Hydroxychloroquine-Chloroquine, QT-Prolongation, and Major Adverse Cardiac Events: A Meta-analysis and Scoping Review.
We aimed to evaluate the high-quality literature on the frequency and nature of major adverse cardiac events (MACE) associated with either hydroxychloroquine (HCQ) or chloroquine (CQ). We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onward using search strategies created in collaboration with medical science librarians. Randomized controlled trials (RCTs) published in English language from January 1996 to September 2022, involving adult patients at least 18 years of age, were selected. Outcomes of interest were death, arrhythmias, syncope, and seizures. Random-effects meta-analyses were performed with a Treatment Arm Continuity Correction for single and double zero event studies. By study drug, there were 31 HCQ RCTs (n = 6677), 9 CQ RCTs (n = 622), and 1 combined HCQ-CQ trial (n = 105). Mortality was the most commonly reported MACE at 220 of 255 events (86.3%), with no reports of torsades de pointes or sudden cardiac death. There was no increased risk of MACE with exposure to HCQ-CQ compared with control (risk ratio [RR] = 0.90, 95% CI = 0.69-1.17, I2 = 0%). These findings have important implications with respect to patient reassurance and updated guidance for prescribing practices of these medications. Despite listing as QT-prolonging meds, HCQ-CQ did not increase the risk of MACE.


Inflammatory pseudotumors of the pancreas and liver with infiltration of IgG4-positive plasma cells.
Recently, it has been reported that autoimmune pancreatitis (AIP) can be complicated with various extrapancreatic lesions. Here, we report a very rare case of pancreatic and hepatic inflammatory pseudotumor (IPT) with the infiltration of IgG4-positive plasmacytes. The patient showed pancreatic and hepatic masses with elevated levels of serum IgG4. Endoscopic retrograde cholangiopancreatography revealed narrowing of the intrapancreatic bile duct. Fluorine-18fluorodeoxyglucose positron emission tomography suggested pancreatic cancer with hepatic metastasis. Histopathologic findings showed fibrosis and infiltration of IgG4-positive plasmacytes, suggesting IPT. The present case suggests a possible common mechanism in the development of AIP and IPT of the liver.


Five-year follow-up of treated patients with glaucoma using resolution perimetry.
The authors describe high-pass resolution perimetry findings during the first five years of antiglaucoma treatment. Thirty-seven patients were examined six times, once a year for five years, with best corrected visual acuity, applanation tonometry, slitlamp examination, funduscopy, and high-pass resolution perimetry. Twenty-nine of these were treated for glaucoma and eight followed for ocular hypertension without treatment. The resolution thresholds in the treated group improved during the first two years and deteriorated after that back to baseline level. Regarding individual patients, the visual fields were improved in 4, unchanged in 16, and deteriorated in 13 of the 29 treated glaucoma patients at the end of the study period. Resolution visual fields showed initial improvement and subsequent deterioration in treated patients with early glaucoma. The conventional therapy, aiming at reducing intraocular pressure, appeared to postpone visual field decay for at least five years in about 50% of the patients.


Neurovascular contact of the brain stem in hypertensive and normotensive subjects: MR findings and clinical significance.
About 20 years ago, a theory was put forward that neurovascular contact of the root entry zone (REZ) of the ninth and 10th cranial nerve is responsible for elevated blood pressure in patients with essential hypertension. To test this hypothesis, we used MR tomography and MR angiography to evaluate the presence and degree of neurovascular contact of the REZ of the ninth and 10th cranial nerves in patients with essential hypertension as compared with patients with renal parenchymal hypertension and normotensive healthy volunteers. Patients with essential hypertension (group 1; n = 33), renal parenchymal hypertension (group 2; n = 30), and normotensive healthy volunteers (group 3; n = 25) underwent high-resolution (axial and coronal) brain stem MR imaging and MR angiography. The images were interpreted consensually by two radiologists who were blinded to the patients' hypertensive status. Neurovascular contact was graded as vessel contact without associated brain stem deformity (grade I), vessel contact with associated brain stem deformity (grade II), or vessel contact with associated deformity and displacement of the brain stem (grade III). Neurovascular contact of the REZ of the ninth and 10th cranial nerve on the left side was found in 48.5% in group 1, in 26.7% in group 2, and in 48.0% in group 3. The rate of neurovascular contact on the right side was 24.2%, 13.3%, and 40.0%, respectively. chi(2) analysis showed no statistical difference between the groups. Neurovascular contact is not more frequent in patients with essential hypertension than in normotensive control subjects or in those with secondary hypertension; therefore, MR imaging cannot aid patient selection for neurosurgical vascular decompression.


Bidirectional Associations between Youth Adjustment and Mothers' and Fathers' Coparenting Conflict.
Research demonstrates significant associations between coparenting conflict and child adjustment problems. However, the implications of youth adjustment for coparenting, especially during youth's adolescence, remain poorly understood. Addressing several gaps in the literature, this study examines the longitudinal trajectory of mothers' and fathers' reported coparenting conflict from youth ages 10-17 and tests bidirectional associations between youth social anxiety, hostility, risk-taking behaviors, and mothers' and fathers' coparenting conflict. Participants include 757 mothers, fathers, and youth in two-parent families (M youth age = 11.28, SD = 0.49; 53% female) who participated in 5 waves of data collection when youth were in the 6th to 9th grades. Multilevel growth curve models revealed significant non-linear change in mothers' and fathers' coparenting conflict, such that coparenting conflict declined through youth's transition to adolescence, leveled off in early adolescence, and declined in the mid-late adolescent years. Cross-lagged models showed significant positive associations between youth social anxiety and hostility and coparenting conflict at the following time point, but coparenting conflict did not predict later youth adjustment problems in these domains. There were significant bidirectional associations between mother-reported coparenting conflict and youth risk-taking behaviors; the associations between coparenting conflict and risk-taking were not significant for fathers. The findings demonstrate that investigating longitudinal associations between youth adjustment and coparenting conflict may provide new insights into the role of child effects for mothers' and fathers' coparenting experiences.


Comparison of fine-needle aspiration cytologic findings of ovarian cysts with ovarian histologic findings.
The purpose of this study was to compare cytologic findings of fluid from ovarian cysts with ovarian histologic findings. Ovaries submitted for pathologic examination were grossly examined for ovarian cysts. Fluid was removed by needle aspiration from intact ovarian cysts and prepared for cytologic examination. The cytologic findings were categorized as benign, malignant, indeterminate, and nondiagnostic. Histologic classification was assigned using the guidelines established by the World Health Organization. A single pathologist evaluated each cytologic specimen and was blinded to the gross appearance and histologic findings of each ovary. Cytologic diagnoses were compared with the histologic diagnoses. The study material consisted of 105 ovaries from 98 women. A comparison of the ovarian histologic findings with the cytologic diagnosis was performed in 89 of 105 cases. Histologic examination of the ovaries revealed 89 benign ovarian tumors and 13 ovarian carcinomas. The sensitivity of ovarian cyst cytologic evaluation was 25%, and the specificity was 90%. The false-positive rate for ovarian cytologic evaluation was 73%, and the false-negative rate was 12%. Cytologic examination of aspirated ovarian cyst fluid does not accurately predict ovarian histologic findings.


Role of executive function in late-life depression.
Late-onset depression has been conceptualized as a neurologic disease. This view has been supported by studies suggesting that late-onset depression is associated with cognitive impairment and neurologic comorbidity that may or may not be clinically evident when depression is first diagnosed. Findings implicating a dysfunction of frontostriatal-limbic pathways in geriatric depression have led to the depression-executive dysfunction (DED) syndrome hypothesis. Subsequent studies suggested that DED has slow, poor, or abnormal response to classical antidepressants. DED is characterized by psychomotor retardation, reduced interest in activities, impaired insight and pronounced behavioral disability. This clinical presentation begs the question whether agents that can selectively activate internal vigilance and therefore improve alertness have beneficial effects on DED. There is early evidence that psychosocial interventions aimed at improving the behavioral deficits of DED patients may also be effective in increasing remission rates and reducing depressive symptoms and disability.


Measurement of Retinal Sensitivity on Tablet Devices in Age-Related Macular Degeneration.
We compared measurements of central retinal sensitivity on a portable, low-cost tablet device to the established method of microperimetry in age-related macular degeneration (AMD). A customized test designed to measure central retinal sensitivity (within the central 1° radius) on a tablet device was developed using an open-source platform called PsyPad. A total of 30 participants with AMD were included in this study, and all participants performed a practice test on PsyPad, followed by four tests of one eye and one test of the other eye. Participants then underwent standardized microperimetry examinations in both eyes. The average test duration on PsyPad was 53.9 ± 7.5 seconds, and no significant learning effect was observed over the examinations performed (P = 1.000). The coefficient of repeatability of central retinal sensitivity between the first two examinations on PsyPad was ±1.76 dB. The mean central retinal sensitivity was not significantly different between PsyPad (25.7 ± 0.4 dB) and microperimetry (26.1 ± 0.4 dB, P = 0.094), and the 95% limits of agreement between the two measures were between -4.12 and 4.92 dB. The measurements of central retinal sensitivity can be performed effectively using a tablet device, displaying reasonably good agreement with those obtained using the established method of microperimetry. These findings highlight the potential of tablet devices as low-cost and portable tools for developing and performing visual function measures that can be easily and widely implemented.


Longterm abrasive and erosive effect of whitening toothpaste on dentin surface.
To evaluate the amount of dentin loss following immersion in or toothbrushing with whitening toothpaste (WT) containing hydrogen peroxide (HP) and citric acid (CA). Additionally, the amount of dentin loss after brushing with a WT alone or in combination with a conventional toothpaste was assessed, and the effects of HP and CA solutions on the dentin surface were investigated. Bovine dentin specimens (n= 350) were randomly assigned to seven solutions of various compositions as toothpaste: The specimens assigned to each solution were then further divided into five treatment groups (n=10 each) : Group A = 1-hour immersion in each solution (ES); Group B = 10,000 brushing in ES; Group C = 1-hour immersion in ES + 10,000 brushing in ES; Group D = 1-hour immersion in ES + 10,000 brushing in reference slurry (RS); Group E = 10,000 brushing in ES + 10,000 brushing in RS. The amount and pattern of dentin loss were determined, and the surfaces were observed using noncontact profilometry. The WT (pH 5.0) caused lower dentin loss than RS after a single brushing cycle; however, the extent of dentin loss after 1 hour of immersion in the WT was significantly greater than that in the RS. Among the specimens treated with WT, a significant difference in dentin loss was observed between Group C and Groups D and E (P< 0.05) but not between Groups D and E. The surfaces exposed to CAS1, CAPB, and WT exhibited U-shaped patterns of dentin loss after brushing or immersion, whereas a wedge-shaped pattern was observed in those that underwent brushing with the RS. The effects (dentin abrasion) of a whitening toothpaste containing hydrogen peroxide and citric acid when used in combination with a conventional toothpaste were similar to those seen with the continuous use of a conventional toothpaste alone.


Attenuated acute salivary α-amylase responses to gustatory stimulation with citric acid in thin children.
Salivary α-amylase (sAA) is responsible for the 'pre-digestion' of starch in the oral cavity and accounts for up to 50 % of salivary protein in human saliva. An accumulating body of literature suggests that sAA is of nutritional importance; however, it is still not clear how sAA is related to individual's nutritional status. Although copy number variations (CNV) of the salivary amylase gene (AMY1) are associated with variation in sAA levels, a significant amount of sAA variation is not explained by AMY1 CNV. To measure sAA responses to gustatory stimulation with citric acid, we used sAA ratio (the ratio of stimulated sAA levels to those of resting sAA) and investigated acute sAA responses to citric acid in children with normal (Normal-BMI, n 22) and low (Low-BMI, n 21) BMI. The AMY1 gene copy number was determined by quantitative PCR. We, for the first time, demonstrated attenuated acute sAA responses (decreased sAA ratio) to gustatory stimulation in Low-BMI (thinness grade 3) children compared with the Normal-BMI children, which suggest that sAA responses to gustatory stimulation may be of nutritional importance. However, child's nutritional status was not directly related to their resting or stimulated sAA levels, and it was not associated with AMY1 gene copy number. Finally, AMY1 CNV might influence, but did not eventually determine, sAA levels in children.


Partial agonist effect influences the CTL response to a heterologous dengue virus serotype.
Activation of dengue serotype-cross-reactive memory CTL during secondary dengue virus (DV) infection is thought to be important in the pathogenesis of dengue hemorrhagic fever. To model this effect, we studied the CTL responses to DV types 2 (D2V) and 3 (D3V) in PBMC from an individual previously infected with D3V. DV-specific CD8+ CTL from this donor recognized two HLA-B62-restricted epitopes on the NS3 protein, aa 71-79 (SVKKDLISY) and 235-243 (AMKGLPIRY). Both D3V-specific and D2V/D3V-cross-reactive CTL clones were detected for each epitope; all D2V-reactive CTL clones could lyse D2V-infected autologous cells. CTL responses to both epitopes were detected in bulk cultures stimulated with D3V, but PBMC stimulated with D2V recognized only the 235-243 epitope. IFN-gamma enzyme-linked immunospot assay showed that the D2V (71-79) peptide (DVKKDLISY) did not efficiently activate T cells. Analysis of a CTL clone suggests that the D2V (71-79) peptide acts as a partial agonist, able to sensitize target cells for lysis and inducing only minimal proliferation at high concentrations. These results suggest that variant peptide sequences present in the heterologous DV serotype can influence the CTL response in vivo during secondary DV infection.


Transcriptome analysis of human colorectal cancer biopsies reveals extensive expression correlations among genes related to cell proliferation, lipid metabolism, immune response and collagen catabolism.
Precise characterization of biological processes critical to proliferation and metastasis of colorectal cancer should facilitate the development of diagnostic and prognostic biomarkers as well as novel treatments. Using mRNA-Seq, we examined the protein coding messenger RNA (mRNA) expression profiles across different histologically defined stages of primary colon cancers and compared them to their patient matched normal tissue controls. In comparing 79 colorectal cancers to their matched normal mucosa, tumors were distinguished from normal non-malignant tissues not only in the upregulation of biological processes pertaining to cell proliferation, inflammation, and tissue remodeling, but even more strikingly, in downregulated biological processes including fatty acid beta oxidization for ATP production and epithelial cell differentiation and function. A network analysis of deregulated genes revealed newly described cancer networks and putative hub genes. Taken together, our findings suggest that, within an inflammatory microenvironment, invasive, dedifferentiated and rapidly dividing tumor cells divert the oxidation of fatty acids and lipids from energy production into lipid components of cell membranes and organelles to support tumor proliferation. A gene co-expression network analysis provides a clear and broad picture of biological pathways in tumors that may significantly enhance or supplant current histopathologic studies.


Comparison of Outcomes before and after Ohio's Law Mandating Use of the FDA-Approved Protocol for Medication Abortion: A Retrospective Cohort Study.
In February 2011, an Ohio law took effect mandating use of the United States Food and Drug Administration (FDA)-approved protocol for mifepristone, which is used with misoprostol for medication abortion. Other state legislatures have passed or enacted similar laws requiring use of the FDA-approved protocol for medication abortion. The objective of this study is to examine the association of this legal change with medication abortion outcomes and utilization. We used a retrospective cohort design, comparing outcomes of medication abortion patients in the prelaw period to those in the postlaw period. Sociodemographic and clinical chart data were abstracted from all medication abortion patients from 1 y prior to the law's implementation (January 2010-January 2011) to 3 y post implementation (February 2011-October 2014) at four abortion-providing health care facilities in Ohio. Outcome data were analyzed for all women undergoing abortion at ≤49 d gestation during the study period. The main outcomes were as follows: need for additional intervention following medication abortion (such as aspiration, repeat misoprostol, and blood transfusion), frequency of continuing pregnancy, reports of side effects, and the proportion of abortions that were medication abortions (versus other abortion procedures). Among the 2,783 medication abortions ≤49 d gestation, 4.9% (95% CI: 3.7%-6.2%) in the prelaw and 14.3% (95% CI: 12.6%-16.0%) in the postlaw period required one or more additional interventions. Women obtaining a medication abortion in the postlaw period had three times the odds of requiring an additional intervention as women in the prelaw period (adjusted odds ratio [AOR] = 3.11, 95% CI: 2.27-4.27). In a mixed effects multivariable model that uses facility-months as the unit of analysis to account for lack of independence by site, we found that the law change was associated with a 9.4% (95% CI: 4.0%-18.4%) absolute increase in the rate of requiring an additional intervention. The most common subsequent intervention in both periods was an additional misoprostol dose and was most commonly administered to treat incomplete abortion. The percentage of women requiring two or more follow-up visits increased from 4.2% (95% CI: 3.0%-5.3%) in the prelaw period to 6.2% (95% CI: 5.5%-8.0%) in the postlaw period (p = 0.003). Continuing pregnancy was rare (0.3%). Overall, 12.6% of women reported at least one side effect during their medication abortion: 8.4% (95% CI: 6.8%-10.0%) in the prelaw period and 15.6% (95% CI: 13.8%-17.3%) in the postlaw period (p < 0.001). Medication abortions fell from 22% (95% CI: 20.8%-22.3%) of all abortions the year before the law went into effect (2010) to 5% (95% CI: 4.8%-5.6%) 3 y after (2014) (p < 0.001). The average patient charge increased from US$426 in 2010 to US$551 in 2014, representing a 16% increase after adjusting for inflation in medical prices. The primary limitation to the study is that it was a pre/post-observational study with no control group that was not exposed to the law. Ohio law required use of a medication abortion protocol that is associated with a greater need for additional intervention, more visits, more side effects, and higher costs for women relative to the evidence-based protocol. There is no evidence that the change in law led to improved abortion outcomes. Indeed, our findings suggest the opposite. In March 2016, the FDA-protocol was updated, so Ohio providers may now legally provide current evidence-based protocols. However, this law is still in place and bans physicians from using mifepristone based on any new developments in clinical research as best practices continue to be updated.


The importance of the virology laboratory in the diagnosis and management of viral meningitis.
Recent advances in cell culture techniques have made possible the rapid and accurate detection of enteroviruses, the most commonly identified cause of aseptic meningitis. Between 1983 and 1985, 69 patients were diagnosed as having enteroviral meningitis by viral culture of cerebrospinal fluid, throat swab, and/or rectal swab or stool specimens. Half of the 49 patients in whom the diagnosis was based on positive cerebrospinal fluid culture benefited directly from viral culture results by early withdrawal of antibiotics, early discharge, or changing of the diagnosis and prognosis of the disease. Enteroviral cultures became positive in as early as 24 hours, and most of the cultures became positive within one week. The cost of viral culture is comparable with that of other microbiologic tests. The virology laboratory has proved useful in the diagnosis and management of patients with enteroviral meningitis.


[Community acquired pneumonia (CAP) in children younger than 5 years of age in southern Israel].
Respiratory tract infections are a major cause of morbidity and mortality in children under the age of 5 years. The child population in southern Israel is divided into two main groups, Jewish and Bedouin, who differ in their socioeconomic status, with the Bedouin population living in lower socioeconomic conditions and overcrowding. Almost all children in southern Israel are treated at the Soroka University Medical Center. To compare the epidemiological and clinical data of Bedouin and Jewish children with community acquired pneumonia (CAP), who were treated at the Soroka University Medical Center. All chest X-rays of children under the age of 5 years, taken at the Pediatric Emergency room (PER) between the dates 4.11.2001 and 31.12.2007, were evaluated for pneumonia. Demographic and clinical data were collected to determine morbidity, hospitalization and mortality rates. Blood cultures and nasopharyngeal washes were taken to determine the pathogens of CAP. A total of 38,045 chest radiographs were evaluated; CAP was diagnosed in 5,965 of them (15.6%). The risk of presenting to the PER with CAP in children under the age of 5 years was 8.3% in Bedouin children and 5.4% in Jewish children (p < 0.01). The cumulative risk for hospitalization due to CAP in children under the age of 5 years was 5.8% for the Bedouin children and 2.2% for the Jewish children (p < 0.01). The Bedouin children were younger than the Jewish children (43.5% under 1 year of age vs. 23.7% respectively, p < 0.01). Tachypnea, hypoxemia and mortality rates (71.9% vs. 61%, 31.7% vs. 18.6% and 3% vs. 0.3%, p < 0.01 respectively) were higher in Bedouin children than in Jewish children. PER visits due to CAP are common, especially in Bedouin children. Bedouin patients were younger, with a more severe clinical course and with higher rates of morbidity, hospitalization and mortality than Jewish children. Improving living conditions, parental perception of disease severity and immunization programs (e.g. pneumococcal and influenza vaccine) could lead to a reduction in the gap between the two populations.


DNA pyrosequencing-based bacterial pathogen identification in a pediatric hospital setting.
Sole reliance on biochemical methods can limit the clinical microbiology laboratory's ability to identify bacterial pathogens. This study describes the incorporation of DNA pyrosequencing-based identification for routine pathogen identification of atypical clinical isolates in a large children's hospital. The assay capitalized on the highly conserved nature of 16S rRNA genes by positioning amplification and sequencing primers in conserved target sequences flanking the variable V1 and V3 regions. A total of 414 isolates of 312 pediatric patients were tested by DNA pyrosequencing during the time period from December 2003 to July 2006. Seventy-eight different genera were specified by DNA pyrosequencing, and isolates were derived from diverse specimen types. By integrating DNA sequencing of bacterial pathogens with conventional microbiologic methods, isolates that lacked a definitive identification by biochemical testing yielded genus- or species-level identifications in approximately 90% of cases by pyrosequencing. Improvements incorporated into the assay process during the period of clinical testing included software enhancements, improvements in sequencing reagents, and refinements in database search strategies. Coupled with isolation by bacteriologic culture and biochemical testing, DNA pyrosequencing-based bacterial identification was a valuable tool that markedly improved bacterial pathogen identification in a pediatric hospital setting.


Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue.
Some animal models suggest that tumor necrosis factor (TNF)-alpha is a key component in obesity-linked insulin resistance because it inhibits insulin receptor signaling and glucose transport in insulin-sensitive tissues. However, in vivo data in humans have given conflicting results regarding the relationship between circulating TNF-alpha levels and insulin sensitivity. In the present study, the potential local role of TNF-alpha on insulin action in human subcutaneous adipose tissue was studied in 42 obese women (BMI 39+/-10 kg/m2). We found a strong inverse correlation between adipose TNF-alpha secretion and maximum insulin-stimulated glucose transport in adipocytes that was independent of fat cell volume, age, and BMI (P < 0.001, r = 0.58). As much as one-third of the variation in insulin-stimulated glucose transport could be accounted for by variations in TNF-alpha secretion. There was no significant correlation (r = 0.11) between secretion of adipose plasminogen activator inhibitor 1 and glucose transport. Furthermore, subcutaneous adipose tissue of 4 obese women (BMI 40+/-4) incubated with TNF-A for 24 h showed a one-third concentration-dependent inhibition of insulin-stimulated glucose transport (P < 0.01). In conclusion, adipose TNF-alpha may be an important specific and local factor in adipose tissue that influences the ability of insulin to stimulate glucose transport in human fat cells, at least in obese women.


Cost-effectiveness of molecular point-of-care testing for influenza viruses in elderly patients at ambulatory care setting.
Early initiation of antiviral therapy in elderly patients with influenza is associated with reduced risk of extra clinic visit, hospitalization and death. This study examined the cost-effectiveness of molecular POCT for detection of influenza viruses in Hong Kong elderly patients with influenza-like illness (ILI) in the outpatient clinics. A decision analytic model was used to simulate outcomes of a hypothetical cohort of elderly patients presented with ILI at outpatient clinics during peak season of influenza with two diagnostic approaches: Rapid molecular assay (POCT-PCR group) and clinical judgement with no POCT. Outcome measures included influenza-associated direct medical cost, hospitalization and mortality rates, quality-adjusted life year loss (QALY loss), and incremental cost per QALY saved (ICER). In base-case analysis, POCT-PCR group was expected to reduce hospitalization (1.38% versus 2.85%) and mortality rate (0.08% versus 0.16%) and save 0.00112 QALYs at higher cost (by USD33.2 per ILI patient), comparing with clinical judgement group. The ICER of POCT-PCR was 29,582 USD/QALY saved. One-way sensitivity analyses found ICER sensitive to: Hospitalization rate without prompt antiviral therapy; odds ratio of hospitalization with prompt therapy; influenza prevalence; patient age and mortality rate of hospitalized patients. POCT-PCR was cost-effective in 60.6% and 99.4% of 10,000 Monte Carlo simulations at willingness-to-pay threshold of 1x and 3x gross domestic product per capita of Hong Kong, respectively. Molecular POCT for influenza detection in elderly patients with ILI at outpatient clinics during peak influenza season appeared to be cost-effective in Hong Kong.


[Motor representation of the limbs in the rabbit cerebral cortex].
Movements elicited by electrical stimulation (ES) of the brain's dorsal surface (train duration 20 msec, frequency 200 c/s) were studied in unanaesthetized slightly fixed rabbits. The stimuli were led through 80 mu in diameter electrodes implanted in the cortex. The responses were estimated visually or electromyographycally. The local responses of the forelimb (FL) were elicited by ES of an area with coordinates A 1-2, L 1-4; local movements of the hind limb (HL)--P 2,5-3,5 L 1-4. Between these areas there is a region whose stimulation caused the movements of the fore- and hind limb simultaneously ("overlapping area"). The thresholds and latencies of the forelimb responses were minimal when the stimuli were applied to the "local responses area". However, the tresholds and latencies of hindlimb responses were higher when stimulation was applied in the "local responses area" as compared with the "overlapping area". Light barbiturate anaesthesia (20 to 25 mg/kg) raised the thresholds of hindlimb movements 13 to 18 times when the stimuli were applied to the "local responses area", and 7 to 8 times, when they were applied to the "overlapping area". The problem of determination of the rabbit "motor centre" is discussed.


Prediction tree for severely head-injured patients.
Prediction tree techniques are employed in the analysis of data from 555 patients admitted to the Medical College of Virginia hospitals with severe head injuries. Twenty-three prognostic indicators are examined to predict the distribution of 12-month outcomes among the five Glasgow Outcome Scale categories. A tree diagram, illustrating the prognostic pattern, provides critical threshold levels that split the patients into subgroups with varying degrees of risk. It is a visually useful way to look at the prognosis of head-injured patients. In previous analyses addressing this prediction problem, the same set of prognostic factors (age, motor score, and pupillary response) was used for all patients. These approaches might be considered inflexible because more informative prediction may be achieved by somewhat different combinations of factors for different patients. Tree analysis reveals that the pattern of important prognostic factors differs among various patient subgroups, although the three previously mentioned factors are still of primary importance. For example, it is noted that information concerning intracerebral lesions is useful in predicting outcome for certain patients. The overall predictive accuracy of the tree technique for these data is 77.7%, which is somewhat higher than that obtained via standard prediction methods. The predictive accuracy is highest among patients who have a good recovery or die; it is lower for patients having intermediate outcomes.


Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice.
We have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice. LDL was incubated with sphingomyelinase, which increased its average particle diameter from 26 to 170 nm, and was then incubated for up to 7 days with human monocyte-derived macrophages. LDL receptor-deficient mice were fed a Western diet (19-22 per group) and some given cysteamine in their drinking water at a dose equivalent to that used in cystinosis patients. The extent of atherosclerosis in the aortic root and the rest of the aorta was measured. Confocal microscopy revealed lipid accumulation in lysosomes in the cultured macrophages. Large amounts of ceroid were produced, which colocalised with the lysosomal marker LAMP2. The antioxidants cysteamine, butylated hydroxytoluene, amifostine and its active metabolite WR-1065, inhibited the production of ceroid. Cysteamine at concentrations well below those expected to be present in lysosomes inhibited the oxidation of LDL by iron ions at lysosomal pH (pH 4.5) for prolonged periods. Finally, we showed that the extent of atherosclerotic lesions in the aortic root and arch of mice was significantly reduced by cysteamine. These results support our hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide a novel therapy for this disease.


Consensus clinical recommendations for the management of plasma lipid disorders in the Middle East: 2021 update.
Disorders of plasma lipids remain key risk factors for the development of atherosclerotic cardiovascular disease (ASCVD) in the Middle East and are estimated to increase more dramatically in the next decade than in any other global region except Africa. This statement is an update to the 2016 consensus clinical recommendations for the management of plasma lipid disorders in the Middle East, following the evaluation of newer cholesterol-lowering agents in randomised controlled cardiovascular outcome trials, as well as the publication of revised international guidelines. A multidisciplinary panel of regional experts was convened to update the consensus clinical recommendations for the management of plasma lipids in the Middle East. The recommendations constructed in 2016 were reviewed against emerging research since publication. Newly developed Middle East ASCVD risk categories were established using the multiple risk group categories from the recently updated international guidelines and the epidemiological evidence from the Gulf Region. These consensus recommendations support a more intensive reduction of LDL-C across cardiovascular risk categories. Alongside low-density lipoprotein cholesterol, we recommend non-high-density lipoprotein cholesterol as a primary treatment target. Lifestyle modifications remain the first-line treatment recommendation for all patients. The first-line pharmacological treatment in patients with dyslipidaemia is statin therapy, with a number of second-line agents available. The selection of a second lipid-lowering agent for combination therapy with statin should be based on the lipid-lowering target of the patient. Guidance is also provided on the management of underlying conditions and special populations; of particular pertinence in the region are familial hypercholesterolaemia, diabetes and metabolic dyslipidaemia. New therapies have emerged from research that found positive outcomes in reducing low-density lipoprotein cholesterol levels. The initial results of these newly researched drugs strongly indicate their inclusion as future therapies in dyslipidaemia management in the Middle East. These updated consensus clinical recommendations provide practicing clinicians with comprehensive, region-specific guidance to improve the detection and management of plasma lipid disorders in patients in the Middle East.


Ischemia-induced lower extremity neurologic impairment after fenestrated endovascular aneurysm repair.
Placement of large sheaths in the iliac system during fenestrated endovascular aneurysm repair (FEVAR) leads to lower extremity (LE) ischemia that can be associated with serious neurologic complications. We sought to determine the effect of LE ischemic time on neurologic impairment after FEVAR. Consecutive patients who underwent FEVAR at a single institution were analyzed. LE ischemic time was calculated from the time of large sheath (≥18F) insertion to the time of sheath removal from the iliac arteries that led to continuous LE ischemia. The primary outcome was neurologic impairment defined as any new sensory or motor deficit in either LE. Outcomes were analyzed using descriptive statistics and modeled with logistic regression with interaction terms. Each individual LE was used as a unit of analysis. We examined 101 patients (202 lower extremities) who underwent FEVAR over a 5-year period. The median LE ischemic time was 2.75 hours (range, 0.8-5.2 hours). Neurologic impairment developed in 18 extremities (9%). Of those, 12 (67%) developed mild sensory loss, 6 (33%) complete sensory loss, 4 (22%) loss of proprioception, and 2 (11%) motor dysfunction. Sensory deficit was permanent in four limbs (2%) and motor dysfunction in one limb (0.5%). In all other cases, the neurologic examination returned to baseline by postoperative day 15. Duration of LE ischemic time (odds ratio, 6.3; 95% confidence interval, 3.1-12.4; P < .001) and common iliac artery (CIA) stenosis to a lumen of 8 mm or less (odds ratio, 2.7; 95% confidence interval, 1.5-7.3; P = .002) were independent predictors for the development of neurologic impairment. An interaction term between LE ischemic time and CIA stenosis was statistically significant (P = .042), indicating that the presence of CIA stenosis modifies the effect of LE ischemic time. In those with CIA stenosis to a lumen of 8 mm or less, the risk of neurologic impairment increased rapidly after 2.5 hours of LE ischemia, and became nearly certain after 4 hours of ischemic time. By contrast, patients without CIA stenosis tolerated longer ischemic times and demonstrated a less steep increase in the risk for LE neurologic impairment. LE neurologic impairment after FEVAR is strongly associated with LE ischemic time and CIA occlusive disease to a lumen of 8 mm or less. Our data indicate that, when the LE ischemic time is expected to exceed 2.5 hours (in patients with CIA stenosis) or 3 hours (in patients without CIA stenosis), measures to ensure LE perfusion should be given consideration.


HIV Incidence and Predictors of HIV Acquisition From an Outside Partner in Serodiscordant Couples in Lusaka, Zambia.
Evaluate the incidence and predictors of HIV acquisition from outside partners in serodiscordant couples. Demographic, behavioral, and clinical exposures were measured quarterly in a cohort of serodiscordant cohabiting couples in Zambia from 1995 to 2012 (n = 3049). Genetic analysis classified incident infections as those acquired from the study partner (linked) or acquired from an outside partner (unlinked). Factors associated with time to unlinked HIV infection were evaluated using multivariable Cox proportional hazards regression stratified by sex. There were 100 unlinked infections in couples followed for a median of 806 days. Forty-five infections occurred in women [1.85/100 couple-years; 95% confidence interval (CI): 1.35 to 2.47]. Risk of female unlinked infection (vs. nonseroconverting females) was associated with reporting being drunk weekly/daily vs. moderate/nondrinkers at baseline [adjusted hazard ratio (aHR) = 5.44; 95% CI: 1.03 to 28.73], genital ulcers (aHR = 6.09; 95% CI: 2.72 to 13.64), or genital inflammation (aHR = 11.92; 95% CI: 5.60 to 25.37) during follow-up adjusting for age, years cohabiting, income, contraceptive use, previous pregnancies, history of sexually transmitted infections, and condomless sex with study partner. Fifty-five infections occurred in men (1.82/100 couple-years; 95% CI: 1.37 to 2.37). Risk of male unlinked infection was associated with genital inflammation (aHR = 8.52; 95% CI: 3.82 to 19.03) or genital ulceration (aHR = 2.31; 95% CI: 2.05 to 8.89), reporting ≥1 outside sexual partner (aHR = 3.86; 95% CI: 0.98 to 15.17) during follow-up, and reporting being drunk weekly/daily vs. moderate/nondrinkers at baseline (aHR = 3.84; 95% CI: 1.28 to 11.55), controlling for age, income, circumcision status, and history of sexually transmitted infection. Predictors of unlinked infection in serodiscordant relationships were alcohol use, genital inflammation, and ulceration. Causes of genital inflammation and ulceration should be screened for and treated in HIV-negative individuals. Counseling on risk of alcohol use and sex with outside partners should be discussed with couples where 1 or both are HIV-negative, including in counseling on use of pre-exposure prophylaxis to prevent HIV acquisition in the HIV-negative partner (when feasible and affordable).


Quantitative comparison and analysis of brain image registration using frequency-adaptive wavelet shrinkage.
In the field of template-based medical image analysis, image registration and normalization are frequently used to evaluate and interpret data in a standard template or reference atlas space. Despite the large number of image-registration (warping) techniques developed recently in the literature, only a few studies have been undertaken to numerically characterize and compare various alignment methods. In this paper, we introduce a new approach for analyzing image registration based on a selective-wavelet reconstruction technique using a frequency-adaptive wavelet shrinkage. We study four polynomial-based and two higher complexity nonaffine warping methods applied to groups of stereotaxic human brain structural (magnetic resonance imaging) and functional (positron emission tomography) data. Depending upon the aim of the image registration, we present several warp classification schemes. Our method uses a concise representation of the native and resliced (pre- and post-warp) data in compressed wavelet space to assess quality of registration. This technique is computationally inexpensive and utilizes the image compression, image enhancement, and denoising characteristics of the wavelet-based function representation, as well as the optimality properties of frequency-dependent wavelet shrinkage.


Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions.
TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations. In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity. We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability. This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.


Association mapping by aerial drone reveals 213 genetic associations for Sorghum bicolor biomass traits under drought.
Sorghum bicolor is the fifth most commonly grown cereal worldwide and is remarkable for its drought and abiotic stress tolerance. For these reasons and the large size of biomass varieties, it has been proposed as a bioenergy crop. However, little is known about the genes underlying sorghum's abiotic stress tolerance and biomass yield. To uncover the genetic basis of drought tolerance in sorghum at a genome-wide level, we undertook a high-density phenomics genome wide association study (GWAS) in which 648 diverse sorghum lines were phenotyped at two locations in California once per week by drone over the course of a growing season. Biomass, height, and leaf area were measured by drone for individual field plots, subjected to two drought treatments and a well-watered control. The resulting dataset of ~ 171,000 phenotypic data-points was analyzed along with 183,989 genotype by sequence markers to reveal 213 high-quality, replicated, and conserved GWAS associations. The genomic intervals defined by the associations include many strong candidate genes, including those encoding heat shock proteins, antifreeze proteins, and other domains recognized as important to plant stress responses. The markers identified by our study can be used for marker assisted selection for drought tolerance and biomass. In addition, our results are a significant step toward identifying specific sorghum genes controlling drought tolerance and biomass yield.


Pleural effusion during bromocriptine exposure in two patients with pre-existing asbestos pleural plaques: a relationship?
Two patients with pleural plaques developed pleural effusion and subsequent diffuse pleural fibrosis 50 and 39 yrs after their first exposure to asbestos. The diagnosis of benign asbestos pleural effusion was suggested, but the work-up finally suggested bromocriptine-induced pleural disease in both patients. These two cases illustrate that drug-induced pleural effusion is an important differential diagnosis of benign asbestos pleural effusion. It is, moreover, possible that pre-existing asbestos pleural lesions, or even asbestos exposure, increases the risk of developing bromocriptine-induced pleural disease.


Leptin does not directly affect CNS serotonin neurons to influence appetite.
Serotonin (5-HT) and leptin play important roles in the modulation of energy balance. Here we investigated mechanisms by which leptin might interact with CNS 5-HT pathways to influence appetite. Although some leptin receptor (LepRb) neurons lie close to 5-HT neurons in the dorsal raphe (DR), 5-HT neurons do not express LepRb. Indeed, while leptin hyperpolarizes some non-5-HT DR neurons, leptin does not alter the activity of DR 5-HT neurons. Furthermore, 5-HT depletion does not impair the anorectic effects of leptin. The serotonin transporter-cre allele (Sert(cre)) is expressed in 5-HT (and developmentally in some non-5-HT) neurons. While Sert(cre) promotes LepRb excision in a few LepRb neurons in the hypothalamus, it is not active in DR LepRb neurons, and neuron-specific Sert(cre)-mediated LepRb inactivation in mice does not alter body weight or adiposity. Thus, leptin does not directly influence 5-HT neurons and does not meaningfully modulate important appetite-related determinants via 5-HT neuron function.


Association of Physical Function With Driving Space and Crashes Among Older Adults.
Balancing both driver mobility and safety is important for the well-being of older adults. However, research on the association of physical function with these 2 driving outcomes has yielded inconsistent findings. This study examined whether physical functioning of older drivers, as measured by the Short Physical Performance Battery (SPPB), is associated with either driving space or crash involvement. Using cross-sectional data of active drivers aged 65-79 years from the AAA Longitudinal Research on Aging Drivers (LongROAD) study (n = 2,990), we used multivariate log-binomial and logistic regressions to estimate the associations of the SPPB with either self-reported restricted driving space in the prior 3 months or any crashes in the past year. Interaction with gender was assessed using likelihood ratio tests. After adjustment, older drivers with higher SPPB scores (higher physical functioning) had lower prevalence of restricted driving space (8-10 vs. 0-7, prevalence ratio [PR] = 0.88, 95% confidence interval [CI]: 0.78-0.99; 11-12 vs. 0-7, PR = 0.78, 95% CI: 0.61-0.99). Fair (8-10), but not good (11-12), scores were significantly associated with reduced crash involvement (8-10 vs. 0-7, odds ratio [OR] = 0.71, 95% CI: 0.60-0.84). Gender was not a significant effect modifier. This study provides evidence that higher physical functioning is associated with better driving mobility and safety and that the SPPB may be useful for identifying at-risk drivers. Further research is needed to understand physical functioning's longitudinal effects and the SPPB's role in older driver intervention programs.


Effect of sympathectomy on mechanical properties of common carotid and femoral arteries.
Sympathetic stimulation is accompanied by a reduction of arterial distensibility, but whether and to what extent elastic and muscle-type arterial mechanics is under tonic sympathetic restraint is not known. We addressed this issue by measuring, in the anesthetized rat, the diameters of the common carotid and femoral arteries with an echo-Doppler device (NIUS 01). Blood pressure was measured by a catheter inserted contralaterally and symmetrically to the vessel where the diameter was measured. Arterial distensibility over the systolic-diastolic pressure range was calculated according to the Langewouters formula. Data were collected in 10 intact (vehicle pretreatment) and 9 sympathectomized (6-hydroxydopamine pretreatment) 3-month-old Wistar-Kyoto rats. Compared with the intact animals, sympathectomized rats showed a marked increase in arterial distensibility over the entire systolic-diastolic pressure range. When quantified by the area under the distensibility-pressure curve, the increase was 59% and 62% for the common carotid and femoral arteries, respectively (P<.01 for both). In the femoral but not in the common carotid artery, sympathectomy was accompanied also by an increase in arterial diameter (+18%, P<.05 versus intact). Therefore, in the anesthetized normotensive rat, sympathetic activity exerts a tonic restraint on large-artery distensibility. This restraint is pronounced in elastic vessels and even more pronounced in muscle-type vessels.


Brain Abnormalities in Becker Muscular Dystrophy: Evaluation by Voxel-Based DTI and Morphometric Analysis.
Although various neuropsychological problems in Becker muscular dystrophy have attracted attention, there have been few related neuroimaging studies. We investigated brain abnormalities in patients with Becker muscular dystrophy using 3D T1WI and DTI. MR images were obtained for 30 male patients and 30 age-matched healthy male controls. We classified patients into Dp140+ and Dp140- subgroups based on their predicted dystrophin Dp140 isoform expression and performed voxel-based comparisons of gray and white matter volumes and DTI metrics among the patients, patient subgroups, and controls. ROI-based DTI analyses were also performed. Significantly decreased fractional anisotropy was observed in the left planum temporale and right superior parietal lobule compared between the Becker muscular dystrophy and control groups. In the Dp140- subgroup, decreased fractional anisotropy was observed in the left planum temporale, but no significant changes were seen in the Dp140+ subgroup. The ROI-based analysis obtained the same results. No significant differences were evident in the gray or white matter volumes or the DTI metrics other than fractional anisotropy between the groups. A DTI metric analysis is useful to detect white-matter microstructural abnormalities in Becker muscular dystrophy that may be affected by the Dp140 isoform expression.


The Effectiveness of Hippotherapy to Recover Gross Motor Function in Children with Cerebral Palsy: A Systematic Review and Meta-Analysis.
Cerebral palsy (CP) is a permanent disorder of the posture and movement, which can result in impairments of gross motor function, among others. Hippotherapy (HPT) is an emerging intervention to promote motor recovery in patients with neurological disorders, providing a smooth, precise, rhythmic, and repetitive pattern of movement to the patient. The main objective of this systematic review and meta-analysis of randomized controlled clinical trials was to analyze the effectiveness of HPT interventions on gross motor function in subjects with CP. The following databases were searched in May 2019: PubMed, Scopus, Embase, and Web of Science. The methodological quality of the randomized controlled trials was assessed using the Physiotherapy Evidence Database (PEDro) scale. A total of 10 studies were analyzed in this review, involving 452 participants. Favorable effects were obtained on the gross motor function (Gross Motor Function Measure-66, standardized mean difference (SMD) = 0.81, 95% confidence interval (CI) = 0.47-1.15, Gross Motor Function Measure-88 dimension A SMD = 0.64, 95% CI = 0.30-0.97, dimension B SMD = 0.42, 95% CI = 0.09-0.75, and dimension E SMD = 0.40, 95% CI = 0.06-0.73). The results obtained in the present review show the potential benefit of HPT intervention in improving gross motor function in children with CP.


Prevention of adolescent depression in the Spanish-speaking world.
This paper aims at presenting programs targeted at the prevention of adolescent depression applied with Spanish-speaking populations that have been developed in Spanish-speaking countries and are mostly published in Spanish. These programs have been developed under different cultural contexts in Spain and Latin-America. The main goal of this paper is to make the studies and movements of the Spanish-speaking literature in this field accessible to the non-Spanish-speaking part of the research community. Therefore, after an introduction referring to possible cultural differences regarding depression in general and epidemiological basics, several programs are introduced. In total 11 programs will be shortly presented and discussed. After revising the programs it can be concluded that in the Spanish-speaking world many programs have been developed and conducted following current state of the art-approaches for adolescent depression prevention. Further research is needed especially targeting possible cultural and contextual aspects of prevention measures and their efficacy and efficiency.


Nanomedicine and therapy of lung diseases.
The use of nanotechnology has significantly increased in different fields of science, including the development of drug delivery systems. Currently, the most modern pharmaceutical nanocarriers, such as liposomes, micelles, nanoemulsions and polymeric nanoparticles, demonstrate extremely useful properties from the point of view of drug therapy. In this context, the development of nanocarriers for pulmonary application has been much debated by the scientific community in recent decades. Although research on the use of nanoparticles for pulmonary application are still in the initial phase, the studies conducted to date suggest that the development of drug delivery systems for systemic or local treatment of diseases that affect the respiratory system may be promising.


Coexistent Helminth Infection-Mediated Modulation of Chemokine Responses in Latent Tuberculosis.
Coexistent helminth infections are known to modulate T cell and cytokine responses in latent infection with Mycobacterium tuberculosis However, their role in modulating chemokine responses in latent tuberculosis (LTB) has not been explored. Because chemokines play a vital role in the protective immune responses in LTB, we postulated that coexistent helminth infection could modulate chemokine production in helminth-LTB coinfection. To test this, we measured the levels of a panel of CC and CXC chemokines at baseline and following mycobacterial Ag or mitogen stimulation in individuals with LTB with (Strongyloides stercoralis +LTB+) or without S. stercoralis (S. stercoralis -LTB+) infection and in individuals without both infections, healthy controls (HC). At baseline (in the absence of a stimulus), S. stercoralis +LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL9, CXCL10, and CXCL11 in comparison with S. stercoralis -LTB+ and/or HC individuals. Upon mycobacterial Ag stimulation, S. stercoralis +LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL2, CXCL9, and CXCL10 in comparison with S. stercoralis -LTB+ and/or HC individuals. No differences were observed upon mitogen stimulation. Finally, after anthelmintic treatment, the baseline levels of CCL1, CCL2, CCL4, CCL11, and CXCL11 and mycobacterial Ag-stimulated levels of CCL1, CCL2, CCL11, CXCL2, and CXCL10 were significantly increased in S. stercoralis +LTB+ individuals. Thus, our data demonstrate that S. stercoralis +LTB+ individuals are associated with a compromised ability to express both CC and CXC chemokines and that this defect is at least partially reversible upon treatment. Hence, coexistent helminth infection induces downmodulation of chemokine responses in LTB individuals with likely potential effects on tuberculosis pathogenesis.


Structural topology of transmembrane helix 10 in the lactose permease of Escherichia coli.
In the lactose permease of Escherichia coli, transmembrane helix 10 has been shown to be functionally important. The structure of this helix has been examined in greater detail in this study. A total of 46 substitution and 8 insertional mutants were constructed and analyzed along the entire length of transmembrane helix 10. The results identified amino acids that are tolerant of substitutions by a variety of amino acids. Since a number of these amino acids (Thr-320, Val-331, Phe-325, and Ile-317) are clustered in one region in a helical wheel projection of transmembrane helix 10, it seems likely that this face of helix 10 is interacting with the membrane. The channel lining domain is thought to consist of the helical face containing Glu-325, Leu-318, Leu-329, His-322, Val-315, Cys-333, Val-326, and Lys-319 based on the results here and from earlier findings. Deleterious mutations along this face tended to greatly increase the Km value for lactose transport with only minor effects on the Vmax. Analysis of insertional mutants revealed that perturbation of the spatial relationship between amino acids at the periplasmic edge is less deleterious than perturbation in the center of the helix or the cytoplasmic edge. Using all of the above information, a detailed structural topology of transmembrane helix 10 is proposed.


Adaptation of red blood cell lysis represents a fundamental breakthrough that improves the sensitivity of Salmonella detection in blood.
Isolation of Salmonella Typhi from blood culture is the standard diagnostic for confirming typhoid fever but it is unavailable in many developing countries. We previously described a Microwave Accelerated Metal Enhanced Fluorescence (MAMEF)-based assay to detect Salmonella in medium. Attempts to detect Salmonella in blood were unsuccessful, presumably due to the interference of erythrocytes. The objective of this study was to evaluate various blood treatment methods that could be used prior to PCR, real-time PCR or MAMEF to increase sensitivity of detection of Salmonella. We tested ammonium chloride and erythrocyte lysis buffer, water, Lymphocyte Separation Medium, BD Vacutainer(®) CPT(™) Tubes and dextran. Erythrocyte lysis buffer was the best isolation method as it is fast, inexpensive and works with either fresh or stored blood. The sensitivity of PCR- and real-time PCR detection of Salmonella in spiked blood was improved when whole blood was first lysed using erythrocyte lysis buffer prior to DNA extraction. Removal of erythrocytes and clotting factors also enabled reproducible lysis of Salmonella and fragmentation of DNA, which are necessary for MAMEF sensing. Use of the erythrocyte lysis procedure prior to DNA extraction has enabled improved sensitivity of Salmonella detection by PCR and real-time PCR and has allowed lysis and fragmentation of Salmonella using microwave radiation (for future detection by MAMEF). Adaptation of the blood lysis method represents a fundamental breakthrough that improves the sensitivity of DNA-based detection of Salmonella in blood.


SP-8356, a (1S)-(-)-verbenone derivative, exerts in vitro and in vivo anti-breast cancer effects by inhibiting NF-κB signaling.
Breast cancer exhibits high lethality in women because it is frequently detected at an advanced stage and aggressive forms such as triple-negative breast cancer (TNBC), which are often characterized by metastasis through colonization of secondary tumors. Thus, developing therapeutic agents that target the metastatic process is crucial to successfully treat aggressive breast cancer. We evaluated SP-8356, an anti-inflammatory synthetic verbenone derivative, with respect to its regulation of breast cancer cell behavior and cancer progression. Treatment of SP-8356 arrested cell cycle and reduced growth in various types of breast cancer cells with mild cytotoxicity. Particularly, SP-8356 significantly reduced the motility and invasiveness of TNBC cells. Assays using an in vivo xenograft mouse model confirmed the cell-specific anti-proliferative and anti-metastatic activity of SP-8356. Functional studies revealed that SP-8356 suppressed serum response element-dependent reporter gene expression and NF-κB-related signaling, resulting in downregulation of many genes related to cancer invasion. We conclude that SP-8356 suppresses breast cancer progression through multimodal functions, including inhibition of NF-κB signaling and growth-related signaling pathways.


Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner.
The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent protection by febuxostat against LPS-induced lung inflammation in rats.


Decreases in dengue transmission may act to increase the incidence of dengue hemorrhagic fever.
Dengue hemorrhagic fever (DHF) is a potentially fatal manifestation of an infection with the mosquito-borne dengue virus. Because of the social and economic costs of DHF, many countries in Asia and South America have initiated public health measures aimed at vector control. Despite these measures, DHF incidence rates do not appear to be declining. The effectiveness of vector control in reducing dengue transmissibility has thereby been questioned. Here, we revisit this conclusion using epidemiological data from Thailand. We first show, with age incidence data, that dengue transmission rates have fallen since 1981; surprisingly, however, these declines are not associated with decreases in DHF incidence. Instead, district-level analyses indicate a nonmonotonic relationship between the basic reproductive number R0 and DHF incidence. To understand this relationship, we formulated three mathematical models, which differ in their assumptions of transient between-serotype cross-protection. Unlike the first two models, the previously unconsidered third model with clinical cross-protection can reproduce this nonmonotonic relationship. Simulation of this model with nonstationary R0 reproduces several previously unexplained patterns of dengue dynamics, including a transition from a approximately 2-year cycle to a approximately 4-year cycle and a transient trough in DHF incidence in provinces with rapid R0 declines. These results imply that DHF incidence can be effectively controlled with a sufficiently large reduction in R0 but that moderate reductions may be counterproductive. More broadly, these results show that assuming parameter stationarity in systems with approximate stationarity in disease incidence is unjustified and may result in missed opportunities to understand the drivers of disease variability.


Lithium: still a major option in the management of bipolar disorder.
Still after more than 50 years, lithium is a major treatment of bipolar disorder, even though it has not been promoted by the pharmaceutical industry over the last decades. In recent years the evidence base on lithium for bipolar disorder has substantially increased due to results from a number of trials. Therefore, a review of this evidence is timely. The efficacy of lithium as an acute treatment and as a maintenance treatment of bipolar disorder was evaluated through a review of the evidence, focusing on modern, randomized, parallel-group designed trials. Additionally, the evidence was sought translated into the proper use of lithium in clinical practice. Lithium's antimanic efficacy has been convincingly demonstrated. However, as blood monitoring due to the risk of toxicity is required and due to an insufficient response in highly agitated patients, lithium monotherapy has a limited place in the acute treatment of severe manic states. For acute bipolar depression, results are conflicting. Recent maintenance trials have added substantially to the documentation of lithium's long-term stabilizing properties in bipolar disorder, and these properties have been demonstrated independently of any acute response to lithium. Finally, it is now beyond doubt that not only does lithium prevent mania, but also depression in bipolar disorder. Lithium is still to be considered a major if not the most important mood- stabilizer, at least for maintaining long-term stability in patients with bipolar disorder. The potential risks of lithium should be weighed up against its benefits and the fact that serious adverse effects are usually avoidable.


Structural space of protein-protein interfaces is degenerate, close to complete, and highly connected.
At the heart of protein-protein interactions are protein-protein interfaces where the direct physical interactions occur. By developing and applying an efficient structural alignment method, we study the structural similarity of representative protein-protein interfaces involving interactions between dimers. Even without structural similarity between individual monomers that form dimeric complexes, ∼90% of native interfaces have a close structural neighbor with similar backbone C(α) geometry and interfacial contact pattern. About 80% of the interfaces form a dense network, where any two interfaces are structurally related using a transitive set of at most seven intermediate interfaces. The degeneracy of interface space is largely due to the packing of compact, hydrogen-bonded secondary structure elements. This packing generates relatively flat interacting surfaces whose geometries are highly degenerate. Comparative study of artificial and native interfaces argues that the library of protein interfaces is close to complete and comprised of roughly 1,000 distinct interface types. In contrast, the number of possible quaternary structures of dimers is estimated to be about 10(4) times larger; thus, an experimentally determined database of all representative quaternary structures is not likely in the near future. Nevertheless, one could in principle exploit the completeness of protein interfaces to predict most dimeric quaternary structures. Finally, our results provide a structural explanation for the prevalence of promiscuous protein interactions. By side-chain packing adjustments, we illustrate how multiprotein specificity can be attained at a promiscuous interface.


Human endothelial dysfunction: EDRFs.
Since the detection of nitric oxide two and a half decades ago, there has been an incredible boost in endothelial function research, which is fascinating the research community. Physiologically, endothelial cells synthesize a number of vasoactive substances. In particular, several endothelium-derived relaxing factors (EDRFs) have been characterized, whereby nitric oxide is the most important. In humans, endothelial dysfunction is one of the first clinically detectable alterations in the development of atherosclerosis and is characterized by an imbalance in the release of vasoactive substances. Thus, it is the aim of this article to give an overview about endothelial function in humans, to summarize the different possibilities to assess endothelial function in this species, and to give an overview of the role of EDRFs in different cardiovascular diseases.


Metabolic risk score and cancer risk: pooled analysis of seven cohorts.
There are few data on the joint influence of metabolic factors on risk of separate cancers. We analysed data on body mass index, blood pressure and plasma levels of glucose, total cholesterol and triglycerides from seven European cohorts comprising 564 596 men and women with a mean age of 44 years. We weighted those factors equally into a standardized metabolic risk score [MRS, mean = 0, standard deviation (SD) = 1], with an individual's level indicated as SDs from the sex- and cohort-specific means. Cancer hazard ratios were calculated by Cox regression with age as timescale and with relevant adjustments including smoking status. All statistical tests were two-sided. During a mean follow-up of 12 years, 21 593 men and 14 348 women were diagnosed with cancer. MRS was linearly and positively associated with incident cancer in total and at sites (P < 0.05). In men, risk per SD MRS was increased by 43% (95% confidence interval: 27-61) for renal cell cancer, 43% (16-76) for liver cancer, 29% (20-38) for colon cancer, 27% (5-54) for oesophageal cancer, 20% (9-31) for rectal cancer, 19% (4-37) for leukaemias, 15% (1-30) for oral cancer and 10% (2-19) for bladder cancer. In women, risk increases per SD MRS were 56% (42-70) for endometrial cancer, 53% (29-81) for pancreatic cancer, 40% (16-67) for renal cell cancer, 27% (9-47) for cervical cancer and 17% (3-32) for rectal cancer. This largest study to date on the joint influence of metabolic factors on risk of separate cancers showed increased risks for several cancers, in particular renal cell and liver cancer in men and endometrial and pancreatic cancer in women.


Regional Variations in Shear Strength and Density of the Human Thoracic Vertebral Endplate and Trabecular Bone.
Previous studies investigated the overall mechanical strength of the vertebral body; however, limited information is available on the biomechanical properties of different regions within the vertebral endplate and cancellous bone. In addition, the correlation between mechanical strength and various density measurements has not been studied yet. Thoracic (T10) vertebrae were harvested from fifteen human cadaveric spines (average age: 77 years old). Twelve cylindrical cores of 7.2 mm (diameter) by 3.2 mm (height) were prepared from each vertebral body. Shear was produced using a stainless steel tubular blade and measured with a load cell from a mechanical testing machine. Optical and bulk densities were calculated before mechanical testing. Apparent, material, and ash densities were measured after testing. Material density and shear strength increased from anterior to lateral regions of both endplate and cancellous bone. Endplate shear strength was significantly lower in the anterior (0.52 ± 0.08 MPa) than in the lateral region (2.72 ± 0.59 MPa) (p=0.017). Trabecular bone maximum load carrying capacity was 5 times higher in the lateral (12 ± 2.74 N) (p=0.09) and 4.5 times higher in the central (10 ± 2.24 N) (p=0.2) than in the anterior (2 ± 0.60 N) regions. Mechanical strength positively correlated with ash density, and even moreso with material density. Shear strength was the lowest at the anterior region and highest at the lateral region for both endplate and cancellous bone. Material density had the best correlation with mechanical strength. Newer spinal implants could optimize the loading in the lateral aspects of both endplate and cancellous bone to reduce the likelihood of screw loosening and the subsidence of disc replacement devices. This study was reviewed by the SUNY Downstate Medical Center IRB Committee; IRB#: 533603-2.


Treatment of cows with parturient paresis using intravenous calcium and oral sodium phosphate.
The goal of this study was to investigate whether intravenous infusion of 1000 ml 40% calcium borogluconate combined with the oral adminstration of 500 g sodium phosphate leads to a better cure rate and longer-lasting normocalcaemia and normophosphataemia than standard intravenous treatment with 500 ml calcium borogluconate in cows with parturient paresis. Forty recumbent cows with hypocalcaemia and hypophosphataemia were alternately allocated to group A or B. Cows of both groups were treated intravenously with 500 ml 40% calcium borogluconate, and cows of group B additionally received another 500 ml calcium borogluconate via slow intravenous infusion and 500 g sodium phosphate administered via an orogastric tube. Thirty-two cows stood within 8 hours after the start of treatment and 8 did not; of the 32 cows that stood, 18 belonged to group A and 14 to group B (90% of group A vs. 70% of group B; P = 0.23). Seven cows relapsed; of these and the 8 that did not respond to initial treatment, 10 stood after two standard intravenous treatments. Downer cow syndrome occurred in 5 cows, 3 of which recovered after aggressive therapy. The overall cure rate did not differ significantly between groups A and B. Twelve (60%) cows of group A and 14 (70%) cows of group B were cured after a single treatment and of the remaining 14, 11 were cured after two or more treatments. Two downer cows were euthanized and one other died of heart failure during treatment. Serum calcium concentrations during the first eight hours after the start of treatment were significantly higher in group B than in group A, and oral sodium phosphate caused a significant and lasting increase in inorganic phosphate. More cows of group B than group A were cured after a single treatment (P > 0.05). These findings, although not statistically significant, are promising and should be verified using a larger number of cows.


Lasing within Live Cells Containing Intracellular Optical Microresonators for Barcode-Type Cell Tagging and Tracking.
We report on a laser that is fully embedded within a single live cell. By harnessing natural endocytosis of the cell, we introduce a fluorescent whispering gallery mode (WGM) microresonator into the cell cytoplasm. On pumping with nanojoule light pulses, green laser emission is generated inside the cells. Our approach can be applied to different cell types, and cells with microresonators remain viable for weeks under standard conditions. The characteristics of the lasing spectrum provide each cell with a barcode-type label which enables uniquely identifying and tracking individual migrating cells. Self-sustained lasing from cells paves the way to new forms of cell tracking, intracellular sensing, and adaptive imaging.


T7 early RNAs and Escherichia coli ribosomal RNAs are cut from large precursor RNAs in vivo by ribonuclease 3.
The early region of T7 DNA is transcribed as a single unit in a Ribonuclease III-deficient E. coli strain to produce large molecules essentially identical to those produced in vitro by E. coli RNA polymerase. As with the in vitro RNAs, these molecules are cut by purified RNase III in vitro to produce the messenger RNAs normally observed in vivo. Thus, the normal pathway for producing the T7 early messenger RNAs in vivo appears to involve endonucleolytic cleavage by RNase III. The uninfected RNase III-deficient strain contains several RNAs not observed in the parent strain. Patterns of labeling in vivo suggest that the largest of these RNAs, about 1.8 x 10(6) daltons, may be a precursor to the 16S and 23S ribosomal RNAs. When this large molecule is treated in vitro with purified RNase III, molecules the size of precursor 16S and 23S ribosomal RNAs are released; hybridization competition experiments also indicate that the 1.8 x 10(6) dalton RNA does indeed represent ribosomal RNA. Thus, RNase III cleavage seems to be part of the normal pathway for producing at least the 16S and 23S ribosomal RNAs in vivo. Several smaller molecules are also released from the 1.8 x 10(6) dalton RNA by RNase III, but it is not yet established whether any of these contain 5S RNA sequences.


Selective on-line extraction of trans-resveratrol and emodin from Polygonum cuspidatum using molecularly imprinted polymer.
High-performance liquid chromatographic separation is performed to extract active components from the traditional Chinese medicine Polygonum cuspidatum using a trans-resveratrol imprinted polymer. Good separation and purification of trans-resveratrol and emodin from the Polygonum cuspidatum extract are achieved after condition optimization. The extraction recoveries are 83% and 99% for trans-resveratol and emodin, respectively. The results show that the molecularly imprinted polymer can be used as a selective extraction material for the extraction and purification of trans-resveratrol and emodin from Polygonum cuspidatum.


Richardson-Lucy deconvolution as a general tool for combining images with complementary strengths.
We use Richardson-Lucy (RL) deconvolution to combine multiple images of a simulated object into a single image in the context of modern fluorescence microscopy techniques. RL deconvolution can merge images with very different point-spread functions, such as in multiview light-sheet microscopes,1, 2 while preserving the best resolution information present in each image. We show that RL deconvolution is also easily applied to merge high-resolution, high-noise images with low-resolution, low-noise images, relevant when complementing conventional microscopy with localization microscopy. We also use RL deconvolution to merge images produced by different simulated illumination patterns, relevant to structured illumination microscopy (SIM)3, 4 and image scanning microscopy (ISM). The quality of our ISM reconstructions is at least as good as reconstructions using standard inversion algorithms for ISM data, but our method follows a simpler recipe that requires no mathematical insight. Finally, we apply RL deconvolution to merge a series of ten images with varying signal and resolution levels. This combination is relevant to gated stimulated-emission depletion (STED) microscopy, and shows that merges of high-quality images are possible even in cases for which a non-iterative inversion algorithm is unknown.


"I know I have arthritis but I don't know what type". Understanding and knowledge of this chronic condition.
"Arthritis" is a common musculoskeletal condition but the knowledge of what type of arthritis people have, may be limited but may have changed over time in response to campaigns, increased awareness and improved health literacy. This paper describes people who did not know what type of arthritis they had, by a range of relevant demographic and socioeconomic variables, and assesses changes over time in the proportion of people who report having arthritis but do not know what type, using representative population surveillance data. Data were collected using the South Australian Monitoring and Surveillance System (SAMSS), a risk factor surveillance system where each month, a representative random sample of South Australians is selected from the Electronic White Pages, with interviews conducted using computer assisted telephone interviewing (CATI). Data were used for the period January 2006 to December 2008 (n = 16465) for respondents aged 18 years and over. Overall, the proportion of respondents who did not know what type of arthritis they had, among people aged 18 years and over, for 2006 to 2008 was 6.5% (95% CI 6.1-6.9). When considering only those respondents reporting that they had been told by a doctor that they had arthritis, 30.1% did not know what type of arthritis they had. Multivariate analysis indicated that males, those with have a trade, certificate or diploma or secondary level of education, who spoke a language other than English at home, were widowed and earned $20,001 to $60,000, more than $80,000 or did not state their income were more likely to maintain that they did not know what type of arthritis they had. Population ageing and an increase in arthritis prevalence in the future will further increase the burden of arthritis. These increases in prevalence are not inevitable, especially if investments are made in public health prevention programs, particularly those addressing cultural and linguistic diversity and differences in socio-economic status and health literacy.


Gestational diabetes mellitus.
Gestational diabetes mellitus (GDM) is defined as glucose intolerance of various degrees that is first detected during pregnancy. GDM is detected through the screening of pregnant women for clinical risk factors and, among at-risk women, testing for abnormal glucose tolerance that is usually, but not invariably, mild and asymptomatic. GDM appears to result from the same broad spectrum of physiological and genetic abnormalities that characterize diabetes outside of pregnancy. Indeed, women with GDM are at high risk for having or developing diabetes when they are not pregnant. Thus, GDM provides a unique opportunity to study the early pathogenesis of diabetes and to develop interventions to prevent the disease.


Therapeutic options for herpes labialis: experimental and natural therapies.
Herpes labialis, a common condition characterized by recurrent vesicular eruptions primarily on the lips and perioral skin, causes pain and discomfort for millions of adults each year. Over the past several years, the major focus of herpes research has been on the treatment of genital herpes. However, several studies have been conducted to evaluate the efficacy of therapies specifically for herpes labialis. Last year in Cutis, we reviewed oral and topical therapies for herpes labialis. In this final part of the series, we review experimental and natural treatments that are available for herpes labialis and its associated symptoms.


Visual and clinical outcomes of explantation versus preservation of the intraocular lens during keratoprosthesis implantation.
To compare the short-term visual and clinical outcomes of explantation versus preservation of a posterior chamber intraocular lens (PC IOL) during keratoprosthesis implantation. Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA. Comparative case series. This study comprised patients who had implantation of an aphakic or a pseudophakic Boston type I keratoprosthesis based on their lenticular status. Only adult patients who were pseudophakic with a PC IOL at the time of surgery and who had at least 1 year of follow-up were included. The postoperative refractive error, uncorrected and corrected visual acuities, and intraoperative and postoperative complications were analyzed. Fifteen patients with an unstable PC IOL had aphakic keratoprosthesis implantation with IOL explantation, and 10 patients had implantation of a pseudophakic keratoprosthesis. The postoperative best-ever visual acuity and magnitude of visual acuity improvement were comparable in the 2 groups. The mean postoperative spherical equivalent refractive error was significantly better in the aphakic group (-0.66 diopter [D] ± 1.59 [SD]) than in the pseudophakic group (-3.25 ± 3.20 D) (P=.04). The rate of postoperative complications in the 2 groups was low (P>.05). In this small short-term study, refractive outcomes were better in aphakic patients than in patients who were left pseudophakic. Although not frequent, posterior segment complications after IOL explantation might necessitate further surgeries and cause decreased visual acuity during long-term follow-up in the aphakic group.


Generation of polarization squeezing with periodically poled KTP at 1064 nm.
We report the experimental demonstration of directly produced polarization squeezing at 1064 nm from a type I optical parametric amplifier (OPA) based on a periodically poled KTP crystal (PPKTP). The orthogonal polarization modes of the polarization squeezed state are both defined by the OPA cavity mode, and the birefringence induced by the PPKTP crystal is compensated by a second, but inactive, PPKTP crystal. Stokes parameter squeezing of 3.6 dB and anti squeezing of 9.4 dB is observed.


Inclusivity of Persons With Disabilities in the Work Sector During the Covid-19 Pandemic in Indonesia.
The COVID-19 pandemic has had a significant impact on all levels of society, including people with disabilities, who in the pre-pandemic period faced obstacles in various sectors of life that affected efforts to fulfill basic living needs due to difficulties in accessing employment. The objective of this study was to identify various factors and causal interaction patterns that affect the inclusiveness of workers with disabilities in pandemic situations, a dynamic system is needed to capture causal interaction patterns related to the inclusiveness of workers with disabilities in pandemic situations. This study used a causal loop diagram approach, which is part of a dynamic system that begins with determining the interaction of causal variables. The process of identifying and extracting data was carried out through a literature review and in-depth interviews with informants who met the principles of appropriateness and adequacy criteria. The interaction pattern between the factors that influence the inclusiveness of disabled workers was depicted in three causal loop diagrams covering three major domains, namely social, educational, and economic aspects. The three causal loop diagrams showed an increasingly dynamic interaction pattern during the COVID-19 pandemic, considering that workers with disabilities have greater vulnerability, which impacts their level of acceptance and inclusiveness at work. There needs to be a specific policy to expand the acceptance of workers with disabilities by strengthening cross-sectoral collaboration and company commitments. The existence of a policy that prioritizes education, increases the budget, and procures adequate infrastructure for people with disabilities is a government commitment that is demanded to be fulfilled during the COVID-19 pandemic.


UCLA anatomic total shoulder arthroplasty.
The UCLA total shoulder arthroplasty was designed to mobilize the shoulder joint in order to permit normal anthropometric range of motion and durable long-term fixation of the components. The prosthesis is fundamentally nonconstrained for the usual arthritic conditions, currently with four sizes of femoral and glenoid components. For patients with deficient and irreparable rotator cuffs, additional restraint may be effected by using a superior glenoid subacromial rim. The first 11 patients have been followed for 1 1/2 to 3 1/2-years; relief of pain has been complete in all but two patients. The function and range of motion results were related to the status of the rotator cuff; five patients achieved excellent results, including two with osteoarthritis who had near normal function. Patients with deficient rotator cuffs achieved functional use of the extremity but without full range of motion. Functionally, in addition to the five patients who were rated excellent, two were rated as being good, three fair, and one poor. In addition to five with excellent range of motion, there were three good and four fair ratings. Two patients, one with grossly deficient musculature caused by a gunshot wound and a second who was posttrauma required revision surgery with a subacromial glenoid prosthesis. This prosthesis is now frequently utilized if muscles and rotator cuff are deficient at the primary surgery, in order to provide additional restraint. Determination of the efficacy of hooded components will require further follow-up. The additional size ranges and components together with improved instrumentation have greatly facilitated recent surgery.


Resident-performed selective laser trabeculoplasty in patients with open-angle glaucoma.
IMPORTANCE To our knowledge, this is the first study to investigate effectiveness and complication rates of resident-performed selective laser trabeculoplasty (SLT). OBJECTIVES To evaluate the effectiveness and complications of SLT performed by resident ophthalmologists and to identify predictors for success. DESIGN, SETTING, AND PARTICIPANTS Retrospective case series of 81 patients with open-angle glaucoma undergoing 110 SLT procedures from November 17, 2009, through December 16, 2011, at the San Francisco Veterans Affairs Medical Center. INTERVENTION Resident-performed SLT. MAIN OUTCOMES AND MEASURES Intraocular pressure (IOP) reduction. Secondary outcomes included change in eyedrop medications, complication rates, and predictors of SLT success defined as a 20% reduction in IOP. RESULTS The mean IOP at baseline, defined as the average IOP of the 2 appointments prior to the SLT procedure, was 18.7 mm Hg. The mean decrease in postoperative IOP compared with baseline was 2.2 mm Hg (12%; 95% CI, 5%-19%) at 12 months and 3.3 mm Hg (18%; 95% CI, 13%-23%), 2.8 mm Hg (15%; 95% CI, 10%-21%), and 3.6 mm Hg (19%; 95% CI, 11%-27%) at 3, 6, and 24 months, respectively (all P < .001, linear mixed-effects regression). Success rates were 36% (95% CI, 27%-47%) at 12 months and 41% (95% CI, 31%-53%), 50% (95% CI, 40%-60%), and 39% (95% CI, 26%-53%) at 3, 6, and 24 months, respectively. The most common complication was a temporary IOP spike, with increases of at least 6 mm Hg occurring in 7% (95% CI, 4%-14%) of the population. The largest IOP spike was 11 mm Hg. Increased number of laser shots performed was not associated with better IOP control but was associated with a reduction in number of eyedrop medications (P = .02). Increased baseline IOP was associated with an odds ratio for success of 1.24 (95% CI, 1.08-1.44) at 3 months, 1.20 (95% CI, 1.05-1.37) at 6 months, and 1.31 (95% CI, 1.13-1.53) at 12 months of follow-up (P = .003, P = .006, and P < .001, respectively, logistic regression). In a multivariate analysis, baseline IOP remained the greatest predictor of effectiveness. CONCLUSIONS AND RELEVANCE Resident-performed SLT obtains outcomes similar to the IOP reduction reported in the literature for attending-performed SLT with low levels of complications. Increasing the number of shots in a treatment session may lead to less long-term need for eyedrop medications. In this patient group, higher baseline IOP was the strongest predictor of treatment effectiveness.


Enzyme-mediated hydrogel encapsulation of single cells for high-throughput screening and directed evolution of oxidoreductases.
Directed evolution of oxidoreductases to improve their catalytic properties is being ardently pursued in the industrial, biotechnological, and biopharma sectors. Hampering this pursuit are current enzyme screening methods that are limited in terms of throughput, cost, time, and complexity. We present a directed evolution strategy that allows for large-scale one-pot screening of glucose oxidase (GOx) enzyme libraries in well-mixed homogeneous solution. We used GOx variants displayed on the outer cell wall of yeasts to initiate a cascade reaction with horseradish peroxidase (HRP), resulting in peroxidase-mediated phenol cross-coupling and encapsulation of individual cells in well-defined fluorescent alginate hydrogel shells within ~10 min in mixed cell suspensions. Following application of denaturing stress to whole-cell GOx libraries, only cells displaying GOx variants with enhanced stability or catalytic activity were able to carry out the hydrogel encapsulation reaction. Fluorescence-activated cell sorting was then used to isolate the enhanced variants. We characterized three of the newly evolved Aspergillus niger GOx enzyme sequences and found up to ~5-fold higher specific activity, enhanced thermal stability, and differentiable glycosylation patterns. By coupling intracellular gene expression with the rapid formation of an extracellular hydrogel capsule, our system improves high-throughput screening for directed evolution of H 2 O 2 -producing enzymes many folds.


Stokes phenomena in discrete Painlevé I.
In this study, we consider the asymptotic behaviour of the first discrete Painlevé equation in the limit as the independent variable becomes large. Using an asymptotic series expansion, we identify two types of solutions which are pole-free within some sector of the complex plane containing the positive real axis. Using exponential asymptotic techniques, we determine Stokes phenomena effects present within these solutions, and hence the regions in which the asymptotic series expression is valid. From a careful analysis of the switching behaviour across Stokes lines, we find that the first type of solution is uniquely defined, while the second type contains two free parameters, and that the region of validity may be extended for appropriate choice of these parameters.


The long-term effects of institutional rearing, foster care intervention and disruptions in care on brain electrical activity in adolescence.
Exposure to early psychosocial deprivation as a result of institutional care disrupts typical brain development. The Bucharest Early Intervention Project (BEIP) is the first longitudinal study to investigate the neurodevelopment of institutionalized infants randomized to a foster care (FCG) intervention versus care as usual (CAUG). Here, we present findings from a follow-up assessment of brain electrical activity as indexed by resting EEG at age 16 years. In addition, we examined the effects of disruption of foster care placement (e.g. the number of moves among foster care placements) on brain electrical activity. Resting-state EEG was collected from 48 CAUG, 46 FCG and 48 never institutionalized (NIG) control participants. Absolute (µV2 ) and relative (proportion) power were computed from eyes closed, resting EEG data for theta, alpha and beta frequency bands. The CAUG displayed higher relative theta and lower relative alpha power compared to the FCG at 16 years of age. The FCG showed brain activity comparable to the NIG. The results further showed that disruptions following the original foster care placement had an adverse effect on brain electrical activity. Within the foster care group, there were no effects of age of placement on EEG power. Placement of children who have experienced early institutional rearing into stable foster care settings ensure long-term improvement in brain functioning.