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Approximately 70% of patients with bipolar disorder (BPD) are initially misdiagnosed, resulting in significantly delayed diagnosis of 7–10 years on average. Misdiagnosis and diagnostic delay adversely affect health outcomes and lead to the use of inappropriate treatments. As depressive episodes and symptoms are the predominant symptom presentation in BPD, misdiagnosis as major depressive disorder (MDD) is common. Self-rated screening instruments for BPD exist but their length and reliance on past manic symptoms are barriers to implementation, especially in primary care settings where many of these patients initially present. We developed a brief, pragmatic bipolar I disorder (BPD-I) screening tool that not only screens for manic symptoms but also includes risk factors for BPD-I (eg, age of depression onset) to help clinicians reduce the misdiagnosis of BPD-I as MDD.
Existing questionnaires and risk factors were identified through a targeted literature search; a multidisciplinary panel of experts participated in 2 modified Delphi panels to select concepts thought to differentiate BPD-I from MDD. Individuals with self-reported BPD-I or MDD participated in cognitive debriefing interviews (N=12) to test and refine item wording. A multisite, cross-sectional, observational study was conducted to evaluate the screening tool’s predictive validity. Participants with clinical interview-confirmed diagnoses of BPD-I or MDD completed a draft 10-item screening tool and additional questionnaires/questions. Different combinations of item sets with various item permutations (eg, number of depressive episodes, age of onset) were simultaneously tested. The final combination of items and thresholds was selected based on multiple considerations including clinical validity, optimization of sensitivity and specificity, and pragmatism.
A total of 160 clinical interviews were conducted; 139 patients had clinical interview-confirmed BPD-I (n=67) or MDD (n=72). The screening tool was reduced from 10 to 6 items based on item-level analysis. When 4 items or more were endorsed (yes) in this analysis sample, the sensitivity of this tool for identifying patients with BPD-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties represent an improvement over the Mood Disorder Questionnaire, while using >50% fewer items.
This new 6-item BPD-I screening tool serves to differentiate BPD-I from MDD in patients with depressive symptoms. Use of this tool can provide real-world guidance to primary care practitioners on whether more comprehensive assessment for BPD-I is warranted. Use of a brief and valid tool provides an opportunity to reduce misdiagnosis, improve treatment selection, and enhance health outcomes in busy clinical practices.
The MITIGATE toolkit was developed to assist urgent care and emergency departments in the development of antimicrobial stewardship programs. At the University of Washington, we adopted the MITIGATE toolkit in 10 urgent care centers, 9 primary care clinics, and 1 emergency department. We encountered and overcame challenges: a complex data build, choosing feasible outcomes to measure, issues with accurate coding, and maintaining positive stewardship relationships. Herein, we discuss solutions to challenges we encountered to provide guidance for those considering using this toolkit.
To describe epidemiologic and genomic characteristics of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in a large skilled-nursing facility (SNF), and the strategies that controlled transmission.
Design, setting, and participants:
This cohort study was conducted during March 22–May 4, 2020, among all staff and residents at a 780-bed SNF in San Francisco, California.
Contact tracing and symptom screening guided targeted testing of staff and residents; respiratory specimens were also collected through serial point prevalence surveys (PPSs) in units with confirmed cases. Cases were confirmed by real-time reverse transcription–polymerase chain reaction testing for SARS-CoV-2, and whole-genome sequencing (WGS) was used to characterize viral isolate lineages and relatedness. Infection prevention and control (IPC) interventions included restricting from work any staff who had close contact with a confirmed case; restricting movement between units; implementing surgical face masking facility-wide; and the use of recommended PPE (ie, isolation gown, gloves, N95 respirator and eye protection) for clinical interactions in units with confirmed cases.
Of 725 staff and residents tested through targeted testing and serial PPSs, 21 (3%) were SARS-CoV-2 positive: 16 (76%) staff and 5 (24%) residents. Fifteen cases (71%) were linked to a single unit. Targeted testing identified 17 cases (81%), and PPSs identified 4 cases (19%). Most cases (71%) were identified before IPC interventions could be implemented. WGS was performed on SARS-CoV-2 isolates from 4 staff and 4 residents: 5 were of Santa Clara County lineage and the 3 others were distinct lineages.
Early implementation of targeted testing, serial PPSs, and multimodal IPC interventions limited SARS-CoV-2 transmission within the SNF.
In this paper we study the receptivity of the boundary layer to suction/blowing in marginally separated flows, like the one on the leading edge of a thin aerofoil. We assume that the unperturbed laminar flow is two-dimensional, and investigate the response of the boundary layer to two-dimensional as well as to three-dimensional perturbations. In both cases, the perturbations are assumed to be weak and periodic in time. Unlike conventional boundary layers, the marginally separated boundary layers cannot be treated using the quasi-parallel approximation. This precludes the normal-mode representation of the perturbations. Instead, we had to solve the linearised integro-differential equation of the marginal separation theory, which was done numerically. For two-dimensional perturbations, the results of the calculations show that the perturbations first grow in the inside of the separation region, but then start to decay downstream. For three-dimensional perturbations, instead of dealing with the integro-differential equation of marginal separation, we found it convenient to work with the Fourier transforms of the fluid-dynamic functions. The equations for the Fourier transforms are also solved numerically. Our calculations show that a three-dimensional wave packet forms downstream of the source of perturbations in the boundary layer.
Childhood Attention deficit hyperactivity disorder (ADHD) symptomatology persists in a substantial proportion of cases into adult life. ADHD is highly heritable but the etiology of ADHD is complex and heterogeneous, involving both genetic and non-genetic factors. In the present paper we analyzed the influence of both genetics and adverse life events on severity of ADHD symptoms in 110 adult ADHD patients. Subjects were genotyped for the norepinephrine transporter (NET), the Catechol-O-methyltransferase (COMT), the serotonin transporter promoter polymorphism (SERTPR) and the more rare A/G variant within SERTPR. Three main outcomes were obtained: (1) adverse events showed a small but positive correlation with current ADHD severity; (2) NET, COMT and the A/G variant within SERTPR were not associated with ADHD severity; (3) taking into account stressors, the long (L) SERTPR variant showed a mild effect on ADHD, being associated with an increased severity, particularly as regard affective dysregulations; on the other hand, in subjects exposed to early stressors, it showed a protective effect, as compared to the S variant (see table). In conclusion, our data support the role of environmental factors in adult ADHD symptomatology. SERTPR may be involved in some features of the illness and act as a moderator of environmental influences in ADHD.
Patients with bipolar disorder experience a wide range of depressive and manic symptoms. Only 2 drugs are FDA-approved to treat episodes of both mania and depression in patients with bipolar disorder, highlighting the need for treatments with proven efficacy at opposite poles of the bipolar spectrum. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, is approved in the US for the treatment of both bipolar depression and manic and mixed episodes associated with bipolar I disorder. Cariprazine has previously demonstrated broad efficacy in patients with bipolar mania, with significantly greater improvement in favor of cariprazine vs placebo (PBO) across all individual symptom domains (P<.001) measured by the Young Mania Rating Scale (YMRS). Additionally, cariprazine has demonstrated efficacy vs PBO in 3 phase II/III clinical studies in patients with depressive episodes associated with bipolar I disorder (NCT01396447, NCT02670538, NCT02670551). To further assess the broad efficacy of cariprazine in patients with bipolar I disorder, we performed post hoc analyses to evaluate the range of depressive symptoms comprising the individual items of the Montgomery-Åsberg Depression Rating Scale (MADRS) in patients from the bipolar depression studies.
Data from the 3 randomized, double-blind, PBO-controlled trials in patients with bipolar depression were pooled. Least squares (LS) mean change from baseline to week 6 in MADRS individual items was assessed in the pooled cariprazine 1.5 and 3 mg/d groups vs PBO using a mixed-effects model for repeated measures in the intent-to-treat (ITT) population.
There were 1383 patients in the ITT population (placebo=460; cariprazine 1.5-3 mg/d=923). At week 6, LS mean change from baseline was significantly greater for cariprazine 1.5-3 mg/d vs PBO on 9 of 10 individual MADRS items: Apparent Sadness (-2.0 vs -1.6, P<.0001); Reported Sadness (-2.0 vs -1.6, P<.0001); Reduced Sleep (-1.6 vs -1.4, P=.0357); Reduced Appetite (-1.2 vs -1.0, P=.0001); Concentration Difficulties (-1.5 vs -1.2, P=.0002); Lassitude (-1.7 vs -1.4, P=.0003); Inability To Feel (-1.7 vs -1.5, P=.0009); Pessimistic Thoughts (-1.4 vs -1.2, P=.0054) and Suicidal Thoughts (-0.3 vs -0.2, P=.0383); differences between cariprazine and PBO on the Inner Tension item were not significant.
Significant improvement in most MADRS single items suggests broad efficacy in depressive symptoms for cariprazine 1.5-3 mg/d vs PBO in patients with bipolar depression. Coupled with broad efficacy in manic symptoms as demonstrated by significant improvement in all YMRS individual items in patients with bipolar mania or mixed episodes, cariprazine appears be effective across the range of symptoms that affect patients with bipolar disorder.
Pharmacogenetic studies in obsessive-compulsive disorder (OCD) primarily focussing on serotonergic and dopaminergic polymorphisms, provided inconsistent findings. There is recent evidence for glutamatergic abnormalities in OCD.
Examine the association glutamatergic genes with serotonin reuptake inhibitor (SRI) response in OCD.
To study pharmacogenetic association between SLC1A1 and GRIN2B polymorphisms with SRI response in OCD.
DSM-IV OCD patients were recruited from a specialty OCD clinic and evaluated using the Yale-Brown obsessive compulsive scale (YBOCS), Mini International Neuropsychiatric Interview (MINI) plus, Clinical Global Impression scale (CGI). They were subsequently reassessed with YBOCS and CGI. To study extreme phenotypes, we included only full responders (> 35% YBOCS improvement and CGI-I score of 1 or 2) to any SRI (n = 191) and non-responders (< 25% YBOCS improvement and CGI-I score ≥ 4) to adequate trial of at least two SRIs (n = 84). Partial responders were excluded. Genotyping was performed using an ABI9700 PCR machine.
Genotype frequencies did not deviate significantly from the values predicted by the Hardy-Weinberg equation. Case-control association analyses revealed no significant association between genotype/allele frequencies with SRI response.
Our data does not show any association between polymorphisms in glutamatergic genes and SRI response in OCD though such associations have been found in other studies. More SNP's in the same gene could be responsible for the pharmacogenetic associations. More homogenous sample considering symptom dimensions and other phenotypic variables may be needed. It may be critical to go beyond “usual suspect” candidate gene research. In this regard, a novel approach to identify SRI response biomarkers is the use of cellular models.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Contemporary treatment guidelines recommend use of second-generation antipsychotics (SGAs) either as mono therapy or in combination with mood stabilizers as first-line treatment. While these drugs have been established to have superior efficacy compared to placebo, there is very less data comparing these antipsychotics with one another. We sought to study differences in the five-year outcome of first episode of mania (FEM) treated with olanzapine or risperidone, either alone or in combination with mood stabilizer.
We conducted a retrospective chart review of patients diagnosed with FEM (ICD-10) in the year 2008 (n = 88) at our centre. We selected the data of patients prescribed either olanzapine or risperidone for the purpose of this analysis. We extracted data about time to recovery and recurrence after FEM, total episodes, drug compliance and response, and number of follow-up visits from 2008 to 2013. The study was approved by the Institute Ethics Committee.
A total of 88 patients received diagnosis of FEM in the year 2008, of which 50 (56.8%) received risperidone and 35 (39.8%) received olanzapine. The two groups were comparable in socio-demographic and clinical symptomatology of FEM (all P > 0.08). Complete recovery was significantly more in the olanzapine group than the risperidone group (χ2 = 4.84, P < 0.05).
Our study indicates that risperidone and olanzapine, either alone or in combination with mood stabilizers have a similar impact on the five-year course of BD following a first manic episode. However, olanzapine is associated with more complete recovery from FEM than risperidone.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Sheath blight caused by soil borne necrotrophic fungus Rhizoctonia solani [teleomorph-Thanatephorus cucumeris (Frank) Donk.] is a major disease of rice. The disease is increasing over the year in India and cause up to 69% yield loss under favourable conditions. A total of 67 accessions of Oryza nivara were screened to identify resistance against sheath blight during 2015. Out of these, 16 accessions were found moderately resistant (MR) which were further evaluated during the year 2016 and 2017. After three years of screening, 12 of them were found to have a consistent moderate resistant reaction whereas four of the O. nivara accessions namely, IRGC81941, IRGC102463C, CR100097 and CR100110A have shown moderately susceptible to susceptible reaction against sheath blight. A correlation study revealed that different disease variables measured were significantly (P < 0.05) correlated. All the genotypes and genotype × environment interaction had a significant (P < 0.001) effect on all the disease variables. Cluster analysis showed that all the accessions were clustered into four groups which showed resistant, MR, moderately susceptible and susceptible reactions. Among all the O. nivara accessions IRGC81941A showed the maximum potential against sheath blight due to a least relative lesion height of 22.80%. None of the accession had complete resistance to the disease. The identified promising accessions such as IRGC81835, IRGC81941A, CR100008 and CR100111B can be utilized in a sheath blight resistance breeding program.
To study 2D and 3D dosimetric values for bladder and rectum, and the influence of bladder volume on bladder dose in high dose rate (HDR) intracavitary brachytherapy (ICBT). The large patient data incorporated in this study would better represent the inherent variations in many parameters affecting dosimetry in HDR-ICBT.
Material and Methods:
We prospectively collected data for 103 consecutive cervical cancer patients (over 310 HDR fractions) undergoing CT-based HDR-ICBT at our centre. Correlation among bladder and rectum maximum volume doses and corresponding International Commission on Radiation Units and Measurement (ICRU) point doses were estimated and analysed. Impact of bladder volume on bladder maximum dose was assessed.
The ICRU point doses to bladder and rectum varied from the volumetric doses to these organs. Further, bladder volume poorly correlated with bladder maximum dose for volume variations encountered in the clinical practice at our centre.
ICRU point doses to bladder and rectum are less likely to correlate with long-term toxicities to these organs. Further, in clinical practice where inter-fraction bladder volume does not vary widely there is no correlation between bladder volume and bladder dose.
We simulate the flow of two immiscible and incompressible fluids separated by an interface in a homogeneous turbulent shear flow at a shear Reynolds number equal to 15 200. The viscosity and density of the two fluids are equal, and various surface tensions and initial droplet diameters are considered in the present study. We show that the two-phase flow reaches a statistically stationary turbulent state sustained by a non-zero mean turbulent production rate due to the presence of the mean shear. Compared to single-phase flow, we find that the resulting steady-state conditions exhibit reduced Taylor-microscale Reynolds numbers owing to the presence of the dispersed phase, which acts as a sink of turbulent kinetic energy for the carrier fluid. At steady state, the mean power of surface tension is zero and the turbulent production rate is in balance with the turbulent dissipation rate, with their values being larger than in the reference single-phase case. The interface modifies the energy spectrum by introducing energy at small scales, with the difference from the single-phase case reducing as the Weber number increases. This is caused by both the number of droplets in the domain and the total surface area increasing monotonically with the Weber number. This reflects also in the droplet size distribution, which changes with the Weber number, with the peak of the distribution moving to smaller sizes as the Weber number increases. We show that the Hinze estimate for the maximum droplet size, obtained considering break-up in homogeneous isotropic turbulence, provides an excellent estimate notwithstanding the action of significant coalescence and the presence of a mean shear.
Dementia is a leading cause of morbidity and mortality without pharmacologic prevention or cure. Mounting evidence suggests that adherence to a Mediterranean dietary pattern may slow cognitive decline, and is important to characterise in at-risk cohorts. Thus, we determined the reliability and validity of the Mediterranean Diet and Culinary Index (MediCul), a new tool, among community-dwelling individuals with mild cognitive impairment (MCI). A total of sixty-eight participants (66 % female) aged 75·9 (sd 6·6) years, from the Study of Mental and Resistance Training study MCI cohort, completed the fifty-item MediCul at two time points, followed by a 3-d food record (FR). MediCul test–retest reliability was assessed using intra-class correlation coefficients (ICC), Bland–Altman plots and κ agreement within seventeen dietary element categories. Validity was assessed against the FR using the Bland–Altman method and nutrient trends across MediCul score tertiles. The mean MediCul score was 54·6/100·0, with few participants reaching thresholds for key Mediterranean foods. MediCul had very good test–retest reliability (ICC=0·93, 95 % CI 0·884, 0·954, P<0·0001) with fair-to-almost-perfect agreement for classifying elements within the same category. Validity was moderate with no systematic bias between methods of measurement, according to the regression coefficient (y=−2·30+0·17x) (95 % CI −0·027, 0·358; P=0·091). MediCul over-estimated the mean FR score by 6 %, with limits of agreement being under- and over-estimated by 11 and 23 %, respectively. Nutrient trends were significantly associated with increased MediCul scoring, consistent with a Mediterranean pattern. MediCul provides reliable and moderately valid information about Mediterranean diet adherence among older individuals with MCI, with potential application in future studies assessing relationships between diet and cognitive function.
Design and development of 2 kW, 3 dB tandem hybrid coupler for the frequency range of 155–225 MHz has been presented in this paper. The developed 3 dB coupler is to be used in a prototype of Ion Cyclotron Resonance Frequency (ICRF) system of Tokamak, which has been developed to test the resilience of ICRF network during continuously variable RF load excursions. The 3 dB coupler divides the RF power between two antennae of the prototype and protects the RF source by coupling of reflected power to the isolated port. The developed coupler shows excellent coupling flatness of −3 ± 0.3 dB over 38% of fractional bandwidth and also provides voltage standing wave ratio (VSWR) <1.3, isolation better than 32 dB and return loss better than 25 dB in full band. The presented work establishes a technique which can be useful for the development of high-power hybrid coupler in the range of high frequency (HF), very high frequency (VHF) and ultra high frequency (UHF).
Background: Reversible splenial lesion syndrome (RESLES) is a rare clinico-radiological entity associated with multiple etiologies including infection, metabolic, and epileptic disorders. We describe the case of a child with a reversible splenial lesion who presented with encephalopathy and prior history of episodic ataxia. Methods: A 3-year-old girl presented to the Stollery Children’s hospital with three days of respiratory symptoms followed by acute onset ataxia and encephalopathy. Blood, respiratory samples, and cerebral spinal fluid (CSF) were drawn to investigate for infectious, autoimmune, and metabolic causes. Magnetic resonance imaging (MRI) brain was done and repeated. Results: A respiratory panel tested positive for respiratory syncytial virus (RSV), enterovirus, and rhinovirus. CSF analysis revealed elevated white blood cell count (283). MRI brain demonstrated diffusion restriction involving the posterior body and splenium of the corpus callosum and bilateral middle cerebral peduncles, which resolved nine days later. The patient received high-dose steroids with gradual improvement in the encephalopathy and ataxia. Conclusions: This report contributes to the complexities in clinical understanding of RESLES, as it highlights a novel presentation with ataxia and encephalopathy. The patient’s diagnosis was complicated by previous ataxic episodes of unknown etiology, which allows further consideration of a metabolic or genetic ataxic syndrome and its relationship to encephalopathy.
Introduction: Situational awareness (SA) is essential for maintenance of scene safety and effective resource allocation in mass casualty incidents (MCI). Unmanned aerial vehicles (UAV) can potentially enhance SA with real-time visual feedback during chaotic and evolving or inaccessible events. The purpose of this study was to test the ability of paramedics to use UAV video from a simulated MCI to identify scene hazards, initiate patient triage, and designate key operational locations. Methods: A simulated MCI, including fifteen patients of varying acuity (blast type injuries), plus four hazards, was created on a college campus. The scene was surveyed by UAV capturing video of all patients, hazards, surrounding buildings and streets. Attendees of a provincial paramedic meeting were invited to participate. Participants received a lecture on SALT Triage and the principles of MCI scene management. Next, they watched the UAV video footage. Participants were directed to sort patients according to SALT Triage step one, identify injuries, and localize the patients within the campus. Additionally, they were asked to select a start point for SALT Triage step two, identify and locate hazards, and designate locations for an Incident Command Post, Treatment Area, Transport Area and Access/Egress routes. Summary statistics were performed and a linear regression model was used to assess relationships between demographic variables and both patient triage and localization. Results: Ninety-six individuals participated. Mean age was 35 years (SD 11), 46% (44) were female, and 49% (47) were Primary Care Paramedics. Most participants (80 (84%)) correctly sorted at least 12 of 15 patients. Increased age was associated with decreased triage accuracy [-0.04(-0.07,-0.01);p=0.031]. Fifty-two (54%) were able to localize 12 or more of the 15 patients to a 27x 20m grid area. Advanced paramedic certification, and local residency were associated with improved patient localization [2.47(0.23,4.72);p=0.031], [-3.36(-5.61,-1.1);p=0.004]. The majority of participants (78 (81%)) chose an acceptable location to start SALT triage step two and 84% (80) identified at least three of four hazards. Approximately half (53 (55%)) of participants designated four or more of five key operational areas in appropriate locations. Conclusion: This study demonstrates the potential of UAV technology to remotely provide emergency responders with SA in a MCI. Additional research is required to further investigate optimal strategies to deploy UAVs in this context.
The U.S. federal government awards a priority review voucher (“PRV”) to a pharmaceutical manufacturer after the Food and Drug Administration (“FDA”) approves a product for one of a list of voucher-eligible indications. The voucher, which can be transferred or sold, allows the company to accelerate the review timeline of another product for any indication. The PRV program was proposed in 2006 as an incentive for research and development for neglected diseases, such as dengue and leishmaniasis.
Neglected tropical diseases (“NTDs”) predominantly affect the world’s poorest populations and are associated with significant morbidity and mortality. Despite their global public health importance, neglected diseases were estimated to account for less than 1% of pharmaceutical research and development expenditures. The voucher program was intended to address this gap between investment and disease burden: “[t]he major obstacle to stimulating the R&D of new medicines for neglected diseases is lowincome nations' inability to pay for such medicines.” The voucher would provide an additional financial incentive to fund clinical development of these products without requiring additional appropriations from Congress.
Jain begins by noting that injury has always been distributed unevenly. But now, well into the twenty-first century, we can’t even point to an untouched, uninjured body capable of being recouped through the promise of a compensatory legal award in a product liability case. Living now means living in a time of injury. While American law, policy, medicine, and experimental science still valorize cause and effect as a necessary condition of regulation, how might “injury” maintain conceptual or political meaning in a post nuclear-testing, post-Monsanto, post-pension world? How might we consider injury as a field rather than as an event constituted by a clear cause and effect? In this chapter, Jain offers a case study of IVF, focusing specifically on the use of hormones and other procedures that have been used off-label or grand-fathered in rather than been fully investigated and deemed safe. Jain disentangles the various aspects of the procedure to better understand how product liability could, in theory, capture the ways in which potential injuries circulate throughout the practice. Jain offers this as a way to understand how injury operates as a field, even a recursive field.
We study 30 solar flare events associated with coronal mass ejections (CMEs) that produced geomagnetic storms as measured in Dst index. Our study reveals that the magnitude of Dst index is significantly associated with maximum solar wind speed, peak of Bz component of the IMF and the product of peak Bz and solar wind speed (minimum and maximum). From our investigations, it can be inferred that CMEs travel with higher speed in the beginning and their speed reduces as they reach L1 location.
We analyze Sun-as-a-star observations spanning over solar cycles 22 – 24 from the ground-based network BiSON and solar cycles 23 – 24 collected by the space-based VIRGO and GOLF instruments on board the SoHO satellite. Using simultaneous observations from all three instruments, our analysis suggests that the structural and magnetic changes responsible for modifying the frequencies remained comparable between cycle 23 and cycle 24 but differ from cycle 22. Thus we infer that the magnetic layer of the Sun has become thinner since the beginning of cycle 23 and continues during the current cycle.
Using continuous observations for 22 years from ground-based network GONG and space-borne instruments MDI onboard SoHO and HMI onboard SDO, we report both global and local properties of the convection zone and their variations with time.