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While national rules regarding the scope, availability and issuance of utility models vary from country to country, most utility model regimes offer protection for tangible products, with many, but not all, jurisdictions excluding processes, biological materials and computer software from the scope of protection. The duration of utility model protection ranges from five to fifteen years, with most countries offering ten years of protection. In most countries, utility model applications are not formally examined and must simply disclose the product in question. Given the lack of examination, obtaining utility models is generally viewed as faster and cheaper than obtaining patents. This combination of speed and cost, in theory, makes utility models potentially attractive to small and medium enterprises (SMEs) that cannot afford to obtain full patent protection. Similar considerations have also been raised as advantageous to innovators in low-income countries.
In laboratory testing, a novel hydrogen peroxide gas plasma endoscope sterilizer consistently reduced vegetative organisms, but not bacterial spores, to undetectable levels in the presence of high organism load (≥6.5 log10) and organic material and salts. These findings highlight the importance of meticulous cleaning of endoscopes prior to sterilization.
Procedure duration is an important predictor of patient outcomes in surgery. However, the relationship between procedure duration and adverse events in congenital cardiac catheterization is largely unexplored.
Methods:
All cases entered into the Congenital Cardiac Catheterization Project on Outcomes from 2014 to 2017 were included. Cases were ordered from shortest to longest case length, minus time spent managing adverse events, for each case type. The outcomes, Level 3bc/4/5 and 4/5 adverse event rates, were calculated for cases above and below the 75th percentile for case length. To identify an independent relationship between case length and outcomes, the case length percentile was added to the CHARM II risk model.
Results:
Among 14,704 catheterizations, longer cases (>75th percentile for case length) had Level 4/5 rates that were 2.2% and 2.7% compared to cases ≤75th percentile with adverse event rates of 0.9% and 1.4% for diagnostic and interventional cases, respectively. Level 3bc/4/5 rates were 5.0% and 8.4% in longer cases compared to 2.4% and 5.4% for diagnostic and interventional cases, respectively. After adding case length to the CHARM II risk model, case length 50th–75th percentile had an odds ratio (OR) of 1.4, 75th–90th percentile an OR of 1.56, and >90th percentile an OR of 2.24 as compared to cases with case length <50th percentile (p ≤ 0.001 for all).
Conclusions:
Longer case lengths are associated with clinically important and life-threatening adverse events in congenital cardiac catheterization, even after accounting for known risk factors. Case length may be an important target for future quality improvement work.
The strategy method (SM) is, in practice, subject to a possibly severe economic-theoretical bias. Although many studies utilize SM to examine responses to rare or off-equilibrium behaviors unattainable through direct elicitation (DE), they ignore the fact that the strategic equivalence between SM and DE holds for the monetary payoff game but not the game participants actually play, which is in terms of utilities. We report three results. First, failing to account for estimation bias when decisions at one information set can influence utility at another may result in significant differences in decision-making. Second, the magnitude of this bias can be substantial, comparable to other measured treatment effects. Third, minor interventions targeting salience can amplify these differences similarly, causing treatment effects to differ significantly between SM and DE, even reversing in direction. These findings emphasize the need for reconsideration of the SM’s reliability for economic research.
This article highlights a potential and significant economic–theoretical bias in the widely used strategy method (SM) technique. Although SM is commonly employed to analyze numerous observations per subject regarding rare or off-equilibrium behaviors unattainable through direct elicitation (DE), researchers often overlook a critical distinction. The strategic equivalence between SM and DE is applicable in the context of monetary payoff games, but not in the actual utility-based games played by participants. This oversight may lead to inaccurate conclusions and demand a reevaluation of existing research in the field. We formalize the mapping from the monetary payoff game to this actual game and delineate necessary and sufficient conditions for strategic equivalence to apply.
Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
Disruptions of antipsychotic therapy lead to greater symptoms and increased likelihood of relapse. One way to improve medication adherence has been with long-acting formulations, usually administered by injection. Implantable technology has been used to support medication continuity in a few therapeutic areas, e.g., contraception. Despite the potential benefits from implants, this modality is not yet available for maintenance treatment of schizophrenia. Delpor, Inc. is developing an investigational risperidone implant (DLP-114) that releases therapeutic drug levels for up to 12-months. Initial clinical findings are reported below.
Methods
The DLP-114 implant is a titanium cylinder approximately 4-5 cm long and 5 mm in diameter. It has membranes mounted on each end and is loaded with a proprietary formulation of risperidone.
The clinical study (NCT04418466) was an open-label study in stable schizophrenia patients to evaluate the safety, tolerability, and pharmacokinetics (PK) of switching from oral risperidone to DLP-114. Schizophrenia patients (N=28), stable on a 2-3 mg dose of oral risperidone for ≥2 weeks were randomized to receive either 6- or 12-month DLP-114 implant devices. Each patient received two DLP-114 devices implanted in the abdomen. Device placements were conducted through a 10-minute procedure using local anesthetic and a custom placement tool. Plasma levels of risperidone and 9-hydroxyrisperidone were tracked over the treatment period, and patients were clinically monitored for signs of relapse. Patient safety (including local tolerance and emergent AEs) and PK were the principal endpoints. Secondary clinical endpoints included PANSS and CGI scores.
Results
The placement and removal procedures were well tolerated. Of 28 enrolled patients, two were lost to follow up and one asked to have the implant removed prior to the end of the dosing period. One nonrelated SAE (pulmonary embolism) was reported. Treatment-related AEs were generally mild, and included implant site pain/soreness/tenderness, drowsiness, ecchymosis, increased appetite, insomnia, and headache. The PK profile in both groups followed near zero-order kinetics with both dosing periods until the end of study. The average steady-state plasma concentration ranged between 7-13 ng/mL. One patient was removed from the study with signs of impending relapse. All other patients were clinically stable for the study duration, with average PANSS scores from 50-60 and CGI-I scores from 3-4. PANSS and CGI-I scores were comparable between the oral and the implant phases of the study.
Conclusions
DLP-114 was well tolerated for up to 12 months. Average PANSS and CGI-I scores were similar between the oral and implant treatment phases, suggesting that, for most patients, DLP-114 provided a comparable therapeutic benefit to 2-3 mg of daily oral risperidone over time. Plasma concentrations of risperidone and 9-hydroxyrisperidone were substantially constant for 6-12 months, but values for steady-state Cave fell slightly below the target of 10-14 ng/mL.
Funding
Research reported in this poster was supported by Delpor, Inc. and by the National Institute of Mental Health of the National Institutes of Health under award number R44MH094036.
Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties.
Aims
To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD.
Method
The Ketamine for Adult Depression Study was a multisite 4-week randomised, double-blind, active (midazolam)-controlled trial. The study initially used fixed low dose ketamine (0.5 mg/kg, cohort 1), before protocol revision to flexible, response-guided dosing (0.5–0.9 mg/kg, cohort 2). This secondary analysis assessed anxiety using the Hamilton Anxiety (HAM-A) scale (primary measure) and ‘inner tension’ item 3 of the Montgomery–Åsberg Depression Rating Scale (MADRS), at baseline, 4 weeks (end treatment) and 4 weeks after treatment end. Analyses of change in anxiety between ketamine and midazolam groups included all participants who received at least one treatment (n = 174), with a mixed effects repeated measures model used to assess the primary anxiety measure. The trial was registered at www.anzctr.org.au (ACTRN12616001096448).
Results
In cohort 1 (n = 68) the reduction in HAM-A score was not statistically significant: −1.4 (95% CI [−8.6, 3.2], P = 0.37), whereas a significant reduction was seen for cohort 2 (n = 106) of −4.0 (95% CI [−10.6, −1.9], P = 0.0058), favouring ketamine over midazolam. These effects were mediated by total MADRS and were not maintained at 4 weeks after treatment end. MADRS item 3 was also significantly reduced in cohort 2 (P = 0.026) but not cohort 1 (P = 0.96).
Conclusion
Ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.
Ward round quality is a pivotal component of surgical care and is intimately associated with patient outcomes. Despite this, ward rounds remain largely understudied and underrepresented in medical literature. Accurate and thorough ward round documentation is known to improve communication and patient outcomes and to reduce hospital expenditure. This study aimed to determine the accuracy of ward round documentation.
Methods
A prospective observational cohort study was performed as a sub-analysis of a larger study by reviewing 135 audiovisual recordings of surgical ward rounds over two years at two hospitals. The recordings were transcribed verbatim, and content was designated a level of importance by an external reviewer. This was then compared to the written case notes to determine the accuracy and importance of omitted documentation. Patient age, sex, and length of stay, as well as the senior doctor leading and the intern documenting the ward round, were assessed using multivariable linear mixed-effect models to determine their impact on documentation accuracy.
Results
Nearly one-third (32.4%) of spoken information on the surgical ward round that was deemed “important”, including discharge plans and bookings for surgery, was absent from the patients’ electronic medical records. Additionally, in 11 percent of case notes there was a major conflict between the ward round discussion and what was documented. Younger patients (p=0.04) and patients who had been on the ward longer (p=0.005) were less likely to have accurate documentation. Some interns were significantly worse at documenting discussions than were others (p<0.0001). Day of the week, location, and the senior doctor present did not affect documentation accuracy.
Conclusions
This study demonstrates that a significant amount of important discussion during surgical ward rounds regarding patient care is not recorded accurately, or at all, in the patient medical record. This can lead to preventable patient complications and longer hospital stays, resulting in increased strain on hospital resources. This study emphasizes the need for further research to address this problem.
We aim to estimate school value-added dynamically in time. Our principal motivation for doing so is to establish school effectiveness persistence while taking into account the temporal dependence that typically exists in school performance from one year to the next. We propose two methods of incorporating temporal dependence in value-added models. In the first we model the random school effects that are commonly present in value-added models with an auto-regressive process. In the second approach, we incorporate dependence in value-added estimators by modeling the performance of one cohort based on the previous cohort’s performance. An identification analysis allows us to make explicit the meaning of the corresponding value-added indicators: based on these meanings, we show that each model is useful for monitoring specific aspects of school persistence. Furthermore, we carefully detail how value-added can be estimated over time. We show through simulations that ignoring temporal dependence when it exists results in diminished efficiency in value-added estimation while incorporating it results in improved estimation (even when temporal dependence is weak). Finally, we illustrate the methodology by considering two cohorts from Chile’s national standardized test in mathematics.
Both childhood adversity (CA) and first-episode psychosis (FEP) have been linked to alterations in cortical thickness (CT). The interactive effects between different types of CAs and FEP on CT remain understudied.
Methods
One-hundred sixteen individuals with FEP (mean age = 23.8 ± 6.9 years, 34% females, 80.2% non-affective FEP) and 98 healthy controls (HCs) (mean age = 24.4 ± 6.2 years, 43% females) reported the presence/absence of CA <17 years using an adapted version of the Childhood Experience of Care and Abuse (CECA.Q) and the Retrospective Bullying Questionnaire (RBQ) and underwent magnetic resonance imaging (MRI) scans. Correlation analyses were used to assess associations between brain maps of CA and FEP effects. General linear models (GLMs) were performed to assess the interaction effects of CA and FEP on CT.
Results
Eighty-three individuals with FEP and 83 HCs reported exposure to at least one CA. CT alterations in FEP were similar to those found in participants exposed to separation from parents, bullying, parental discord, household poverty, and sexual abuse (r = 0.50 to 0.25). Exposure to neglect (β = −0.24, 95% CI [−0.37 to −0.12], p = 0.016) and overall maltreatment (β = −0.13, 95% CI [−0.20 to −0.06], p = 0.043) were associated with cortical thinning in the right medial orbitofrontal region.
Conclusions
Cortical alterations in individuals with FEP are similar to those observed in the context of socio-environmental adversity. Neglect and maltreatment may contribute to CT reductions in FEP. Our findings provide new insights into the specific neurobiological effects of CA in early psychosis.
In the winter of 2022–2023, hundreds of the Atlantic puffins (Fratercula arctica) appeared dead in the coast of the Canary Islands, a rare event considering their cold-living habits, normally occupying the North Atlantic Ocean. In this work, investigation about the parasites present in the Atlantic puffins found in the biggest islands of the Archipelago was carried out from a population portion. Necropsies of 39 birds were made and, during the examination of the urinary tracts, helminths were found. Morphoanatomical analysis under microscope allowed to identify them into Renicola genus with high similarity to Renicola sloanei. After that, DNA was extracted and NADH dehydrogenase subunit 1 gene were amplificated by a polymerase chain reaction method followed by sequencing and phylogenetic analysis. The molecular results demonstrated that in fact R. sloanei was the helminth parasite present in the urinary tracts of the Atlantic puffins found in the Canary Islands.
Despite societal perceptions of older adults as vulnerable, literature on resilience suggests that exposure to adversity and resources gained with life experience contribute to adaptation. One way to explore the nature of resilience is to document assets supporting adaptation. Interviews were conducted with older adults living in Canada at two time points during the COVID-19 pandemic, September 2020–May 2021 (T1) and January–August 2022 (T2). Reflexive thematic analysis was completed to report on what older adults identified as assets and how they understood the value of those assets for resilience. Participants indicated that the potential value of their contributions went largely untapped at the level of the community but supported individual and household adaptation. In line with calls for an all-of-society approach to reduce disaster risk and support resilience, creating a culture of inclusivity that recognizes the potential contributions of older adults should be paired with opportunities for action.
Visceral leishmaniasis (VL) is a tropical disease that can be fatal if acute and untreated. Diagnosis is difficult, the treatment is toxic and prophylactic vaccines do not exist. Leishmania parasites express hundreds of proteins and several of them are relevant for the host's immune system. In this context, in the present study, 10 specific T-cell epitopes from 5 parasite proteins, which were identified by antibodies in VL patients’ sera, were selected and used to construct a gene codifying the new chimeric protein called rCHI. The rCHI vaccine was developed and thoroughly evaluated for its potential effectiveness against Leishmania infantum infection. We used monophosphoryl lipid A (MPLA) and polymeric micelles (Mic) as adjuvant and/or delivery system. The results demonstrated that both rCHI/MPLA and rCHI/Mic significantly stimulate an antileishmanial Th1-type cellular response, with higher production of IFN-γ, TNF-α, IL-12 and nitrite in vaccinated animals, and this response was sustained after challenge. In addition, these mice significantly reduced the parasitism in internal organs and increased the production of IgG2a isotype antibodies. In vivo and in vitro toxicity showed that rCHI is safe for the mammalians, and the recombinant protein also induced in vitro lymphoproliferative response and production of Th1-type cytokines by human cells, which were collected from healthy subjects and treated VL patients. These data suggest rCHI plus MPLA or micelles could be considered as a vaccine candidate against VL.
Rotor-stator flows are known to exhibit instabilities in the form of circular and spiral rolls. While the spirals are known to emanate from a supercritical Hopf bifurcation, the origin of the circular rolls is still unclear. In the present work we suggest a quantitative scenario for the circular rolls as a response of the system to external forcing. We consider two types of axisymmetric forcing: bulk forcing (based on the resolvent analysis) and boundary forcing using direct numerical simulation. Using the singular value decomposition of the resolvent operator the optimal response is shown to take the form of circular rolls. The linear gain curve shows strong amplification at non-zero frequencies following a pseudo-resonance mechanism. The optimal energy gain is found to scale exponentially with the Reynolds number $Re$ (for $Re$ based on the rotation rate and interdisc spacing $H$). The results for both types of forcing are compared with former experimental works and previous numerical studies. Our findings suggest that the circular rolls observed experimentally are the effect of the high forcing gain together with the roll-like form of the leading response of the linearised operator. For high enough Reynolds number it is possible to delineate between linear and nonlinear responses. For sufficiently strong forcing amplitudes, the nonlinear response is consistent with the self-sustained states found recently for the unforced problem. The onset of such non-trivial dynamics is shown to correspond in state space to a deterministic leaky attractor, as in other subcritical wall-bounded shear flows.
Objectives: Evaluate the chronobiological rhythm of elderly people with type I bipolar disorder (BD), stable and without dementia, compared to controls.
Methods: A cross-sectional study was performed with 20 patients diagnosed with type I bipolar disorder, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and 20 controls. Actigraphic records were gathered from all participants over 7 days, besides clinical and demographic information. Non-parametric chronobiological measurements were calculated to evaluate the activity-rest cycle. Comparisons between groups were evaluated using Student’s t-test or Mann-Whitney test, for data with normal and non- normal distribution, respectively. All procedures were conducted following the principles outlined in the Declaration of Helsinki.
Results: Compared to controls, patients with type I BD exhibited lower M10 values, which represent the average activity during the 10 hours of peak movement within 24 hours. Additionally, they showed increased daytime and nighttime inactivity, decreased exposure to nighttime light, and higher sleep fragmentation, as evaluated by the Hurst exponent. No differences were observed between the groups about L5 values, a parameter that indicates the average activity time in the 5 hours of least activity within 24 hours, exposure to daylight, and autocorrelation, a measure that assesses sleep synchronization.
Conclusions: Differences in chronobiological patterns were observed between elderly patients with type I BD and controls. In general, patients exhibited reduced activity levels, both during the daytime and nighttime. These findings may be related to the progression of the disease, as well as prolonged exposure to medications to treat BD, such as mood stabilizers and antipsychotics. The increased sleep fragmentation observed in patients may also be associated with these factors. To date, there is a lack of data assessing the chronobiological rhythm and sleep patterns in elderly individuals with TB, underscoring the need for further studies involving thispopulation.
In this chapter we consider aspects of phonology for bimodal bilinguals, whose languages span distinct modalities (spoken/signed/written). As for other bilinguals, the primary issues concern the representation of the phonology for each language individually, ways that the phonological representations interact with each other (in grammar and in processing), and the development of the two phonologies, for children developing as simultaneous bilinguals or for learners of a second language in a second modality. Research on these topics has been sparse, and some have hardly been explored at all. Findings so far indicate that despite the modality difference between their two languages, phonological interactions still occur for bimodal bilinguals, providing crucial data for linguistic theories about the locus and mechanisms for such interactions, and important practical implications for language learners.
Finding effective ways to monitor laying hen welfare is challenging as UK flock sizes can reach 16,000 birds. Eggs provide potential for welfare monitoring, as they are a daily output with previous evidence of links to stress. We explored the associations between stressors and eggs using two complementary studies. In Study 1, hens experienced social or heat stressors and eggs were scored daily for defects in shell characteristics. All eggs were scored on a three-point scale: 1 (no defect); 2 (minor defects); or 3 (unsuitable for whole egg sale in the UK). Texture defects were higher after stress treatments and were explored further as a promising proxy measure of welfare. In Study 2, eggshell texture from five commercial flocks was scored before versus at the onset of an avian influenza-enforced indoor housing, and scores were correlated with industry data for egg quality. Eggs were more likely to have texture defects after the enforced indoor housing, and manually scored texture correlated significantly with shell strength and shell colour during automated grading. Shell strength was weaker immediately after the enforced indoor housing and eggs were darker. We suggest that eggshell texture could be a useful addition to assessing changes or stresses in a hen’s environment for both research and commercial purposes, but further validation is needed to understand the generalisability of these results to other stressors. Additionally, data already collected in factories, such as shell strength and colour, may provide information on stress and could be valorised for understanding hen welfare.
Genetic vulnerability to mental disorders has been associated with coronavirus disease-19 (COVID-19) outcomes. We explored whether polygenic risk scores (PRSs) for several mental disorders predicted poorer clinical and psychological COVID-19 outcomes in people with pre-existing depression.
Methods
Data from three assessments of the Australian Genetics of Depression Study (N = 4405; 52.2 years ± 14.9; 76.2% females) were analyzed. Outcomes included COVID-19 clinical outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection and long COVID, noting the low incidence of COVID-19 cases in Australia at that time) and COVID-19 psychological outcomes (COVID-related stress and COVID-19 burnout). Predictors included PRS for depression, bipolar disorder, schizophrenia, and anxiety. The associations between these PRSs and the outcomes were assessed with adjusted linear/logistic/multinomial regressions. Mediation (N = 4338) and moderation (N = 3326) analyses were performed to explore the potential influence of anxiety symptoms and resilience on the identified associations between the PRSs and COVID-19 psychological outcomes.
Results
None of the selected PRS predicted SARS-CoV-2 infection or long COVID. In contrast, the depression PRS predicted higher levels of COVID-19 burnout. Anxiety symptoms fully mediated the association between the depression PRS and COVID-19 burnout. Resilience did not moderate this association.
Conclusions
A higher genetic risk for depression predicted higher COVID-19 burnout and this association was fully mediated by anxiety symptoms. Interventions targeting anxiety symptoms may be effective in mitigating the psychological effects of a pandemic among people with depression.
In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.
Methods:
A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.
Results:
We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.
Conclusion:
The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.