bluuebunny/crossref_metadata_2025 huggingface dataset:
Humanitarian Medical Aid Mission in the Middle of a Pandemic – Israeli Experience in Equatorial Guinea
Authors: Shlaifer Amir , Berman Asaf , Benov Avi , Friedman Guy , Koller Tomer , Ankory Ran , Almog Ofer , Bar On Elhanan , Shapira Shachar , Harats Moti , Glassberg Elon , Fink Noam
Published: April 2022

Introduction:

In March 2021, a series of explosions shook a military base in Bata, Equatorial Guinea. As a response to government officials’ request, the Israel Defense Forces Medical Corps (IDF-MC) deployed an emergency aid team that faced two major challenges: (1) understanding the scenario, the injury patterns, and the needs of the local medical system; and (2) minimizing the coronavirus disease 2019 (COVID-19) outbreak threats. This report describes the team design, the activities performed before and during the deployment, analyzes the pathology encountered, and shares lessons learned from the mission.

Sources:

Data were collected from the delegation protocols and IDF medical records. All activities of the Israeli delegation were coordinated with the local government.

Observations:

The local authorities reported that a total of 107 people were killed and more than 700 people were wounded. The team was the first international team to arrive at the scene and assisted the local medical teams to treat 231 patients in the three local hospitals and 213 patients in field clinics in the villages surrounding Bata. The COVID-19 pandemic influenced the operation of this mission, and caution measures were activated.

Analysis:

Unplanned explosions at munitions sites (UEMS) are a growing problem causing the medical teams to face unique challenges. By understanding the expected challenges, the team was reinforced with a plastic surgeon, portable ultrasound devices, a large amount and a variety of antibiotics, whole blood units, and freeze-dried plasma. Rehabilitation experts were needed in some cases in the week following the injury. An important key for the success of this kind of medical aid delegation is the collaboration with the local medical teams, which enhances patient care.
Predictors of Risk Stratification and Value of Point-of-Care of High-Sensitivity Cardiac Troponin-I in EMS Management of Non-ST-Segment Elevation Myocardial Infarction: A Retrospective Study
Authors: Pavlovsky Thomas , Obadia Mathias , Ragot Stéphanie , Douay Benedicte , Casalino Enrique , Ghazali Daniel Aiham
Published: April 2022

Introduction:

The European Society of Cardiology (ESC) 2020 guidelines propose an algorithm for in-hospital management of non-ST-elevation myocardial infarction (NSTEMI) based on risk stratification according to clinical, electrocardiographic, and biological data. However, out-of-hospital management is not codified.

Study Objective:

The objective of the present study was to evaluate the role of high-sensitivity cardiac troponin-I in out-of-hospital management of NSTEMI by Emergency Medical Services (EMS).

Methods:

This monocentric, retrospective, observational study analyzed the files of all patients having received a troponin assay in the EMS of Beaujon University Hospital, AP-HP (Paris region, France) from January 1, 2020 through December 31, 2020. Patients were classified as low risk, high risk, or very high risk according to the ESC 2020 algorithm at the time of their hospital treatment. The relationship between troponin in point-of-care and risk level according to time to onset of pain was analyzed using logistic regression. A search for predictors of risk level was performed using multivariate analysis. A P value <.05 was considered significant.

Results:

Out of 309 patients in the file, 233 were included. Men were 61% and the median age was 63 years. A positive troponin assay was associated with high-risk or very high-risk stratification regardless of the time to onset of pain (P <.0001). Predictive factors for being classified as high or very high risk in hospital were: a history of atrial fibrillation (P = .03), electrocardiogram (ECG) modifications such as negative T wave or ST-segment depression (P <.0001), and positive troponin (P <.0001).

Conclusion:

The use of point-of-care troponin in EMS, combined with clinical and electrical criteria, allows risk stratification of NSTEMI patients from the prehospital management stage and optimization of referral to an appropriate care pathway. Patients classified as low risk should be referred to the emergency department (ED) and patients classified as high risk or very high risk to the cardiac intensive care unit or percutaneous coronary intervention (PCI) center.
Healthcare Resource Use and Quality of Life Associated with Cognitive Impairment Among Patients with Schizophrenia
Authors: Kadakia Aditi , Fan Qi , Fan Angela , Shepherd Jason , Bailey Hollie , Dembek Carole , Williams Rhys
Published: April 2022

Objectives

To investigate the association between cognitive impairment and hospitalizations, quality of life and satisfaction with life among patients with schizophrenia.

Methods

A point-in-time survey was conducted between July and October 2019 via the Adelphi Schizophrenia Disease Specific Programme across the United States of America. Patients were stratified as mild or severe based on the level of cognitive impairment reported by their psychiatrist (normal, mild = mild; moderate, severe, very severe = severe). Multiple regression analysis was used to model the association between cognitive impairment and outcomes, adjusting for baseline characteristics.

Results

Data were provided by 124 psychiatrists for 651 mildly and 484 severely impaired patients with schizophrenia; PSCs were completed by 349 mildly and 206 severely impaired patients. Severe cognitive impairment was associated with increased odds of hospitalization due to schizophrenia relapse since diagnosis (2.10 odds ratio [OR], P = .004) and within 12 months (1.95 OR, P < .001) compared to mild impairment. Moreover, patients with severe cognitive impairment had poorer quality of life according to the EuroQoL 5-dimension (EQ-5D) Health Index (−0.085 coefficient, P < .001) and EQ-5D Visual Analogue Scale (−6.24 coefficient, P = .041) compared to patients with mild cognitive impairment. Severe cognitive impairment was also associated with lower overall life satisfaction according to the Quality-of-Life Enjoyment and Satisfaction Questionnaire (−8.13 coefficient, P = .006) compared to mild cognitive impairment.

Conclusion

Schizophrenia patients with severe cognitive impairment had more hospitalizations due to relapse than patients with mild cognitive impairment. Additionally, patients with severe cognitive impairment had significantly lower quality of life and overall satisfaction with life compared to patients with mild cognitive impairment.

Funding

Sunovion Pharmaceuticals
The Economic Burden of Schizophrenia in the United States in 2019
Authors: Kadakia Aditi , Fan Angela , Marden Jessica , Dembek Carole , Catillon Maryaline , Anderson Annika , Williams Rhys
Published: April 2022

Background

Schizophrenia is associated with health, social, and financial burdens for patients, caregivers, and society. Major systemic changes, reforms, and technological advances have happened in the USA since the prior estimate of the societal cost of schizophrenia, $155.7B in 2013. This study analyzes the most recent data and literature to update this estimate.

Methods

Direct and indirect costs associated with schizophrenia in the US in 2019 were estimated using a prevalence-based approach (ICD-10 codes: F20, F25). Direct healthcare costs were assessed retrospectively using a matched cohort design in the IBM Watson Health MarketScan Commercial, Medicare, and Medicaid databases from October 1, 2015, through December 31, 2019. Patients were matched to controls on demographics, insurance type, and index year. Direct nonhealthcare costs were estimated using published literature and government data. Indirect costs were estimated using a human capital approach and the value of quality-adjusted life years lost. Cost offsets were applied to account for basic living costs avoided. Excess costs, comparing costs for individuals with and without schizophrenia, were reported in 2019 USD.

Results

The estimated excess economic burden of schizophrenia in the US in 2019 was $330.6B, including $62.3B in direct healthcare costs (19%), $19.7B in direct nonhealthcare costs (5%), and $251.9B in excess indirect costs (76%). The largest drivers of indirect costs were caregiving ($112.3B), premature mortality ($77.9B), and unemployment ($54.2B).

Conclusions

The estimated societal burden of schizophrenia in the USA in 2019 was $330.6B, which represented a 93.5% increase from 2013 to 2019, after accounting for inflation. This study underscores the increasing and apparent burden of schizophrenia not only on the patient, but also on caregivers and society.

Funding

Sunovion Pharmaceuticals
These Are Not the Droids You Are Looking For: Mechanical Variant of Cotard’s Syndrome
Authors: Chaudhry Ahmed A. , Shah Syeda A. , Hirsch Alan R.
Published: April 2022

Introduction

Cotard’s syndrome is a nihilistic delusion where the individual believes they are dead, partly dead, or replaced by an animal. The delusion that their body has been replaced by a purely inanimate azooic (but physical entity), such as a robot or a droid, has not hitherto been described.

Methods

Case study: This 60-year-old, right-handed, female, with a past history of schizophrenia presented with complaints of depression, irritability, and anger. When confronted with commitment papers signed by her father, she denied their truthfulness, insisting that he had been replaced by an imposter. This belief persisted unabated, despite treatment with 20 mg of haloperidol per day. Over time, she expressed the belief that she had been replaced by another person, whom she refused to identify. The following day she refused all food and water proclaiming that she had died and been replaced by a machine revealing, “I am not her. I am a robot.” Soon thereafter she developed tremulousness, stiffness, and rigidity. After haloperidol was decreased and benztropine started, these parkinsonism symptoms subsided, but her delusions persisted.

Results

Abnormalities in physical examination: General: decreased blink frequency. Neurologic examination: Mental status examination: bradyphrenia, hypoverbal, blunted affect. Oriented ×2. Motor examination: bradykinetic, cogwheel rigidity in both upper extremities. Gait examination: slow shuffling gait, reduced bilateral arm swing. Cerebellar examination: resting tremor in both upper extremities at 3 cycles per second. Other: EEG: focal sharp transients in the left temporal region. MRI with and without contrast: normal. Toxicological, metabolic, endocrine screening: normal.

Conclusion

This illustrated sequential presentations of three delusions of misidentification. Upon presentation, she exhibited Capgras syndrome, the delusional belief that a familiar person has been replaced by a double. The nidus for this may have been the discovery that her father had signed her commitment papers. This was followed by the belief she was a double of herself, which is the syndrome of Reverse Subjective Doubles. Finally, she manifested Cotard’s syndrome in a previously undescribed manner, believing she had died and become a robot. Cotard’s and Capgras syndromes are known to present sequentially rather than concurrently, whereas the patient presented concurrently with all three syndromes. Drug-induced parkinsonism may have made the patient subjectively feel stiff, which she interpreted as being rigid like a robot. She was bradykinetic, did not eat or drink, and had rigidity, suggesting that these were somatic manifestations of her underlying delusion of being a robot or alternatively, may have been the somatic nidus for the delusion. Those who present with Cotard’s syndrome warrant evaluation for underlying medical conditions, serving as a substrate for this delusion.

Funding

No funding
Improved MOCA Scores While on Clozapine Gains Insight into HIV
Authors: Seamon Amanda , Shashank Reddy
Published: April 2022

Introduction

Many patients suffer from comorbid HIV and Schizophrenia diagnoses. Patients with schizophrenia and other psychosis are at increased risk of contracting HIV due to numerous psychosocial factors including increased frequency of drug use, increased rates of victimization, and increased propensity for high-risk sexual behaviors. In addition to deficits in functioning related to psychiatric illness, patients with HIV also suffer from virus-related neurocognitive insults. It is quite possible that inflammation associated with an untreated HIV infection could compound the pre-existing neurocognitive decline seen in patients with schizophrenia and other psychosis, creating poor outcomes and treatment-resistant pathology. The benefit of clozapine treatment for schizophrenia patients with comorbid HIV extends beyond just symptomatic control. Long-term and consistent treatment of schizophrenia can be a stepping-stone for the improvement of many psychosocial aspects of life. Patients with well-controlled schizophrenia can lead relatively unaffected lives with improved insight and self-care. Improved insight allows patients to better understand their illness, treatment regimen, and follow-up needs. Improved self-care contributes to increased adherence to treatment regimens and overall health. It is likely that patients who are consistently treated for their schizophrenia will have an increased capacity to understand their HIV diagnosis. With gained understanding, these patients may be more likely to adhere to HAART therapy for HIV and to attend follow-up appointments with infectious disease or primary care. Furthermore, with adherence to HAART therapy, patients can enjoy an improved quality and duration of life by raising CD4 counts and preventing progression to AIDS or succumbing to AIDS-related opportunistic infections.

Methods

A patient with schizophrenia and HIV diagnosis was monitored and interviewed with repeated MOCA scoring over a lengthy hospitalization period. During this time, he was titrated to an effective dose of clozapine totaling 400 mg at bedtime. His MOCA scores were compared over this period.

Results

In this case, we have observed that starting a patient on clozapine with therapeutic levels for adequate period has improved MOCA scores. Low MOCA scores could be due to untreated HIV, untreated underlying psychosis. Improved MOCA scores have led the patient to gain insight into his HIV diagnosis. For the first time, he felt the need to be on antiretroviral medication and understood the chronic nature of his illness.

Conclusions

In conclusion, this case describes a patient with untreated HIV and comorbid schizophrenia who is started on clozapine to gain insight into his medical conditions and become more adherent with HIV HAART. The patient shows improvement in PANSS and MOCA scores, supporting an increased awareness of his illness and an increased ability to remain on treatment.

Funding

No funding
Anosmia as an Enantiopathy for Migraines
Authors: Singh Amrinder , Rubani Sidhu , Ribeiro Estevao , Kaur Vikram Preet , Hirsch Alan
Published: April 2022

Introduction

Elimination of olfactory sensory perception with a reduction in odor-induced migraine has not heretofore been reported.

Methods

Case study: A 64-year-old right-handed woman presented with a history of common migraines since childhood. The headaches were bilateral, throbbing, pulsatile, and without aura and were associated with lightheadedness, photophobia, sonophobia, nausea, and vomiting. They would be precipitated by ambient aromas, such as perfumes and bath products, and she became agoraphobic, fearful of going out of her domicile and being exposed to odors. She avoided stores, perfume counters, and public places; scared that it would initiate a disabling headache. Twenty-five years prior to presentation, the patient fell on ice, striking her head and causing a transient loss of consciousness and persistent absence of smell and taste. From that point forwards, while she would have an occasional headache independent of an odor, she no longer experienced odor-induced headaches. Her agoraphobia had resolved. Since the head trauma, her smell remained at 10% to 20%. Her taste remained at 30% of normal.

Results

Abnormalities on neurological examination: Motor examination: Drift testing: Right pronator drift with right abductor digiti minimi sign. Cerebellar examination: Bilateral finger-to-nose dysmetria. Rapid alternating movements: decreased in the left upper extremity. Reflexes: Bilateral upper extremity 3+. Absent bilateral ankle jerks. Bilateral palmomental and Hoffmann reflexes present. Chemosensory testing: Olfaction: Brief Smell Identification Test (B-SIT): 7 (hyposmia), Alcohol Sniff Test: 0 (anosmia). Retronasal Olfaction: Retronasal Smell Index: 4 (hyposmia). Gustation: Propylthiouracil Disc Taste Test: 10 (normogeusia). While performing the B-SIT and sniffing the aroma of rose, the patient noted the sudden onset of a headache, even though she could not detect any odor present.

Discussion

The temporal relationship between loss of sense of smell and elimination of odor-induced migraines suggests a causal relationship. Conscious recognition of odor may induce a stimulus-response paradigm, whereby migraine occurs. Head trauma-induced anosmia, by elimination of conscious perception of the odor, may thus be the modality whereby her headaches resolved. Alternatively, odors may induce an autonomic response, and conscious recognition of such autonomic response may induce a headache. To tergiversate, that the rose aroma in the B-SIT induced a headache, without any conscious detection of the odor, implies that either unconscious perception is enough to precipitate a headache or that these odors act not as odorants, but rather as an exogenous ambient chemical inducing headaches. Possibly the production of temporary anosmia by use of nose clips may be utilized as a prophylactic device for those with odor-induced migraines. Further investigation into this is warranted.

Funding

No funding
A Structured Benefit-Risk Assessment to Evaluate a Combination of Olanzapine and Samidorphan for the Treatment of Schizophrenia and Bipolar I Disorder
Authors: Roy Brittany D. , McDonnell David , Yu Bei , Graham Christine , Jiang Ying , Yagoda Sergey , Bhupathi Vasudev , DiPetrillo Lauren
Published: April 2022

Background

A combination of olanzapine and samidorphan (OLZ/SAM) that provides the efficacy of olanzapine while mitigating weight gain was recently approved by the FDA for the treatment of schizophrenia and bipolar I disorder. To improve communication of the OLZ/SAM benefit-risk profile, a structured framework was utilized.

Methods

The Benefit-Risk Action Team framework was used to evaluate OLZ/SAM, with analyses completed for each pivotal study. ENLIGHTEN-1 evaluated antipsychotic efficacy and safety. ENLIGHTEN-2 evaluated the weight profile of OLZ/SAM vs olanzapine. Benefit-risk outcomes were selected based on study outcome parameters, known risks of olanzapine and samidorphan, and public health importance. A subset of opioid antagonist risks was not assessed due to clinical trial exclusions; however, they were factored into the overall evaluation. Risk differences and confidence intervals were analyzed.

Results

In ENLIGHTEN-1, OLZ/SAM had a lower risk of psychiatric discontinuation and nonresponse to treatment compared with placebo; higher risks of hyperprolactinemia, weight gain (≥7%), sedation, and worsening of fasting triglycerides and glucose, and no difference for fasting total and LDL cholesterol, neutropenia, orthostatic hypotension, and movement disorders. In ENLIGHTEN-2, OLZ/SAM had reduced risks of weight gain and waist circumference increase compared to olanzapine along with similar risks of relapse and psychiatric discontinuation and no difference in metabolic worsening, neutropenia, hyperprolactinemia, orthostatic hypotension, sedation, and movement disorders.

Discussion

Based on this assessment, OLZ/SAM has comparable efficacy and a safety profile consistent with olanzapine, with reduced weight gain. A structured approach to assessing the benefit-risk profile of a product facilitates transparent evaluation and communication.

Funding

Alkermes, Inc.
Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose Study to Evaluate the Efficacy and Safety of the Amphetamine Extended-Release Tablet in Adults with Attention-Deficit/Hyperactivity Disorder
Authors: Cutler Andrew J. , Childress Ann C. , Pardo Antonio , Rafla Eman , Duhoux Stephanie , Kando Judith C. , Dansie Lori
Published: April 2022

Background

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by pervasive impairment in symptoms of inattention, hyperactivity, and impulsivity. Psychopharmacologic treatment is targeted at the management of symptoms of ADHD, and evidence exists that ADHD persists into adulthood. Clinical practice guidelines recommend a combination of behavior therapy and psychostimulant medication for the treatment of ADHD in children, adolescents, and adults. Psychostimulants are often prescribed for ADHD in adults, and amphetamine long has been considered a mainstay of treatment for this population. As adult patients seek relief from ADHD symptoms early in the workday and into the early evening hours, with fewer required doses, extended-release formulations with an early onset of efficacy and an extended duration of effect are considered very desirable. The amphetamine-extended release tablet (AMPH ER TAB) was developed to provide a portable, easy-to-use amphetamine tablet dosage option that can be chewed or swallowed whole.

Objectives

To evaluate the efficacy and safety of an Amphetamine Extended-Release Tablet (AMPH ER TAB) in adults with ADHD aged 18 to 60 years. Methods: In a 5-week forced dose-titration phase, eligible subjects were randomized to either oral double-blind AMPH ER TAB 5 mg starting dose or matching placebo, once daily in the morning beginning the day after the Baseline Visit. Subjects were titrated up (5 mg increments) each week. Safety and efficacy assessments were done weekly. After Visit 3, subjects received 20 mg for 14 (3) days before Visit 5 (V5). Subjects who could not tolerate study drugs discontinued. A Permanent Product Measure of Performance (PERMP) placement test was done at Screening or Baseline. At V5, efficacy assessments included the administration of serial PERMPs predose, 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours postdose. The primary efficacy endpoint was the mean PERMP-T score across postdose time points during the Visit 5 serial PERMPs. Safety was monitored by AEs assessed at each visit, C-SSRS, vital signs, weight, and assessment of sleep, appetite, mood, and psychotic AEs.

Results

The mean postdose PERMP-T score over all postdose time points at V5 was statistically significantly higher in the AMPH ER TAB group vs placebo (302.8 vs 279.6; P = .0043). Common adverse events were decreased appetite, insomnia, and dry mouth. The majority of TEAEs were mild to moderate in severity, and no SAEs were reported.

Conclusion

The AMPH ER TAB demonstrated efficacy in the treatment of symptoms of ADHD in adults, with an anticipated safety profile.

Funding

Tris Pharma, Inc.
Social Cognition and Behavioral Variant of Frontotemporal Dementia: Evaluative Utility for the Health and Forensic Field
Authors: Mazzoglio y Nabar Martin J. , Leidi Terren Emmanuel E. , Silva Daniel H.
Published: April 2022

Introduction

The behavioral variant of frontotemporal dementia presents clinical specificities and difficulties for its early diagnosis in the initial stages due to the overlap of symptoms with other psychiatric pathologies. The delay in diagnosis places the subject in a state of vulnerability because the treatment will not be adequate and the alteration in the psycho-functional capacity can expose him to risks.

Objective

The objective of this research was to describe the importance at the forensic and health level of the neuropsychological evaluation of social cognition in people with behavioral variant frontotemporal dementia and to correlate the results with the clinical manifestations of the patients.

Materials and Methods

Forty-five patients with behavioral variant frontotemporal dementia were studied with social cognition tests (Reading the Mind in the Eyes and Faux Pas Tests) and staged with standardized scales (CDR [Clinical Dementia Rating], GDS [Global Deterioration Scale], and the FTD-FRS [Frontotemporal Dementia Rating Scale]). The results were analyzed with descriptive and inferential statistical tests and the current ethical-legal requirements were met (requirement of informed consent, reservation of the identity of the participants, compliance with the GCP-Good clinical practice-, ANMAT provision 6677/10 and adherence to the Ethical Principles derived from the Declaration of Helsinki).

Results

We found a significant prevalence of alterations in social cognition tests, mainly in Faux Pas Test, from the initial stages of the disease, which were correlated with the clinical stage of the patient.

Conclusions

The behavioral variant of frontotemporal dementia is a condition with significant diagnostic complexity in its initial stages that affects decision-making, the type of treatment to be instituted and presents the consequences for the subject and their environment. Early detection with a deep assessment of social tools will provide clinical tools for pharmacological treatment, as well as to know the capacity and safeguard the rights of the subject and implement the necessary support measures. It was confirmed that the alterations in the social cognition tests were correlated with the clinical stage in the FTD-FRS scale and high implication in the results of the Faux Pas Test mainly, and secondarily in the Reading the Mind in the Eyes Test.

Funding

No funding
Efficacy, Tolerability, and Safety of Atypical Antipsychotics in East Asian Ethnicity
Authors: Hina Mehwish , Sultana Tania , Youn Sophia
Published: April 2022

Background

A number of intrinsic (age, gender, physical comorbidities, genetic factors, and ethnicity), and extrinsic factors (diet, concomitant medications, alcohol use, and smoking) influence an individual’s response to psychotropic medications. Data suggest that ethnicity may affect medication efficacy, tolerability, and safety through different pharmacokinetics and pharmacodynamics. Asians have been found to have a high frequency of reduced function of CYP2D6 allele (CYP2D6*10), which contributes to the slower metabolism of some medications compared to other ethnic groups. The previous study has shown East Asians appear to have a clinically relevant decrease in clozapine clearance compared with Caucasians. This review will explore the magnitude of the impact of ethnicity, especially the East Asian population on psychotropic medications such as atypical antipsychotics.

Objective

To understand the efficacy, safety, and tolerability of atypical antipsychotics in East Asian ethnicity. To emphasize the importance of ethnicity in clinical practice while offering/prescribing atypical antipsychotic medications.

Discussion

Several previous studies reported the diverse response to the antipsychotics among different ethnicities secondary to differences in pharmacokinetics and pharmacodynamics. One study revealed White Europeans may require higher doses of therapeutic antipsychotics than Asians and Hispanics. Aripiprazole in Asians had a relatively higher rate of akathesia, and a significantly increased risk of tremor compared to placebo. A significantly increased risk of weight gain and fasting total cholesterol from olanzapine were observed in Japanese patients. Olanzapine was also associated with somnolence and dizziness. Quetiapine XR was associated with a significant increase risk of somnolence and dizziness in Chinese patients.

Conclusion

It is indicated from previous studies antipsychotics respond in various ways in different ethnicity in terms of metabolism, clearance, and adverse effects. Further research could be beneficial on what is clinically most effective dosing of different antipsychotics among different populations including East Asians.

Funding

No funding
Long-Term Efficacy and Safety of Deutetrabenazine in Patients with Tardive Dyskinesia by Concomitant Dopamine-Receptor Antagonist Use
Authors: Hauser Robert A. , Barkay Hadas , Fernandez Hubert H. , Factor Stewart A. , Jimenez-Shahed Joohi , Gross Nicholas , Marinelli Leslie , Wilhelm Amanda , Gordon Mark Forrest , Savola Juha-Matti , Anderson Karen E.
Published: April 2022

Introduction

Tardive dyskinesia (TD) is an involuntary movement disorder that can result from exposure to dopamine-receptor antagonists (DRAs). Deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores in the 12-week pivotal trials (ARM-TD/AIM-TD). This post hoc analysis assessed the long-term efficacy and safety of deutetrabenazine by baseline DRA use.

Methods

Patients who completed ARM-TD or AIM-TD enrolled in the 3-year, open-label extension (OLE) study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in total motor AIMS score, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and adverse event (AE) rates were analyzed in subgroups by baseline DRA use.

Results

Of 337 patients in the OLE study, 254 were taking DRAs at baseline (mean age, 56 years; 48% male; 6.0 years since diagnosis) and 83 were not (mean age, 60 years; 31% male; 4.9 years since diagnosis). Mean ± SE dose at week 145 was 39.9 ± 1.0 mg/day in patients taking DRAs (n = 108) and 38.5 ± 1.5 mg/day in patients not taking DRAs (n = 53). At week 145, mean ± SE change from baseline in AIMS score was −6.1 ± 0.43 and −7.5 ± 0.71; 64% and 62% achieved PGIC treatment success; and 69% and 81% achieved CGIC treatment success, respectively. Overall AE incidence was low (exposure-adjusted incidence rates [incidence/patient-years]: any, 1.08 and 1.97; serious, 0.10 and 0.12; leading to discontinuation, 0.06 and 0.05).

Conclusion

This analysis suggests that deutetrabenazine for long-term treatment of TD is beneficial, with a favorable safety profile, regardless of concomitant DRA use.

Funding

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
The Rey Auditory Verbal Learning Test: Cross-validation of Mayo Normative Studies (MNS) demographically corrected norms with confidence interval estimates
Authors: Loring David W. , Saurman Jessica L. , John Samantha E. , Bowden Stephen C. , Lah James J. , Goldstein Felicia C.
Published: April 2022

Objective:

The Mayo Normative Studies (MNS) represents a robust dataset that provides demographically corrected norms for the Rey Auditory Verbal Learning Test. We report MNS application to an independent cohort to evaluate whether MNS norms accurately adjust for age, sex, and education differences in subjects from a different geographic region of the country. As secondary goals, we examined item-level patterns, recognition benefit compared to delayed free recall, and derived Auditory Verbal Learning Test (AVLT) confidence intervals (CIs) to facilitate clinical performance characterization.

Method:

Participants from the Emory Healthy Brain Study (463 women, 200 men) who were administered the AVLT were analyzed to demonstrate expected demographic group differences. AVLT scores were transformed using MNS normative correction to characterize the success of MNS demographic adjustment.

Results:

Expected demographic effects were observed across all primary raw AVLT scores. Depending on sample size, MNS normative adjustment either eliminated or minimized all observed statistically significant AVLT differences. Estimated CIs yielded broad CI ranges exceeding the standard deviation of each measure. The recognition performance benefit across age ranged from 2.7 words (SD = 2.3) in the 50–54-year-old group to 4.7 words (SD = 2.7) in the 70–75-year-old group.

Conclusions:

These findings demonstrate generalizability of MNS normative correction to an independent sample from a different geographic region, with demographic adjusted performance differences close to overall performance levels near the expected value of T = 50. A large recognition performance benefit is commonly observed in the normal aging process and by itself does not necessarily suggest a pathological retrieval deficit.
An Outstanding Claim: The Ryukyu/Okinawa Peoples’ Right to Self-Determination under International Human Rights Law
Authors: ABE Ai
Published: April 2022

This paper aims to examine the legitimacy of Ryukyuans/Okinawans’1right to self-determination (RSD) under international human rights law. To this end, it first details the evolution of the RSD from the traditional right to independence for colonial peoples, to the continuing right to self-governance for wider groups of peoples, which is followed by an analysis of holders of the RSD. The paper then turns to Ryukyu/Okinawa to discuss the RSD of its peoples. Three historical events, the Disposition of Ryukyu, the Treaty of San Francisco, and the reversion of Okinawa to Japan, are analysed from a legal perspective, followed by an examination of the peoplehood of Ryukyuans/Okinawans. These lead to the conclusion that the Ryukyuans/Okinawans may legitimately claim that they possess the “unexercised” RSD as a quasi-non-self-governing people, and that they are entitled to claim the RSD as a “people” under the International Covenant on Civil and Political Rights, International Covenant on Economic, Social, and Cultural Rights, and other United Nations declarations.
On Psychosis
Authors: Prudent Cécile , Kleiger James H. , Husain Odile , De Tychey Claude
Published: April 2022

Abstract. This manuscript presents a single case study of a psychotically disturbed adult male (whom we call “Peter”), focusing on similarities and differences in Rorschach interpretation based on three different Rorschach approaches. Specific questions were raised as to whether the client suffered from a paranoid psychosis (paranoia) or paranoid schizophrenia. Three distinct models of psychopathology and Rorschach interpretation are initially presented. We then address Peter’s psychotic symptoms, according to the Parisian approach (specifically the Nancy French subgroup), the Lausanne Rorschach approach, and the American Rorschach approach (Comprehensive System and R-PAS). Analysis shows many convergences between the three approaches on the client’s nature of conflicts and links to reality, object relations, self-representation and anxiety, defense mechanisms, and disordered thinking, but interpretation of these variables differed somewhat despite agreement on a diagnosis within the psychotic spectrum. Concluding remarks discuss the divergences and point out the limitations of a case study method. Future research is suggested.
Influence of the South American Low‐Level Jet on the Austral Summer Precipitation Trend in Southeastern South America
Authors: Varuolo‐Clarke A. M. , Williams A. P. , Smerdon J. E. , Ting M. , Bishop D. A.
Published: April 2022

Austral summer precipitation increased by 27% from 1902 to 2020 over southeastern South America (SESA), one of the largest centennial precipitation trends observed globally. We assess the influence of the South American low‐level jet on the SESA precipitation trend by analyzing low‐level moisture fluxes into SESA in two reanalysis datasets from 1951 to 2020. Increased moisture flux through the jet accounts for 20%–45% of the observed SESA precipitation trend. While results vary among reanalyzes, both point to increased humidity as a fundamental driver of increased moisture flux and SESA precipitation. Increased humidity within the jet is consistent with warming sea surface temperatures driven by anthropogenic forcing, although additional natural climate variations also may have played a role. The jet's velocity also increased, further enhancing precipitation, but without a clear connection to anthropogenic forcing. Our findings indicate the SESA precipitation trend is partly attributable to jet intensification arising from both natural variability and anthropogenic forcing.
Analysis of Venusian Wrinkle Ridge Morphometry Using Stereo‐Derived Topography: A Case Study From Southern Eistla Regio
Authors: Bethell E. M. , Ernst R. E. , Samson C.
Published: April 2022

We present an analysis of 503 topographic profiles taken across 40 ENE‐WSW trending wrinkle ridges from Southern Eistla Regio, Venus, using stereo‐derived topography. We find that their average widths and heights are on the order of 10 km and 100 m, respectively. While the majority of the wrinkle ridges are asymmetric and display vergence to the southeast, some are quasi‐symmetric, possibly representing pop‐up structures, and possess multiple peaks along the backslope, potentially indicating the presence of secondary backthrust faults. Fault geometry modeling in which the average observed wrinkle ridge topographic profile is matched to the calculated surface deformation while varying various faulting parameters indicates that the wrinkle ridges studied have dips of 30°, penetrate to depths of 5 km or less, are blind and reach to within 2 km of the surface, have accommodated approximately 200 m of slip, and possess a planar geometry. These results imply that the wrinkle ridges formed through a thin‐skinned deformation style. The spacing and distribution of the wrinkle ridges at a regional scale displays a clear relationship between wrinkle ridge deformation and lithospheric properties. We therefore conclude that the distribution of wrinkle ridges in the study area is a direct reflection of the regional strain which, in turn, is a result of mantle dynamics coupled with lithospheric thickness. The accumulation of contractional deformation expressed as wrinkle ridges appears to be the result of mantle downwelling along the peripheries of Eistla Regio.
A New Index to Quantify River Fragmentation
Authors: Pardikar Rishika
Published: April 2022

Researchers have developed a new analysis based on a river’s catchment area as opposed its length.
Acoustofluidics for simultaneous nanoparticle-based drug loading and exosome encapsulation
Authors: Wang Zeyu , Rich Joseph , Hao Nanjing , Gu Yuyang , Chen Chuyi , Yang Shujie , Zhang Peiran , Huang Tony Jun
Published: April 2022

Nanocarrier and exosome encapsulation has been found to significantly increase the efficacy of targeted drug delivery while also minimizing unwanted side effects. However, the development of exosome-encapsulated drug nanocarriers is limited by low drug loading efficiencies and/or complex, time-consuming drug loading processes. Herein, we have developed an acoustofluidic device that simultaneously performs both drug loading and exosome encapsulation. By synergistically leveraging the acoustic radiation force, acoustic microstreaming, and shear stresses in a rotating droplet, the concentration, and fusion of exosomes, drugs, and porous silica nanoparticles is achieved. The final product consists of drug-loaded silica nanocarriers that are encased within an exosomal membrane. The drug loading efficiency is significantly improved, with nearly 30% of the free drug (e.g., doxorubicin) molecules loaded into the nanocarriers. Furthermore, this acoustofluidic drug loading system circumvents the need for complex chemical modification, allowing drug loading and encapsulation to be completed within a matter of minutes. These exosome-encapsulated nanocarriers exhibit excellent efficiency in intracellular transport and are capable of significantly inhibiting tumor cell proliferation. By utilizing physical forces to rapidly generate hybrid nanocarriers, this acoustofluidic drug loading platform wields the potential to significantly impact innovation in both drug delivery research and applications.
The relationship between immune and cognitive dysfunction in mood and psychotic disorder: a systematic review and a meta-analysis
Authors: Morrens M. , Overloop C. , Coppens V. , Loots E. , Van Den Noortgate M. , Vandenameele S. , Leboyer M. , De Picker L.
Published: April 2022

Background

In psychotic and mood disorders, immune alterations are hypothesized to underlie cognitive symptoms, as they have been associated with elevated blood levels of inflammatory cytokines, kynurenine metabolites, and markers of microglial activation. The current meta-analysis synthesizes all available clinical evidence on the associations between immunomarkers (IMs) and cognition in these psychiatric illnesses.

Methods

Pubmed, Web of Science, and Psycinfo were searched for peer-reviewed studies on schizophrenia spectrum disorder (SZ), bipolar disorder (BD), or major depressive disorder (MDD) including an association analysis between at least one baseline neuropsychological outcome measure (NP) and one IM (PROSPERO ID:CRD42021278371). Quality assessment was performed using BIOCROSS. Correlation meta-analyses, and random effect models, were conducted in Comprehensive Meta-Analysis version 3 investigating the association between eight cognitive domains and pro-inflammatory and anti-inflammatory indices (PII and AII) as well as individual IM.

Results

Seventy-five studies (n = 29,104) revealed global cognitive performance (GCP) to be very weakly associated to PII (r = −0.076; p = 0.003; I2 = 77.4) or AII (r = 0.067; p = 0.334; I2 = 38.0) in the combined patient sample. Very weak associations between blood–based immune markers and global or domain-specific GCP were found, either combined or stratified by diagnostic subgroup (GCP x PII: SZ: r = −0.036, p = 0.370, I2 = 70.4; BD: r = −0.095, p = 0.013, I2 = 44.0; MDD: r = −0.133, p = 0.040, I2 = 83.5). We found evidence of publication bias.

Discussion

There is evidence of only a weak association between blood-based immune markers and cognition in mood and psychotic disorders. Significant publication and reporting biases were observed and most likely underlie the inflation of such associations in individual studies.
MyD88 in hepatic stellate cells enhances liver fibrosis via promoting macrophage M1 polarization
Authors: Zhang Jie , Liu Yu , Chen Haiqiang , Yuan Qi , Wang Jinyan , Niu Meng , Hou Lingling , Gu Jianchun , Zhang Jinhua
Published: April 2022

During liver fibrosis, quiescent HSCs (qHSCs) are activated to become activated HSCs (aHSCs)/myofibroblasts. The signal adapter MyD88, an essential component of TLR signaling, plays an important role in liver fibrosis. However, far less is known about the specific effects of MyD88 signaling in both qHSCs and aHSCs in the progress of liver fibrosis. Here, we used a CCl4-induced mouse fibrosis model in which MyD88 was selectively depleted in qHSCs (GFAPMyD88−/− mice) or aHSCs (α-SMAMyD88−/− mice). MyD88 deficiency in qHSCs or aHSCs attenuated liver fibrosis in mice and inhibited α-SMA-positive cell activation. Inhibition of MyD88 in HSCs decreased α-SMA and collagen I levels, inflammatory cell infiltration, and pro-inflammatory gene expression. Furthermore, MyD88 signaling in HSCs increased the secretion of CXCL10, which promoted macrophage M1 polarization through CXCR3, leading to activation of the JAK/STAT1 pathway. Inhibition of CXCL10 attenuated macrophage M1 polarization and reduced liver fibrosis. Thus, MyD88 signaling in HSCs crucially contributes to liver fibrosis and provides a promising therapeutic target for the prevention and treatment of liver fibrosis.
Defective hematopoietic differentiation of immune aplastic anemia patient-derived iPSCs
Authors: Tellechea Maria Florencia , Donaires Flávia S. , de Carvalho Vinícius S. , Santana Bárbara A. , da Silva Fernanda B. , Tristão Raissa S. , Moreira Lílian F. , de Souza Aline F. , Armenteros Yordanka M. , Pereira Lygia V. , Calado Rodrigo T.
Published: April 2022

In acquired immune aplastic anemia (AA), pathogenic cytotoxic Th1 cells are activated and expanded, driving an immune response against the hematopoietic stem and progenitor cells (HSPCs) that provokes cell depletion and causes bone marrow failure. However, additional HSPC defects may contribute to hematopoietic failure, reflecting on disease outcomes and response to immunosuppression. Here we derived induced pluripotent stem cells (iPSCs) from peripheral blood (PB) erythroblasts obtained from patients diagnosed with immune AA using non-integrating plasmids to model the disease. Erythroblasts were harvested after hematologic response to immunosuppression was achieved. Patients were screened for germline pathogenic variants in bone marrow failure-related genes and no variant was identified. Reprogramming was equally successful for erythroblasts collected from the three immune AA patients and the three healthy subjects. However, the hematopoietic differentiation potential of AA-iPSCs was significantly reduced both quantitatively and qualitatively as compared to healthy-iPSCs, reliably recapitulating disease: differentiation appeared to be more severely affected in cells from the two patients with partial response as compared to the one patient with complete response. Telomere elongation and the telomerase machinery were preserved during reprogramming and differentiation in all AA-iPSCs. Our results indicate that iPSCs are a reliable platform to model immune AA and recapitulate clinical phenotypes. We propose that the immune attack may cause specific epigenetic changes in the HSPCs that limit adequate proliferation and differentiation.
A reversibly gated protein-transporting membrane channel made of DNA
Authors: Dey Swarup , Dorey Adam , Abraham Leeza , Xing Yongzheng , Zhang Irene , Zhang Fei , Howorka Stefan , Yan Hao
Published: April 2022

Controlled transport of biomolecules across lipid bilayer membranes is of profound significance in biological processes. In cells, cargo exchange is mediated by dedicated channels that respond to triggers, undergo a nanomechanical change to reversibly open, and thus regulate cargo flux. Replicating these processes with simple yet programmable chemical means is of fundamental scientific interest. Artificial systems that go beyond nature’s remit in transport control and cargo are also of considerable interest for biotechnological applications but challenging to build. Here, we describe a synthetic channel that allows precisely timed, stimulus-controlled transport of folded and functional proteins across bilayer membranes. The channel is made via DNA nanotechnology design principles and features a 416 nm2opening cross-section and a nanomechanical lid which can be controllably closed and re-opened via a lock-and-key mechanism. We envision that the functional DNA device may be used in highly sensitive biosensing, drug delivery of proteins, and the creation of artificial cell networks.
Implementing in-situ self-organizing maps with memristor crossbar arrays for data mining and optimization
Authors: Wang Rui , Shi Tuo , Zhang Xumeng , Wei Jinsong , Lu Jian , Zhu Jiaxue , Wu Zuheng , Liu Qi , Liu Ming
Published: April 2022

A self-organizing map (SOM) is a powerful unsupervised learning neural network for analyzing high-dimensional data in various applications. However, hardware implementation of SOM is challenging because of the complexity in calculating the similarities and determining neighborhoods. We experimentally demonstrated a memristor-based SOM based on Ta/TaOx/Pt 1T1R chips for the first time, which has advantages in computing speed, throughput, and energy efficiency compared with the CMOS digital counterpart, by utilizing the topological structure of the array and physical laws for computing without complicated circuits. We employed additional rows in the crossbar arrays and identified the best matching units by directly calculating the similarities between the input vectors and the weight matrix in the hardware. Using the memristor-based SOM, we demonstrated data clustering, image processing and solved the traveling salesman problem with much-improved energy efficiency and computing throughput. The physical implementation of SOM in memristor crossbar arrays extends the capability of memristor-based neuromorphic computing systems in machine learning and artificial intelligence.