Effects of etidronate disodium on crystallizations in synthetic urine and calcium oxalate crystal adhesion to Madin-Darby canine kidney (MDCK) cells.
Several reports in the 1970s suggested that etidronate disodium might be clinically useful to prevent calcium stones, but the use of etidronate in the urolithiasis field was discontinued due to adverse effects of this drug on skeletal turnover and mineralization. Because the drug might affect not only crystallization, but also crystal-tubular interactions, we investigated the minimum dose of etidronate necessary to effectively prevent stone recurrence without adverse side effects. We examined the effect of etidronate on the crystallization of calcium oxalate, calcium phosphate and magnesium ammonium phosphate using synthetic urine and measured by an aggregometer. We also studied its effect on the adhesion of calcium oxalate monohydrate crystals to Madin-Darby canine kidney (MDCK) cells in vitro. Etidronate affected the crystallization+ of not only calcium phosphate and calcium oxalate, but also magnesium ammonium phosphate in synthetic urine. The inhibitory activities on these crystallizations were detected at extremely low drug concentrations. Etidronate also had a strong inhibitory activity against the adhesion of calcium oxalate crystals to MDCK cells. Although further studies are necessary regarding the effects of etidronate on crystallization and crystal adhesion both in vivo and in vitro, and the appropriate schedule of dosing to prevent side effects, it is possible that etidronate may be useful in the treatment of urinary stones.


Histone Deacetylases May Mediate Surgery-Induced Impairment of Learning, Memory, and Dendritic Development.
Postoperative cognitive dysfunction (POCD) affects millions of patients each year in the USA and has been recognized as a significant complication after surgery. Epigenetic regulation of learning and memory has been shown. For example, an increase of histone deacetylases (HDACs), especially HDAC2, which epigenetically regulates gene expression, impairs learning and memory. However, the epigenetic contribution to the development of POCD is not known. Also, the effects of living situation on POCD have not been investigated. Here, we showed that mice that lived alone before the surgery and lived in a group after the surgery and mice that lived in a group before surgery and lived alone after surgery had impairment of learning and memory compared with the corresponding control mice without surgery. Surgery increased the activity of HDACs including HDAC2 but not HDAC1 and decreased brain-derived neurotrophic factor (BDNF), dendritic arborization, and spine density in the hippocampus. Suberanilohydroxamic acid (SAHA), a relatively specific inhibitor of HDAC2, attenuated these surgery effects. SAHA did not change BDNF expression, dendritic arborization, and spine density in mice without surgery. Surgery also reduced the activity of nuclear histone acetyltransferases (HATs). This effect was not affected by SAHA. Our results suggest that surgery activates HDACs, which then reduces BDNF and dendritic arborization to develop POCD. Thus, epigenetic change contributes to the occurrence of POCD.


Highly sensitive quantification of site-specific 5-hydroxymethylcytosine at single-base resolution by HpaII-mediated ligation PCR.
A highly sensitive HpaII-mediated ligation PCR assay that can precisely discriminate 5hmC from 5mC and C is developed for the quantitative determination of site-specific 5hmC in genomic DNA samples.


Comparison of morphine and hydromorphone analysis on reversed phase columns with different diameters.
A comparison of a reversed phase high-performance liquid chromatographic (HPLC) method performed on columns with different internal diameters is reported for the quantitative routine determination of morphine.HCl and hydromorphone.HCl in solutions used for intramuscular injection. The method is based on the ion-pairing properties of sodium dodecyl sulphate (SDS) with alkaloids on a reversed phase LiChrospher RP-18 packing material and UV-detection at 230 nm. The mobile phase consisted of an acetonitrile: water mixture 35:65 (v/v) containing 0.5% (w/v) SDS and 0.4% (v/v) acetic acid. Precision, linearity and limit of detection were compared on the 2, 3 and 4 mm i.d. x 125 mm columns. A robustness test for the determination of hydromorphone.HCl was also evaluated.


Crush injury in pregnancy: an unusual experience in obstetrics.
Crush injury is the result of prolonged pressure to the limbs when individuals are trapped under the debris of earthquakes, bombings, and other disasters. Muscle integrity is compromised, and the local and systemic manifestations, including rhabdomyolysis, hyperkalemia, renal failure, and disseminated intravascular coagulation may be fatal. A 32-year-old woman, gravida 2, para 1, was trapped under fallen masonry at 6 weeks' gestation for approximately 6 hours. On initial examination, she showed early signs of hypovolemic shock and crush injury, including hyperkalemia. Prompt management with fluid therapy and careful monitoring led to a rapid recovery. Antenatal follow-up was routine and concluded in spontaneous delivery of a healthy infant. The unique physiology of the pregnant woman may affect the outcome of crush injury, and it presents a particular challenge to the trauma team. The obstetrician should be aware of its dangers and should be an active participant in the prompt management of pregnant victims of crush injury to ensure a satisfactory outcome for both mother and fetus.


Selective inhibition of sodium-linked and sodium-independent bicarbonate/chloride antiport in Vero cells.
The effects of compounds previously described to inhibit anion transport were tested for their ability to inhibit anion antiport in Vero cells as measured by uptake of 36Cl- by chloride self-exchange and as bicarbonate-linked uptake of 22Na+. While 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid inhibited both processes, ethacrynic acid and probenecid selectively inhibited the uptake of 36Cl-. Low concentrations of pyridoxal phosphate and picrylsulfonic acid selectively inhibited the bicarbonate linked uptake of 22Na+, while higher concentrations of these compounds also inhibited the uptake of 36Cl-. Measurements of the internal pH indicated that ethacrynic acid inhibits Na+-independent HCO-3/Cl- exchange, while it has no measurable effect on Na+-linked bicarbonate-dependent regulation of the internal pH. Conversely, picrylsulfonic acid selectively inhibits the latter process. The results indicate that anion antiport in Vero cells occurs by two independent processes.


Role of Phox2b and Mash1 in the generation of the vestibular efferent nucleus.
The inner ear (vestibular and cochlear) efferent neurons are a group of atypical motor-like hindbrain neurons which innervate inner ear hair cells and their sensory afferents. They are born in the fourth rhombomere, in close association with facial branchial motor neurons, from which they subsequently part through a specific migration route. Here, we demonstrate that the inner ear efferents depend on Phox2b for their differentiation, behaving in that respect like hindbrain visceral and branchial motor neurons. We also show that the vestibular efferent nucleus is no longer present at its usual site in mice inactivated for the bHLH transcription factor Mash 1. The concomitant appearance of an ectopic branchial-like nucleus at the location where both inner ear efferents and facial branchial motor neurons are born suggests that Mash1 is required for the migration of a subpopulation of rhombomere 4-derived efferents.


The impact of charlson comorbidity index on mortality from SARS-CoV-2 virus infection and A novel COVID-19 mortality index: CoLACD.
The aim of this study is to find out the potential risk factors including charlson comorbidity index (CCI) score associated with death in COVID-19 patients hospitalised because of pneumonia and try to find a novel COVID-19 mortality score for daily use. All patients diagnosed as confirmed or probable COVID-19 pneumonia whom hospitalised in our Chest Diseases Education and Research Hospital between March 11, 2020 and May 15, 2020 were enrolled. The optimal cut-off values, sensitivity and specificity values and odds ratios to be used in mortality prediction of the novel scoring system created from these parameters were calculated by ROC analysis according to the area under the curve and Youden index. Over 383 patients (n: 33 deceased, n: 350 survivors) univariate and multivariate regression analysis showed that CCI and lymphocyte ratio were prognostic factors for COVID-19-related mortality. Using this analysis, a novel scoring model CoLACD (CoVID-19 Lymphocyte ratio, Age, CCI score, Dyspnoea) was established. The cut-off value of this scoring system, which determines the mortality risk in patients, was 2.5 points with 82% sensitivity and 73% specificity (AUC = 0.802, 95% CI 0.777-0.886, P < .001). The risk of mortality was 11.8 times higher in patients with a CoLACD mortality score higher than 2.5 points than patients with a score lower than 2.5 (OR = 11.8 95% CI 4.7-29.3 P < .001). This study showed that by using the CoLACD mortality score, clinicians may achieve a prediction of mortality in COVID-19 patients hospitalised for pneumonia.


Relative Lability and Chemoselective Transmetallation of NHC in Hybrid Phosphine-NHC Ligands: Access to Heterometallic Complexes.
The relative lability and transmetallation aptitude of trialkylphosphine and NHC donors, integrated in semi-rigid hybrid ligands attached to [Ag4Br4] pseudo-cubanes, lies in favor of the NHC and is used to selectively access unprecedented NHC complexes with heterobimetallic cores, such as Ag-Cu (4(Cy)) and Ag-Ir (5(tBu)). These can be viewed as an arrested state before the full transmetallation of both donors, which gives the homodinuclear Cu (3(Cy)) and Ir (6(Cy)) complexes. The observed NHC transmetallation aptitude and reactivity urges caution in the common notion that views the NHC as a universal spectator.


The Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Events Depends on Haptoglobin Phenotype Among White and Black ACCORD Participants.
Intensive glycemic therapy reduced coronary artery disease (CAD) events among White participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with the haptoglobin (Hp)2-2 phenotype, while participants without the Hp2-2 phenotype had no CAD benefit. The association between achieved glycated hemoglobin (HbA1c) and CAD for each Hp phenotype remains unknown. Achieved HbA1c was similar in each phenotype throughout the study. Prospectively collected HbA1c data (categorized as <6.0%, 6.0-6.5%, 6.6-6.9%, or ≥8.0% compared with 7.0-7.9%) from the ACCORD study, updated every 4 months over a median of 4.7 years, were analyzed in relation to CAD in the Hp2-2 (n = 3,322) and non-Hp2-2 (n = 5,949) phenotypes separately overall, and within White (63%, 37% Hp2-2) and Black (19%, 26% Hp2-2) participants using Cox proportional hazards regression with time-varying covariables. Compared with HbA1c of 7.0-7.9%, having HbA1c ≥8.0% was associated with CAD risk among White (adjusted HR [aHR] 1.43, 95% CI 1.03-1.98) and Black (2.86, 1.09-7.51) participants with the Hp2-2 phenotype, but not when all Hp2-2 participants were combined overall (1.30, 0.99-1.70), and not among participants without the Hp2-2 phenotype. HbA1c <7.0% was not associated with a lower risk of CAD for any Hp phenotype. Achieving HbA1c >8.0% compared with 7.0-7.9% was consistently associated with incident CAD risk among White and Black ACCORD participants with the Hp2-2 phenotype, while no association was observed among participants without the Hp2-2 phenotype. We found no evidence that HbA1c concentration <7.0% prevents CAD in either Hp phenotype group.


Radiocesium accumulation in edible wild mushrooms from coniferous forests around the Nuclear Centre of Mexico.
Cs-137 and K-40 have been determined in soil samples and in wild edible mushrooms from a forest ecosystem located at the Nuclear Centre of Mexico (NCM) and in several surrounding localities. The transfer factors for Cs-137 were studied in 21 mushroom species from 1993 to 1997. The Cs-137 and K-40 determinations were performed using a gamma spectrometer system of low level counting with a high purity germanium (HPGe) detector. The local mushroom species that were found to show higher Cs-137 transfer factors were Clavariadelphus truncatus, Cortinarius caerulescens, Gomphus floccosus and Lyophyllum decastes. The Cs-137 levels obtained at the NCM in some mushroom samples were slightly lower than those from surrounding localities indicating that the nuclear facility has not emitted Cs-137 to the atmosphere.


Management and work-up procedures of patients with head and neck malignancies treated by radiation.
Radiotherapy alone or in association with systemic treatment plays a major role in the treatment of head and neck tumours, either as a primary treatment or as a postoperative modality. The management of these tumours is multidisciplinary, requiring particular care at every treatment step. We present the update of the recommendations of the French Society of Radiation Oncology on the radiotherapy of head and neck tumours from the imaging work-up needed for optimal selection of treatment volume, to optimization of the dose distribution and delivery.


In vitro production of N-degron fused proteins and its application.
The N-degron pathway, first discovered several decades ago by Varshavsky's laboratory, controls the half-life of target proteins depending on their N-terminal residues. In vivo cell biology studies have established the physiological role of the N-degron pathway. However, in vitro studies such as biochemical assays and structural biology studies are relatively limited. The N-degron substrates cannot be obtained via simple protein expression. The N-degron residues are exposed via the proteolytic process from the translated nascent polypeptide chains. Thus, methods for the fusion expression with several cleavable tags and subsequent treatment with specific proteases to design the exposed N-degron signals have been introduced. Recently, we developed a unique fusion technique using microtubule-associated protein 1A/1B light chain 3B (LC3B), a key marker protein of autophagy, to obtain a high yield of the purified target proteins with variable N-terminal residues for various biochemical studies including enzymatic and binding assays, and crystallization of N-degron complex. This chapter describes the protocols that include the vector map designed for producing LC3B fused target proteins, methods for expression and purification of an example protein, p62/SQSMT1, using different N-terminal residues, and methods to obtain the purified ATG4B protease, which is used for processing LC3B tag and exposing the required N-terminal residues of the target protein.


Pediatric dermatologic surgery for the primary care pediatrician.
Surgical procedures on the skin are commonplace in the practice of pediatric dermatology. Dermatologists are trained in their residencies to perform office surgery, including biopsies, excisions with repairs, cryosurgery, chemosurgery, and laser surgery. Although most dermatologists treat patients of all ages, some treat children only. Within this group, some are concentrating on pediatric dermatologic surgery. Many dermatologists take additional training in dermatologic and laser surgery, treating both adults and children. New techniques and developing technology present pediatricians and dermatologists with many options in choosing the best and most appropriate treatment modalities.


Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial.
Among patients with locally advanced metastatic pancreatic adenocarcinoma, gemcitabine has been shown to improve outcomes compared with fluorouracil. To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma. Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions. Chemotherapy with either fluorouracil (continuous infusion of 250 mg/m2 per day; n = 230) or gemcitabine (30-minute infusion of 1000 mg/m2 once per week; n = 221) for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy. Chemoradiation with a continuous infusion of fluorouracil (250 mg/m2 per day) was the same for all patients (50.4 Gy). Survival for all patients and survival for patients with pancreatic head tumors were the primary end points. Secondary end points included toxicity. A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%). The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant. clinicaltrials.gov Identifier: NCT00003216.


Kaposi's sarcoma: histopathological study of 159 cases from Malawi.
The histological features of 168 lesions of Kaposi's sarcoma from 159 patients in Malawi, where the disease is commoner than elsewhere, were characteristic. All showed well-developed areas of tumour and could be grouped fairly readily into those with a mixed pattern, a predominantly spindle cell pattern, and an anaplastic group, though intermediate patterns were seen. Hyaline bodies were present in nearly all tumours of skin. The cell of origin of Kaposi's sarcoma is uncertain and possibly has multipotential capabilities. Differential diagnosis may be difficult. Clinically the lesion may be confused with granuloma pyogenicum and may also be like it histologically. The presence of hyaline bodies and deposits of haemosiderin indicate Kaposi's sarcoma. The spindle cell predominant type may be confused with leiomyoma, leiomyosarcoma, or fibrosarcoma. The presence of hyaline bodies and the formation of vascular channels between spindle cells point to a diagnosis of Kaposi's sarcoma.


Proteomic characterization of human platelet-derived microparticles.
Microparticles (MPs) are small fragments of apoptotic or activated cells that may contribute to pathological processes in many diseases. Platelet-derived MPs (PMPs) are the most abundant type of MPs in human blood. To characterize the proteins in PMPs we used a shotgun proteomics approach by nanoHPLC separation followed by MS analysis on an LTQ Orbitrap XL. PMPs were produced from isolated platelets stimulated with adenosine diphosphate (ADP). We developed an analytical platform constituted by two different steps: in the first one we used a standard shotgun strategy; in the second one, to improve low-molecular weight, low-abundance-proteins identification, the samples were fractionated using hydrogel nanoparticles, an enrichment system based on a mixed mechanism of dimensional exclusion and colorant affinity. This was chosen to tackle a common issue with shotgun approaches, in which the low-abundance proteins are not detected when surveys are on a broad scale. By means of the entire analytical platform, we identified 603 proteins, 243 of which were not previously identified. A simple and straightforward procedure for the study of PMPs was provided, producing a tool for further understanding their biological and pathological roles, and a baseline for future studies aimed at discovering biomarkers involved in several diseases.


Knitting Ripples.
Ripples are common in both biological systems and human clothes. Knitters have long exploited the ability of fabric to curl out of plane, by either removing or adding stitches to the material as it is created. Here, we present two knitting patterns for scarves to illustrate how ripples can arise through such additive processes.


Financial Capability and Asset Building (FCAB) for Persons with Disabilities in Ghana: the Role of Social Workers.
Persons with disabilities (PWDs) are over-represented among the poorest populations in developing countries. They often encounter several challenges in accessing financial services and are financially vulnerable and prone to poverty. Most PWDs in developing countries, such as Ghana, are less likely to have the requisite economic socialisation and education leading to gainful employment, compared to their counterparts without disabilities. This could worsen their economic resilience and adversely impact their daily lives. Pragmatic and robust policy interventions are required to reverse these financial vulnerabilities for PWDs in Ghana. Guided by the financial capability framework, this paper argues that financial capability and asset building (FCAB) interventions are imperative in promoting financial inclusion and literacy for PWDs. In lieu of this, social workers have very critical roles to play, as they often work with financially vulnerable populations like PWDs. Social workers could work as advocates, mobilisers, facilitators and educators in FCAB interventions in the pursuit of breaking the cycle of poverty among PWDs.


C-reactive protein is an independent predictor of severity in community-acquired pneumonia.
C-reactive protein (CRP) is an acute phase protein synthesized by the liver primarily in response to interleukin-6. Initial studies have suggested that inflammatory markers may have a role in predicting severity. We investigated whether admission and day 4 CRP could predict severity in community-acquired pneumonia. A prospective study was carried out over a 2-year period in a large teaching hospital. CRP was measured on admission and on day 4. The outcomes of interest were: 30-day mortality; need for mechanical ventilation and/or inotropic support; development of complicated pneumonia (lung abscess, empyema, or complicated parapneumonic effusion); the value of predictive tests were assessed using multivariate logistic regression. There were 570 patients included in the study; 30-day mortality was 9.6%. Low CRP levels showed a high negative predictive value for excluding 30-day mortality (CRP <10 mg/L=100%, CRP <50=99.1%, CRP <100=98.9%, CRP <200=94.9%). Low admission CRP levels <100 mg/L were independently associated with reduced 30-day mortality (odds ratio [OR] 0.18; 0.04-0.85), P=.03; need for mechanical ventilation and/or inotropic support (OR 0.21; 0.14-0.4), P=.002; and complicated pneumonia (OR 0.05; 0.01-0.35), P=.003. A CRP that fails to fall by 50% or more within 4 days of admission is independently associated with increased 30 day mortality (OR 24.5; 6.4-93.4), P <.0001; need for mechanical ventilation and/or inotropic support (OR 7.1; 2.8-17.8), P <.0001 and complicated pneumonia (OR 15.4; 6.32-37.6), P <.0001. Admission CRP <100 mg/L has reduced risk for 30-day mortality, need for mechanical ventilation and/or inotropic support, and complicated pneumonia. Failure of CRP to fall by 50% or more at day 4 leads to an increased risk for 30-day mortality, need for mechanical ventilation and/or inotropic support, and complicated pneumonia. C-reactive protein is an independent marker of severity in community-acquired pneumonia.


[Validity and Reliability of ARQ-K (Korean Version of the Assault Response Questionnaire) for Emergency Department Nurses in Korea].
To investigate the validity and reliability of the Korean Version of the Assault Response Questionnaire (ARQ-K) measuring the intensity of reaction to victimization of emergency nurses in Korea. An internal consistency reliability and construct validity using exploratory and confirmatory factor analysis were conducted using SPSS WIN (20.0) and AMOS (20.0). Survey data were collected from 321 nurses who worked in 3 levels - wide regional emergency centers, regional emergency centers, appointed emergency centers - of emergency care facilities in Busan, Korea. The Cronbach's alpha values regarding internal consistency were .77~.93 for the subscales of ARQ-K. Factor loadings of the 26 items on the four subscales ranged from .59 to .84. The four-subscale model was validated by confirmatory factor analysis (χ²/df=3.85, p<.001, RMR=.06, GFI=.80, NFI=.81, TLI=.83, CFI=.85, RMSEA=.09). This study shows that the Korean Version of the Assault Response Questionnaire is a valid and reliable instrument to assess nurses' reaction to victimization of emergency nurses in Korea.


The view from 10,000 procedures: technical tips and wisdom from master pancreatic surgeons to avoid hemorrhage during pancreaticoduodenectomy.
Pancreaticoduodenectomy remains the exclusive technique for surgical resection of cancers located within both the pancreatic head and periampullary region. Amongst peri-procedural complications, hemorrhage is particularly problematic given that allogenic blood transfusions are known to increase the risk of infection, acute lung injury, cancer recurrence and overall 30-day morbidity and mortality rates. Because blood loss can be considered a modifiable factor that reflects surgical technique, rates of perioperative blood loss and transfusion have been advocated as robust quality indicators. We present a correspondence manuscript that outlines peri-procedural concepts detailing a successful pancreaticoduodenectomy with minimal hemorrhage. These tips were collated from master pancreatic surgeons throughout the globe who have performed over 10,000 cumulative pancreaticoduodenectomies. At risk scenarios for hemorrhage include dissections of the superior mesenteric - portal vein, gastroduodenal artery, and retroperitoneal soft tissue margin. General principles in limiting slow continuous hemorrhage that may accumulate into larger total case losses are also discussed. While many of the techniques and tips proposed by master pancreas surgeons are intuitive and straight forward, when taken as a collective they represent a significant contribution to improved outcomes associated with the pancreaticoduodenectomy over the past 100 years.


Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma.
To determine the effects of highly active antiretroviral therapy (HAART) on survival in AIDS-related primary central nervous system lymphoma (PCNSL). Survival in consecutive patients with PCNSL at a large county teaching hospital from 1995 to 2001 were analyzed by the log rank test and Cox proportional hazards ratios (HR) were calculated for factors potentially affecting survival. During the study period, 25 patients were diagnosed with PCNSL: 19 definite and 6 probable. At diagnosis, median CD4 cell count was 12 x 10(6) cells/l (range 1-151) and median HIV viral load was 5.3 log(10) copies/ml (range 3.9-5.9). Sixteen patients died (median survival 87 days; range, 0 to > 2112). Longer survival was noted for patients who received HAART after diagnosis [HR for death, 0.06; 95% confidence interval (CI), 0.01-0.48]. Six of seven HAART-treated patients were alive versus 0/18 untreated patients at a median follow-up time of 667 days (P = 0.0007 by log rank test). A survival benefit was seen for patients who had >/= 0.5 log(10) copies/ml decrease in HIV viral load after diagnosis (n = 6; HR, 0.07; 95% CI, 0.01-0.55) and for patients with a significant CD4 cell rebound (increase >/= 50 x 106 cells/l) in response to HAART (n = 6): all survived versus 0/19 survived (P = 0.0003). Cranial radiation therapy (n = 13) prolonged survival (HR, 0.20; 95% CI, 0.07-0.58). Median survival was only 29 days for 11 patients who received neither radiation nor HAART. Receipt of HAART after diagnosis is associated with a significantly longer survival in patients with AIDS-related CNS lymphoma.


Automated scene analysis of CT scans.
Since the advent of computed tomography, there has been an increasing realization that CT scans contain quantitative as well as qualitative information useful in the diagnostic process. Often however, the use of this information is impeded by the tedious manual outlining of the areas of interest in the scan. To alleviate this problem, we have developed a scene segmentation algorithm which will automatically delineate areas of interest in a CT scan. This procedure uses known information about the expected objects in the scan in conjuction with an algorithm to label those objects. The resultant scene segmentation divides the scan into four anatomical areas: skull, normal brain, high density lesions and CSF. After an area of interest is interactively selected by the clinician, volume, density or other quantitative measures may be computed. Limitations of the algorithm and its clinical applications are discussed.


Modulation of T cells and macrophages by cholera toxin treatment in vivo and in vitro.
Cholera Toxin influences the antibody response to SRBC. Enhanced responses occur in vivo and in vitro when CT is added together with antigen. However, CT depresses antibody formation when given in vivo before antigen but enhances in vitro responses under the same conditions. Modulation of antibody formation appeared due to effects of T lymphocytes as well as macrophages. Co-cultivation of immunologically impaired spleen cells from CT pretreated animals with macrophage-rich peritoneal cells or educated T cells increased the antibody response.


Canonical Wnt signaling regulates the proliferative expansion and differentiation of fibrocytes in the murine inner ear.
Otic fibrocytes tether the cochlear duct to the surrounding otic capsule but are also critically involved in maintenance of ion homeostasis in the cochlea, thus, perception of sound. The molecular pathways that regulate the development of this heterogenous group of cells from mesenchymal precursors are poorly understood. Here, we identified epithelial Wnt7a and Wnt7b as possible ligands of Fzd-mediated β-catenin (Ctnnb1)-dependent (canonical) Wnt signaling in the adjacent undifferentiated periotic mesenchyme (POM). Mice with a conditional deletion of Ctnnb1 in the POM exhibited a complete failure of fibrocyte differentiation, a severe reduction of mesenchymal cells surrounding the cochlear duct, loss of pericochlear spaces, a thickening and partial loss of the bony capsule and a secondary disturbance of cochlear duct coiling shortly before birth. Analysis at earlier stages revealed that radial patterning of the POM in two domains with highly condensed cartilaginous precursors and more loosely arranged inner mesenchymal cells occurred normally but that proliferation in the inner domain was reduced and cytodifferentiation failed. Cells with mis/overexpression of a stabilized form of Ctnnb1 in the entire POM mesenchyme sorted to the inner mesenchymal compartment and exhibited increased proliferation. Our analysis suggests that Wnt signals from the cochlear duct epithelium are crucial to induce differentiation and expansion of fibrocyte precursor cells. Our findings emphasize the importance of epithelial-mesenchymal signaling in inner ear development.


Topoisomerase inhibitors: Pharmacology and emerging nanoscale delivery systems.
Topoisomerase enzymes have shown unique roles in replication and transcription. These enzymes which were initially found in Escherichia coli have attracted considerable attention as target molecules for cancer therapy. Nowadays, there are several topoisomerase inhibitors in the market to treat or at least control the progression of cancer. However, significant toxicity, low solubility and poor pharmacokinetic properties have limited their wide application and these characteristics need to be improved. Nano-delivery systems have provided an opportunity to modify the intrinsic properties of molecules and also to transfer the toxic agent to the target tissues. These delivery systems leads to the re-introduction of existing molecules present in the market as novel therapeutic agents with different physicochemical and pharmacokinetic properties. This review focusses on a variety of nano-delivery vehicles used for the improvement of pharmacological properties of topoisomerase inhibitors and thus enabling their potential application as novel drugs in the market.


Anandamide reduces the migration of lymphocytes to the intestine by CB2 activation and reduces TNF-α in the target organs, protecting mice from graft-versus-host disease.
Graft-versus-host disease (GVHD) is a serious inflammatory illness that often occurs as a secondary complication of bone marrow transplantation. Current therapies have limited effectiveness and fail to achieve a balance between inflammation and the graft-versus-tumor effect. In this study, we investigate the effects of the endocannabinoid anandamide on the complex pathology of GVHD. We assess the effects of an irreversible inhibitor of fatty acid amine hydrolase or exogenous anandamide and find that they increase survival and reduce clinical signs in GVHD mice. In the intestine of GVHD mice, treatment with exogenous anandamide also leads to a reduction in the number of CD3+, CD3+CD4+, and CD3+CD8+ cells, which reduces the activation of CD3+CD4+ and CD3+CD8+ cells, as assessed by enhanced CD28 expression, a T cell co-stimulatory molecule. Exogenous AEA was also able to reduce TNF-α and increase IL-10 in the intestine of GVHD mice. In the liver, exogenous AEA reduces injury, TNF-α levels, and the number of CD3+CD8+ cells. Interestingly, anandamide reduces Mac-1α, which lowers the adhesion of transplanted cells in mesenteric veins. These effects are mimicked by JWH133-a CB2 selective agonist-and abolished by treatment with a CB2 antagonist. Furthermore, the effects caused by anandamide treatment on survival were related to the CB2 receptor, as the CB2 antagonist abolished it. This study shows the critical role of the CB2 receptor in the modulation of the inflammatory response of GVHD by treatment with anandamide, the most prominent endocannabinoid.


Comparison of mini-open repair system and percutaneous repair for acute Achilles tendon rupture.
To reduce incision complications, minimally invasive operative approaches for treatment with acute Achilles tendon rupture have been developed, such as Mini-open repair and percutaneous repair. Which technique is the better surgical option? In the present study, we compared the two surgical procedures- modified Mini-open repair versus percutaneous repair-in the treatment of acute Achilles tendon rupture. From January 2016 to November 2018, 68 matched patients with acute Achilles tendon rupture were divided into treatment group (Mini-open with modified Ma-Griffith technique) and control group (the Ma-Griffith technique). The patients were then treated with different surgical techniques and followed up for no less than 24 months, and the functional outcome scores and complications were retrospectively evaluated. The mean follow-up time in Mini-open repair group was 29.0±2.9 months, and that in control group was 27.9±2.9 months (P=0.147). The Mini-open repair group showed reliably higher American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score and Achilles tendon Total Rupture Score (ATRS) than the control group in functional assessment (95.0±3.8 vs. 92.3±5.3, P=0.000; 93.8±3.8 vs. 90.9±4.5,P=0.000). There was no cases of sural nerve injury in Mini-open repair group, whereas the percutaneous repair group had 5 cases of the same (P=0.027). No significant differences were found in the calf circumference (32.3±3.9 vs. 31.8±3.6) (P=0.564), range of motion of the ankle (51.3±4.8 vs. 50.5±4.2, P=0.362), or wound complications (34/0 vs. 34/0) (P=1.000) between the two groups at the end of the follow-up time. However, the percutaneous repair group had a shorter average operating time (23.1±5.2 min) than that of the Mini-open repair group (27.7±4.3 min) (P=0.000). Acute Achilles tendon ruptures may be treated successfully with a new Mini-open repair system or percutaneous repair technique. However, the Mini-open repair system may represent a superior surgical option, since it offers advantages in terms of direct visual control of the repair, AOFAS Ankle-Hindfoot Score, Achilles tendon Total Rupture Score and risk of sural nerve palsy. Case-control studies, Level of evidence, 3.


Surgical Treatment for Persistent Cervical Anastomotic Fistulas With Sinus Formation.
A refractory cervical anastomotic fistula with sinus formation will seriously impede a patient's return to normal life. It is necessary to find ways to shorten the recovery time for such patients. We used a multilayered, pursestring inverted suture-embedding method for 7 patients, 6 of whom recovered; 1 patient with severe anastomotic stricture and failed. A multilayered, pursestring inverted suture-embedding method can be used to treat persistent neck anastomotic fistula with sinus formation, but it is not suitable for patients who still have a fistula to the mediastinum, thoracic cavity, or severely narrowed anastomoses.


The Need to Help Journalists with Data and Information Visualization.
As news migrates to mobile phones, media companies are turning to data visualization to wet readers' appetites for stories they can read at length on their home or work computers. Journalists are trained to write stories, not in statistics or coding, however. The big news organizations have the funds to hire computer graphics experts, but local news organizations need help.


Uveal melanoma radiation. 125I brachytherapy versus helium ion irradiation.
The optimum radiation therapy for uveal melanoma is uncertain. Both helium ion irradiation and 125I brachytherapy have been used to treat this neoplasm. This investigation analyzed the control and complication rates of uveal melanomas treated with helium ions of 125I plaques. In both a retrospective and a prospective dynamically balanced study, the control rates appeared to be similar. There were more posterior segment complications after 125I plaques and more anterior segment complications, including neovascular glaucoma, after helium ion irradiation. The follow-up period is too short to draw definitive conclusions on the radiation complications. Overall, approximately 89% of eyes were retained and less than 4% of treated eyes were removed because of failure to control the tumor.


Q-Score: development of a new metric for continuous glucose monitoring that enables stratification of antihyperglycaemic therapies.
Continuous glucose monitoring (CGM) has revolutionised diabetes management. CGM enables complete visualisation of the glucose profile, and the uncovering of metabolic 'weak points'. A standardised procedure to evaluate the complex data acquired by CGM, and to create patient-tailored recommendations has not yet been developed. We aimed to develop a new patient-tailored approach for the routine clinical evaluation of CGM profiles. We developed a metric allowing screening for profiles that require therapeutic action and a method to identify the individual CGM parameters with improvement potential. Fifteen parameters frequently used to assess CGM profiles were calculated for 1,562 historic CGM profiles from subjects with type 1 or type 2 diabetes. Factor analysis and varimax rotation was performed to identify factors that accounted for the quality of the profiles. We identified five primary factors that determined CGM profiles (central tendency, hyperglycaemia, hypoglycaemia, intra- and inter-daily variations). One parameter from each factor was selected for constructing the formula for the screening metric, (the 'Q-Score'). To derive Q-Score classifications, three diabetes specialists independently categorised 766 CGM profiles into groups of 'very good', 'good', 'satisfactory', 'fair', and 'poor' metabolic control. The Q-Score was then calculated for all profiles, and limits were defined based on the categorised groups (<4.0, very good; 4.0-5.9, good; 6.0-8.4, satisfactory; 8.5-11.9, fair; and ≥12.0, poor). Q-Scores increased significantly (P <0.01) with increasing antihyperglycaemic therapy complexity. Accordingly, the percentage of fair and poor profiles was higher in insulin-treated compared with diet-treated subjects (58.4% vs. 9.3%). In total, 90% of profiles categorised as fair or poor had at least three parameters that could potentially be optimised. The improvement potential of those parameters can be categorised as 'low', 'moderate' and 'high'. The Q-Score is a new metric suitable to screen for CGM profiles that require therapeutic action. Moreover, because single components of the Q-Score formula respond to individual weak points in glycaemic control, parameters with improvement potential can be identified and used as targets for optimising patient-tailored therapies.


Microbial air-sampling equipment, part 2: experiences of compounding pharmacists.
The most recent changes to Chapter 797 of the United States Pharmacopeia-National Formulary initiated an intense controversy about the frequency of cleanroom air sampling that is required to prevent the contamination of sterile preparations. For compounders who must purchase an air sampler to use in the cleanroom, choices abound. This article summarizes discussions from compounding pharmacists and their experiences with air sampling devices.


Oil induces chlorophyll deficient propagules in mangroves.
In Australia, some trees of the mangrove, Avicennia marina, growing in a chronic oil polluted site, produce chlorophyll deficient (albino) propagules. We tested the hypothesis that albinism was due to an oil-induced mutant allele that controls photosynthesis. We determined whether there are genetic differences between normal and chlorophyll deficient propagules. Four gene regions (nuclear 18S-26S cistron; chloroplast - trnH-psbA, rsp16 and matK) were sequenced and analysed for normal and albino propagules. Mutations occurred in both nuclear (ITS) and coding chloroplast (matK) genes of albino propagules. There were 10 mutational differences between normal and albino propagules in the matK samples. Analysis of molecular variation (AMOVA) of the matK dataset indicated highly significant genetic differentiation between normal and albino propagules. Our study suggests for the first time that PAHs from a chronic oil polluted site resulted in mutations in both nuclear and chloroplast genes, resulting in the production of albino propagules.


Ni-electrocatalytic Csp3-Csp3 doubly decarboxylative coupling.
Cross-coupling between two similar or identical functional groups to form a new C-C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling1,2. The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C-C bond3-12. As one of the oldest known Csp3-Csp3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates13. In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century5, thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%.


Responses of median preoptic neurons projecting to the hypothalamic paraventricular nucleus to osmotic stimulation in Wistar-Kyoto and spontaneously hypertensive rats.
Twenty-one median preoptic nucleus (MnPO) neurons in normotensive Wistar-Kyoto rats (WKY) and 18 MnPO neurons in spontaneously hypertensive rats (SHR) were antidromically activated by electrical stimulation of the hypothalamic paraventricular nucleus (PVN) under urethane anesthesia. No significant differences in the latency, conduction velocity, or threshold of antidromic activation were observed between WKY and SHR. The spontaneous discharge rate was significantly higher in SHR than in WKY. The activity of these identified MnPO units was examined for response to intracarotid injections of isotonic (0.15 M NaCl solution, 0.05 ml) or hypertonic (0.3 M NaCl solution, 0.05 ml) saline. All the units did not change their activity to the injections of isotonic saline. Of these units, 14 units in WKY and 12 units in SHR displayed and 3 units in WKY and 4 units in SHR exhibited a reduction in neuronal activity following the injections of hypertonic saline, while the remaining 4 units in WKY and 2 units in SHR were unresponsive. The duration and frequency of excitatory response, but not the inhibitory response, caused by the osmotic stimulation was much greater in SHR than in WKY. These results show that MnPO neurons projecting to the PVN may carry the information from osmosensitive elements and that there is a difference between WKY and SHR in the responsivity of these MnPO neurons to the osmotic stimulation.


Cigarette smoking and colorectal cancer risk in Germany: a population-based case-control study.
Studies have shown fairly consistent positive relationships between smoking and risk of colorectal adenomas, but have yielded inconsistent results for colorectal cancer. Issues relating to the duration, cumulative dose of smoking and the effect of smoking cessation on colorectal cancer risk still need clarification. In a population-based case-control study in Germany, we recruited 540 incident cases of colorectal cancer and 614 controls matched to cases by sex, 5-year age groups and county of residence from January 2003 to June 2004. Subjects were aged>or=30 years, and provided information on risk factors of colorectal cancer, including lifetime cigarette smoking habits, in personal interviews. Odds ratios (OR) and 95% confidence intervals (CI) were computed using conditional logistic regression models, adjusting for potential confounders. Compared with nonsmokers, there was an increased risk for smoking for >or=30 years (OR: 1.25, 95% CI: 0.90-1.75) and a significant risk increase for >or=40 pack-years of smoking (OR: 1.92, 95% CI: 1.13-3.28). Stratification by sex yielded higher risk estimates among females than that among males, with adjusted ORs of 3.5 (95% CI: 1.29-9.52) and 1.15 (0.69-1.91) for women and men, respectively, following >or=30 pack-years of smoking (pinteraction=0.18). Among smokers, risk reduction was observed after >or=20 years of quitting smoking and was significant for >or=40 years (OR: 0.46; 95% CI: 0.21-0.98), when compared to current smokers (p for linear trend=0.05). This study supports the hypothesis that smoking for a long duration at a high cumulative dose increases the risk for colorectal cancer, particularly among women, and suggests that there is risk reduction after longterm smoking cessation.


Changes in mental health symptoms and sociocultural factors across the COVID-19 pandemic in mothers of Mexican descent.
Latinos have been disproportionately affected by the COVID-19 pandemic in the US. Little is known about the lasting effects on mental health, particularly among mothers of young children, who historically report high levels of depression and anxiety. We examined if anxiety and depression symptoms worsened for mothers of Mexican descent across the pandemic and identified the role of sociocultural risk and protective factors on these changes. Mothers of Mexican descent (n = 141) with young children (ages 0-7) were administered surveys on mental health symptoms (anxiety and depression), stress-related sociocultural factors (perceived discrimination) before (pre-pandemic), within 3 months (early pandemic), and 18 months after the COVID-19 stay-at-home order (late pandemic). Another sociocultural factor, acculturative stress, was only measured pre-pandemic while during the later phase of the pandemic mothers reported their levels of loneliness, optimism, and coping styles. Repeated measures (RM) ANOVA demonstrated that depressive and anxiety symptoms as well as perceived discrimination increased from pre to early months of the COVID-19 pandemic and slightly lowered in late-COVID but did not return to pre-COVID levels. Two-way RM ANOVA showed that acculturative stress and perceived discrimination predicted worse mental health trajectories across the pandemic while moderations revealed that optimism buffered against, and avoidant coping increased the adverse effects of sociocultural factors on mental health. The effects of the COVID pandemic on mental health are lingering in mothers of young children; however, optimism may be a protective factor. The results also highlight the damaging effects of external factors, such as discrimination, on maternal mental health during times of crisis.


Responsiveness and Minimal Clinically Important Difference of the Chinese Version of the Motor Function Measure-32 in Children and Adolescents with Duchenne Muscular Dystrophy.
This study aimed to examine the responsiveness and minimal clinically important difference of the Motor Function Measure 32-Chinese version (MFM 32-CN) in children and adolescents with Duchenne muscular dystrophy (DMD). This observational, prospective cohort study assessed changes in motor function over 12 months using the MFM 32-CN in 108 pediatric patients with DMD. Moderate to high internal responsiveness was found for MFM total, D1, and D2 scores (SRM = 0.46-0.83). Sufficient external responsiveness was observed in all MFM scores, as determined by a good correlation with the Patient Global Impression of Change (PGIC) ratings (r = 0.54-0.72, p < .01). The estimated MCID values derived from different anchor-based methods ranged from 4.7 to 6.0, with a median of 5.0 points (%). The MFM 32-CN demonstrates sufficient internal and external responsiveness as a measure of motor function in children and adolescents with DMD. The present study established the MCID of MFM-32 in pediatric patients with DMD.


Multiparametric imaging using 18F-FDG PET/CT heterogeneity parameters and functional MRI techniques: prognostic significance in patients with primary advanced oropharyngeal or hypopharyngeal squamous cell carcinoma treated with chemoradiotherapy.
In this study, PET heterogeneity was combined with functional MRI techniques to refine the prediction of prognosis in patients with oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC). A total of 124 patients with primary advanced OHSCC who underwent pretreatment 18F-FDG PET/CT, dynamic contrast-enhanced MR imaging (DCE-MRI), and diffusion-weighted MR imaging (DWI) were enrolled. Conventional and heterogeneity parameters from 18F-FDG PET as well as perfusion parameters from DCE-MRI and diffusion parameter from DWI of primary tumors were analyzed in relation to recurrence-free survival (RFS) and overall survival (OS). Multivariate analysis identified hypopharyngeal tumors (P = 0.038), alcohol drinking (P = 0.006), K trans ≤ 0.5512 (P = 0.017), and K ep ≤ 0.8872 (P = 0.005) as adverse prognostic factors for RFS. Smoking (p = 0.009), K trans ≤ 0.5512 (P = 0.0002), K ep ≤ 0.8872 (P = 0.004), and the PET heterogeneity parameter uniformity ≤ 0.00381 (P = 0.028) were independent predictors of poor OS. The combination of PET uniformity with DCE-MRI parameters and smoking allowed distinguishing four prognostic groups, with 3-year OS rates of 100%, 76.6%, 57.4%, and 7.1%, respectively (P < 0.0001). This prognostic system appeared superior to both the TNM staging system (P = 0.186) and the combination of conventional PET parameters with DCE-MRI (P = 0.004). Multiparametric imaging based on PET heterogeneity and DCE-MRI parameters combined with clinical risk factors is superior to the concomitant use of functional MRI coupled with conventional PET parameters. This approach may improve the prognostic stratification of OHSCC patients.


Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles.
Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood-brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate-coated nanoparticles crossed the intact blood-brain barrier, thus reaching therapeutic concentrations in the brain. Here, we investigated the therapeutic potential of this formulation of doxorubicin in vivo using an animal model created by implantation of 101/8 glioblastoma tumor in rat brains. Groups of 5-8 glioblastoma-bearing rats (total n = 151) were subjected to 3 cycles of 1.5-2.5 mg/kg body weight of doxorubicin in different formulations, including doxorubicin bound to polysorbate-coated nanoparticles. The animals were analyzed for survival (% median increase of survival time, Kaplan-Meier). Preliminary histology including immunocytochemistry (glial fibrillary acidic protein, ezrin, proliferation and apoptosis) was also performed. Rats treated with doxorubicin bound to polysorbate-coated nanoparticles had significantly higher survival times compared with all other groups. Over 20% of the animals in this group showed a long-term remission. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. All groups of animals treated with polysorbate-containing formulations also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. Additionally, binding to nanoparticles may reduce the systemic toxicity of doxorubicin. This study showed that therapy with doxorubicin bound to nanoparticles offers a therapeutic potential for the treatment of human glioblastoma.


Characterization of non-linear behaviour of an animal membrane using electro-kinetic studies.
Electro-kinetic studies of water, aqueous solutions of urea, thiourea, glucose, creatinine and urine solution across urinary bladder membranes of goat have been used to explain non-linear behaviour. It has been found that fluxes are non-linearly related with forces. The structure of the membrane is a decisive factor when the range of driving forces is not too high. Stability of the steady state has also been examined and has been found to remain quite stable even in non-linear regions. The results have been examined using the methodology of non-equilibrium thermodynamics.


Effects of glycosylation on the secretion and enzyme activity of Mucor rennin, an aspartic proteinase of Mucor pusillus, produced by recombinant yeast.
The Mucor rennin gene encoding a prepro form of the fungal aspartic proteinase from Mucor pusillus was expressed under the control of the yeast GAL7 promoter in Saccharomyces cerevisiae. The mature M. pusillus rennin secreted efficiently by yeast was a highly glycosylated protein. Analysis by a combination of site-directed mutagenesis of each of the three possible glycosylation sites and treatment of the secreted M. pusillus rennins with endo-beta-N-acetylglucosaminidase H revealed that the mature yeast M. pusillus rennin contained two asparagine-linked glycosylation sites among the three possible glycosylation sites. A mutation of the 2 glycosylated asparagine residues of M. pusillus rennin resulted in significant decreases in the level of secretion by yeast cells. In addition, the extent of glycosylation of M. pusillus rennin was found to affect the enzyme properties such as milk-clotting and proteolytic activities.


An analysis of officer-reported TASER X2™ probe discharge effectiveness in the United Kingdom.
Conducted energy devices (CEDs) are designed to immobilise aggressive individuals through the application of an electrical discharge administered via probes fired at the subject. Although the discharge is intended to disrupt voluntary movement, CEDs have their limitations and several factors are qualitatively understood to adversely influence CED effectiveness. The introduction of the twin-cartridge TASER X2™ into UK policing in 2017 provided a unique opportunity to undertake a quantitative assessment of the factors modulating probe discharge effectiveness based on data reported by police officers firing the device operationally. The overall operational subdual effectiveness of the TASER X2™ was 68.5%. However, several factors were identified that could alter the likelihood of achieving subdual of the subject. The officer-reported data show that probe discharge was highly effective at subduing subjects when both probes had penetrated the skin, least effective when both probes were in clothing and confirmed the reduced effectiveness of narrow probe spreads. The most commonly cited reasons why probe discharge failed to subdue the subject were thick or loose clothing, probe misses and narrow probe spread. These findings, which are likely to generalise to other types of CED, may be used to inform tactics and training to optimise the likelihood of achieving incapacitation when probes are deployed, with benefits for the safety of both the police and the public. The findings may also assist investigations requiring the reconstruction of incidents in which probe discharge has been deployed.


Evaluation of inhibition of F4ac positive Escherichia coli attachment with xanthine dehydrogenase, butyrophilin, lactadherin and fatty acid binding protein.
Neonatal and post-weaning colibacillosis caused by enterotoxigenic E. coli is responsible for substantial economic losses encountered by the pork industry. Intestinal colonization of young piglets by E. coli depends on the efficiency of bacterial attachment to host gastrointestinal epithelium that is mediated by fimbriae. We tested the effect of porcine individual milk fat globule membrane (MFGM) proteins on F4ac positive E. coli attachment to porcine enterocytes in vitro. Butyrophilin, lactadherin and fatty acid binding protein inhibited fimbriae-dependent adherence of E. coli to enterocytes in vitro, while xanthine dehydrogenase did not. The inhibiting activity was dose-dependent for all three proteins, but the inhibiting efficiency was different. The results indicate that MFGM proteins may interfere with attachment of E. coli to porcine neonatal intestinal mucosa.


LncRNA MAFG-AS1 deregulated in breast cancer affects autophagy and progression of breast cancer by interacting with miR-3612 and FKBP4 invitro.
We aimed to explore the function and competing endogenous RNA (ceRNA) pathway of MAFG-AS1 in breast cancer. qRT-PCR assay identified the expression of MAFG-AS1, miR-3612 and FKBP4. We used Western blot analysis to test the autophagy related protein levels in breast cancer cells. Functional assays such as Cell Counting Kit-8 (CCK8) assay, BrdU proliferation assay, Caspase-3 activity detection were used to identify the function of MAFG-AS1, miR-3612 and FKBP4 in breast cancer cells. Mechanism assays were used to verify the interacting relationship among MAFG-AS1, miR-3612 and FKBP4, including RNA pull down assay, RNA immunoprecipitation (RIP) assay and luciferase reporter assay. MAFG-AS1 and FKBP4 were both up-regulated in breast cancer tissues. MAFG-AS1 could function as an oncogene in breast cancer to activate cell proliferation, and inhibit cell apoptosis and autophagy. Meanwhile, MAFG-AS1 could sponge miR-3612 to elevate the expression of FKBP4. Besides, FKBP4 could activate the cell proliferation and inhibit cell apoptosis and autophagy, which could relieve the inhibitory effect of miR-3612 on breast cancer cells. MAFG-AS1 could activate breast cancer progression via modulating miR-3612/FKBP4 axis in vitro.


Pressure/Temperature Sensing Bimodal Electronic Skin with Stimulus Discriminability and Linear Sensitivity.
Human skin imperfectly discriminates between pressure and temperature stimuli under mixed stimulation, and exhibits nonlinear sensitivity to each stimulus. Despite great advances in the field of electronic skin (E-skin), the limitations of human skin have not previously been overcome. For the first time, the development of a stimulus-discriminating and linearly sensitive bimodal E-skin that can simultaneously detect and discriminate pressure and temperature stimuli in real time is reported. By introducing a novel device design and using a temperature-independent material, near-perfect stimulus discriminability is realized. In addition, the hierarchical contact behavior of the surface-wrinkled microstructure and the optimally reduced graphene oxide in the E-skin contribute to linear sensitivity to applied pressure/temperature stimuli over wide intensity range. The E-skin exhibits a linear and high pressure sensitivity of 0.7 kPa-1 up to 25 kPa. Its operation is also robust and exhibits fast response to pressure stimulus within 50 ms. In the case of temperature stimulus, the E-skin shows a linear and reproducible temperature coefficient of resistance of 0.83% K-1 in the temperature range 22-70 °C and fast response to temperature change within 100 ms. In addition, two types of stimuli are simultaneously detected and discriminated in real time by only impedance measurements.


Report on the American Society of Hospital Attorneys of the American Hospital Association.
Since the time of its formation, the American Society of Hospital Attorneys has provided focus and leadership in the field of health law. It was, for example, the principal force in moving the American Bar Association in 1974 to recognize "health care and hospital law" as a field of law that can be listed in legal directories such as Martindale-Hubbell. It membership includes most of the leaders in the field of health law, including the elected and administrative heads of most other health law groups. Because it had a dedicated and active leadership, an extensive and diverse membership, and a unique relationship with the American Hospital Association, the Society with continue to play a major role in the development and exposition of "health care and hospital" law. In so doing, it will always attempt to hew to its original purpose: service to the attorneys representing the nation's hospitals, to enable them to better represent their client institutions.


Centroid method: an alternative method of determining coronal curvature in scoliosis. A comparative study versus Cobb method in the degenerative spine.
Although the Cobb method is considered the gold standard, the centroid method may offer a reasonable alternative in adult scoliosis because it has better inter- and intraobserver reliabilities in adolescent scoliosis. To compare the reliabilities of the Cobb and the centroid methods for measuring coronal curvature in degenerative scoliosis in older patients. Observational study involving three examiners. Sixty whole spine posteroanterior (PA) radiographs were collected. Data were analyzed to determine inter- and intraobserver reliabilities. Sixty whole spine PA radiographs of patients older than 60 years were collected to compare the reliabilities of the centroid and the Cobb methods for measuring coronal curvature in degenerative scoliosis. Three examiners using both methods independently measured radiographs twice. Data were analyzed to determine inter- and intraobserver reliabilities. Intraobserver comparisons of all the 60 radiographs revealed that inter- and intraclass correlation coefficients (ICCs) of the Cobb and the centroid methods were both excellent (greater than 0.979 vs. greater than 0.918), and mean absolute differences (MADs) were similar (less than 1.58 vs. less than 2.02). In interobserver comparisons, ICCs of the Cobb method were higher than that of the centroid method (greater than 0.922 vs. greater than 0.799), and the MADs of the Cobb method were lower than that of the centroid method (less than 2.91 vs. less than 4.84). Comparisons of radiographs subdivided by severity showed that the ICCs of the Cobb and the centroid methods were both excellent (greater than 0.819 vs. greater than 0.801), and their MADs were similar (less than 2.29 vs. less than 2.53) for intraobserver comparisons. Interobserver comparisons showed that ICCs and MADs were dependent on the severity of coronal curvature, and the ICCs of the Cobb method (greater than 0.698) were greater than that of the centroid method (greater than 0.507). Furthermore, MAD values for the Cobb method were lower than that for the centroid method (less than 3.59 vs. less than 6.07). Moreover, these results are contradictory to the previous study, which showed the higher reliability of the centroid method in measures of adolescent scoliosis. In the present study, the reliability of the centroid method was found to be more susceptible to the severity of disease in older patients, despite its demonstrated greater reliability in adolescent scoliosis. Our findings show that the selective use of these two methods in old and young patients can increase the reliabilities of measurements made.


Surgical Outcomes of Selective Laminectomy for Patients With Cervical Kyphosis: A Retrospective Study of 379 Cases.
A retrospective study. This study aimed to investigate the impact of cervical kyphosis on patients with cervical spondylotic myelopathy (CSM) following selective laminectomy (SL) regarding posterior spinal cord shift (PSS), and a number of SLs. We evaluated 379 patients with CSM after SL. The patients with kyphosis (group K) were compared with those without kyphosis (group L). Moreover, groups K and L were divided into subgroups KS and KL (SLs ≤ 2) and LS and LL (SLs ≥ 3), respectively, and analyzed. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of the C2-C7 angle for satisfactory surgical outcomes, which was defined as a Japanese Orthopaedic Association (JOA) recovery rate of ≥50% in group KS. The average PSS (mm) in group K was smaller than that in group L (.8 vs 1.4; P < .01), but the JOA recovery rate was comparable between the 2 groups. Meanwhile, the mean PSS and JOA recovery rate (%) in group KS was lower than those in group KL, respectively (.3 vs 1.0; P < .01, 35.1 vs 52.3; P = .047). Moreover, the average PSS of group KS (.6) was smaller than those of other subgroups ( < .01). In addition, the ROC curve analysis showed that the C2-C7 angle of -14.5° could predict satisfactory surgical outcomes in group KS. Selective laminectomy is not contraindicated for patients with kyphosis, but a larger number of SLs may be indicated for the patients with C2-C7 angles of ≤ -14.5°.


Transcutaneous immunization in mice: induction of T-helper and cytotoxic T lymphocyte responses and protection against human papillomavirus-induced tumors.
Previous reports have shown that transcutaneous immunization (TCI) with proteins or peptides in combination with adjuvants efficiently induces specific cellular and humoral immune responses. However, depending on the kind of skin pretreatment, induction of cellular immune responses was restricted to generation of either specific cytotoxic T lymphocytes (CTLs) or T-helper (Th) cells. In this study, we induced antigen-specific CTL responses together with the appropriate Th responses by TCI of C57BL/6 mice. We applied ovalbumin protein or an ovalbumin-derived fusion peptide containing a CTL and Th epitope together with a combination of cholera toxin (CT) and CpG oligodeoxynucleotide (CpG) onto cold wax-depilated and hydrated bare skin. TCI with the ovalbumin fusion peptide induced more robust CTL and Th responses than that with ovalbumin protein. The fusion peptide in combination with the nontoxic CT derivative CTA1-D2D1 and CpG induced an antigen-specific CTL response, albeit less efficiently than in combination with complete CT. Further, we compared the potency of HPV-16 E7 oncoprotein-derived peptides containing single (CTL) or multiple (CTL + Th + B cell) epitopes to induce effective CTL responses. Strong E7-specific CTL responses were detected only after TCI with the E7 multiepitope peptide. This peptide was also shown to protect mice against tumor growth after challenge with HPV-16 E7-positive tumor cells. TCI with E7 protein and CT/CpG led to formation of an E7-specific humoral immune response.


Delayed visual NA potential in remitted schizophrenia: a new vulnerability marker for psychotic relapse under low-dose medication.
Lasting cognitive dysfunction throughout remission has been regarded as a biological vulnerability in schizophrenia, which may produce psychotic relapses with characteristic symptoms. Our hypothesis was that an abnormality in event-related potentials (ERPs) may be a neurophysiological marker of vulnerability to psychotic relapse in remitted schizophrenia. We conducted a 2-year follow-up study after evaluating ERP abnormalities to find a new ERP marker for schizophrenic relapse. Visual ERPs were recorded from outpatients with remitted schizophrenia under maintenance pharmacotherapy (n = 44) and normal controls (n = 20) during a letter discrimination task. Based on the prospective study, the patients were divided into a relapse group (n = 20) and a nonrelapse group (n = 24). ERP findings that related to psychotic relapse within 2 years were analyzed. Compared with controls, the relapsers showed ERP abnormalities in the NA, N2, and P3 components, and the nonrelapsers in the P3 component. The peak latency of the NA potential was delayed significantly in the relapse group relative to the nonrelapse group, and predicted a psychotic relapse with about 90% probability. The delayed NA, which reflects early perceptual disorganization, may be a promising neurophysiological predictor of psychotic relapse in remitted schizophrenia under maintenance pharmacotherapy.


Relative efficiency of unequal cluster sizes in stepped wedge and other trial designs under longitudinal or cross-sectional sampling.
A cluster trial with unequal cluster sizes often has lower precision than one with equal clusters, with a corresponding inflation of the design effect. For parallel group trials, adjustments to the design effect are available under sampling models with a single intracluster correlation. Design effects for equal clusters under more complex scenarios have appeared recently (including stepped wedge trials under cross-sectional or longitudinal sampling). We investigate the impact of unequal cluster size in these more general settings. Assuming a linear mixed model with an exchangeable correlation structure that incorporates cluster and subject autocorrelation, we compute the relative efficiency (RE) of a trial with clusters of unequal size under a size-stratified randomization scheme, as compared to an equal cluster trial with the same total number of observations. If there are no within-cluster time effects, the RE exceeds that for a parallel trial. In general, the RE is a weighted average of the RE for a parallel trial and the RE for a crossover trial in the same clusters. Existing approximations for parallel designs are extended to the general setting. Increasing the cluster size by the factor (1 + CV2 ), where CV is the coefficient of variation of cluster size, leads to conservative sample sizes, as in a popular method for parallel trials. Methods to assess experimental precision for single-period parallel trials with unequal cluster sizes can be extended to stepped wedge and other complete layouts under longitudinal or cross-sectional sampling. In practice, the loss of precision due to unequal cluster sizes is unlikely to exceed 12%.


Assessment of sources variability of riverine particulate organic matter with land use and rainfall changes using a three-indicator (δ13C, δ15N, and C/N) Bayesian mixing model.
In intensive agricultural watersheds, riverine particulate organic matter (POM) may be transported from many sources such as rice paddies, crop uplands, forests, and livestock farming areas during rainy seasons. However, the impacts of land-use and rainfall changes on the POM sources are not well understood. In this study, changes in the sources of riverine POM were investigated in an agricultural area of Korea between 2014 and 2020/21. During this period, land-use and rainfall patterns changed dramatically. The δ13C, δ15N, and C/N of the POM sources as well as those of riverine POM were analyzed, and a stable isotope analysis in R (SIAR) model was utilized for source apportionment. There were differences in δ13C, δ15N, and C/N among the sources. For example, manure had higher δ13C (-22.6 ± 3.3‰) and δ15N (+10.6 ± 5.9‰) than soils (from -28.0 ± 0.8‰ to -25.1 ± 1.2‰ for δ13C and +3.6 ± 1.7‰ to +9.8 ± 1.4‰ for δ15N). For soils, the δ13C and δ15N were higher for upland soils, while C/N was greater for forest soils than for others. For riverine POM, the δ15N marginally changed; however, the δ13C and C/N increased from -26.1 ± 0.9‰ to -20.8 ± 5.3‰ and from +7.7 ± 1.7 to +18.8 ± 8.3 between 2014 and 2020/21, respectively. The SIAR model showed that the contributions of paddy (from 41.0% to 14.9%) and upland fields (from 48.1% to 23.7%) to riverine POM decreased between the periods due to decreased paddy area and the implementation of best management practice on upland fields, respectively. However, the contribution of forests (from 3.5% to 28.0%) and manure (from 7.4% to 33.5%) increased probably due to improper management of forest clear-cutting sites and livestock manure storage sites. The contributions of agricultural soils to riverine POM decreased in drier years. Our study suggests that land management rather than land-use area is critical in riverine POM management, particularly in wetter years.


Evaluation of a hospital-based accident flying squad using an injury scoring system.
The records of 250 patients treated by a hospital-based flying squad have been analysed retrospectively to determine the value of such a unit in preventing death following various types of accident. To facilitate analysis two analytical methods have been used, one of which showed that flying squad action saved two lives. However, on clinical grounds we conclude that measures taken at the scene unequivocally led to the survival of 6 per cent of those alive at the scene.


Impact of COVID -19 pandemic lockdown on distribution of inorganic pollutants in selected cities of Nigeria.
The COVID-19 global pandemic has necessitated some drastic measures to curb its spread. Several countries around the world instituted partial or total lockdown as part of the control measures for the pandemic. This presented a unique opportunity to study air pollution under reduced human activities. In this study, we investigated the impact of the lockdown on air pollution in three highly populated and industrious cities in Nigeria. Compared with historical mean values, NO2 levels increased marginally by 0.3% and 12% in Lagos and Kaduna respectively. However, the city of Port Harcourt saw a decrease of 1.1% and 215.5% in NO2 and SO2 levels respectively. Elevated levels of O3 were observed during the period of lockdown. Our result suggests that there are other sources of air pollution apart from transportation and industrial sources. Our findings showed that the COVID-19-induced lockdown was responsible for a decrease in NO2 levels in two of the locations studied. These results presents an opportunity for country wide policies to mitigate the impact of air pollution on the health of citizens.


The clinical course of diabetics who require emergent foot surgery because of infection or ischemia.
For the past 15 years at our institution, all acute diabetic foot problems have been treated on the vascular surgery service. The treatment approach has emphasized aggressive local foot surgery and frequent use of revascularization to avoid amputation. A total of 212 urgent or emergent foot operations were performed on 138 limbs in 114 diabetic patients for indications of infection, gangrene, or infected neurotrophic ulcers. The average number of operations per limb was 1.5 (range one to six) and per patients was 1.9 (range one to nine). Ischemia was sufficiently severe to require concurrent lower extremity revascularization in 48 limbs in 43 patients. Follow-up ranged from 1 month to 11 years (mean 3 years). Ultimately 36 major lower extremity amputations were required in 33 patients at time intervals ranging from zero to 86 months (mean 7 months) after the initial operation on the affected limb. These data indicate that an aggressive program of surgical treatment of diabetic foot problems combined with liberal use of lower extremity revascularization resulted in long-term salvage of 73% of threatened limbs in these high-risk patients. These results form the basis for our recommendation that major lower extremity amputations be considered only as a last resort in diabetic patients with limbs threatened by foot infection or localized gangrene.


Kinematic draping simulation optimization of a composite B-pillar geometry using particle swarm optimization.
The present work presents an algorithmic approach to determine the optimal starting point for any complex geometry draping processes. The time-efficient Kinematic Draping Simulation (KDS) is used to assess the drapability of a geometry depending on many different starting points. The optimization problem is then solved by applying Particle Swarm Optimization (PSO). The proposed methodology is applied to and validated with complex geometry and a common part of the automobile industry: the B-Pillar geometry. The results show that the PSO algorithm may improve random search up to 78 times. After several experiments, PSO particles have discrete coordinates and are located at optimum global and local regions most of the time, leading to solutions for complex objective functions. The global solution is such that the starting point is located near the geometrical centre of the B-Pillar. The novelty of the work is evident: it uses optimization for a real engineering application, and it draws pattern-related conclusions for other geometries. Experimental results are shown to be consistent with simulation results.


Object and spatial visualizers have different object-processing patterns: behavioral and ERP evidence.
Both behavioral and neurophysiological evidence shows the advantage of object visualizers in object-related tasks relative to spatial visualizers. It is still unclear, in which stage the advantage appears. In this study, a behavioral experiment revealed that spatial visualizers' performance decreased evidently from short delay to long delay in a high-load condition, but object visualizers performed stably. In addition, an event-related potential experiment found the slow cortical potentials for the spatial visualizer to be more negative in relation to object visualizers in the 1800-3800 ms stage, although spatial visualizers performed worse than the object visualizers. Therefore, the processing advantage of object visualizers, which is caused by the higher neural efficiency of object visualizers than spatial visualizers in object tasks, seems to be at the retention stage rather than the encoding stage.


Effect of Coronavirus Disease 2019 on Transplantation and Nephrology in India: A Nationwide Report From India.
The effect of coronavirus disease 2019 (COVID-19) on a developing nation is sparsely reported and, more importantly, the discrepancies in public and private sectors are underexplored. We retrospectively investigated the data on the effect of COVID-19 on renal transplantation between 2019 and 2020 in a nationwide analysis from 8 public and 10 private sector hospitals of India. On comparing the yearly data, the number of living-related transplants and deceased donor transplants declined by 48% (2610 vs 1370) and 49% (194 vs 99), respectively. The outpatient numbers and in-center admissions decreased by 40.4% (616,741 vs 367,962) and 30.8 % (73,190 vs 49,918). respectively. There was no increase in the number of renal or graft biopsies in the COVID-19 era. The number of waitlisted patients on hemodialysis was higher in public (304,898 vs 338,343) when compared with private (163,096 vs 150,292) in the last 2 years. Similarly, the number of waitlisted patients on peritoneal dialysis (4655 vs 3526) was higher in the public sector compared with private sector (932 vs 745). The decline in living transplants during the pandemic was higher in public sectors (58%) compared with the private (49%). However, the decline in deceased donation was higher in private (57.9%) relative to public (50.6%). COVID-19 has adversely affected the transplantation activities across the Indian transplantation centers, with a disproportionately higher impact on waitlisted patients in public sector programs. A sound prioritization of health care resources is mandated to safeguard the most deprived and high-risk waitlisted patients during the pandemic.


Genome-material costs and functional trade-offs in the autopolyploid Solidago gigantea (giant goldenrod) series.
Increased genome-material costs of N and P atoms inherent to organisms with larger genomes have been proposed to limit growth under nutrient scarcities and to promote growth under nutrient enrichments. Such responsiveness may reflect a nutrient-dependent diploid versus polyploid advantage that could have vast ecological and evolutionary implications, but direct evidence that material costs increase with ploidy level and/or influence cytotype-dependent growth, metabolic, and/or resource-use trade-offs is limited. We grew diploid, autotetraploid, and autohexaploid Solidago gigantea plants with one of four ambient or enriched N:P ratios and measured traits related to material costs, primary and secondary metabolism, and resource-use. Relative to diploids, polyploids invested more N and P into cells, and tetraploids grew more with N enrichments, suggesting that material costs increase with ploidy level. Polyploids also generally exhibited strategies that could minimize material-cost constraints over both long (reduced monoploid genome size) and short (more extreme transcriptome downsizing, reduced photosynthesis rates and terpene concentrations, enhanced N-use efficiencies) evolutionary time periods. Furthermore, polyploids had lower transpiration rates but higher water-use efficiencies than diploids, both of which were more pronounced under nutrient-limiting conditions. N and P material costs increase with ploidy level, but material-cost constraints might be lessened by resource allocation/investment mechanisms that can also alter ecological dynamics and selection. Our results enhance mechanistic understanding of how global increases in nutrients might provide a release from material-cost constraints in polyploids that could impact ploidy (or genome-size)-specific performances, cytogeographic patterning, and multispecies community structuring.


The relationship between KRAS gene mutations and HLA class I antigen downregulation in the metastasis of non-small cell lung cancer.
To investigate the association between v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mutations and levels of human leucocyte antigen (HLA) class I antigen in primary lung tumours and metastatic lymph nodes of patients with non-small cell lung cancer (NSCLC). Patients with NSCLC undergoing tumour resection were enrolled. KRAS codon 12 mutations were analysed in normal lung and lymph node tissue, primary lung tumours and metastatic lymph nodes using polymerase chain reaction-restriction fragment length polymorphism analysis. HLA class I antigen immunostaining was examined using flow cytometry. A total of 65 patients participated in the study. All normal lung tissues had positive HLA class I antigen immunostaining. The majority of primary lung tumours (56/65) and all of the metastatic lymph nodes (31/31) had downregulated HLA class I antigen immunostaining. There was a positive correlation between downregulated HLA class I antigen in primary tumours and metastatic lymph nodes. There was a negative correlation between KRAS codon 12 mutations and the level of HLA class I antigen in primary and metastatic tumours. KRAS codon 12 mutations appear to be important in the downregulation of HLA class I antigen in NSCLC. Abnormal activation of the oncogenic KRAS pathway might provide a new treatment target for NSCLC.


Analgesic effect of auricular point acupressure for acute pain in patients with dementia: study protocol for a randomized controlled trial.
Common and frequent as acute pain is, it is often underestimated and undertreated in older people with dementia in nursing homes and inadequate pain management remains an issue. The study is designed to be a randomized, sham-controlled trial and is underway in nursing homes located in China. A total of 206 dementia patients are being recruited from nursing homes in Yinchuan, China. They are randomly allocated to an intervention or a controlled group in a 1:1 ratio. The intervention group will be treated with true APP therapy, while the other group will receive APP at sham point stimulation therapy. The patients will be assessed at baseline (T0), at 5 min during performing the intervention (T1), and at 5 min after completion of the intervention (T2). The primary outcome is the level of pain relief at T1 and T2. Physiological parameters, side effects and additional use of analgesics during the procedure, satisfaction from caregivers, and acceptance of patients are evaluated as secondary outcomes. The results of this study are expected to verify the analgesic effect of APP for acute pain in patients with mild dementia in nursing homes. It has the potential to prompt APP therapy to be implemented widely in dementia patients with acute pain in nursing homes. Chinese Clinical Trial Registry ChiCTR2100047932 . Registered on 27 June 2021. Currently, patient recruitment is ongoing. Recruitment is expected to take place from December 2020 to December 2021.


Reductions in all-cause and cause-specific mortality among HIV-infected individuals receiving antiretroviral therapy in British Columbia, Canada: 2001-2012.
Since 2006, the British Columbia HIV/AIDS Drug Treatment Program (DTP) has expanded enrolment and dramatically increased its number of participants. We examined the effect this expansion has had on the underlying cause of death in HIV-infected individuals. We analysed data from participants aged 18 years and older in the DTP to measure 2-year mortality rates and causes of death from 2001 to 2012. We conducted tests of trend for all-cause and cause-specific mortality, and compared demographics and characteristics of individuals. Cox proportional hazard models were used to determine the risk of death. A total of 8185 participants received antiretroviral therapy (ART) during the study period. Mortality declined from 3.88 per 100 person-years (PY) in 2001-2002 to 2.15 per 100 PY in 2011-2012 (P = 0.02). There were significant decreases in HIV-related deaths (2.34 to 0.56 per 100 PY; P = 0.02) and deaths attributable to chronic liver disease (0.20 to 0.09 per 100 PY; P = 0.01), cardiovascular disease (0.24 to 0.05 per 100 PY; P = 0.03) and suicides (0.47 to 0 per 100 PY; P = 0.003). Multivariate models, adjusted for age, gender, history of injecting drug use, AIDS diagnoses and baseline CD4 cell counts, demonstrated that initiation of ART in all time periods after 2001-2002 was independently associated with reduced mortality (P < 0.001). We observed declines in HIV-related mortality and certain non-HIV-related causes of death among participants in the BC DTP from 2001 to 2012. These findings suggest that there may be broader benefits to the increasingly liberal HIV treatment guidelines, including reductions in death caused by cardiovascular disease and chronic liver disease.


Glutamate receptor subunit delta2 is highly expressed in a novel population of glial-like cells in rat pineal glands in culture.
The mammalian pineal gland uses L-glutamate as an intercellular chemical transmitter to regulate negatively melatonin synthesis. To receive glutamate signals, pinealocytes express at least three kinds of glutamate receptors: metabotropic receptor types 3 and 5 and an ionotropic receptor, GluR1. In this study, we examined whether or not the fourth class of ionotropic receptor, delta, which is known for its nondefinitive molecular function and its unique expression pattern in brain, is expressed in pineal gland. RT-PCR analyses with specific probes indicated the expression of mRNA of delta2 but not that of delta1 in pineal gland and cultured pineal cells. Western blotting analysis with polyclonal antibodies specific to the carboxyl-terminal region of the delta2 receptor recognized a single 110-kDa polypeptide of cerebellar membranes and specifically immunostained Purkinje cells. The delta2 antibodies recognized a 110-kDa polypeptide of pineal membranes and specifically immunostained huge glial-like cells with the occasional presence of several long, branching processes in a pineal cell culture. delta2 is not uniformly distributed throughout the cells and is relatively abundant at the periphery of the cell bodies and long processes, where the terminals of synaptophysin-positive processes of pinealocytes, a site for glutamate secretion, are frequently present. The delta2-positive cells constitute a very minor population among total pineal cells (approximately 0.03%). Double immunolabeling with delta2 antibodies and antibodies against marker proteins for pineal interstitial cells clearly distinguishes delta2-positive pineal cells and other known interstitial cells, including glial fibrillary acidic protein- or vimentin-positive glial-like cells. These results indicated that the delta2 glutamate receptor is expressed in a novel subpopulation of pineal glial-like cells in culture and suggest the presence of a glutamate-mediated intercellular signal transduction mechanism between pinealocytes and delta2-expressing cells. The pineal cells may provide a good experimental system for studies on the function of glutamate receptor delta2.


Improved home management of oral pediatric anticancer drugs as a result of an intervention comprising practical training, written instructions and movie clips: A pilot study.
Long term treatment of pediatric patients with oral anticancer drugs (OADs) requires the parents/caregivers to prepare the drug at home. The handling procedures in the home setting are, however, not regulated by Swedish law and the parents are often left without guidance on how to handle OADs in a safe way. The aim of this study was to increase understanding of how OADs are handled by parents/caregivers in the home setting before and after an intervention. Parents of pediatric cancer patients were observed and videotaped during their handling of OADs in the home setting before and after the intervention. During the intervention, the parents were provided with written instructions, movie clips and practical training on handling the OADs. Four checklists were used to compare and score the four handling procedures (measuring an oral suspension, cutting tablets, dissolving tablets, and opening capsules) for each parent before and after the intervention. The intervention significantly improved the OAD handling procedures among the studied parents. The median score for correct handling was 19% (IQR: 3.6 to 30%) before the intervention and 89.5% (IQR: 71.5 to 94.5%) after the intervention (p < 0.0001). An intervention comprising practical training and information presented in different forms improved the handling of OADs at home by parents. There is an urgent need to implement this method in all oncology centers in Sweden, educate HCPs to standardize the presentation of information. There is also a great need to provide parents with age-appropriate oral drug formulations from the local hospital pharmacies in Sweden.


Immunization compliance outside the health plans. A non-HMO report card.
To assess the rate of completed immunizations by age 24 months in children cared for by a private medical practice. A chart review of all children born between January 1, 1990, and June 30, 1992, and seen by a provider in this private medical practice at least once between ages 15 months and 24 months. Overall, 77% of children received four DTP immunizations, 78% received at least three OPV immunizations, and 82% at least one MMR by 24 months of age. Seventy-two percent received the recommended combination of one MMR, three OPV, and four DTP immunizations by age 2. Rates were about 5% to 10% higher in children delivered by physicians of the group practice where the study occurred. The presence of a serious medical problem did not statistically significantly change the rates of completed immunizations. The rate of missed opportunities was almost three times as high in those not completing the basic DTP, OPV, MMR immunization series by age 24 months. Rates of immunizations are high in this private group practice and comparable to those reported by HMOs that care exclusively for children with insurance. However, the rate of missed opportunities is also high, with three to four visits for each child who did not complete the basic immunization series by age 24 months. This private practice report card will be used to improve immunization practices in our medical group.


The clinical significance of myeloid-derived suppressor cells in dengue fever patients.
Myeloid-derived suppressor cells (MDSCs) play immunosuppressive roles in cancers and some infectious diseases; however, their role in dengue fever (DF) remains unknown. This study evaluated the clinical significance of MDSCs in DF patients. This study comprised 178 non-severe DF patients, 20 non-dengue fever (NDF) controls, and 30 healthy donors. The DF patients were divided into the following five groups based on the fever duration from its onset to the day of sample collection: fever duration of 1-2, 3-4, 5-6, 7-8, and > 9 days. Among these DF patients, 14 were monitored for eight days, and their peripheral blood samples were collected every two days. The mononuclear cells were isolated and analyzed using flow cytometry. The correlation between the MDSCs and clinical and immunological indicators of the DF patients was evaluated using Spearman analysis. The count of the peripheral blood MDSCs, especially monocytic MDSCs, of the 178 DF patients were dramatically higher than those of the NDF and healthy controls, and remarkably decreased with the fever duration. Moreover, the MDSC count correlated with some indicators, including the dengue viral load (rho = 0.367, p < .001), body temperature (rho = 0.263, p = .005), prothrombin time (rho = 0.475, p < .001), CD4+ T cell number (rho = - 0.317, p < .001), CD8+ T cell number (rho = - 0.361, p < .001), "programmed cell death protein 1" (PD-1) (rho = - 0.347, p < .001), "T cell immunoglobulin domain and mucin domain-3" (Tim3) (rho = - 0.258, p = .001), interferon-α (IFN-α) (rho = 0.43, p < .001), and "regulated upon activation normal T-cell expressed and secreted" (RANTES) (rho = 0.278, p = .019). Furthermore, the level of arginase-1, but not nitric oxide, was higher in the DF patients than in the healthy controls and was closely related to the number of MDSCs (rho = 0.265, p = .024). Our study reveals a significant correlation between MDSCs and DF clinical indicators, posing MDSCs as potential target cells for DF treatment.


Alternative mechanisms associated with silencing of CDKN1C in Beckwith-Wiedemann syndrome.
Mutations in the imprinted gene CDKN1C account for approximately 10% of Beckwith-Wiedemann syndrome (BWS) cases. Fibroblasts from BWS patients with loss of methylation (LOM) at the imprinting control region (ICR) KvDMR1 have reduced CDKN1C expression. Another group of BWS patients with downregulated CDKN1C expression but with normal methylation at KvDMR1 has been identified. To investigate the mechanism of CDKN1C silencing in BWS in these two classes of patients. The CDKN1C promoter region was analysed for changes in DNA methylation using bisulphite sequencing, and for alterations in chromatin structure using the chromatin immunoprecipitation (ChIP) assay. There was only spurious CpG methylation of the CDKN1C promoter in fibroblast DNA from both normal individuals and patients with BWS, irrespective of the methylation status of KvDMR1. There was no detectable change in chromatin structure at the CDKN1C promoter in patients with LOM at KvDMR1. BWS patients with downregulated CDKN1C and normal methylation at KvDMR1 had depletion of dimethylated H3-K4 and enrichment of dimethylated H3-K9 and HP1gamma at the CDKN1C promoter, suggesting that in these cases gene silencing is associated with repressive chromatin changes. CDKN1C may be downregulated by multiple mechanisms including some that do not involve promoter methylation. In BWS patients with normal methylation at KvDMR1 and reduced expression of CDKN1C, repressive chromatin may play a role, but the absence of methylation and repressive chromatin structure at the CDKN1C promoter in BWS patients with LOM at KvDMR1 argues for a direct role of this epimutation in silencing CDKN1C.