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Differential susceptibility theory (DST) posits that individuals differ in their developmental plasticity: some children are highly responsive to both environmental adversity and support, while others are less affected. According to this theory, “plasticity” genes that confer risk for psychopathology in adverse environments may promote superior functioning in supportive environments. We tested DST using a broad measure of child genetic liability (based on birth parent psychopathology), adoptive home environmental variables (e.g., marital warmth, parenting stress, and internalizing symptoms), and measures of child externalizing problems (n = 337) and social competence (n = 330) in 54-month-old adopted children from the Early Growth and Development Study. This adoption design is useful for examining DST because children are placed at birth or shortly thereafter with nongenetically related adoptive parents, naturally disentangling heritable and postnatal environmental effects. We conducted a series of multivariable regression analyses that included Gene × Environment interaction terms and found little evidence of DST; rather, interactions varied depending on the environmental factor of interest, in both significance and shape. Our mixed findings suggest further investigation of DST is warranted before tailoring screening and intervention recommendations to children based on their genetic liability or “sensitivity.”
Hydrogen lithography has been used to template phosphine-based surface chemistry to fabricate atomic-scale devices, a process we abbreviate as atomic precision advanced manufacturing (APAM). Here, we use mid-infrared variable angle spectroscopic ellipsometry (IR-VASE) to characterize single-nanometer thickness phosphorus dopant layers (δ-layers) in silicon made using APAM compatible processes. A large Drude response is directly attributable to the δ-layer and can be used for nondestructive monitoring of the condition of the APAM layer when integrating additional processing steps. The carrier density and mobility extracted from our room temperature IR-VASE measurements are consistent with cryogenic magneto-transport measurements, showing that APAM δ-layers function at room temperature. Finally, the permittivity extracted from these measurements shows that the doping in the APAM δ-layers is so large that their low-frequency in-plane response is reminiscent of a silicide. However, there is no indication of a plasma resonance, likely due to reduced dimensionality and/or low scattering lifetime.
Leg weakness (LW) issues are a great concern for pig breeding industry. And it also has a serious impact on animal welfare. To dissect the genetic architecture of limb-and-hoof firmness in commercial pigs, a genome-wide association study was conducted on bone mineral density (BMD) in three sow populations, including Duroc, Landrace and Yorkshire. The BMD data were obtained by ultrasound technology from 812 pigs (including Duroc 115, Landrace 243 and Yorkshire 454). In addition, all pigs were genotyped using genome-by-sequencing and a total of 224 162 single-nucleotide polymorphisms (SNPs) were obtained. After quality control, 218 141 SNPs were used for subsequent genome-wide association analysis. Nine significant associations were identified on chromosomes 3, 5, 6, 7, 9, 10, 12 and 18 that passed Bonferroni correction threshold of 0.05/(total SNP numbers). The most significant locus that associated with BMD (P value = 1.92e−14) was detected at approximately 41.7 Mb on SSC6 (SSC stands for Sus scrofa chromosome). CUL7, PTK7, SRF, VEGFA, RHEB, PRKAR1A and TPO that are located near the lead SNP of significant loci were highlighted as functionally plausible candidate genes for sow limb-and-hoof firmness. Moreover, we also applied a new method to measure the BMD data of pigs by ultrasound technology. The results provide an insight into the genetic architecture of LW and can also help to improve animal welfare in pigs.
Introduction: Patients with poorly-controlled diabetes often visit the emergency department (ED) for treatment of hyperglycemia. While previous qualitative studies have examined the patient experience of diabetes as a chronic illness, there are no studies describing patients’ perceptions of ED care for hyperglycemia. The objective of this study was to explore the patient experience regarding ED hyperglycemia visits, and to characterize perceived barriers to adequate glycemic control post-discharge. Methods: This study was conducted at a tertiary care academic centre in London, Ontario. A qualitative constructivist grounded theory methodology was used to understand the experience of adult patient partners who have had an ED hyperglycemia visit. Patient partners, purposively sampled to capture a breadth of age, sex, disease and presentation frequency were invited to participate in a semi-structured individual interview to probe their experiences. Sampling continued until a theoretical framework representing key experiences and expectations reached sufficiency. Data were collected and analyzed iteratively using a constant comparative approach. Results: 22 patients with type 1 or 2 diabetes were interviewed. Participants sought care in the ED over other options because of their concern of having a potentially life-threatening condition, advice from a healthcare provider or family member, or a perceived lack of convenient alternatives to the ED based on time and location. Participants’ care expectations centred around symptom relief, glycemic control, reassurance and education, and seeking referral to specialist diabetes care post-discharge. Finally, perceived system barriers that challenged participants’ glycemic control included affordability of medical supplies and medications, access to follow-up and, in some cases, the transition from pediatric to adult diabetes care. Conclusion: Patients with diabetes utilize the ED for a variety of urgent and emergent hyperglycemic concerns. In addition to providing excellent medical treatment, ED healthcare providers should consider patients’ expectations when caring for those presenting with hyperglycemia. Future studies will focus on developing strategies to help patients navigate some of the barriers that exist within our current limited healthcare system, enhance follow-up care, and improve short- and long-term health outcomes.
To evaluate the efficacy and tolerability of once-daily quetiapine XR monotherapy in outpatients with moderate-to-severe GAD without major depressive disorder.
10-week (8-week active treatment, randomised phase; 2-week post-treatment drug-discontinuation/tapering phase), multicentre, double-blind, placebo-controlled, parallel-group comparison with paroxetine study (D1448C00011). 873 patients were randomised to receive quetiapine XR 50mg/day (n=221), 150mg/day (n=218), paroxetine 20mg/day (n=217) or placebo (n=217). Primary endpoint: change from baseline to Week 8 in HAM-A total score. Secondary outcomes included: change from baseline to Week 8 in HAM-A psychic and somatic clusters.
Mean HAM-A total score (overall baseline mean, 26.98) was significantly reduced at Week 8 by quetiapine XR 50mg/day (-13.95, p<0.05), 150mg/day (-15.96, p<0.001) and paroxetine (-14.45, p<0.01) versus placebo (-12.30).
At Week 8, mean HAM-A psychic cluster score (overall baseline mean, 14.40) was significantly reduced by quetiapine XR 50mg/day (-7.42, p<0.01), 150mg/day (-8.64, p<0.001) and paroxetine (-7.70, p<0.001) versus placebo (-6.27). Mean HAM-A somatic cluster score (overall baseline mean, 12.58) was significantly reduced by quetiapine XR 150mg/day (-7.37, p<0.001) versus placebo (-6.00), but not quetiapine XR 50mg/day (-6.54, p=0.15) or paroxetine (-6.74, p=0.05).
The incidence of serious AEs was low (<2%) in all treatment groups. During Weeks 1-8, most common AEs (>10%) were dry mouth, somnolence, fatigue, dizziness and headache with quetiapine; headache with placebo; and somnolence, dizziness, headache and nausea with paroxetine.
Once-daily oral treatment with quetiapine XR (50 and 150mg/day) was well tolerated and significantly reduced anxiety symptoms, demonstrating effects on both somatic and psychic symptoms, in patients with GAD.
To examine the long-term efficacy and safety of quetiapine in combination with lithium (Li) or divalproex (DVP) in the prevention of recurrent mood events (manic, mixed, or depressed).
Patients with bipolar I disorder (DSM-IV, most recent episode manic, mixed or depressed) received open-label quetiapine (400–800 mg/day; flexible, divided doses)+Li/DVP (target serum concentrations 0.5–1.2 mEq/L and 50–125 μg/mL) for up to 36 weeks to achieve ≥12 weeks of clinical stability. Patients were subsequently randomized to double-blind treatment with quetiapine (400–800 mg/day)+Li/DVP or placebo+Li/DVP for up to 104 weeks. Primary endpoint was time to recurrence of any mood event defined by medication initiation, hospitalization, YMRS or MADRS scores ≥20 at two consecutive assessments, or study discontinuation due to a mood event.
1953 patients entered the stabilization phase and 623 were randomized and received ≥1 dose of study medication. Rates of recurrence of a mood event were 20.3% (63/310) vs 52.1% (163/313) for quetiapine and placebo groups, respectively, a risk reduction of 68% (HR 0.32; P<0.0001). Risk reductions were similar for manic and depressed events (HRs 0.30 and 0.33, respectively; P<0.0001). Safety data were consistent with the recognized safety profile of quetiapine. However, a greater incidence of blood glucose ≥126 mg/dL was observed in the quetiapine treatment group.
Maintenance treatment with quetiapine+Li/DVP was significantly more effective than placebo+Li/DVP in increasing the time to recurrence of a mood event in stable patients with bipolar I disorder.
Supported by funding from AstraZeneca Pharmaceuticals LP.
Post-stroke depression (PSD) is the most common psychiatric complication facing stroke survivors and has been associated with increased distress, physical disability, poor rehabilitation, and suicidal ideation. However, the pathophysiological mechanisms underlying PSD remain unknown, and no objective laboratory-based test is available to aid PSD diagnosis or monitor progression.
Here, an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach was performed to identify differentially expressed proteins in plasma samples obtained from PSD, stroke, and healthy control subjects.
The significantly differentiated proteins were primarily involved in lipid metabolism and immunoregulation. Six proteins associated with these processes – apolipoprotein A-IV (ApoA-IV), apolipoprotein C-II (ApoC-II), C-reactive protein (CRP), gelsolin, haptoglobin, and leucine-rich alpha-2-glycoprotein (LRG) – were selected for Western blotting validation. ApoA-IV expression was significantly upregulated in PSD as compared to stroke subjects. ApoC-II, LRG, and CRP expression were significantly downregulated in both PSD and HC subjects relative to stroke subjects. Gelsolin and haptoglobin expression were significantly dysregulated across all three groups with the following expression profiles: gelsolin, healthy control > PSD > stroke subjects; haptoglobin, stroke > PSD > healthy control.
Early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of PSD. The combination of increased gelsolin levels accompanied by decreased haptoglobin levels shows promise as a plasma-based diagnostic biomarker panel for detecting increased PSD risk in post-stroke patients.
We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after three weeks of repetitve transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms.
We report six cases (four females) 15–21 years of age with treatment-resistant MDD. Participants had a mean age of 18.7 years and a mean IQ of 102.3. Short echo proton magnetic resonance spectroscopy (H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5cc) before and after rTMS treatment. rTMS was localized to the left DLPFC and applied for 15 consecutive weekdays. Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores (Ham-D).1H-MRS data was analyzed with LCModel to determine glutamate concentration.
Following rTMS, treatment responders (N=4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Ham-D score reduction). Treatment non-responders (N=2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (−10%). Procedures were generally well tolerated with no adverse events.
rTMS is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by Induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement. Transcranial Magnetic Stimulation for Adolescent Depression (TMSAD)
Two 6-week, double-blind, placebo-controlled studies evaluated quetiapine XR (QTP-XR) adjunct to ongoing antidepressant therapy in patients with MDD and an inadequate response to prior antidepressant treatment (D1448C00006/D1448C00007).
Objective and aim:
A post hoc pooled analysis examined clinical and demographic characteristics as potential predictors of response to adjunct QTP-XR
Pooled MITT population (n = 616 QTP-XR [both doses]; n = 303 placebo) data were analysed from the two adjunct QTP-XR (150 or 300 mg/day) studies.
Effects of psychiatric history and baseline demographic and disease characteristics on efficacy were evaluated in subgroups based on Week 6 MADRS total score reduction: ≥50% reduction (responders: n = 345 QTP-XR, n = 140 placebo) versus < 50% (non-responders: n = 271 QTP-XR, n = 163 placebo); ≥75% reduction (responders: n = 175 QTP-XR, n = 60 placebo) versus < 25% (non-responders: n = 125 QTP-XR, n = 89 placebo).
Impact of baseline CGI-S score and number of episodes (0, 1, 2–3, 4–10, ≥10) over previous year and lifetime on Week 6 MADRS total score change was evaluated. Effect of baseline MADRS individual item (1–10) scores on Week 6 change in CGI-I score was evaluated.
No major differences between responders and non-responders to QTP-XR were observed for patient characteristics. there was no predictive association between baseline CGI-S score, number of depressive episodes, and baseline MADRS item scores and efficacy outcomes for adjunct QTP-XR.
This pooled analysis showed no major differences between responders and non-responders, and no suggestion of a predictive association between the parameters assessed and efficacy outcomes for adjunct QTP-XR. Further investigation including logistic regression may be required.
Studies in countries with high immunisation coverage suggest that the re-emergence of pertussis may be caused by a decreased duration of protection resulting from the replacement of whole-cell pertussis vaccine (WPV) with the acellular pertussis vaccine (APV). In China, WPV was introduced in 1978. The pertussis vaccination schedule advanced from an all-WPV schedule (1978–2007), to a mixed WPV/APV schedule (2008–2009), then to an all-APV schedule (2010–2016). Increases in the incidence of pertussis have been reported in recent years in Jinan and other cities in China. However, there have been few Chinese-population-based studies focused on the impact of schedule changes. We obtained annual pertussis incidences from 1956 to 2016 from the Jinan Notifiable Conditions Database. We used interrupted time series and segmented regression analyses to assess changes in pertussis incidence at the beginning of each year, and average annual changes during the intervention. Pertussis incidence decreased by 1.11 cases per 100 000 population (P = 0.743) immediately following WPV introduction in 1978 and declined significantly by 1.21 cases per 100 000 population per year (P < 0.0001) between 1978 and 2001. Immediately after APV replaced the fourth dose of WPV in 2008, the second and third doses in 2009, then replaced all four doses in 2010, pertussis incidence declined by 1.98, 1.98 and 1.08 cases per 100 000 population, respectively. However, the results were not statistically significant. There were significant increasing trends in pertussis incidence after APV replacements: 1.63, 1.77 and 1.78 cases/year in 2008–2016, 2009–2016 and 2010–2016, respectively. Our study shows that the impact of an all-WPV schedule may be less than the impacts of the sequential WPV/APV schedules. The short-term impact of APV was better than that of WPV; however, the duration of APV-induced protection was not ideal. The impact and duration of protective immunity resulting from APVs produced in China need further evaluation. Further research on the effectiveness of pertussis vaccination programme in Jinan, China is also necessary.
Crystal structure and electronic structure of YMnO3 were investigated by X-ray diffraction and transmission electron microscopy related techniques. According to the density of states (DOS), the individual interband transitions to energy loss peaks in the low energy loss spectrum were assigned. The hybridization of O 2p with Mn 3d and Y 4d analyzed by the partial DOS was critical to the ferroelectric nature of YMnO3. From the simulation of the energy loss near-edge structure, the fine structure of O K-edge was in good agreement with the experimental spectrum. The valence state of Mn (+3) in YMnO3 was determined by a comparison between experiment and calculations.
Quantifying reasonable crop yield gaps and determining potential regions for yield improvement can facilitate regional plant structure adjustment and promote crop production. The current study attempted to evaluate the yield gap in a region at multi-scales through model simulation and farmer investigation. Taking the winter wheat yield gap in the Huang-Huai-Hai farming region (HFR) for the case study, 241 farmers’ fields in four typical high-yield demonstration areas were surveyed to determine the yield limitation index and attainable yield. In addition, the theoretical and realizable yield gap of winter wheat in 386 counties of the HFR was assessed. Results showed that the average field yield of the demonstration plots was 8282 kg/ha, accounting for 0.72 of the potential yield, which represented the highest production in the region. The HFR consists of seven sub-regions designated 2.1–2.7: the largest attainable yield gap existed in the 2.6 sub-region, in the southwest of the HFR, while the smallest was in the 2.2 sub-region, in the northwest of the HFR. With a high irrigated area rate, the yield gap in the 2.2 sub-region could hardly be reduced by increasing irrigation, while a lack of irrigation remained an important limiting factor for narrowing the yield gap in 2.3 sub-region, in the middle of the HFR. Therefore, a multi-scale yield gap evaluation framework integrated with typical field survey and crop model analysis could provide valuable information for narrowing the yield gap.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
Introduction: Increasing opioid prescribing has been linked to an epidemic of opioid misuse. Our objective was to synthesize available evidence about patient-, prescriber-, medication-, and system-level risk factors for developing opioid misuse from prescribed opioids among patients presenting with pain unrelated to cancer. Our hypothesis was that we would identify risk factors predisposing patients to developing opioid misuse. Methods: We developed a systematic search strategy and applied it to nine electronic reference databases and six clinical trial registries. We hand searched related journals and conference proceedings, the reference lists of included studies, and the top 100 hits on Google. We included studies where a medical professional exposed adults or children to an opioid through a prescription. We excluded studies with over 50% cancer patients, palliative patients, and those with illicit opioid initiation. Two reviewers independently reviewed titles, abstracts, and full texts, and extracted data using standardized forms. We assessed study quality using risk of bias. We synthesized effect sizes of dichotomous risk factors on opioid misuse using inverse variance random-effects meta-analysis, and the inverse variance-weighted mean difference between opioid misusers and non-misusers for continuously measured factors. We conducted an a priori defined subgroup analysis among opioid-naïve patients. Results: Among 9,629 studies, 67 met our inclusion criteria. Among those who had been prescribed outpatient opioids, the following factors were associated with the development of misuse: a prior history of illicit drug use (OR: 4.21, 95% CI: 2.31-7.65), recent benzodiazepine use (OR: 2.57, 95% CI: 1.23-5.38), any mental health diagnosis (OR: 2.45, 95% CI: 1.91-3.15), any short acting (IR) opioid prescription (OR: 2.40, 95% CI: 1.15-5.02), younger age (OR: 2.19, 95%CI: 1.81-2.64), and male sex (OR: 1.23, 95% CI: 1.10-1.36). Among studies limiting their population to opioid-naïve patients, younger age was the most significant risk factor for opioid misuse (OR: 5.42, 95% CI:1.51-19.43). Conclusion: Of the risk factors examined, non-cancer pain patients with a prior history of substance use or mental health diagnoses were at highest risk for prescription opioid misuse. Younger opioid-naïve patients were at highest risk of misuse. Clinicians should consider these risk factors when managing acute pain in the emergency department.
Sodium and chloride are the key factors maintaining normal osmotic pressure (OSM) and volume of the extracellular fluid, and influencing the acid–base balance of body fluids. The experiment was conducted to investigate the effects of dietary Na+ and Cl− level on growth performance, excreta moisture, blood biochemical parameters, intestinal Na+–glucose transporter 1 (SGLT1) messenger RNA (mRNA), and Na+–H+ exchanger 2 (NHE2) mRNA, and to estimate the optimal dietary sodium and chlorine level for yellow-feathered chickens from 22 to 42days. A total of 900 22-day-old Lingnan yellow-feathered male chickens were randomly allotted to five treatments, each of which included six replicates of 30 chickens per floor pen. The basal control diet was based on corn and soybean meal (without added NaCl and NaHCO3). Treatments 2 to 5 consisted of the basal diet supplemented with equal weights of Na+ and Cl−, constituting 0.1%, 0.2%, 0.3% and 0.4% of the diets. Supplemental dietary Na+ and Cl− improved the growth performance (P<0.05). Average daily gain (ADG) showed a quadratic broken-line regression to increasing dietary Na+ and Cl− (R2=0.979, P<0.001), and reached a plateau at 0.1%. Supplemental Na+ and Cl− increased (P<0.05) serum Na+ and OSM in serum and showed a quadratic broken-line regression (R2=0.997, P=0.004) at 0.11%. However, supplemental Na+ and Cl− decreased (P<0.05) serum levels of K+, glucose (GLU) and triglyceride. Higher levels of Na+and Cl− decreased duodenal NHE2 transcripts (P<0.05), but had no effect on ileal SGLT1 transcripts. The activity of Na+ /K+-ATPase in the duodenum decreased (P<0.05) with higher levels of dietary Na+ and Cl−. In conclusion, the optimal dietary Na+ and Cl− requirements for yellow-feathered chickens in the grower phase, from 22 to 42 days of age, to optimize ADG, serum Na+, OSM, K+ and GLU were 0.10%, 0.11%, 0.11%,0.17% and 0.16%, respectively, by regression analysis.
This study aims to investigate the prevalence and genotype distribution of anal human papillomavirus (HPV) infection among men with different sexual orientations with or without human immunodeficiency virus (HIV) in China. A cross-sectional study was conducted during 2016–2017 in Taizhou City, Zhejiang Province. Convenient sampling was used to recruit male participants from HIV voluntary counselling and testing clinics and Center for Disease Control and Prevention. A face-to-face questionnaire interview was administered and an anal-canal swab was collected for HPV genotyping. A total of 160 HIV-positive and 113 HIV-negative men participated in the study. The prevalence of any type HPV was 30.6% for heterosexual men, 74.1% for homosexual and 63.6% for bisexual men among HIV-positive participants, while the prevalence was 8.3%, 29.2% and 23.8% respectively among HIV-negatives. The most prevalent genotypes were HPV-58 (16.9%), HPV-6 (15.6%) and HPV-11 (15.0%) among HIV-positive men, and were HPV-16 (4.4%), HPV-52 (4.4%) and HPV-6 (3.5%) among HIV-negative men. Having ever had haemorrhoids and having ever seen blood on tissue after defaecation was associated with HPV infection. One-fourth of the HPV infections in this study population can be covered by the quadrivalent vaccine in market. The highly prevalent anal HPV infection among men especially HIV-infected men calls for close observation and further investigation for anal cancer prevention.
Starch digestion in the small intestines of the dairy cow is low, to a large extent, due to a shortage of syntheses of α-amylase. One strategy to improve the situation is to enhance the synthesis of α-amylase. The mammalian target of rapamycin (mTOR) signalling pathway, which acts as a central regulator of protein synthesis, can be activated by leucine. Our objectives were to investigate the effects of leucine on the mTOR signalling pathway and to define the associations between these signalling activities and the synthesis of pancreatic enzymes using an in vitro model of cultured Holstein dairy calf pancreatic tissue. The pancreatic tissue was incubated in culture medium containing l-leucine for 3 h, and samples were collected hourly, with the control being included but not containing l-leucine. The leucine supplementation increased α-amylase and trypsin activities and the messenger RNA expression of their coding genes (P <0.05), and it enhanced the mTOR synthesis and the phosphorylation of mTOR, ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E-binding protein 1 (P <0.05). In addition, rapamycin inhibited the mTOR signal pathway factors during leucine treatment. In sum, the leucine regulates α-amylase and trypsin synthesis in dairy calves through the regulation of the mTOR signal pathways.