, 296, and 486 of cytochrome P450 2D6 in the stimulatory and inhibitory effects of psychotropic agents on dopamine formation from p-tyramine.
The effects of psychotropic agents such as fluvoxamine, fluoxetine, paroxetine, milnacipran, and fluphenazine on dopamine formation from p-tyramine catalysed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared with the effects on dopamine formation from p-tyramine by CYP2D6.1. Michaelis constants (Km) and maximal velocity (kcat) values for dopamine formation and inhibition constants (Ki) of the psychotropic agents were determined.For CYP2D6.39, the kcat values for fluvoxamine, fluoxetine, and milnacipran, but not for paroxetine and fluphenazine, gradually increased with increasing concentrations, indicating activation of the catalysed reaction.Fluphenazine competitively inhibited dopamine formation catalysed by all variants, with a higher Ki value for CYP2D6.10. Among the three compounds that have a trifluoromethyl group in their chemical structure, only fluvoxamine and fluoxetine, as well as milnacipran that does not have this group, decreased Km values and/or increased kcat values for dopamine formation, suggesting that the group may not be essential for the activation.These findings indicate that substitution of amino acids at positions 34 and 486 can affect the affinity (Km) and enzymatic activity (kcat), respectively, for milnacipran and that the effect of substitution of arginine to cysteine at the 296th position on the activation would be effector dependent.


Trends in Use of Prescription Nonsteroidal Anti-inflammatory Medications Before vs After Implementation of a Florida Law Restricting Opioid Prescribing for Acute Pain.
Previous research has shown an immediate reduction in new opioid users and use after implementation of the opioid supply restriction laws. Assessment of the association between opioid restrictions and alternative treatment options, such as nonsteroidal anti-inflammatory drugs (NSAIDs), is needed to evaluate potential unintended consequences for patients requiring analgesia. To evaluate the association between an opioid restriction law in Florida and use of prescription NSAIDs. This quality improvement study used interrupted time series analyses accounting for autocorrelation to estimate immediate and trend changes in the prescribing and use of prescription NSAIDs in Florida before and after implementation of a state law limiting opioid prescriptions to a 3-day supply. Participants were enrollees in a single private health plan of a large university and health system employer in Florida from January 2015 to June 2019. Prescriptions for NSAIDs, ascertained from pharmacy claims data. The following outcomes were calculated monthly per 1000 plan enrollees: (1) number of NSAID users; (2) mean days' supply of NSAIDs per prescription; and (3) mean number of NSAID prescriptions. Individuals were classified as NSAID users if they had at least 1 NSAID prescription in a given month. Analysis was stratified by route of NSAID administration (oral or nonoral). Among 46 783 NSAID users with 79 089 NSAID prescriptions during the study period, the median age was 47 years (interquartile range, 35-57 years). After implementation of the opioid restriction law, the number of NSAID users immediately increased, but the difference was not significant (change, 0.82 per 1000 patients; 95% CI, -0.67 to 2.30 per 1000 patients). No significant change in the days' supply of oral NSAID users occurred (change, 0.21 days per prescription; 95% CI, -1.66 to 2.08 days per prescription). Before implementation of the law, there was a nonsignificant decreasing trend in NSAID prescriptions (rate of change, -0.03 per month per 1000 enrollees; 95% CI, -0.13 to 0.07 per month per 1000 enrollees; after implementation, there was a nonsignificant increase in the number of oral and nonoral NSAID prescriptions (change, 1.49 per 1000 enrollees; 95% CI, -3.38 to 6.37 per 1000 enrollees). In this quality improvement study, prescribing and use of prescription NSAIDs did not increase after implementation of a law restricting opioid analgesic prescriptions in Florida. These findings suggest possible greater use of over-the-counter NSAIDs after implementation of the law, but further research is needed to evaluate changes in the use of nonopioid analgesics and alternative pain therapies.


Cultural adaptation and psychometric evaluation of the Kinyarwanda version of the diabetes-39 (D-39) questionnaire.
In recent years, more importance is being given to the assessment of quality of life (QoL) among diabetic patients as a measure of their health and the goal of all health interventions. Other studies have reported a high prevalence of diabetes-related effects on; however, there is a knowledge gap in the region of Sub-Saharan Africa, as is the case for Rwanda, where the prevalence of diabetes is expected to rise over the next decade. The aim of this study is to report on the translation and cultural adaptation of the Diabetes-39 (D-39) questionnaire into the Kinyarwanda and its psychometric properties among diabetic patients in Rwanda. The D-39 questionnaire-a five-scale, disease-specific QoL questionnaire-was translated from English to Kinyarwanda, then back-translated to English. A consensus meeting discussed discrepancies and agreed on changes. Interviews were conducted with 26 participants before producing a final version. For the psychometric evaluation, the adapted version was administered to 309 patients with diabetes mellitus. Participants either came from a separate cluster-randomised controlled trial or were recruited ad hoc for this study. The evaluation included testing internal consistency, known group validity, and construct validity. Participants' mean age was 51 ± 12.7 years with a predominance of women (64%) in the sample. All five scales of the questionnaire showed a good internal consistency, with composite reliability of above 0.7. The five-factor model of the questionnaire was fitted to the 39 items. Although the fit was not exact, there was a satisfactory approximate fit (CFI = 0.93, TLI = 0.92, RMSEA = 0.05). There was a good discriminant validity except for the "social burden" and "anxiety and worry" scales (inter-factor correlation = 0.80). Diabetes-39 is a questionnaire developed in English that was adapted and translated into Kinyarwanda. The Kinyarwanda version of D-39 is a reliable and valid instrument to measure QoL among diabetic patients in Rwanda. The questionnaire can be helpful in research and clinical practice improving health outcomes for patients with diabetes in Rwanda and other Kinyarwanda-competent areas in the sub-region. However, certain cross-cultural differences should be considered.


Production of monoclonal antibodies against avidin.
Monoclonal antibodies of the IgG1 subclass were generated against chicken avidin. These antibodies were shown to be as sensitive as polyclonal antiserum in detecting avidin by radioimmunoassay (RIA) and enzyme linked immunosorbent assay (ELISA) methods. Furthermore, the monoclonal antibodies were considerably more specific. Our results with a monoclonal anti-avidin RIA support previous findings that in inflammatory conditions avidin is synthesized also in other organs than the oviduct, although in the liver a major part of the activity detected by polyclonal anti-avidin RIA or biotin-bentonite assay was not due to avidin.


The oncologic safety of left colectomy with modified complete mesocolic excision for distal transverse colon cancer: Comparison with descending colon cancer.
The optimal surgical approach for distal transverse colon cancer has not been well established. This study aimed to evaluate the oncologic safety of left colectomy with a modified complete mesocolic excision for distal transverse colon cancer as compared with descending colon cancer. This study involved 383 patients who underwent left colectomy with modified complete mesocolic excision for non-metastatic distal transverse and splenic flexure colon (transverse group, N = 110) and descending colon cancer (descending group, N = 237) from 3 institutions. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups. Baseline characteristics between the two groups were similar except for the length of the distal margin (transverse group = 11.0 cm vs descending group = 9.0 cm, p = 0.004). During a median follow-up of 47.0 months, RFS and OS were not different between the transverse and descending groups (5-year RFS: 82% vs 71%, p = 0.139; 5-year OS: 83% vs 79%, p = 0.416, respectively). In multivariable analysis, RFS and OS were not different between the two groups (transverse group vs. descending group: adjusted hazard ratio [aHR] = 1.557, 95% CI = 0.786-3.084, p = 0.204; aHR = 1.251, 95% CI = 0.530-2.952, p = 0.609). The oncologic outcomes of left colectomy with a modified complete mesocolic excision of distal transverse colon cancer were comparable to those of descending colon cancer. Left colectomy with a modified complete mesocolic excision can be an acceptable surgical treatment for distal transverse colon cancer.


Reduced orthostatic tolerance following 4 h head-down tilt.
The cardiovascular responses to a 10-min 1.22 rad (70 degrees) head-up tilt orthostatic tolerance test (OST) was observed in eight healthy men following each of a 5-min supine baseline (control), 4 h of 0.1 rad (6 degrees) head-down tilt (HDT), or 4 h 0.52 rad (30 degrees) head-up tilt (HUT). An important clinical observation was presyncopal symptoms in six of eight subjects following 4 h HDT, but in no subjects following 4 h HUT. Immediately prior to the OST, there were no differences in heart rate, stroke volume, cardiac output, mean arterial pressure and total peripheral resistance for HDT and HUT. However, stroke volume and cardiac output were greater for the control group. Mean arterial pressure for the control group was less than HDT but not HUT. Over the full 10-min period of OST, the mean arterial pressure was not different between groups. Heart rate increased to the same level for all three treatments. Stroke volume decreased across the full time period for control and HDT, but only at 3 and 9 min for HUT. There was a higher total peripheral resistance in the HDT group than control or HUT. The pre-ejection period to left ventricular ejection time ratio was less in HDT than for control or HUT groups. These data indicate a rapid adaptation of the cardiovascular system to 4 h HDT that appears to be inappropriate on reapplication of a head to foot gravity vector. We speculate that the cause of the impaired orthostatic tolerance is decreased tone in venous capacitance vessels so that venous return is inadequate.