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Akathisia is a common adverse effect associated with use of dopamine receptor blocking agents.1,2 Symptoms of akathisia, in severe cases, may lead to discontinuation of treatment. Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist approved to treat schizophrenia and acute manic, mixed, and depressive episodes of bipolar 1 disorder. Cariprazine is well tolerated in patients across its indications, but is associated with a higher incidence of akathisia compared with placebo.3,4 This pooled post hoc analysis of data from phase 3 clinical trials of adjunctive cariprazine aimed to characterize the incidence, severity, and management of akathisia and other extrapyramidal symptoms (EPS) in adult patients with MDD.
Methods
Patients with MDD and inadequate response to ongoing antidepressant therapy (ADT) were randomized to cariprazine 1.5 mg/d + ADT, cariprazine 3 mg/d + ADT, or placebo + ADT for 6 weeks of double-blind treatment. Post hoc analysis evaluated incidence, severity, and time to resolution of akathisia, restlessness, and other EPS; use of rescue medications; and the rate of discontinuation due to these treatment-emergent adverse events (TEAEs).
Results
A total of 1508 patients (cariprazine + ADT: 1.5 mg/d, n=502, 3 mg/d, n=503; placebo + ADT, n=503) were included in these 2 studies. The incidence of akathisia was greater with cariprazine 3 mg/d + ADT (9.7%) than with cariprazine 1.5 mg/d + ADT (6.4%) and placebo + ADT (2.0%). Most patients treated with cariprazine + ADT (94%) experienced only mild or moderate akathisia. The incidence of restlessness was 3.8% for patients treated with cariprazine 3 mg/d + ADT, 3.6% for cariprazine 1.5 mg/d + ADT, and 1.8% for placebo + ADT. The incidence of EPS excluding akathisia and restlessness was 4.4% for patients treated with cariprazine 3 mg/d + ADT, 4.6% for cariprazine 1.5 mg/d + ADT, and 3.2% for placebo + ADT. For patients treated with cariprazine + ADT and placebo + ADT, respectively, EPS-related study discontinuations were 1.4% and 0.4% due to akathisia, 0.2% and 0.0% due to restlessness, and 0.1% and 0.4% due to EPS excluding akathisia and restlessness. Rescue medications were used to treat EPS-related TEAEs during the double-blind treatment period in 3% of cariprazine-treated patients and 0.4% of placebo-treated patients. The mean time to resolution of akathisia during treatment was slightly shorter in cariprazine-treated patients (15.6 days) versus placebo-treated patients (19.5 days).
Importance
Incidence of akathisia was higher for cariprazine than placebo, with a lower incidence observed for patients treated with cariprazine 1.5 + ADT than with cariprazine 3 mg/d + ADT, suggestive of a dose related effect. Most patients experienced mild or moderate akathisia. Rates of study discontinuation and rescue medication use due to akathisia were low, suggesting that akathisia was tolerated by most patients.
This data was previously presented at the CINP World Congress; Montreal, Canada; May 7-10, 2023.
Anhedonia, a multidimensional domain including the reduced ability to experience pleasure, is a core diagnostic symptom of major depressive disorder (MDD) and a common residual symptom. In patients with MDD, anhedonia has been associated with poor treatment outcomes, suicide and reduced functioning and quality of life. This post-hoc analysis of data from a phase 3 trial (NCT03738215) evaluated the efficacy of adjunctive cariprazine (CAR) treatment on anhedonia symptoms in patients with MDD.
Methods
Patients with MDD and inadequate response to ongoing antidepressant therapy (ADT) were randomized to CAR 1.5 mg/d + ADT, CAR 3 mg/d + ADT, or placebo + ADT for 6 weeks of double-blind treatment. Post hoc analyses evaluated the change from baseline to Week 6 in Montgomery–Åsberg Depression Rating Scale (MADRS) total score, MADRS anhedonia subscale score (items: 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]), and MADRS anhedonia item 8 in the overall modified intent-to-treat (mITT) population and in subgroups of patients with baseline MADRS anhedonia item 8 score of ≥4 or baseline anhedonia subscale score of ≥18. Least square (LS) mean change from baseline to Week 6 was analyzed using a mixed-effects model for repeated measures.
Results
There were 751 patients in the mITT population (CAR + ADT: 1.5 mg/d=250, 3 mg/d=252; placebo + ADT=249). At baseline, 508 (67.6%) patients had MADRS anhedonia item 8 scores ≥4, and 584 (77.8%) had MADRS anhedonia subscale scores ≥18. In the overall mITT population, LS mean change from baseline to Week 6 in anhedonia subscale score was significantly greater for CAR 1.5 mg/d + ADT (-8.4) and CAR 3 mg/d + ADT (-7.9) than for placebo + ADT (-6.8; both P<.05). The LS mean change from baseline in MADRS individual item 8 was also significantly greater for CAR 1.5 mg/d + ADT (-1.7) vs placebo + ADT (-1.3; P=.0085). In both subgroups of patients with baseline anhedonia, CAR 1.5 mg/d + ADT was associated with significantly greater reduction in MADRS total score, MADRS anhedonia subscale score, and MADRS item 8 score compared with placebo + ADT (all P<.05). In the CAR 3 mg/d + ADT group, significantly greater reductions vs placebo + ADT were observed for MADRS total score and MADRS anhedonia subscale score in the subgroup of patients with baseline anhedonia subscale scores ≥18 (both P<.05).
Importance
Adjunctive treatment with CAR was associated with a reduction in symptoms of anhedonia relative to adjunctive placebo in patients with MDD and inadequate response to ADT alone. In subgroups of patients with moderate-to-severe anhedonia at baseline, CAR + ADT demonstrated greater improvements than placebo + ADT in overall depressive symptoms and symptoms of anhedonia. These results suggest that adjunctive CAR treatment may be effective for improving symptoms of anhedonia in patients with MDD who have symptoms of anhedonia.
In the early modern period, both legal and illegal maritime predation was a common occurrence, but the expansion of European maritime empires exacerbated existing and created new problems of piracy across the globe. This collection of original case studies addresses these early modern problems in three sections: first, states' attempts to exercise jurisdiction over seafarers and their actions; second, the multiple predatory marine practices considered 'piracy'; and finally, the many representations made about piracy by states or the seafarers themselves. Across nine chapters covering regions including southeast Asia, the Atlantic archipelago, the North African states, and the Caribbean Sea, the complexities of defining and criminalizing maritime predation is explored, raising questions surrounding subjecthood, interpolity law, and the impacts of colonization on the legal and social construction of ocean, port, and coastal spaces. Seeking the meanings and motivations behind piracy, this book reveals that while European states attempted to fashion piracy into a global and homogenous phenomenon, it was largely a local and often idiosyncratic issue.
This article analyzes how under conditions of crisis certain social actors shift the metasemiotic frames through which minority languages may be approached in order to suit place-branding purposes and to make them more widely accessible for business usage. In the cases we investigate in Shetland and Western Ireland, the new meanings associated with language are connected with how crises are framed and constructed in discourse. We thus examine two types of crises in which certain social actors view language as part of the solution to ward off specific trouble: economic recession (Ireland) and depopulation (Shetland). With the branding potential of these languages then positioned as part of the solutions to “crises,” new indexical alignments exemplify the neoliberal metasemiotic framework through which all elements of social and cultural life may be strategically made marketable—in this case on the intra- and international markets on which people themselves are vied for.
Fifty-three tests designed to measure aspects of creative thinking were administered to 410 air cadets and student officers. The scores were intercorrelated and 16 factors were extracted. Orthogonal rotations resulted in 14 identifiable factors, a doublet, and a residual. Nine previously identified factors were: verbal comprehension, numerical facility, perceptual speed, visualization, general reasoning, word fluency, associational fluency, ideational fluency, and a factor combining Thurstone's closure I and II. Five new factors were identified as originality, redefinition, adaptive flexibility, spontaneous flexibility, and sensitivity to problems.
Next generation high-power laser facilities are expected to generate hundreds-of-MeV proton beams and operate at multi-Hz repetition rates, presenting opportunities for medical, industrial and scientific applications requiring bright pulses of energetic ions. Characterizing the spectro-spatial profile of these ions at high repetition rates in the harsh radiation environments created by laser–plasma interactions remains challenging but is paramount for further source development. To address this, we present a compact scintillating fiber imaging spectrometer based on the tomographic reconstruction of proton energy deposition in a layered fiber array. Modeling indicates that spatial resolution of approximately 1 mm and energy resolution of less than 10% at proton energies of more than 20 MeV are readily achievable with existing 100 μm diameter fibers. Measurements with a prototype beam-profile monitor using 500 μm fibers demonstrate active readouts with invulnerability to electromagnetic pulses, and less than 100 Gy sensitivity. The performance of the full instrument concept is explored with Monte Carlo simulations, accurately reconstructing a proton beam with a multiple-component spectro-spatial profile.
The clay minerals formed in a deeply weathered boulder conglomerate of Middle Old Red Sandstone (Devonian) age in north-east Scotland have been studied by a variety of physical and chemical techniques. The granite and granulite boulders in this deposit are completely weathered. With the exception of microcline, all the feldspars in these rocks—orthoclase feldspar, orthoclase-microperthite, albite, and oligoclase—weather to a Cheto-type montmorillonite, poor in iron. Electron and optical microscopy indicate that the weathering transformation is a direct one, without the intervention of any intermediate crystalline or well-defined amorphous phase. Structural control of the primary mineral over the formation of the montmorillonite seems to have been a minimal factor and the evidence suggests that the clay mineral crystallized from the soluble or colloidal products arising from the decomposed feldspars. Smaller amounts of kaolinite also formed during weathering but largely from the weathering of muscovite. The environment in which these changes occurred seems to have been alkaline in a relatively closed system. Chemical analyses of related cores and weathered shells of granite and granulite bounders show only a slight decrease of silica and an increase in magnesia. Judging from the extent of alteration to secondary clay minerals, the order of resistance towards weathering of the primary minerals in these rocks is plagioclase = orthoclase < muscovite < biotite < microcline < quartz.
We present a deep learning approach for near real-time detection of Global Navigation Satellite System (GNSS) radio frequency interference (RFI) based on a large amount of aircraft data collected onboard from the Global Positioning System (GPS) and Attitude and Heading Reference System (AHRS). Our approach enables detection of GNSS RFI in the absence of total GPS failure, i.e. while the receiver is still able to estimate a position, which means RFI sources with low power or at larger distance can be detected. We demonstrate how deep one-class classification can be used to detect GNSS RFI. Furthermore, thanks to a unique dataset from the Swiss Air Force and Swiss Air-Rescue (Rega), preprocessed by Swiss Air Navigation Services Ltd. (Skyguide), we demonstrate application of deep learning for GNSS RFI detection on real-world large scale aircraft data containing flight recordings impacted by real jamming. The approach we present is highly general and can be used as a foundation for solving various automated decision-making problems based on different types of Communications, Navigation and Surveillance (CNS) and Air Traffic Management (ATM) streaming data. The experimental results indicate that our system successfully detects GNSS RFI with 83$\,\cdot\,$5% accuracy. Extensive empirical studies demonstrate that the proposed method outperforms strong machine learning and rule-based baselines.
Success of atrioventricular septal defect repair is defined by post-operative atrioventricular valve function and presence of residual intracardiac shunting. We evaluated differences in interpretation of atrioventricular valve function and residual defects between transesophageal and transthoracic echocardiography in a contemporary cohort of infants undergoing atrioventricular septal defect repair. Among 106 patients, we identified an increase in left and right atrioventricular valve regurgitation, right atrioventricular valve inflow gradient, and increased detection rate of residual intracardiac shunting on transthoracic compared to transesophageal echocardiograms, although residual shunts identified only on transthoracic echocardiogram were not haemodynamically significant. Findings may help inform expectation of post-operative transthoracic echocardiogram findings based on intraoperative assessment.
Background: Employment and personal income loss after traumatic brain injury (TBI) is a major source of post-injury stress and barrier to societal reintegration for affected patients. We sought to quantify the labor market implications for tax-filing adult TBI survivors. Methods: We performed a matched difference-in-difference analysis using a national retrospective cohort of working adult TBI survivors injured between 2007-2017. Linear and logistic mixed effects regressions were used to estimate the magnitude of personal income loss and proportion of patients displaced from the workforce in the three post-injury years (Y+1 to Y+3). Results: Among 18,050 patients identified with TBI, the adjusted average loss of personal annual income was $-7,635 dollars in Y+1 and $-5,000 in Y+3. An additional -7.8% individuals were newly unemployed compared to the pre-injury baseline. For mild, moderate, and severe TBI subgroups, income loss was $-3354, $-6750, and $-17375 respectively in Y+3; the proportion of newly unemployed individuals in Y+3 was 5.8%, 9.2%, and 20% lower than baseline. We estimated 500 million dollars of incurred labor markets losses related to TBI in Canada. Conclusions: This work represents the first national cohort data quantifying the labor market implications of TBI. These results may be used to inform post-injury care pathways and vocational rehabilitation.
Background: Meningiomas are the most common intracranial tumor with surgery, dural margin treatment, and radiotherapy as cornerstones of therapy. Response to treatment continues to be highly heterogeneous even across tumors of the same grade. Methods: Using a cohort of 2490 meningiomas in addition to 100 cases from the prospective RTOG-0539 phase II clinical trial, we define molecular biomarkers of response across multiple different, recently defined molecular classifications and use propensity score matching to mimic a randomized controlled trial to evaluate the role of extent of resection, dural marginal resection, and adjuvant radiotherapy on clinical outcome. Results: Gross tumor resection led to improved progression-free-survival (PFS) across all molecular groups (MG) and improved overall survival in proliferative meningiomas (HR 0.52, 95%CI 0.30-0.93). Dural margin treatment (Simpson grade 1/2) improved PFS versus complete tumor removal alone (Simpson 3). MG reliably predicted response to radiotherapy, including in the RTOG-0539 cohort. A molecular model developed using clinical trial cases discriminated response to radiotherapy better than standard of care grading in multiple cohorts (ΔAUC 0.12, 95%CI 0.10-0.14). Conclusions: We elucidate biological and molecular classifications of meningioma that influence response to surgery and radiotherapy in addition to introducing a novel molecular-based prediction model of response to radiation to guide treatment decisions.
Background: Meningiomas have significant heterogeneity between patients, making prognostication challenging. For this study, we prospectively validate the prognostic capabilities of a DNA methylation-based predictor and multiomic molecular groups (MG) of meningiomas. Methods: DNA methylation profiles were generated using the Illumina EPICarray. MG were assigned as previously published. Performance of our methylation-based predictor and MG were compared with WHO grade using generalized boosted regression modeling by generating time-dependent receiver operating characteristic (ROC) curves and computing area under the ROC curves (AUCs) along with their 95% confidence interval using bootstrap resampling. Results: 295 meningiomas treated from 2018-2021 were included. Methylation-defined high-risk meningiomas had significantly poorer PFS and OS compared to low-risk cases (p<0.0001). Methylation risk increased with higher WHO grade and MG. Higher methylome risk (HR 4.89, 95%CI 2.02-11.82) and proliferative MG (HR 4.11, 95%CI 1.29-13.06) were associated with significantly worse PFS independent of WHO grade, extent of resection, and adjuvant RT. Both methylome-risk and MG classification predicted 3- and 5-year PFS and OS more accurately than WHO grade alone (ΔAUC=0.10-0.23). 42 cases were prescribed adjuvant RT prospectively although RT did not significantly improve PFS in high-risk cases (p=0.41). Conclusions: Molecular profiling outperforms conventional WHO grading for prognostication in an independent, prospectively collected cohort of meningiomas.
Among Líĺwat people of the Interior Plateau of British Columbia, an oral tradition relays how early ancestors used to ascend Qẃelqẃelústen, or Mount Meager. The account maintains that those climbers could see the ocean, which is not the case today, because the mountain is surrounded by many other high peaks, and the Strait of Georgia is several mountain ridges to the west. However, the mountain is an active and volatile volcano, which last erupted circa 2360 cal BP. It is also the site of the largest landslide in Canadian history, which occurred in 2010. Given that it had been a high, glacier-capped mountain throughout the Holocene, much like other volcanoes along the coastal range, we surmise that a climber may have reasonably been afforded a view of the ocean from its prior heights. We conducted viewshed analyses of the potential mountain height prior to its eruption and determined that one could indeed view the ocean if the mountain were at least 950 m higher than it is today. This aligns with the oral tradition, indicating that it may be over 2,400 years old, and plausibly in the range of 4,000 to 9,000 years old when the mountain may have been at such a height.
Understanding characteristics of healthcare personnel (HCP) with SARS-CoV-2 infection supports the development and prioritization of interventions to protect this important workforce. We report detailed characteristics of HCP who tested positive for SARS-CoV-2 from April 20, 2020 through December 31, 2021.
Methods:
CDC collaborated with Emerging Infections Program sites in 10 states to interview HCP with SARS-CoV-2 infection (case-HCP) about their demographics, underlying medical conditions, healthcare roles, exposures, personal protective equipment (PPE) use, and COVID-19 vaccination status. We grouped case-HCP by healthcare role. To describe residential social vulnerability, we merged geocoded HCP residential addresses with CDC/ATSDR Social Vulnerability Index (SVI) values at the census tract level. We defined highest and lowest SVI quartiles as high and low social vulnerability, respectively.
Results:
Our analysis included 7,531 case-HCP. Most case-HCP with roles as certified nursing assistant (CNA) (444, 61.3%), medical assistant (252, 65.3%), or home healthcare worker (HHW) (225, 59.5%) reported their race and ethnicity as either non-Hispanic Black or Hispanic. More than one third of HHWs (166, 45.2%), CNAs (283, 41.7%), and medical assistants (138, 37.9%) reported a residential address in the high social vulnerability category. The proportion of case-HCP who reported using recommended PPE at all times when caring for patients with COVID-19 was lowest among HHWs compared with other roles.
Conclusions:
To mitigate SARS-CoV-2 infection risk in healthcare settings, infection prevention, and control interventions should be specific to HCP roles and educational backgrounds. Additional interventions are needed to address high social vulnerability among HHWs, CNAs, and medical assistants.
Sperlingite, (H2O)K(Mn2+Fe3+)(Al2Ti)(PO4)4[O(OH)][(H2O)9(OH)]⋅4H2O, is a new monoclinic member of the paulkerrite group, from the Hagendorf-Süd pegmatite, Oberpfalz, Bavaria, Germany. It was found in corrosion pits of altered zwieselite, in association with columbite, hopeite, leucophosphite, mitridatite, scholzite, orange–brown zincoberaunite sprays and tiny green crystals of zincolibethenite. Sperlingite forms colourless prisms with pyramidal terminations, which are predominantly only 5 to 20 μm in size, rarely to 60 μm and frequently are multiply intergrown and are overgrown with smaller crystals. The crystals are flattened on {010} and slightly elongated along [100] with forms {010}, {001} and {111}. Twinning occurs by rotation about c. The calculated density is 2.40 g⋅cm–3. Optically, sperlingite crystals are biaxial (+), α = 1.600(est), β = 1.615(5), γ = 1.635(5) (white light) and 2V (calc.) = 82.7°. The optical orientation is X = b, Y = c and Z = a. Neither dispersion nor pleochroism were observed. The empirical formula from electron microprobe analyses and structure refinement is A1[(H2O)0.96K0.04]Σ1.00A2(K0.52□0.48)Σ1.00M1(Mn2+0.60Mg0.33Zn0.29Fe3+0.77)Σ1.99M2+M3(Al1.05Ti4+1.33Fe3+0.62)Σ3.00(PO4)4X[F0.19(OH)0.94O0.87]Σ2.00[(H2O)9.23(OH)0.77]Σ10.00⋅3.96H2O. Sperlingite has monoclinic symmetry with space group P21/c and unit-cell parameters a = 10.428(2) Å, b = 20.281(4) Å, c = 12.223(2) Å, β = 90.10(3)°, V = 2585.0(8) Å3 and Z = 4. The crystal structure was refined using synchrotron single-crystal data to wRobs = 0.058 for 5608 reflections with I > 3σ(I). Sperlingite is the first paulkerrite-group mineral to have co-dominant divalent and trivalent cations at the M1 sites; All other reported members have Mn2+ or Mg dominant at M1. Local charge balance for Fe3+ at M1 is achieved by H2O → OH– at H2O coordinated to M1.
Piracy and the historical study of it has brought many problems for states and scholars alike. In the early modern period, both legal and illegal maritime predation was a common occurrence in seas and oceans across the globe. Piracy in all its forms was, and still is, a worldwide phenomenon. As has been recently shown, too, it is persistent, ebbing and surging in response to political and economic pressures but never dying out completely. Though piracy therefore reaches far beyond Europe historically and geographically, the expansion of European maritime empires in the early modern period exacerbated existing and created new problems of piracy, which states had to navigate and address. At times, European states addressed this problem in different ways according to their resources and interests. They might attempt to contain piracy to certain regions, co-opt maritime raiders for the state's benefit, deny maritime predation or their involvement in it, or suppress predation militarily and legally. As we have written elsewhere, contrary to the popularly held myth of pirates as the common enemies of all peoples, states only exercised power over pirates occasionally and for specific purposes. This present volume extends that argument, deeply examining the relationship between European states and maritime predation, especially in Asian, Atlantic, and European waters between the fifteenth and eighteenth centuries.
In the early modern period, there were many different forms of maritime predation. Most raids were deemed lawful, conducted by either public or private agents of widely recognised states, but a significant minority was considered unlawful and therefore branded “piracy” by some or all of the states. Hans Hagerdal points to the “porous line between state-condoned warfare and sheer piracy,” meaning that at times the only difference between the two was one of perception or interpretation. States therefore eagerly sought to draw clear lines to distinguish between them in law and popular perception in order to justify their own predation and vilify that which diminished their power. Definitions of piracy abounded in early modern law, especially in the nascent field of international law that some European jurists tried to create. But due to competing interests between states, making a universal definition of piracy was easier said than done. Since there were so many ways to be a pirate, and no one could agree at the time what piracy was, one of the first problems scholars come across is a definitional one.