Frozen-thawed embryo transfer in a natural or mildly hormonally stimulated cycle in women with regular ovulatory cycles: a RCT.
Can ovarian stimulation with low dose hMG improve the implantation rate (IR) per frozen-thawed embryo transferred (FET) when compared with natural cycle in an FET programme in women with a regular ovulatory cycle? Both IR and live birth rate (LBR) per FET were similar in the group with mild ovarian stimulation and the natural cycle group. Different cycle regimens for endometrial preparation are used prior to FET: spontaneous ovulatory cycles, cycles with artificial endometrial preparation using estrogen and progesterone hormones, and cycles stimulated with gonadotrophins or clomiphene citrate. At present, it is not clear which regimen results in the highest IR or LBR. More specifically, there are no RCTs in ovulatory women comparing reproductive outcome after FET during a natural cycle and during a hormonally stimulated cycle. A total of 410 women scheduled for FET during 579 cycles (December 2003-September 2013) were enrolled in an open-label RCT to natural cycle (NC FET group, n = 291) or to a cycle hormonally stimulated with s.c. gonadotrophins (hMG FET group, 37.5-75 IU per day, n = 288). A total of 672 embryos were transferred during 434 cycles (332 embryos and 213 cycles in the NC FET group; 340 embryos and 221 cycles in the hMG FET group). Assuming a = 0.05 and 80% power, it was calculated that 219 frozen-thawed embryos were required for transfer in each group to demonstrate a difference of 10% in IR. Women were eligible according to the following inclusion criteria: regular ovulatory cycle, female age ≥21 years and ≤45 years, informed consent. FET cycles with preimplantation genetic screening were excluded. The primary outcome was IR per embryo transferred. Secondary outcomes included IR with fetal heart beat (FHB), LBR per embryo transferred and endometrial thickness on the day of hCG administration. Statistical analysis was by intention to treat and controlled for the presence of multiple measures, as eligible women could be randomized in more than one cycle. Chi-square and independent t-test were used to compare categorical and continuous variables. The relative risk (RR) was estimated using a Poisson model with log link. Hierarchical models with random intercepts for patient and cycle were considered to account for clustering of cycles within patients and of embryos within cycles. The primary outcome, IR per embryo transferred, was not statistically different between the NC FET group (41/332 (12.35%)) and in the hMG FET group (55/340 (16.18%)) (RR 1.3 (95% confidence interval (CI) 0.9-2.0), P = 0.19). Similarly, the secondary outcome, IR with FHB per embryo transferred, was 34/332 (10.24%) in the NC FET group and 48/340 (14.12%) in the hMG FET group (RR 1.4 (95% CI 0.9-2.1), P = 0.15). The LBR per embryo transferred was 32/332 (9.64%) in the NC FET group and 45/340 (13.24%) in the hMG FET group (RR 1.4 (95% CI 0.9-2.2), P = 0.17). Endometrial thickness was also similar in both groups [8.9 (95% CI 8.7-9.1) in the NC FET group and 8.9 (95% CI 8.7-9.1) in the hMG FET group]. The duration of the follicular phase was significantly shorter (P < 0.001) in the hMG FET group [13.7 days (95% CI 13.2-14.2)] than in the NC FET group [15.4 days (95% CI 14.8-15.9)]. Randomization of cycles instead of patients; open-label design; relatively long period of recruitment. Our observation that the IR per embryo transferred is not significantly increased after FET during natural or gonadotrophin stimulated cycle, suggests that the effect of mild hormonal stimulation with gonadotrophins is smaller than what was considered clinically relevant with respect to reproductive outcome after FET. These data suggest that endometrial receptivity is not relevantly improved, but also not impaired after hormonal stimulation with gonadotrophins. Since FET during a natural cycle is cheaper and more patient-friendly, we recommend this regimen as the treatment of choice for women with regular cycles undergoing FET. clinicaltrials.gov NCT00492934. 26 June 2007. 1 December 2003.


A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice.
Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RBhighCD4+ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.


The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4.
Ileal Crohn's disease (CD), a chronic mucosal inflammation, is characterized by two pertinent features: a specific decrease of Paneth cell-produced antimicrobial alpha-defensins and the presence of mucosal-adherent bacteria. A mutation in NOD2, the muramyl dipeptide recognition receptor, is found in some patients, which leads to an even more pronounced alpha-defensin decrease. However, the underlying mechanism remains unclear for the majority of patients. In this study, we report a reduced expression in ileal CD of the Wnt-signaling pathway transcription factor Tcf-4, a known regulator of Paneth cell differentiation and alpha-defensin expression. Within specimens, the levels of Tcf-4 mRNA showed a high degree of correlation with both HD5 and HD6 mRNA. The levels of Tcf-4 mRNA were decreased in patients with ileal disease irrespective of degree of inflammation, but were not decreased in colonic CD or ulcerative colitis. As a functional indicator of Tcf-4 protein, quantitative binding analysis with nuclear extracts from small intestine biopsies to a Tcf-4 high-affinity binding site in the HD-5 and HD-6 promoters showed significantly reduced activity in ileal CD. Furthermore, a causal link was shown in a murine Tcf-4 knockout model, where the comparably reduced expression of Tcf-4 in heterozygous (+/-) mice was sufficient to cause a significant decrease of both Paneth cell alpha-defensin levels and bacterial killing activity. Finally, the association between Paneth cell alpha-defensins and Tcf-4 was found to be independent of the NOD2 genotype. This new link established between a human inflammatory bowel disease and the Wnt pathway/Tcf-4 provides a novel mechanism for pathogenesis in patients with ileal CD.


Host and Microbial Tryptophan Metabolic Profiling in Multiple Sclerosis.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is associated with demyelination and neuronal loss. Over recent years, the immunological and neuronal effects of tryptophan (Trp) metabolites have been largely investigated, leading to the hypothesis that these compounds and the related enzymes are possibly involved in the pathophysiology of MS. Specifically, the kynurenine pathway of Trp metabolism is responsible for the synthesis of intermediate products with potential immunological and neuronal effects. More recently, Trp metabolites, originating also from the host microbiome, have been identified in MS, and it has been shown that they are differently regulated in MS patients. Here, we sought to discuss whether, in MS patients, a specific urinary signature of host/microbiome Trp metabolism can be potentially identified so as to select novel biomarkers and guide toward the identification of specific metabolic pathways as drug targets in MS.


Temporo-parietal brain activity as a longitudinal predictor of response to educational interventions among middle school struggling readers.
Spatiotemporal brain activation profiles were obtained from 27 middle school students experiencing difficulties in reading comprehension as well as word-level skills (RD) and 23 age- and IQ-matched non-reading impaired students during performance of an oral pseudoword reading task using Magnetoencephalography (MEG). Based on their scores on standardized reading fluency tests 1 year later, students with RD who showed significant improvement were classified as Adequate Responders (AR) whereas those not demonstrating such gains were classified as Inadequate Responders (IR). At baseline, activation profiles of the AR group featured increased activity in the left supramarginal and angular gyri, as well as in the superior and middle temporal gyri, bilaterally compared to IR. The degree of activity in these regions was a significant predictor of the amount of subsequent gains in reading fluency. These results extend previous functional brain imaging findings of beginning readers, suggesting that recruitment of brain areas that typically serve as key components of the brain circuit for reading is an important factor in determining response to intervention in older struggling readers.


Pilot ejection, parachute, and helicopter crash injuries.
USAF Pararescuemen (PJs) respond to downed aircrew as a fundamental mission for personnel recovery (PR), one of the Air Force's core functions. In addition to responding to these in Military settings, the PJs from the 212 Rescue Squadron routinely respond to small plane crashes in remote regions of Alaska. While there is a paucity of information on the latter, there have been articles detailing injuries sustained from helicopter crashes and while ejecting or parachuting from fixed wing aircraft. The following represents a new chapter added to the Pararescue Medical Operations Handbook, Sixth Edition (2014, editors Matt Wolf, MD, and Stephen Rush, MD, in press). It was designed to be a quick reference for PJs and their Special Operations flight surgeons to help with understanding of mechanism of injury with regard to pilot ejection, parachute, and helicopter accident injuries. It outlines the nature of the injuries sustained in such mishaps and provides an epidemiologic framework from which to approach the problem.


A hybrid metal artifact reduction algorithm for x-ray CT.
Presence of metal artifacts is a major reason of degradation of computed tomography image quality and there is still no standard solution to this issue. A class of recently investigated metal artifact reduction (MAR) methods based on forward projection of a prior image that is artifact-free to replace the metal affected projection data have shown promising results. However, usually it is hard to get a good prior image which is close to the true image without artifacts. This work aims at creating a good prior image so that the forward projection can replace the metal affected projection data well. The proposed method consists of four steps based on the forward projection MAR framework. First, metal implants in the reconstructed image are segmented and the corresponding metal traces in the projection domain are identified. Then the prior image is obtained by two steps. A processed precorrected image is generated as an initial prior image first and then in the next step it is used as the initial image of the iterative reconstruction from the unaffected projection data to generate a better prior image. In order to deal with severe artifacts, the iteration incorporates the total variation minimization constraint as well as a novel constraint which forces the soft tissue region near metal to be as flat as possible. Finally, the projection is completed using forward projection of the prior image and the corrected image is reconstructed by FBP. A linear interpolation MAR method and two recently reported forward projection based methods are performed simultaneously for comparison. The proposed method shows outstanding performance on both phantoms' and patients' datasets. This approach can reduce artifacts dramatically and restore tissue structures near metal to a large extent. Unlike competing MAR methods, it can effectively prevent introduction of new artifacts and false structures. Moreover, the proposed method has the lowest RMSE in regions of both soft tissue and bone tissue among the corrected images and is ranked as the best method for evaluation, by radiologists. Both subjective and quantitative evaluations of the results demonstrate the superior performance of the proposed algorithm, compared to that of the competing methods. This method offers a remarkable improvement of the image quality.


Expectations for consultations and antibiotics for respiratory tract infection in primary care: the RTI clinical iceberg.
Respiratory tract infection (RTI) is the commonest indication for community antibiotic prescriptions. Prescribing is rising and is influenced by patients' consulting behaviour and beliefs. To build up a profile of the 'RTI clinical iceberg' by exploring how the general public manage RTI, visit GPs and why. Two-phase qualitative and quantitative study in England. Qualitative interviews with 17 participants with acute RTI visiting pharmacies in England, and face-to-face questionnaire survey of 1767 adults ≥15 years in households in England during January 2011. Qualitative interviews: interviewees with RTI visited GPs if they considered their symptoms were prolonged, or severe enough to cause pain, or interfered with daily activities or sleep. Questionnaire: 58% reported having had an RTI in the previous 6 months, and 19.7% (95% CI = 16.8 to 22.9%) of these contacted or visited their GP surgery for this, most commonly because 'the symptoms were severe'; or 'after several days the symptoms hadn't improved'; 10.3% of those experiencing an RTI (or 53.1% of those contacting their GP about it) expected an antibiotic prescription. Responders were more likely to believe antibiotics would be effective for a cough with green rather than clear phlegm. Perceptions of side effects of antibiotics did not influence expectations for antibiotics. Almost all who reported asking for an antibiotic were prescribed one, but 25% did not finish them. One-fifth of those with an RTI contact their GP and most who ask for antibiotics are prescribed them. A better public understanding about the lack of benefit of antibiotics for most RTIs and addressing concerns about illness duration and severity, could reduce GP consultations and antibiotic prescriptions for RTI.


Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.
Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primary biliary cirrhosis (PBC). However, some patients show an incomplete response to UDCA therapy. Treatment with corticosteroids may be of benefit although at the expense of systemic side effects. Budesonide, a corticosteroid with an extensive first-pass hepatic metabolism appeared promising for the treatment of PBC. The aim of this study was to evaluate the safety and estimate the efficacy of budesonide in patients with PBC, who have shown a suboptimal response to UDCA. Twenty-two patients with PBC, 16 women, median age of 50 who had been on UDCA (13-15 mg/kg/d) for a mean of 46 months (range 6-108 months) and had shown a persistent elevation of alkaline phosphatase activity at least 2 times the upper limit of normal were enrolled. Oral budesonide, 9 mg daily was administered for 1 year and patients continued on the same dosage of UDCA. There was a significant, but transitory improvement in serum levels of total bilirubin (P =.001) and a significant, but marginal improvement in serum alkaline phsophatase (P =.001) with combination therapy. The Mayo risk score increased significantly (P =.02) and there was a significant loss of bone mass (P <.001) of the lumbar spine. Budesonide-induced hyperglycemia and cosmetic adverse effects were noted in 2 patients. In conclusion, oral budesonide appears to add minimal, if any, additional benefit to UDCA, and it is associated with a significant worsening of osteoporosis in patients with PBC.


Lymph node metastases and prognosis in patients with stage IA2 cervical cancer.
Ninety-four patients with squamous cell carcinoma invading the cervical stroma to a depth of >3.0-5.0 mm with 7 mm or less in horizontal spread (FIGO Stage IA2) were evaluated. Depth and lateral extent of stromal invasion were verified using an ocular micrometer. Cell type and lymph vascular space invasion (LVSI) were recorded in each case. Patients were treated primarily by radical hysterectomy with pelvic lymphadenectomy, and those with lymph node metastases were offered postoperative radiation. Following treatment, patients were seen at 3-month intervals for 2 years, and every 6 months thereafter. The mean duration of follow-up was 6.9 years (range 0.4-23.5 years). Seven of 94 patients (7.4%) had lymph node metastases. Five patients had 1 positive node, 1 patient had 2 positive nodes, and 1 patient had 3 positive nodes. Five patients developed recurrent cancer and 4 died of disease. LVSI was present in 31 cases (33%). Tumor recurrence was significantly increased in patients with positive LVSI (9.7% vs 3.2%). The 5-year survival rate of patients with LVSI was 89% vs 98% in patients without this finding (P = 0.058). The 5-year survival rate of all Stage IA2 cervical cancer patients was 95%. Patients with Stage IA2 cervical cancer have a significant risk of lymph node metastases and should be treated by radical hysterectomy with pelvic lymphadenectomy. LVSI is an important prognostic variable in these patients and should be recorded in all cases.


Spontaneous hypoglycemia associated with chronic renal failure--a preventable life-threatening complication.
Hypoglycemia has been reported in three non-diabetic uremic patients undergoing maintenance hemodialysis. There were one female and two males, ranging in age from 26 to 45 years. Only one hypoglycemic episode per patient was documented, and measured blood glucose levels were less than 1.1 mmol/L. Contributing factors of hypoglycemia in CRF patients were hepatic dysfunction, and drug side effects (isoniazid, rifampin and propranolol). The treatment of choice was intravenous hypertonic glucose administration. Proper nutrition, the judicious use of any medication that has the potential for inducing hypoglycemia, the early detection and treatment of associated diseases, and the use of dialysate fluid with glucose in hemodialysis patients can diminish the risks of this potentially lethal complication.


CNN-based lung CT registration with multiple anatomical constraints.
Deep-learning-based registration methods emerged as a fast alternative to conventional registration methods. However, these methods often still cannot achieve the same performance as conventional registration methods because they are either limited to small deformation or they fail to handle a superposition of large and small deformations without producing implausible deformation fields with foldings inside. In this paper, we identify important strategies of conventional registration methods for lung registration and successfully developed the deep-learning counterpart. We employ a Gaussian-pyramid-based multilevel framework that can solve the image registration optimization in a coarse-to-fine fashion. Furthermore, we prevent foldings of the deformation field and restrict the determinant of the Jacobian to physiologically meaningful values by combining a volume change penalty with a curvature regularizer in the loss function. Keypoint correspondences are integrated to focus on the alignment of smaller structures. We perform an extensive evaluation to assess the accuracy, the robustness, the plausibility of the estimated deformation fields, and the transferability of our registration approach. We show that it achieves state-of-the-art results on the COPDGene dataset compared to conventional registration method with much shorter execution time. In our experiments on the DIRLab exhale to inhale lung registration, we demonstrate substantial improvements (TRE below 1.2 mm) over other deep learning methods. Our algorithm is publicly available at https://grand-challenge.org/algorithms/deep-learning-based-ct-lung-registration/.


Assessing the mechanical properties of tissue-mimicking phantoms at different depths as an approach to measure biomechanical gradient of crystalline lens.
We demonstrate the feasibility of using the dominant frequency of the sample surface response to a mechanical stimulation as an effective indicator for sensing the depthwise distribution of elastic properties in transparent layered phantom samples simulating the cortex and nucleus of the crystalline lens. Focused ultrasound waves are used to noninvasively interrogate the sample surface. A phase-sensitive optical coherence tomography system is utilized to capture the surface dynamics over time with nanometer scale sensitivity. Spectral analysis is performed on the sample surface response to ultrasound stimulation and the dominant frequency is calculated under particular loading parameters. Pilot experiments were conducted on homogeneous and layered tissue-mimicking phantoms. Results indicate that the mechanical layers located at different depths introduce different frequencies to the sample surface response, which are correlated with the depth-dependent elasticity of the sample. The duration and the frequency of the ultrasound excitation are also investigated for their influences on this spectrum-based detection. This noninvasive method may be potentially applied for localized and rapid assessment of the depth dependence of the mechanical properties of the crystalline lens.


Antipneumococcal seroprevalence and pneumococcal carriage during a meningococcal epidemic in Burkina Faso, 2006.
To better understand the high incidence of pneumococcal meningitis in the African meningitis belt, we conducted a pneumococcal seroprevalence study during a meningococcal meningitis epidemic in Western Burkina Faso, March 2006. In 3 villages experiencing epidemics, we included 624 healthy persons (1-39 years) by cluster sampling. We determined pneumococcal serum immunoglobulin G (IgG) antibody concentrations against 12 serotypes contained in 13-valent pneumococcal conjugate vaccine, and evaluated determinants for IgG ≥ 0.35 μg/mL by multivariate logistic regression. The percentage of subjects with serotype-specific IgG concentrations ≥0.35 μg/mL increased with age and was similar for the different serotypes: it was 20%-43% among 1-4-year-olds and 56%-90% among 20-39-year-olds. Prevalence of IgG ≥ 0.35 μg/mL against serotype 1 was up to 71% after age 10 years. During multivariate analyses, determinants of IgG concentrations ≥0.35 μg/mL varied by serotype; for 5 and 6 serotypes, respectively, female sex (around 2-fold increased odds) and cigarette smoking (about 5-fold reduced odds) predicted elevated titers. Despite a substantially higher historical pneumococcal meningitis incidence in Burkina Faso, the general population has an antibody seroprevalence against 12 pneumococcal serotypes similar to that reported from the United Kingdom. The role of putatively protective antibody seroprevalence in preventing pneumococcal meningitis in the meningitis belt requires more thorough evaluation.


Effect of aqueous extract of neem (Azadirachta indica) leaves on offensive and diffensive gastric mucosal factors in rats.
Standardized aqueous extract of Neem (Azadirachta indica) leaves (AIE) has been reported to show both ulcer protective and ulcer healing effects in normal as well as in diabetic rats. To study the mechanism of its ulcer protective/healing actions, effects of AIE (500 mg/ kg) was studied on various parameters of offensive acid-pepsin secretion in 4 hr pylorus ligation, pentagastrin (PENTA, 5 microg/kg/hr)-stimulated acid secretion and gastric mucosal proton pump activity and defensive mucin secretion including life span of gastric mucosal cells in rats. AIE was found to inhibit acid-pepsin secretion in 4 hr pylorus ligated rats. Continuous infusion of PENTA significantly increased the acid secretion after 30 to 180 min or in the total 3 hr acid secretion in rat stomach perfusate while, AIE pretreatment significantly decreased them. AIE inhibited the rat gastric mucosal proton pump activity and the effect was comparable with that of omeprazole (OMZ). Further, AIE did not show any effect on mucin secretion though it enhanced life span of mucosal cells as evidenced by a decrease in cell shedding in the gastric juice. Thus, our present data suggest that the ulcer protective activity of AIE may be due to its anti-secretary and proton pump inhibitory activity rather than on defensive mucin secretion. Further, acute as well as sub acute toxicity studies have indicated no mortality with 2.5 g/kg dose of AIE in mice and no significant alterations in body or tissues weight, food and water intake, haematological profile and various liver and kidney function tests in rats when treated for 28 days with 1 g/kg dose of AIE.


Processing Temporal Growth Factor Patterns by an Epidermal Growth Factor Receptor Network Dynamically Established in Space.
The proto-oncogenic epidermal growth factor (EGF) receptor (EGFR) is a tyrosine kinase whose sensitivity and response to growth factor signals that vary over time and space determine cellular behavior within a developing tissue. The molecular reorganization of the receptors on the plasma membrane and the enzyme-kinetic mechanisms of phosphorylation are key determinants that couple growth factor binding to EGFR signaling. To enable signal initiation and termination while simultaneously accounting for suppression of aberrant signaling, a coordinated coupling of EGFR kinase and protein tyrosine phosphatase activity is established through space by vesicular dynamics. The dynamical operation mode of this network enables not only time-varying growth factor sensing but also adaptation of the response depending on cellular context. By connecting spatially coupled enzymatic kinase/phosphatase processes and the corresponding dynamical systems description of the EGFR network, we elaborate on the general principles necessary for processing complex growth factor signals.


Epidermal growth factor receptor cross-talks with ligand-occupied estrogen receptor-alpha to modulate both lactotroph proliferation and prolactin gene expression.
Both estrogen (E2) and EGF regulate lactotrophs, and we recently demonstrated that EGF phosphorylates S118 on estrogen receptor-alpha (ERalpha) and requires ERalpha to stimulate prolactin (PRL) release. However, the interactions between ligand-occupied ERalpha and activated ErbB1 and its impact on lactotroph function are unknown. Using rat GH3 lactotrophs, we found that both E2 and EGF independently stimulated proliferation and PRL gene expression. Furthermore, their combination resulted in an enhanced stimulatory effect on both cell proliferation and PRL gene expression. Inhibitors of ER as well as ErbB1 blocked the combined effects of E2 and EGF. Pretreatment with UO126 abolished the combined effects, demonstrating Erk1/2 requirement. Although bidirectionality in ER-ErbB1 cross-talk is a well-accepted paradigm, interestingly in lactotrophs, ErbB1 kinase inhibitor failed to block the effect of E2 on proliferation and stimulation of PRL gene expression, suggesting that ER does not require ErbB1 to mediate its effects. Furthermore, E2 did not affect the ability of EGF to induce c-Fos expression or modulate AP-1 activity. However, both E2 and EGF combine to enhance S118 phosphorylation of ERalpha, leading to enhanced E2-mediated estrogen response element transactivation. Taken together, our results suggest that, in lactotrophs, activated ErbB1 phosphorylates ERalpha to enhance the stimulatory effect of E2, thereby providing the molecular basis by which EGF amplifies the response of E2.


Fine-mapping and mutation analysis of TRPM1: a candidate gene for leopard complex (LP) spotting and congenital stationary night blindness in horses.
Leopard Complex spotting occurs in several breeds of horses and is caused by an incompletely dominant allele (LP). Homozygosity for LP is also associated with congenital stationary night blindness (CSNB) in Appaloosa horses. Previously, LP was mapped to a 6 cm region on ECA1 containing the candidate gene TRPM1 (Transient Receptor Potential Cation Channel, Subfamily M, Member 1) and decreased expression of this gene, measured by qRT-PCR, was identified as the likely cause of both spotting and ocular phenotypes. This study describes investigations for a mutation causing or associated with the Leopard Complex and CSNB phenotype in horses. Re-sequencing of the gene and associated splice sites within the 105 624 bp genomic region of TRPM1 led to the discovery of 18 SNPs. Most of the SNPs did not have a predictive value for the presence of LP. However, one SNP (ECA1:108,249,293 C>T) found within intron 11 had a strong (P < 0.0005), but not complete, association with LP and CSNB and thus is a good marker but unlikely to be causative. To further localize the association, 70 SNPs spanning over two Mb including the TRPM1 gene were genotyped in 192 horses from three different breeds segregating for LP. A single 173 kb haplotype associated with LP and CSNB (ECA1: 108,197,355- 108,370,150) was identified. Illumina sequencing of 300 kb surrounding this haplotype revealed 57 SNP variants. Based on their localization within expressed sequences or regions of high sequence conservation across mammals, six of these SNPs were considered to be the most likely candidate mutations. While the precise function of TRPM1 remains to be elucidated, this work solidifies its functional role in both pigmentation and night vision. Further, this work has identified several potential regulatory elements of the TRPM1 gene that should be investigated further in this and other species.


Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men.
Transdermal delivery of testosterone (T) represents an effective alternative to injectable androgens. Transdermal T patches normalize serum T levels and reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irritation and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the pharmacokinetic profiles after 1, 30, 90, and 180 days of daily application of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/day, respectively) and a permeation-enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel formulation when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 9-14% of the T applied was bioavailable. After 90 days of T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplication serum T levels were outside the normal adult male range. Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch application. Our previous study showed that steady state T levels were achieved 48-72 h after first application of the gel. The pharmacokinetic parameters for serum total and free T were very similar on days 30, 90, and 180 in all treatment groups. After repeated daily application of the T formulations for 180 days, the average serum T level over the 24-h sampling period (C(avg)) was highest in the 100 mg T gel group (1.4- and 1.9-fold higher than the C(avg) in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable over the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the C(avg), whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients. Serum free T levels paralleled those of serum total T, and the percent free T was not changed with transdermal T preparations. The serum dihydrotestosterone C(avg) rose 1.3-fold above baseline after T patch application, but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day, respectively, resulting in a small, but significant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed proportionately with serum T in all study groups; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate.


Risks and burdens of incident diabetes in long COVID: a cohort study.
There is growing evidence suggesting that beyond the acute phase of SARS-CoV-2 infection, people with COVID-19 could experience a wide range of post-acute sequelae, including diabetes. However, the risks and burdens of diabetes in the post-acute phase of the disease have not yet been comprehensively characterised. To address this knowledge gap, we aimed to examine the post-acute risk and burden of incident diabetes in people who survived the first 30 days of SARS-CoV-2 infection. In this cohort study, we used the national databases of the US Department of Veterans Affairs to build a cohort of 181 280 participants who had a positive COVID-19 test between March 1, 2020, and Sept 30, 2021, and survived the first 30 days of COVID-19; a contemporary control (n=4 118 441) that enrolled participants between March 1, 2020, and Sept 30, 2021; and a historical control (n=4 286 911) that enrolled participants between March 1, 2018, and Sept 30, 2019. Both control groups had no evidence of SARS-CoV-2 infection. Participants in all three comparison groups were free of diabetes before cohort entry and were followed up for a median of 352 days (IQR 245-406). We used inverse probability weighted survival analyses, including predefined and algorithmically selected high dimensional variables, to estimate post-acute COVID-19 risks of incident diabetes, antihyperglycaemic use, and a composite of the two outcomes. We reported two measures of risk: hazard ratio (HR) and burden per 1000 people at 12 months. In the post-acute phase of the disease, compared with the contemporary control group, people with COVID-19 exhibited an increased risk (HR 1·40, 95% CI 1·36-1·44) and excess burden (13·46, 95% CI 12·11-14·84, per 1000 people at 12 months) of incident diabetes; and an increased risk (1·85, 1·78-1·92) and excess burden (12·35, 11·36-13·38) of incident antihyperglycaemic use. Additionally, analyses to estimate the risk of a composite endpoint of incident diabetes or antihyperglycaemic use yielded a HR of 1·46 (95% CI 1·43-1·50) and an excess burden of 18·03 (95% CI 16·59-19·51) per 1000 people at 12 months. Risks and burdens of post-acute outcomes increased in a graded fashion according to the severity of the acute phase of COVID-19 (whether patients were non-hospitalised, hospitalised, or admitted to intensive care). All the results were consistent in analyses using the historical control as the reference category. In the post-acute phase, we report increased risks and 12-month burdens of incident diabetes and antihyperglycaemic use in people with COVID-19 compared with a contemporary control group of people who were enrolled during the same period and had not contracted SARS-CoV-2, and a historical control group from a pre-pandemic era. Post-acute COVID-19 care should involve identification and management of diabetes. US Department of Veterans Affairs and the American Society of Nephrology.


Discriminative stimulus effects of cocaine in squirrel monkeys: involvement of dopamine receptor subtypes.
The involvement of dopamine (DA) receptor subtypes in the discriminative stimulus effects of cocaine was investigated in squirrel monkeys trained to discriminate cocaine from vehicle using a two-lever choice procedure. Lever pressing was maintained under a 10-response fixed-ratio schedule of food presentation. In substitution tests, (-)-cocaine and its high-affinity analogs 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) and 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (CCT) engendered dose-related increases in the proportion of cocaine-appropriate responses. Full (97-100%) substitution for the training dose of cocaine was observed with all three drugs, the rank order of potency being: CCT greater than CFT greater than cocaine. DA agonists differing in selectivity for D1 and D2 receptor subtypes [6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 81297), 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3- benzazepine (SKF 82958), (+)-4-propyl-9-hydroxynapthoxazine [(+)-PHNO], quinpirole, quinelorane, (-)-4,6,6a,7,8,-12b-hexahydro-7-methyl-indolo[4,3-ab]phen ant hridine (CY 208-243) and (-)-apomorphine] also engendered dose-related increases in cocaine-appropriate responses. However, maximally effective doses of these drugs occasioned an average of only 54 to 77% responses on the cocaine-associated lever and markedly reduced response rates. Combinations of the D1 agonist SKF 81297 and the D2 agonist (+)-PHNO did not engender a consistently higher proportion of cocaine-appropriate responses than did either drug alone.(ABSTRACT TRUNCATED AT 250 WORDS)


High-resolution MR imaging of the orbit in patients with retinoblastoma.
Retinoblastoma is the most common intraocular childhood malignancy, with a prevalence of one in 18,000 children younger than 5 years old in the United States. In 80% of patients, retinoblastoma is diagnosed before the age of three, and in 95% of patients, retinoblastoma is diagnosed before the age of five. Although reports exist of retinoblastoma in adults, onset beyond 6 years of age is rare. Broadly, retinoblastoma may be classified into two groups: sporadic and heritable. In either case, the origin of the tumor is a biallelic mutation in primitive neuroepithelial cells. Although their details vary, several staging schemes are used to describe the extent of retinoblastoma according to the following four general criteria: intraocular location, extraocular (extraorbital) location, central nervous system disease, and systemic metastases. In the past decade, substantial changes have taken place in terms of staging and monitoring treatment in patients with retinoblastoma. Diagnosis and treatment of retinoblastoma involve a multidisciplinary approach, for which imaging is a vital component. Increasing awareness and concerns about the effects of radiation in patients with retinoblastoma have led to a shift away from external-beam radiation therapy and toward chemotherapy and locoregional treatment, as well as the establishment of magnetic resonance imaging as the most important imaging modality for diagnosis, staging, and treatment monitoring.


The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.
Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.


The impact of concentration and administration time on the radiomodulating properties of undecylprodigiosin in vitro.
Undecylprodigiosin pigment (UPP) is reported to display cytotoxic activity towards various types of tumours. Nevertheless, its efficacy in modifying the cellular response to ionising radiation is still unknown. In this study, the radiomodulating effects of UPP were investigated. The effects of UPP were assessed in vitro by treating cultures of human peripheral blood with UPP and ionising radiation using two treatment regimens, the UPP pre-irradiation treatment and UPP post-irradiation treatment. The activity of UPP was investigated evaluating its effects on the radiation-induced micronuclei formation, cell proliferation, and induction of apoptosis. The redox modulating effects of UPP were examined measuring the catalase activity and the level of malondialdehyde, as a measure of oxidative stress. The results showed that UPP effects on cellular response to ionising radiation depend on its concentration and the timing of its administration. At low concentration, the UPP displayed radioprotective effects in γ-irradiated human lymphocytes while at higher concentrations, it acted as a radiosensitiser enhancing either mitotic catastrophe or apoptosis depending on the treatment regimen. The UPP modified redox processes in cells, particularly when it was employed prior to γ-irradiation. Our data highlight the importance of further research of the potential of UPP to sensitize tumour cells to radiation therapy by inhibiting pathways that lead to treatment resistance.


Docosahexaenoic and eicosapentaenoic acids increase prion formation in neuronal cells.
The transmissible spongiform encephalopathies, otherwise known as prion diseases, occur following the conversion of the cellular prion protein (PrPC) to an alternatively folded, disease-associated isoform (PrPSc). Recent studies suggest that this conversion occurs via a cholesterol-sensitive process, as cholesterol synthesis inhibitors reduced the formation of PrPSc and delayed the clinical phase of scrapie infection. Since polyunsaturated fatty acids also reduced cellular cholesterol levels we tested their effects on PrPSc formation in three prion-infected neuronal cell lines (ScGT1, ScN2a and SMB cells). We report that treatment with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) or the cholesterol synthesis inhibitor simvastatin reduced the amounts of free cholesterol in membrane extracts from prion-infected neuronal cells. Simvastatin reduced cholesterol production while DHA and EPA promoted the conversion of free cholesterol to cholesterol esters. Crucially, while simvastatin reduced PrPSc formation, both DHA and EPA significantly increased the amounts of PrPSc in these cells. Unlike simvastatin, the effects of DHA and EPA on PrPSc content were not reversed by stimulation of cholesterol synthesis with mevalonate. Treatment of ScGT1 cells with DHA and EPA also increased activation of cytoplasmic phospholipase A2 and prostaglandin E2 production. Finally, treatment of neuronal cells with DHA and EPA increased the amounts of PrPC expressed at the cell surface and significantly increased the half-life of biotinylated PrPC. We report that although treatment with DHA or EPA significantly reduced the free cholesterol content of prion-infected cells they significantly increased PrPSc formation in three neuronal cell lines. DHA or EPA treatment of infected cells increased activation of phospholipase A2, a key enzyme in PrPSc formation, and altered the trafficking of PrPC. PrPC expression at the cell surface, a putative site for the PrPSc formation, was significantly increased, and the rate at which PrPC was degraded was reduced. Cholesterol depletion is seen as a potential therapeutic strategy for prion diseases. However, these results indicate that a greater understanding of the precise relationship between membrane cholesterol distribution, PrPC trafficking, cell activation and PrPSc formation is required before cholesterol manipulation can be considered as a prion therapeutic.


The ABSCISIC ACID-INSENSITIVE3, FUSCA3, and LEAFY COTYLEDON1 loci act in concert to control multiple aspects of Arabidopsis seed development.
Previous studies have shown that recessive mutations at the Arabidopsis ABSCISIC ACID-INSENSITIVE3 (ABI3), FUSCA3 (FUS3), and LEAFY COTYLEDON1 (LEC1) loci lead to various abnormalities during mid-embryogenesis and late embryogenesis. In this study, we investigated whether these loci act in independent regulatory pathways or interact in controlling certain facets of seed development. Several developmental responses were quantified in abi3, fus3, and lec1 single mutants as well as in double mutants combining either the weak abi3-1 or the severe abi3-4 mutations with either fus3 or lec1 mutations. Our data indicate that ABI3 interacts genetically with both FUS3 and LEC1 in controlling each of the elementary processes analyzed, namely, accumulation of chlorophyll and anthocyanins, sensitivity to abscisic acid, and expression of individual members of the 12S storage protein gene family. In addition, both FUS3 and LEC1 regulate positively the abundance of the ABI3 protein in the seed. These results suggest that in contrast to previous models, the ABI3, FUS3, and LEC1 genes act synergistically to control multiple elementary processes during seed development.


Implicit gender stereotyping in judgments of fame.
Implicit (unconscious) gender stereotyping in fame judgments was tested with an adaptation of a procedure developed by L. L. Jacoby, C. M. Kelley, J. Brown, and J. Jasechko (1989). In Experiments 1-4, participants pronounced 72 names of famous and nonfamous men and women, and 24 or 48 hr later made fame judgments in response to the 72 familiar and 72 unfamiliar famous and nonfamous names. These first experiments, in which signal detection analysis was used to assess implicit stereotypes, demonstrate that the gender bias (greater assignment of fame to male than female names) was located in the use of a lower criterion (beta) for judging fame of familiar male than female names. Experiments 3 and 4 also showed that explicit expressions of sexism or stereotypes were uncorrelated with the observed implicit gender bias in fame judgments.


Editors' Review and Introduction: Learning Grammatical Structures: Developmental, Cross-Species, and Computational Approaches.
Human languages all have a grammar, that is, rules that determine how symbols in a language can be combined to create complex meaningful expressions. Despite decades of research, the evolutionary, developmental, cognitive, and computational bases of grammatical abilities are still not fully understood. "Artificial Grammar Learning" (AGL) studies provide important insights into how rules and structured sequences are learned, the relevance of these processes to language in humans, and whether the cognitive systems involved are shared with other animals. AGL tasks can be used to study how human adults, infants, animals, or machines learn artificial grammars of various sorts, consisting of rules defined typically over syllables, sounds, or visual items. In this introduction, we distill some lessons from the nine other papers in this special issue, which review the advances made from this growing body of literature. We provide a critical synthesis, identify the questions that remain open, and recognize the challenges that lie ahead. A key observation across the disciplines is that the limits of human, animal, and machine capabilities have yet to be found. Thus, this interdisciplinary area of research firmly rooted in the cognitive sciences has unearthed exciting new questions and venues for research, along the way fostering impactful collaborations between traditionally disconnected disciplines that are breaking scientific ground.


Mind-body techniques, race-ethnicity, and depression among urban senior center participants.
As the older adult population grows and becomes more diverse, more of its members are turning to complementary and alternative medicine (CAM). There are mixed findings regarding racial and ethnic differences in the use of CAM. This article explores racial and ethnic differences in use of a category of CAM known as mind-body techniques (MBT) among senior center participants with symptoms of depression. It also examines the relationship between use of MBT and depression severity. A cross-sectional survey was conducted with a representative sample of senior center participants in New York City, from which a subsample of those with depressive symptoms was drawn. Racial and ethnic differences in MBT use were identified, as was a significant negative relationship between MBT use and depression severity. African American elders were more likely to have used MBT than other racial or ethnic groups. When controlling for race or ethnicity, health status, and barriers to medical care, predictors of depression severity included health status, experiencing barriers to medical care, and Hispanic identity. Findings suggest that being female or younger is associated with a higher likelihood of using CAM. Contrary to some prior research, education level was not associated with use of MBT.


The Plastomes of Two Species in the Endoparasite Genus Pilostyles (Apodanthaceae) Each Retain Just Five or Six Possibly Functional Genes.
The 23 species of mycoheterotrophic or exoparasitic land plants (from 15 genera and 6 families) studied so far all retain a minimal set of 17 of the normally 116 plastome genes. Only Rafflesia lagascae, an endoparasite concealed in its host except when flowering, has been reported as perhaps lacking a plastome, although it still possesses plastid-like compartments. We analyzed two other endoparasites, the African Apodanthaceae Pilostyles aethiopica and the Australian Pilostyles hamiltonii, both living inside Fabaceae. Illumina and 454 data and Sanger resequencing yielded circularized plastomes of 11,348 and 15,167 bp length, with both species containing five possibly functional genes (accD, rps3, rps4, rrn16, rrn23) and two/three pseudogenes (rpoC2 in P. aethiopica and rpl2 and rps12 in both species; rps12 may be functional in P. hamiltonii). Previously known smallest land plant plastomes contain 27-29 genes, making these Apodanthaceae plastomes the most reduced in size and gene content. A similar extent of divergence might have caused the plastome of Rafflesia to escape detection. The higher plastome degeneration in both these families of endoparasites, Rafflesiaceae and Apodanthaceae, of similar high age, compared with exoparasites points to a difference of plastome function between those two modes of parasitic life.


Complete telomere-to-telomere de novo assembly of the Plasmodium falciparum genome through long-read (>11 kb), single molecule, real-time sequencing.
The application of next-generation sequencing to estimate genetic diversity of Plasmodium falciparum, the most lethal malaria parasite, has proved challenging due to the skewed AT-richness [∼80.6% (A + T)] of its genome and the lack of technology to assemble highly polymorphic subtelomeric regions that contain clonally variant, multigene virulence families (Ex: var and rifin). To address this, we performed amplification-free, single molecule, real-time sequencing of P. falciparum genomic DNA and generated reads of average length 12 kb, with 50% of the reads between 15.5 and 50 kb in length. Next, using the Hierarchical Genome Assembly Process, we assembled the P. falciparum genome de novo and successfully compiled all 14 nuclear chromosomes telomere-to-telomere. We also accurately resolved centromeres [∼90-99% (A + T)] and subtelomeric regions and identified large insertions and duplications that add extra var and rifin genes to the genome, along with smaller structural variants such as homopolymer tract expansions. Overall, we show that amplification-free, long-read sequencing combined with de novo assembly overcomes major challenges inherent to studying the P. falciparum genome. Indeed, this technology may not only identify the polymorphic and repetitive subtelomeric sequences of parasite populations from endemic areas but may also evaluate structural variation linked to virulence, drug resistance and disease transmission.


Simple surface modification of poly(epsilon-caprolactone) for apatite deposition from simulated body fluid.
Poly(epsilon-caprolactone) (PCL) with a bone-like apatite layer bound to its surface could be useful as a scaffold for tissue engineering applications. In the present study, the surface of PCL was treated with aqueous NaOH to introduce carboxylate groups onto the surface. The NaOH-treated material was subsequently dipped in aqueous CaCl(2) and K(2)HPO(4).3H(2)O alternately three times to deposit apatite nuclei on the surface. The surface-modified material successfully formed a dense and uniform bone-like surface apatite layer after incubation for 24 h in simulated body fluid with ion concentrations approximately equal to those of human blood plasma.


Effect of physical training on exercise-induced hyperkalemia in chronic heart failure. Relation with ventilation and catecholamines.
The exercise-induced rise in arterial potassium concentration ([K+]a) may contribute to exercise hyperpnea and could play a role in exertional fatigue. This study was designed to determine whether the exercise-induced rise in [K+]a is altered in patients with chronic heart failure (CHF) and whether physical training affects K+ homeostasis. We evaluated 10 subjects with CHF (ejection fraction, 23 +/- 3.9%) and 10 subjects with normal left ventricular function (NLVF) who had undergone previous coronary artery graft surgery (ejection fraction, 63 +/- 8.6%). Subjects performed an incremental cycle ergometer exercise test before and after a physical training or detraining program. Changes in [K+]a and ventilation (VE) during exercise were closely related in both groups. Subjects with CHF did less absolute work and had reduced maximal oxygen consumption (VO2max) compared with subjects with NLVF (P < .01). Exercise-induced rises in [K+]a, VE, norepinephrine, lactate, and heart rate were greater at matched absolute work rates in subjects with CHF than in subjects with NLVF (P < .01). However, when the rise in [K+]a was plotted against percentage of VO2max to match for relative submaximal effort, there were no differences between the two groups. Physical training resulted in reduced exercise-induced hyperkalemia at matched submaximal work rates in both groups (P < .01) despite no associated change in the concentration of arterial catecholamines. At maximal exercise when trained, peak increases in [K+]a were unaltered, but peak concentrations of catecholamines were raised (P < .05). The decrease in VE at submaximal work rates after training was not significant with this incremental exercise protocol, but both groups had an increased peak VE when trained (P < .01). Exercise-induced rises in [K+]a, catecholamines, and VE are greater at submaximal work rates in subjects with CHF than in subjects with NLVF. Physical training reduces the exercise-induced rise in [K+]a but does not significantly decrease VE during submaximal exercise with this incremental cycle ergometry protocol. The reduction in exercise-induced hyperkalemia after training is not the result of altered concentrations of arterial catecholamines. The pathophysiological significance of the increased exercise-induced hyperkalemia in CHF and the mechanisms of improved K+ homeostasis with training have yet to be established.


SAGE of the developing wheat caryopsis.
Understanding the development of the cereal caryopsis holds the future for metabolic engineering in the interests of enhancing global food production. We have developed a Serial Analysis of Gene Expression (SAGE) data platform to investigate the developing wheat (Triticum aestivum) caryopsis. LongSAGE libraries have been constructed at five time-points post-anthesis to coincide with key processes in caryopsis development. More than 90,000 LongSAGE tags have been sequenced generating 29,261 unique tag sequences across all five libraries. Tag abundance, generated from cumulative tag counts, provides insight into the redundancy and diversity of each library. Annotation of the 500 most abundant tags spanning development highlights the array of functional groups being expressed. The relative frequency of these more abundant transcripts allows quantitative analysis of patterns of expression during grain development. We have identified activities of cellular proliferation/differentiation, the accumulation of storage proteins and starch biosynthesis. The abundance of calcium-dependent protein kinases indicate their importance in signalling across development. Acquisition of a broad array of defence coincides with storage accumulation and is dominated by inhibitors of amylase activity. Differential expression profiles of abundant tags from each library reveal the coordinated expression of genes responsible for the cellular events constituting caryopsis development. This SAGE platform has also provided a resource of novel sequence and expression information including the identification of potentially useful promoter activities. Further investigations into both the abundant and low expressing transcripts will provide greater insight into wheat caryopsis development and assist in wheat improvement programmes.


Patterns of prescription drugs use among pregnant women at Sultan Qaboos University Hospital and Sultan Qaboos University Hospital Family and Community Medicine Clinic, Oman.
This study evaluates the patterns of prescription drugs use among women attending antenatal clinic at Sultan Qaboos University Hospital (SQUH) and SQUH Family and Community Medicine clinic (FAMCO), Oman. The study was a descriptive retrospective cross-sectional study on pregnant women who attended the antenatal clinic at SQUH and FAMCO from February to April 2014 and received a prescription containing at least one drug. Patients' information was extracted from SQUH electronic records. A total of 105 pregnant women were included in the study. Among the recruited pregnant women, 35 (33.3%) had at least one chronic disease. The average number of drugs prescribed per patient per prescription during the period of pregnancy was 2.33 ± 1.43. Vitamins and minerals were the most frequently prescribed class of drugs (30.60%) followed by analgesics (11.19%) and antidiabetic drugs (10.13%). According to the Food and Drug Administration risk classification, most of the prescribed drugs were from category B (30.0%) and C (27.14%). No drug was prescribed from category X. There was a significant decrease in prescribing category A drugs over the three trimesters (20.7%, 12.7%, and 9.3%, respectively) (P < 0.047). The study gives an overview of the extent of drug prescription during pregnancy and increases the awareness of health-care providers and women about the potential risks of drug use during pregnancy.


Effects of body position and extension of the neck and extremities on lung volume measured via computed tomography in red-eared slider turtles (Trachemys scripta elegans).
To determine the effects of body position and extension of the neck and extremities on CT measurements of ventilated lung volume in red-eared slider turtles (Trachemys scripta elegans). Prospective crossover-design study. 14 adult red-eared slider turtles. CT was performed on turtles in horizontal ventral recumbent and vertical left lateral recumbent, right lateral recumbent, and caudal recumbent body positions. In sedated turtles, evaluations were performed in horizontal ventral recumbent body position with and without extension of the neck and extremities. Lung volumes were estimated from helical CT images with commercial software. Effects of body position, extremity and neck extension, sedation, body weight, and sex on lung volume were analyzed. Mean ± SD volume of dependent lung tissue was significantly decreased in vertical left lateral (18.97 ± 14.65 mL), right lateral (24.59 ± 19.16 mL), and caudal (9.23 ± 12.13 mL) recumbent positions, compared with the same region for turtles in horizontal ventral recumbency (48.52 ± 20.08 mL, 50.66 ± 18.08 mL, and 31.95 ± 15.69 mL, respectively). Total lung volume did not differ among positions because of compensatory increases in nondependent lung tissue. Extension of the extremities and neck significantly increased total lung volume (127.94 ± 35.53 mL), compared with that in turtles with the head, neck, and extremities withdrawn into the shell (103.24 ± 40.13 mL). Vertical positioning of red-eared sliders significantly affected lung volumes and could potentially affect interpretation of radiographs obtained in these positions. Extension of the extremities and neck resulted in the greatest total lung volume.


Lovastatin suppresses invasiveness of anaplastic thyroid cancer cells by inhibiting Rho geranylgeranylation and RhoA/ROCK signaling.
Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, inhibits the conversion of mevalonate from HMG-CoA. Previously, we have reported that lovastatin treatment induced the occurrence of apoptosis and differentiation in ARO anaplastic thyroid cancer cells. Here, we demonstrated that lovastatin inhibited the ARO cell invasiveness and delineated the underlying molecular mechanism. Lovastatin significantly suppressed the EGF-induced cell adhesion, actin filament reorganization and transmigration. Lovastatin also reduced EGF-induced increases in the levels of phosphorylated p125(FAK) and paxillin. These inhibitory effects mediated by lovastatin can be prevented by pretreatment of the cells with mevalonate or geranylgeraniol (GGOH), but not farnesol (FOH). Accordingly, the consuming and depletion of geranylgeranyl pyrophosphate and consequent suppression of the protein geranylgeranylation, which is essential for activation of Rho GTPases, might account for the lovastatin-induced inhibition of cell motility and invasion. Western blot analysis showed that lovastatin inhibited membrane translocation of Rho (e.g. RhoA and Rac1) through decreasing post-translational geranylgeranyl modification of Rho. In addition, treatment of the cells with specific inhibitors against Rho (Clostridium botulinum C3 transferase) or ROCK (Y-27632) abolished the GGOH-mediated prevention of, and restored the lovastatin-induced decrease of cell invasion. Taken together, our results suggested that lovastatin suppressed EGF-induced ARO cell invasiveness through the reduction of Rho geranylgeranylation, which in turn suppressed the membrane translocation, and subsequent suppression of Rho/ROCK and FAK/paxillin signaling.


Development of a nanosecond discharge-enhanced laser plasma spectroscopy.
A nanosecond pulse discharge circuit is developed and used to enhance the optical emission of laser plasma. An intense discharge spark was observed with a peak discharge current of 1.9 kA and a peak power of 6.5 MW. The main electric energy deposition only lasted for ∼40 ns. An intense optical emission was observed. The line intensity of plasma emission was greatly increased along with an improved signal-to-noise ratio, in comparison with that using a microsecond pulse discharge circuit. From the measured spectra, electron temperature and electron number density were estimated. The mechanism of the optical emission enhancement was briefly discussed.


From biophysics to cognition: reward-dependent adaptive choice behavior.
In neurobiological studies of various cognitive abilities, neuroscientists use mathematical models to fit behavioral data from well-controlled experiments and look for neural activities that are correlated with parameters in those models. The pinpointed neural correlates are often taken as evidence that a given task is performed according to the prescription of the applied model, and the relevant brain areas encode parameters of such a model. However, to go beyond correlations toward causal understanding, it is necessary to elucidate at multiple levels the neural circuit mechanisms of cognitive processes. This review focuses on recent studies of reward-based decision-making that have begun to tackle this challenge.


CT and radiographic analysis of sagittal profile changes following thoracoscopic anterior scoliosis surgery.
Previous studies report an increase in thoracic kyphosis after anterior approaches and a flattening of sagittal contours following posterior approaches. Difficulties with measuring sagittal parameters on radiographs are avoided with reformatted sagittal CT reconstructions due to the superior endplate clarity afforded by this imaging modality. A prospective study of 30 Lenke 1 adolescent idiopathic scoliosis (AIS) patients receiving selective thoracoscopic anterior spinal fusion (TASF) was performed. Participants had ethically approved low dose CT scans at minimum 24 months after surgery in addition to their standard care following surgery. The change in sagittal contours on supine CT was compared to standing radiographic measurements of the same patients and with previous studies. Inter-observer variability was assessed as well as whether hypokyphotic and normokyphotic patient groups responded differently to the thoracoscopic anterior approach. Mean T5-12 kyphosis Cobb angle increased by 11.8 degrees and lumbar lordosis increased by 5.9 degrees on standing radiographs two years after surgery. By comparison, CT measurements of kyphosis and lordosis increased by 12.3 degrees and 7.0 degrees respectively. 95% confidence intervals for inter-observer variability of sagittal contour measurements on supine CT ranged between 5-8 degrees. TASF had a slightly greater corrective effect on patients who were hypokyphotic before surgery compared with those who were normokyphotic. Restoration of sagittal profile is an important goal of scoliosis surgery, but reliable measurement with radiographs suffers from poor endplate clarity. TASF significantly improves thoracic kyphosis and lumbar lordosis while preserving proximal and distal junctional alignment in thoracic AIS patients. Supine CT allows greater endplate clarity for sagittal Cobb measurements and linear relationships were found between supine CT and standing radiographic measurements. In this study, improvements in sagittal kyphosis and lordosis following surgery were in agreement with prior anterior surgery studies, and add to the current evidence suggesting that anterior correction is more capable than posterior approaches of addressing the sagittal component of both the instrumented and adjacent non instrumented segments following surgical correction of progressive Lenke 1 idiopathic scoliosis.


Seasonal variation of diet quality in a large middle-aged and elderly Dutch population-based cohort.
Several studies have reported seasonal variation in intake of food groups and certain nutrients. However, whether this could lead to a seasonal pattern of diet quality has not been addressed. We aimed to describe the seasonality of diet quality, and to examine the contribution of the food groups included in the dietary guidelines to this seasonality. Among 9701 middle-aged and elderly participants of the Rotterdam Study, a prospective population-based cohort, diet was assessed using food-frequency questionnaires (FFQ). Diet quality was measured as adherence to the Dutch dietary guidelines, and expressed in a diet quality score ranging from 0 to 14 points. The seasonality of diet quality and of the food group intake was examined using cosinor linear mixed models. Models were adjusted for sex, age, cohort, energy intake, physical activity, body mass index, comorbidities, and education. Diet quality had a seasonal pattern with a winter-peak (seasonal variation = 0.10 points, December-peak) especially among participants who were men, obese and of high socio-economic level. This pattern was mostly explained by the seasonal variation in the intake of legumes (seasonal variation = 3.52 g/day, December-peak), nuts (seasonal variation = 0.78 g/day, January-peak), sugar-containing beverages (seasonal variation = 12.96 milliliters/day, June-peak), and dairy (seasonal variation = 17.52 g/day, June-peak). Diet quality varies seasonally with heterogeneous seasonality of food groups counteractively contributing to the seasonal pattern in diet quality. This seasonality should be considered in future research on dietary behavior. Also, season-specific recommendations and policies are required to improve diet quality throughout the year.


The burden of invasive early-onset neonatal sepsis in the United States, 2005-2008.
Sepsis in the first 3 days of life is a leading cause of morbidity and mortality among infants. Group B Streptococcus (GBS), historically the primary cause of early-onset sepsis (EOS), has declined through widespread use of intrapartum chemoprophylaxis. We estimated the national burden of invasive EOS cases and deaths in the era of GBS prevention. Population-based surveillance for invasive EOS was conducted in 4 of the Centers for Disease Control and Prevention's Active Bacterial Core surveillance sites from 2005 to 2008. We calculated incidence using state and national live birth files. Estimates of the national number of cases and deaths were calculated, standardizing by race and gestational age. Active Bacterial Core surveillance identified 658 cases of EOS; 72 (10.9%) were fatal. Overall incidence remained stable during the 3 years (2005: 0.77 cases/1000 live births; 2008: 0.76 cases/1000 live births). GBS (∼ 38%) was the most commonly reported pathogen followed by Escherichia coli (∼ 24%). Black preterm infants had the highest incidence (5.14 cases/1000 live births) and case fatality (24.4%). Nonblack term infants had the lowest incidence (0.40 cases/1000 live births) and case fatality (1.6%). The estimated national annual burden of EOS was approximately 3320 cases (95% confidence interval [CI]: 3060-3580), including 390 deaths (95% CI: 300-490). Among preterm infants, 1570 cases (95% CI: 1400-1770; 47.3% of the overall) and 360 deaths (95% CI: 280-460; 92.3% of the overall) occurred annually. The burden of invasive EOS remains substantial in the era of GBS prevention and disproportionately affects preterm and black infants. Identification of strategies to prevent preterm births is needed to reduce the neonatal sepsis burden.


Determination of knowledge of Turkish midwifery students about human papilloma virus infection and its vaccines.
Human papilloma virus (HPV) is one of the most common sexually transmitted agents and its infection is the most established cause of cervical cancer. Midwives play a key position in the implementation of cervical cancer. This descriptive study aimed to determine the level of knowledge concerning HPV and HPV vaccination among 268 midwifery students. Data were collected between November 15 and 30, 2011, through a self-reported questionnaire. The mean age of participants was 20.75 ± 1.60. Among all students, 44.4% had heard of HPV, while 40.4% had heard of HPV vaccinatiob. The relationship between the midwifery student knowledge on HPV and HPV vaccine and their current educational year was significant (p=0.001). In conclusion midwifery students have moderate level of knowledge about HPV and its vaccine and relevant information should be included in their teaching curriculum.


Evaluation of exercise-induced hypertension post endovascular stenting of coarctation of aorta.
Coarctation of the aorta (COA) is a defect that accounts for 5-8% of all congenital heart diseases. Balloon angioplasty as a treatment for COA is increasingly performed, with endovascular stents having been proposed as a means of improving the efficacy and safety of the procedure. The aim of this study was to evaluate the systolic blood pressure gradient at rest and during maximal exercise at follow-up in patients post endovascular stenting of COA. Thirteen patients (4 native and 9 re-coarctation cases of COA after surgery or balloon angioplasty) with a mean age of 11.1 ± 4.7 years underwent endovascular stenting between November 2007 and December 2009 via standard techniques for native COA as an alternative to surgical repair. Doppler echocardiography was performed pre and post stenting. Resting and exercise assessment of blood pressure was performed at follow-up. Post stent implantation, no angiographic major complications were evident. Systolic blood pressure gradient decreased from 42 ± 8.8 mm Hg before stent placement to 7 ± 10 mm Hg at follow-up (p value < 0.001). Peak Doppler pressure gradient decreased from 30 ± 14 mm Hg to 14 ± 10 mm Hg at follow-up (p value < 0.007). One case of exercise-induced hypertension was seen in patients. Endovascular stenting for native COA in older children and post-surgical COA repair in patients with residual COA and re-coarctation is a reasonable alternative to surgical correction. During early follow-up, stenting effectively alleviates the aortic arch obstruction with normalization of the systemic blood pressure both at rest and during maximal exercise.


A comparative study of the indoor radon level with the radon exhalation rate from soil in Alexandria city.
The assessment of the radiological risk related to the inhalation of radon and radon its progeny is based mainly on the integrated measurement of radon in both indoor and outdoor environments. The exhalation of radon from the earth's crust and building materials forms the main source of radon in the indoor environment. This study has been undertaken for the purpose of health risk assessment. In this comparative study, the indoor radon level, radium content, radon exhalation rate and concentration of soil radon are measured using the Can Technique. Soil samples were collected simultaneously from different geological formations of the same area for laboratory measurement of the radon exhalation rate. The radon exhalation rate was measured in the laboratory using LR-115 type II plastic track detectors. The indoor radon concentrations in this study area were found to vary from 44±9 to 132±31 Bq m(-3) with an average of 72±29 Bq m(-3). The seasonal variations of the indoor radon reveal the maximum values in the winter and in summer in different dwellings of Alexandria city. The annual effective dose varies from 0.75 to 2.2 mSv with an average value of 1.34 mSv. The radon exhalation rate was found to vary in the ranges 8.31-233.70×10(-3) Bq kg(-1) h(-1), 0.48-15.37 Bq m(-2) h(-1) with an average 47.97×10(-3) Bq kg(-1) h(-1), (3.14 Bq m(-2) h(-1)). The radium content in soil varies from 3.14 to 39.60 Bq kg(-1) with an average of 11.55 Bq kg(-1). The significance of this study is discussed in details from the point of view of radiation protection.


Influence of cell and collagen concentration on the cell-matrix mechanical relationship in a corneal stroma wound healing model.
The effect of different collagen and cell concentrations on the mechanical and remodeling behaviors of corneal stroma wound healing models consisting of collagen hydrogels seeded with human corneal fibroblasts during a 25 day culture period were examined. Human corneal fibroblasts were seeded at 1 × 10(5), 3 × 10(5) or 5 × 10(5) cells per hydrogel, and collagen concentrations of 2.5 mg/ml, 3.5 mg/ml or 4.5 mg/ml were examined. Two non-destructive techniques, spherical indentation and optical coherence tomography, were used to measure the elastic modulus and dimensional changes respectively at several time-points over the culture period. The elastic modulus of the hydrogels increased continuously over 25 days. Hydrogels with higher initial cell seeding densities and lower initial collagen concentrations were found to increase in elastic modulus faster and possessed a higher elastic modulus by the end of the culture period when compared to the other hydrogels. A mathematical equation was applied to accurately fit the change in elastic modulus over time. This study demonstrates a robust in vitro technique able to monitor the effect of different parameters on the cell-matrix mechanical relationship in a corneal stroma model during prolonged culture periods and enhances our understanding on corneal wound healing processes.


Comparison of estimates of population levels of physical activity using two measures.
To compare estimates of population levels of 'adequate activity' for health benefit in different age and sex groups using two different measures--kilocalories (kcals) and Mets.mins. 10,464 mid-age women (47-52 years) from the second survey of the Australian Longitudinal Study on Women's Health (ALSWH, 1998) and 2,500 men and women (18-75 years) from the 1997 Active Australia national survey, answered questions about physical activity. Kcals and Mets.mins were calculated from self-reported time spent in walking, moderate and vigorous activity, and self-reported body weight. 'Adequate activity' was defined as a minimum of 800 kcals or 600 Mets.mins. There were differences in the estimates of 'adequate activity' using the two methods among women participants in both surveys, but not among the male participants in the Active Australia survey. A significant proportion of the women in both surveys (6.4% of the ALSWH women and 8.5% of the Active Australia women, mean weight 60 kg) were classified as 'inactive' when the kcals method was used despite reporting levels of activity commensurate with good health. Fewer than 1% (mean weight 105 kg) were classified as 'active' using kcals when reporting lower than recommended levels of activity. Agreement between the two methods was better among men; only 3% were misclassified because of low or very high weight. The Mets.mins method of estimating 'adequate' activity assesses physical activity independently of body weight and is recommended for use in future population surveys, as it is less likely to under-estimate the prevalence of physical activity in women. Women and men aged 45-59 and women aged > 60 should be the target of specific health promotion strategies to increase population levels of physical activity.


Catalytic properties of a cobalt metal-organic framework with a zwitterionic ligand synthesized in situ.
Herein we describe the high yield synthesis of a highly crystalline cobalt(ii) MOF with a novel zwitterionic ligand made up of 3,3',4,4'-BPTC and 1,4-cyclohexanediamine, obtained in situ during the hydrothermal synthesis. The compound with the molecular formula C46H38N4O14Co·2H2O has a molecular mass of 965.7783 g mol-1, a triclinic crystalline system (a = 5.86 Å, b = 9.28 Å, c = 19.92 Å, α = 83.93°, β = 88.01°, γ = 78.59), it is thermally stable up to 300 °C and presents structural stability before and after removing the solvent molecules from its pores. This novel material showed catalytic properties in an electrophilic substitution reaction of indoles and aldehydes allowing the syntheses of bis(indolyl)methanes in high yields under mild reaction conditions and can be reused at least once with the same catalytic activity.


In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain.
The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and uncoupling protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57Bl/6 background (exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. Therefore, we have examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known to be obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-knockout mice were fed chow or a high-fat or a cafeteria diet for 4 wk. The absence of UCP1 augmented obesity (weight gain, body fat mass, %body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly, high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain.


Holdaway measurement norms in Turkish adults.
The aims of this study were to establish the cephalometric norms for Turkish adults by means of the Holdaway analysis and to investigate the cephalometric differences between Turkish women and men. The study materials consisted of 100 cephalometric head films taken at the natural head position. The 50 men and 50 women who volunteered for the study had to be older than 18 years and had to have parents of Turkish origin, acceptable facial structure, ideal dental occlusion, no visual or hearing disorders, and all the teeth present in their mouths except the third molar teeth. The selected subjects had not undergone orthodontic treatment or orthognathic surgery, had no burns, injuries, or scar tissue in the head and neck regions, and had no breathing or swallowing disorder. The measurements of hard and soft tissues were carried out on lateral cephalometric radiographs taken at natural head position. The measurements were evaluated with a computer software program. The effects of sex on the measurements were investigated by means of Student's t test. The differences between men and women in nose prominence, basic upper lip thickness, upper lip thickness, inferior sulcus to the H line, and soft tissue chin thickness were statistically significant. The upper lip, nose, and chin are more protruded in men than they are in women.


Evidence for the Participation of Acid-Sensing Ion Channels (ASICs) in the Antinociceptive Effect of Curcumin in a Formalin-Induced Orofacial Inflammatory Model.
Curcumin, a major bioactive component of turmeric, has diverse therapeutic effects such as anti-inflammatory, antioxidant, anticancer, and antinociceptive activities. The acid-sensing ion channels (ASICs), which can be activated by acute drops in the extracellular pH, play an important role in nociception. However, very little is known about the interaction between ASICs and curcumin in nociception of inflammation. In our study, we investigated whether the antinociceptive effects of curcumin are mediated via ASICs using an orofacial nociceptive model and in vitro western blotting, immunofluorescence, whole-cell patch-clamp recordings in the trigeminal system. Intraperitoneally administered curcumin at a dose of 50 mg/kg can reduce hyperalgesia in both the phases of a formalin-induced orofacial nociceptive model. Curcumin reduced the amplitude of ASICs currents in a dose-dependent manner in trigeminal ganglion (TG) neurons, and curcumin also reduced the protein quantity but did not change the distribution of ASICs in TG. Thus, our results indicate that curcumin can reduce formalin-induced ASICs activation and thus inhibit ASICs-mediated inflammatory pain hypersensitivity.


Bonebridge Implantation for Conductive Hearing Loss in a Patient with Oval Window Atresia.
The occurrence of oval window atresia is a rare anomaly with conductive hearing loss. Traditional atresia surgeries involve challenging surgical techniques with risks of irreversible inner ear damage. Recent reports on Bonebridge (Medel, Innsbruck, Austria), a novel implantable bone conduction hearing aid system, assert that the device is safe and effective for conductive hearing loss. We present a case of Bonebridge implantation in an eight-year-old girl with bilateral oval window atresia.


Toxoplasmosis not transmitted by cat bite, but high prevalence of antibodies to Toxoplasma gondii in patients bitten by their own cat.
The aims of the study were to investigate the prevalence of antibodies to Toxoplasma gondii in a group of patients bitten by cats, and also to determine if toxoplasmosis can be transferred by cat bite. Seventy-two patients who attended the emergency wards at 3 hospitals in Stockholm, Sweden, due to infection by cat bite, were investigated for specific IgM and IgG antibodies to T. gondii in the acute phase, as well as in the convalescent phase about 2 weeks later. Specific IgG antibodies to T. gondii (> or =8 IU/ml) were found in 17/72 patients (24%) in the acute phase. No case of seroconversion occurred. Patients who were bitten by their own cat had positive antibody titres to T. gondii significantly more often than those bitten by a foreign cat; 30% and 5%, respectively (p = 0.02). This suggests that regular contact with cats may contribute to the transmission of the parasite.


Elucidation of the interactions of an anticancer ruthenium complex in clinical trials with biomolecules utilizing capillary electrophoresis hyphenated to inductively coupled plasma-mass spectrometry. Short communication.
The application of capillary electrophoresis (CE) combined with highly sensitive inductively-coupled-plasma mass spectrometric (ICP-MS) detection allows the interactions of metal complexes with biomolecules to be characterized. This technique has been used to provide new insights into the mode of action of the ruthenium-based anticancer drug candidate indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019). While the compound binds rapidly and efficiently to serum proteins, especially albumin, its reactivity towards the model DNA compound 2'-deoxyguanosine 5'-monophosphate (5'-dGMP) is moderate.


Effects of Protein-Rich Nutritional Composition Supplementation on Sarcopenia Indices and Physical Activity during Resistance Exercise Training in Older Women with Knee Osteoarthritis.
Older adults with knee osteoarthritis (KOA) are at high risk of sarcopenia. Protein-rich nutritional composition supplementation (PS) combined with resistance exercise training (RET) improves muscle gains and facilitates physical activity in older adults. However, whether PS augments the effects of RET on muscle mass and PA in patients with KOA remains unclear. Therefore, this study identified the effects of PS on sarcopenic indices and PA in older women with KOA subjected to an RET program. Eligible older women aged 60-85 years and diagnosed as having KOA were randomly assigned to either the experimental group (EG) or the control group (CG). Both groups performed RET twice a week for 12 weeks. The EG received additional PS during this period. Outcome measures included appendicular lean mass index, walking speed, physical activity, and scores on the Western Ontario and McMaster Universities Osteoarthritis Index-WOMAC). All measures were tested at baseline and after intervention. With participant characteristics and baseline scores as covariates, analysis of variance was performed to identify between-group differences in changes in all outcome measures after intervention. Statistical significance was defined as p < 0.05. Compared with the CG, the EG achieved greater changes in appendicular lean mass index (adjusted mean difference (aMD) = 0.19 kg/m2, p < 0.01), physical activity (aMD = 30.0 MET-hour/week, p < 0.001), walking speed (aMD = 0.09 m/s, p < 0.05), and WOMAC global function (aMD = -8.21, p < 0.001) after intervention. In conclusion, PS exerted augmentative effects on sarcopenic indices, physical activity, and perceived global WOMAC score in older women with KOA through 12 weeks of RET.


Hypothesis: dynamics of classical malaria epidemics show Plasmodium falciparum's survival strategy.
Areas of marginal transmission can generate enormous lethal falciparum malaria epidemics when factors favoring the parasite shift only slightly. Although usually described in terms of vectorial capacity, medical scientists working in India in the early 20th century came to the conclusion that "an epidemic of relapses" was the key triggering event of malaria epidemics. This explanation has been largely discarded, because the biology of Plasmodium falciparum recrudescence has since been differentiated from P. vivax relapse. Using data from the Punjab in 1908 and Ceylon in 1934-1935, the genesis of malaria epidemics has been re-examined to inform current control efforts. The epidemics were focused geographically depending on recent rainfall or drought. Epidemics arose very suddenly and simultaneously in several places. Malaria spleen surveys indicated very little recent malaria transmission, and blood smears showed very few gametocytes just before the epidemic. Population stress as indicated by high grain prices because of a poor harvest caused by drought the previous year was a risk factor for malaria epidemics. Although increased female Anopheline survival because of increased humidity played an important part in the magnification of the epidemic, it does not explain its genesis. Human population stress triggering a shift toward gametocytogenesis is hypothesized as the key initiation factor for malaria epidemics. Its evolutionary significance may be that it allows the parasite to match the tropical agricultural cycle.


International Study of Chaplains' Attitudes About Research.
An online survey was conducted by twelve professional chaplain organizations to assess chaplains' attitudes about and involvement in research. A total of 2,092 chaplains from 23 countries responded to the survey. Over 80% thought research was definitely important and nearly 70% thought chaplains should definitely be research literate. Just over 40% said they regularly read research articles and almost 60% said they occasionally did. The respondents rated their own research literacy as 6.5 on a 0-10 scale. Significant positive inter-correlations were found among all four measures: importance of (a) research and (b) research literacy; (c) frequency of reading articles; and (d) research literacy rating. Approximately 35% were never involved, 37% had been involved, 17% were currently involved, and 11% expected to be involved in research. The last three groups were significantly more likely to think research and research literacy were important and to read research articles than chaplains who were never involved in research. Given chaplains' interest in research, actions should be undertaken to facilitate further research engagement.


Na1.5La1.5TeO6: Na+ conduction in a novel Na-rich double perovskite.
Increasing demand for lithium batteries for automotive applications, coupled with the necessity to move to large-scale energy storage systems, is driving a push towards new technologies and has seen Na-ion batteries emerge as a leading alternative to Li-ion. Amongst these, all solid-state configurations represent a promising route to achieving higher energy densities and increased safety. Remaining challenges include the need for Na+ solid electrolytes with the requisite ionic conductivities crucial for use in a solid-state cell. Here, we present the novel Na-rich double perovskite, Na1.5La1.5TeO6. The transport properties, explored at the macroscopic and local level, reveal a low activation energy barrier for Na+ diffusion and great promise for use as an electrolyte for all solid-state Na-batteries.


In-hospital infective endocarditis following transcatheter aortic valve replacement: a cross-sectional study of the National Inpatient Sample database in the USA.
While the utilization of transcatheter aortic valve replacement (TAVR) for patients with severe aortic stenosis has been increasing, in-hospital infective endocarditis (IE) following TAVR has not been well described. To identify in-hospital IE following TAVR. All patients who underwent TAVR between 2012 and 2014 were identified using the National Inpatient Sample database. Multi-variate logistic regression was performed to identify the predictors of in-hospital IE after TAVR. Of the 41,025 patients who received TAVR, 120 patients (0.3%) developed in-hospital IE. Viridans group streptococci (20.8%) was the most frequent causative organism for in-hospital IE, followed by Staphylococcus aureus (16.7%) and enterococci (8.3%). Patients who developed in-hospital IE after TAVR had significantly higher rates of death (20.8% vs 4.1%, P<0.001), septic shock (16.7% vs 0.8%, P<0.001), cardiogenic shock (12.5% vs 3.4%, P=0.02), acute kidney injury requiring haemodialysis (16.7% vs 1.6%, P<0.001), bleeding requiring transfusion (29.2% vs 11.3%, P=0.01), myocardial infarction (12.5% vs 2.1%, P<0.001) and permanent pacemaker removal (4.2% vs 0.05%, P<0.001) compared with patients without IE. Independent predictors of in-hospital IE after TAVR include younger age [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89-0.95], drug abuse (OR 48.9, 95% CI 6.9-347.3) and human immunodeficiency virus (HIV) infection (OR 7.8, 95% CI 1.4-44.4). IE occurred in 0.3% of patients after TAVR during the same hospitalization, resulting in higher rates of adverse outcomes including mortality. Patients with younger age, a history of drug abuse or HIV infection are at greater risk of in-hospital IE following TAVR, and would benefit from vigilant preventive measures perioperatively.


Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines.
Evaluate the cytotoxicity and genotoxicity of short- and long-term e-cigarette vapor exposure on a panel of normal epithelial and head and neck squamous cell carcinoma (HNSCC) cell lines. HaCaT, UMSCC10B, and HN30 were treated with nicotine-containing and nicotine-free vapor extract from two popular e-cigarette brands for periods ranging from 48 h to 8 weeks. Cytotoxicity was assessed using Annexin V flow cytometric analysis, trypan blue exclusion, and clonogenic assays. Genotoxicity in the form of DNA strand breaks was quantified using the neutral comet assay and γ-H2AX immunostaining. E-cigarette-exposed cells showed significantly reduced cell viability and clonogenic survival, along with increased rates of apoptosis and necrosis, regardless of e-cigarette vapor nicotine content. They also exhibited significantly increased comet tail length and accumulation of γ-H2AX foci, demonstrating increased DNA strand breaks. E-cigarette vapor, both with and without nicotine, is cytotoxic to epithelial cell lines and is a DNA strand break-inducing agent. Further assessment of the potential carcinogenic effects of e-cigarette vapor is urgently needed.


Scaling to the Organism: An Innovative Model of Dynamic Exposure Hotspots in Stream Systems.
In flowing systems, fluctuations in the frequency, magnitude, and duration of exposure occurs due to turbulence and geomorphology, causing spatial and temporal variations in chemical exposure at the scale of the organism. Spatial models representing toxicant distribution at the appropriate scales of stream organisms are noticeably missing from the literature. To characterize the fine scale distribution of pollutants in freshwater streams at the scale of a benthic organism, nine artificial stream habitats were created (riffle, pool, run, bend, woody debris) with either sand or gravel substrate. Dopamine was released as a chemical tracer, mimicking a groundwater source, and measurements were recorded with a microelectrode and Epsilon electrochemical recording system. Proxies for the frequency, magnitude, and duration of chemical exposure were extracted. Geographic information systems and an inverse distance weight interpolation technique were used to predict spatially the chemical distribution throughout the habitats. Spatial and temporal variations of exposure were exhibited within and across habitats, indicating that the frequency, magnitude, and duration of exposure is influenced by the organism's location within a habitat and the habitat it resides in. The run and pool with sand substrate contained the greatest frequency, magnitude, and duration of exposure, suggesting a more detrimental exposure compared to other habitats. Differences in peak heights within and across habitats are orders of magnitude in value. Spatial and temporal fluctuations of fine scale exposure need to be considered in both ecotoxicology and water quality modeling to represent and understand the exposure of pollutants impacting benthic organisms.