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Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotic medications that jeopardizes adherence to treatment and reduces quality of life. The recognition and management of TD can be challenging in many instances. An online activity was developed to assess the ability of continuing medical education (CME) to improve awareness of the recognition and management of TD among psychiatrists.
The online CME activity consisted of a 30-minute video discussion between three expert faculty. Educational effect was assessed by comparing a matched sample of psychiatrists’ responses to four identical questions pre- and post-activity. A chi-square test identified significant differences between pre- and post-assessment responses. Cramer’s V was used to calculate the effect size of the online education (≥ 0.16 is considerable). Data were collected between June 26 and August 6, 2019.
Activity participation resulted in a considerable educational effect among psychiatrists (n=739; V=0.25, P<0.001). The following areas showed significant (P <0.05) pre- vs post-educational improvements: recognition of incidence of TD associated with different antipsychotic therapies, differentiation of TD from parkinsonism, and the personalized selection of therapies for the management of TD. 37% of psychiatrists had a measurable increase in confidence in understanding the role of the interprofessional team in recognizing TD after activity participation.
The results indicated that a CME-certified 30-minute video activity was effective at improving knowledge among psychiatrists for the recognition and management of TD. Future education should continue to address best practices in the care of patients with TD.
The gastropod parasitic nematode Phasmarhabditis hermaphrodita has been formulated into a successful biological control agent (Nemaslug®, strain DMG0001) used to kill slugs on farms and gardens. When applied to soil, P. hermaphrodita uses slug mucus and faeces to find potential hosts. However, there is little information on what cues other species of Phasmarhabditis (P. neopapillosa and P. californica) use to find hosts and whether there is natural variation in their ability to chemotax to host cues. Therefore, using chemotaxis assays, we exposed nine wild isolates of P. hermaphrodita, five isolates of P. neopapillosa and three isolates of P. californica to mucus from the pestiferous slug host Deroceras invadens, as well as 1% and 5% hyaluronic acid – a component of slug mucus that is highly attractive to these nematodes. We found P. hermaphrodita (DMG0010) and P. californica (DMG0018) responded significantly more to D. invadens mucus and 1% hyaluronic acid than other strains. Also, P. hermaphrodita (DMG0007), P. neopapillosa (DMG0015) and P. californica (DMG0017) were superior at locating 5% hyaluronic acid compared to other isolates of the same genera. Ultimately, there is natural variation in chemoattraction in Phasmarhabditis nematodes, with some strains responding significantly better to host cues than others.
Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these “pipeline” ADHD medications has a unique chemical structure and differs in its pharmacologic profile in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents with ADHD.
Background: Because of a patient death from a blood transfusion, a large hospital in Houston, Texas, underwent one of the largest unannounced CMS surveys in 2019. Methods: A 520-bed quaternary-care hospital was surveyed in one of the nation’s largest CMS surveys in March 2019, with a resurvey in June 2019. In an anticipated but unannounced arrival, ∼30 CMS surveyors evaluated the hospital and 10 Clinical Laboratory Improvement Amendments surveyors looked at the laboratory. They stayed for 11 consecutive days in March. On day 4, they declared that the hospital was in immediate jeopardy in infection control for the same observations noted by several surveyors. In addition, 11 CMS surveyors returned for a shorter resurvey in June. Results: The following 14 issues were listed under the infection control heading during the first survey, which led to the immediate jeopardy designation. The hospital’s infection prevention department committed to putting remediation processes, procedures, and audits in place during the first survey, which led to lifting the IJ before the surveyors left. The following shortcomings were recorded:
(1) Inappropriate donning and doffing of personal protective equipment (PPE) for patients in isolation
Standardized donning and doffing processes of PPE developed to include train-the-trainer and return demonstrations from >4,000 employees and providers followed by a minimum of fifty (50) audits/week with the goal of achieving 100% proper PPE donning and doffing for a minimum of three months, followed by a minimum of fifty (50) quarterly observations.
(2) Environment Service (EVS) cleaning issues in isolation rooms
Two-person isolation room cleaning process developed, implemented, and audited a minimum of ten (10) times/week.
(3) Incorrect set-up of dialysis machines
Minimum of five (5) dialysis machine set-ups audited/week.
(4) Biohazard trash left in dialysis room between patients
Minimum random audits twice/week to look for biohazard trash.
(5) Need for maintenance and cleanliness in the operating rooms (OR)
Minimum three times/week audits of rotating ORs in all locations.
(6) Rust noted on OR equipment
Minimum of twice/week audits looking for rust on OR equipment.
(7) Insects noted in OR
Observations for living insects will be audited twice/week.
(8) Improper cleaning and high-level disinfection (HLD) of transvaginal probes
Minimum of three times/week, cleaning and HLD processes of probes will be observed.
(9) Matching patient to probes in their medical records needed clarification
Minimum of twice/week, logs will be audited to check that appropriate patient/probe linkage occurs.
(10) Contaminated gloves used on a blood bag in ambulatory setting
Once/month, removal of blood bag from transport container will be observed to observe clean/dirty glove use
(11) Lack of cleaning between patients of durable medical equipment
Cleaning of DME will be observed for thoroughness a minimum of three times/week.
(12) Sanitation and mislabeling issues in the kitchen
A minimum of one (1) complete audit and two (2) abbreviated audits of kitchen sanitation and food labeling will be conducted per week.
(13) Endoscopy misuse of test strips
Test strip audits showing appropriate labeling and use will be auditing a minimum of twice/week.
(14) Process of air blowing of automatic endoscopic reprocessor (AER) needed improvement.
Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged antipsychotic use. RE KINECT, a real-world screening study of antipsychotic-treated outpatients, included patients with movements that were clinician-confirmed as possible TD (Cohort 2) and patients with no involuntary movements (Cohort 1). Baseline data from the patient rated EuroQoL 5-Dimension 5-Level questionnaire (EQ-5D-5L) and Sheehan Disability Scale (SDS) were analyzed to evaluate health related quality of life (Cohort 2 vs. Cohort 1) and the effects of possible TD on quality of life (Cohort 2).
Assessments included EQ-5D-5L utility score (0=equivalent to death to 1=perfect health); SDS total score (0=no impact to 30=highest impact); patient- and clinician-rated severity of possible TD in 4 body regions (0=none, 1=some, and 2=a lot; summary score, 0 to 8); and patient-rated impact of possible TD in 7 daily activities (0=none, 1=some, and 2=a lot; summary score, 0 to 14). Populations included Cohort 1 (N=450); full Cohort 2 (N=204); and limited Cohort 2 (N=111, patients who self-reported “some” or “a lot” of TD severity in ≥1 body region). Mean differences between Cohort 2 and Cohort 1 in EQ-5D-5L utility and SDS total scores were analyzed using a generalized linear regression model that was adjusted for potentially confounding factors (e.g., age, sex, psychiatric diagnosis). Associations between TD summary scores (severity, impact) and quality of life (EQ-5D-5L utility, SDS total) were analyzed using a regression model.
The mean score difference between full Cohort 2 (N=204) and Cohort 1 (N=450) was significant for EQ-5D-5L utility (-0.037; P<0.05 [adjusted analysis]) but not SDS total (0.267; P>0.05). However, when limited to Cohort 2 patients who self-reported “a lot” of TD severity (n=53) or impact (n=33), both EQ 5D 5L utility and SDS total scores were significantly worse than in Cohort 1 (P<0.05). Regression coefficients indicated significant associations between patient-rated impact and EQ 5D-5L utility in the full Cohort 2 (-0.021, P<0.001) and limited Cohort 2 (-0.024, P<0.001). A significant association was also found with patient rated severity in limited Cohort 2 (P<0.05), but not with clinician-rated severity. Similar results were found for SDS total score.
RE-KINECT patients were consistent in evaluating the severity and impact of TD, whether based on subjective assessments or standardized patient-reported instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD. Patient self-assessments (focused on symptom impact) can be clinically relevant; incorporating such measures into everyday practice may provide a more comprehensive approach to TD assessment and management.
Guanfacine extended release (GXR) is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD).
To separate efficacy and sedative treatment-emergent adverse events (TEAEs) associated with GXR in four randomized, controlled trials in children (6–12 years) and adolescents (13–17 years) with ADHD.
SPD503-301 (n = 345) and SPD503-304 (n = 324) were 8 and 9 week studies of fixed-dose GXR (≤ 4 mg/day). SPD503-312 (n = 314; adolescents only) and SPD503-316 (n = 338) were 10–13 week studies of dose-optimized GXR (1–7 mg/day).
In fixed-dose studies, pooled incidences of sedative TEAEs with GXR were highest at week 1 (GXR, 13.9–18.7%; placebo, 8.7%) and decreased to placebo levels at week 8 (0–1.4%; placebo, 0%). In contrast, proportions of responders (≥ 30% reduction from baseline in ADHD Rating Scale IV [ADHD-RS-IV] total score) increased from week 1 (GXR, 29.6–34.8%; placebo, 25.0%) through endpoint (GXR, 66.7–72.2%; placebo, 42.6%). Incidences of sedative TEAEs, but not proportions of responders, increased with GXR dosing. GXR was associated with a statistically significant reduction in ADHD-RS-IV total score from baseline to endpoint in patients without sedative TEAEs in both fixed-dose and dose-optimized studies (GXR versus placebo, effect size = 0.49 and 0.67, respectively; P < 0.001). GXR was associated with statistically significant improvements compared with placebo in both ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscale scores (P < 0.001).
These data from pooled GXR clinical trials indicate that incident sedative TEAEs do not contribute to increased treatment response over time, and that sedation and symptomatic improvement are distinct effects of GXR.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Depression is among the most prevalent mental disorders worldwide, and a substantial proportion of patients do not respond adequately to standard antidepressants. Our understanding of the pathophysiology of depression is no longer limited to the chemical imbalance of neurotransmitters, but also involves the interplay of proinflammatory modulators in the central nervous system, as well as folate metabolism. Additional factors such as stress and metabolic disorders also may contribute. Multiple inflammatory, metabolic, and genetic markers have been identified and may provide critical information to help clinicians individualize treatments for patients to achieve optimal outcomes. Recent advancements in research have clarified underlying causes of depression and have led to possible new avenues for adjunctive treatment. Among these is L-methylfolate, a medical food that is thought to enhance synthesis of monoamines (serotonin, norepinephrine, and dopamine), suppress inflammation, and promote neural health. Clinical studies that assessed supplemental use of L-methylfolate in patients with usual care-resistant depression found that it resulted in improved outcomes. Patients with selective serotonin reuptake inhibitor-resistant depression, and particularly subgroups with biomarkers of inflammation or metabolic disorders or folate metabolism-related genetic polymorphisms (or ≥2 of these factors), had the best responses. Considering this, the goals of this review are to 1) highlight recent advances in the pathophysiology of major depressive disorder as it pertains to folate and associated biomarkers and 2) establish the profiles of patients with depression who could benefit most from supplemental use of L-methylfolate.
Twins Research Australia (TRA) is a community of twins and researchers working on health research to benefit everyone, including twins. TRA leads multidisciplinary research through the application of twin and family study designs, with the aim of sustaining long-term twin research that, both now and in the future, gives back to the community. This article summarizes TRA’s recent achievements and future directions, including new methodologies addressing causation, linkage to health, economic and educational administrative datasets and to geospatial data to provide insight into health and disease. We also explain how TRA’s knowledge translation and exchange activities are key to communicating the impact of twin studies to twins and the wider community. Building researcher capability, providing registry resources and partnering with all key stakeholders, particularly the participants, are important for how TRA is advancing twin research to improve health outcomes for society. TRA provides researchers with open access to its vibrant volunteer membership of twins, higher order multiples (multiples) and families who are willing to consider participation in research. Established four decades ago, this resource facilitates and supports research across multiple stages and a breadth of health domains.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
The objective of this work was to describe treatment-emergent sexual dysfunction (TESD) and tolerability following a switch from selective serotonin reuptake inhibitor (SSRI: citalopram, paroxetine, or sertraline) monotherapy to vortioxetine or escitalopram monotherapy in adults with well-treated major depressive disorder (MDD) and SSRI-induced sexual dysfunction.
Data were analyzed from the primary study, an 8-week, randomized, double-blind, head-to-head study in which participants with well-treated depressive symptoms but experiencing TESD with SSRIs were directly switched to flexible doses (10/20 mg) of vortioxetine or escitalopram. Sexual functioning was assessed by the Changes in Sexual Functioning Questionnaire-14 (CSFQ-14), efficacy by the Montgomery–Åsberg Depression Rating Scale scores (MADRS) and Clinicians Global Impression of Severity/Improvement (CGI-S/CGI-I), and tolerability by adverse events. Efficacy and tolerability were assessed by pre-switch SSRI therapy where possible, and by participant characteristics.
Greater improvements in TESD were seen in the vortioxetine compared with escitalopram groups based on: participant demographics (≤45 years, women; P = 0.045), prior SSRI treatment (P = 0.044), number of prior major depressive episodes (MDEs) (1–3; P = 0.001), and duration of prior SSRI therapy (>1 year; P = 0.001). Prior SSRI treatment did not appear to influence the incidence or severity of TEAEs, except for nausea. Regardless of prior SSRI, both treatments maintained antidepressant efficacy after 8 weeks.
Results suggest that vortioxetine is a safe and effective switch therapy for treating SSRI-induced sexual dysfunction in adults with well-treated MDD. Also, improvement in sexual dysfunction with vortioxetine or escitalopram may be influenced by prior SSRI usage, sex, age, and history of MDEs.
Investigations into an outbreak of foodborne disease attempt to identify the source of illness as quickly as possible. Population-based reference values for food consumption can assist in investigation by providing comparison data for hypothesis generation and also strengthening the evidence associated with a food product through hypothesis testing. In 2014–2015 a national phone survey was conducted in Canada to collect data on food consumption patterns using a 3- or 7-day recall period. The resulting food consumption values over the two recall periods were compared. The majority of food products did not show a significant difference in the consumption over 3 days and 7 days. However, comparison of reference values from the 3-day recall period to data from an investigation into a Salmonella Infantis outbreak was shown to support the conclusion that chicken was the source of the outbreak whereas the reference values from a 7-day recall did not support this finding. Reference values from multiple recall periods can assist in the hypothesis generation and hypothesis testing phase of foodborne outbreak investigations.
Buprenorphine (BUP)/samidorphan (SAM) combination is an opioid system modulator being investigated as an adjunctive treatment for major depressive disorder (MDD). BUP/SAM is a fixed-dose combination of BUP, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and SAM, a µ-opioid receptor antagonist added to address the abuse and dependence potential of BUP.1,2
We assessed the effects of SAM on the abuse potential of BUP in the BUP/SAM combination in two ways: (1) a human abuse potential (HAP) study in volunteers; and (2) an evaluation of the clinical experience across studies of patients with MDD.
Study 212 (ClinicalTrials.gov ID: NCT02413281) was a HAP study in nondependent, recreational, adult opioid users. Following a qualification period, participants were randomized to 6 treatments in a blinded, crossover design: placebo (PBO), BUP/SAM at the target therapeutic dose (BUP/SAM 2mg/2mg), at 8mg/8mg and 16mg/16mg , and BUP alone (8mg and 16mg). The primary endpoint was maximum effect (Emax) for “At The Moment” Drug Liking Visual Analog Scale (VAS).
The clinical program for BUP/SAM included 4 PBO-controlled studies of patients with MDD (n=961). Pooled safety data were evaluated for adverse events (AEs) that may be associated with abuse, dependence, or withdrawal, as well as for objective signs of withdrawal with the Clinical Opioid Withdrawal Scale (COWS).
In Study 212 (n=38), Emax Drug Liking VAS scores for the BUP/SAM 2mg/2mg dose were similar to those for PBO (median within-subject difference [90% CI]: 2.5 [0.0–9.0]). Emax Drug Liking VAS scores for all BUP/SAM dose groups, including supratherapeutic doses, were significantly lower than those observed for either of the BUP doses. The supratherapeutic doses of BUP/SAM (8mg/8mg and 16mg/16mg) had higher Emax Drug Liking VAS scores than PBO, but the differences were small.
In the MDD controlled studies, the incidence of euphoria-related AEs was low for BUP/SAM 2mg/2mg and PBO (1.6% vs 0.2%, respectively) and there was no evidence of abuse or dependence behavior. Euphoria-related events typically occurred with treatment initiation and resolved with continued treatment. There was minimal evidence of withdrawal by reported AEs or COWS assessment.
These findings indicate that SAM mitigates the abuse potential of BUP in the BUP/SAM combination.
Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with antipsychotic treatment. RE KINECT (NCT03062033), a real-world study of outpatients prescribed antipsychotics, was designed to identify the presence of possible TD and characterize the impact of involuntary movements on functioning and quality of life. Data from RE-KINECT were used to compare the impact of possible TD in patients with schizophrenia/schizoaffective disorder [SZD] versus mood/other psychiatric disorders [Mood].
Adults with ≥3months of lifetime exposure to antipsychotics and ≥1 psychiatric disorder were recruited. The presence of possible TD was based on clinicians’ observation of involuntary movements in 4 body regions (head, trunk, upper extremities, and lower extremities). Baseline outcomes included demographics, medication history, location/severity of abnormal movements, impact of abnormal movements on daily activities, the Sheehan Disability Scale (SDS), and the EuroQoL 5-Dimensional questionnaire (EQ-5D-5L).
Of 204 patients with clinician-confirmed possible TD, 111 (54.4%) had a SZD diagnosis and 93 (45.6%) had a mood/other psychiatric diagnosis. Significant differences found between groups (Mood vs SZD) included: mean age (56.9 vs 52.7 years; P=0.0263); male sex (33.3% vs 62.2%; P<0.0001); African-American race (7.5% vs 26.1%; P=0.0005); mean lifetime exposure to antipsychotics (9.5 vs 19.5 years; P<0.0001); and percentage of patients currently taking ≥2 psychiatric medications (93.5% vs 79.3%; P=0.0093). Based on clinician observation, there were no significant differences between diagnosis groups in the number of body regions impacted by abnormal movements, maximum severity score across all 4 regions, or patient awareness of possible TD. Over 30% of patients in both groups reported that involuntary movements had “some” or “a lot” of impact on their ability to continue usual activities, be productive, and socialize. No significant differences between the diagnosis groups (Mood vs SZD) were found for mean SDS total score (12.8 vs 10.8), SDS domain scores (work/school [4.1 vs 4.2], social life [4.3 vs 3.7], family life [4.1 vs 3.5]), EQ-5D-5L utility score (0.68 vs 0.74), or EQ-5D-5L health state VAS (64.8 vs 68.5).
In this cohort of outpatients with possible TD, those with Mood disorders were more likely to be older, female, and white than patients with SZD. The ability to function and quality of life were equally impaired in both groups. Further studies on the impact of TD are needed.
Funding Acknowledgements: Neurocrine Biosciences, Inc.
The efficacy of valbenazine (INGREZZA) in tardive dyskinesia (TD) was demonstrated in placebo-controlled clinical trials, based on the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7). In these trials, mean changes in the AIMS total score were significantly greater with valbenazine 80 mg than with placebo. Currently, no minimal clinically important difference (MCID) has been established for the AIMS total score in patients with TD. Using valbenazine trial data, analyses were conducted to establish a MCID for AIMS total score in TD.
Data were pooled from three 6-week trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), KINECT 3 (NCT02274558). Using the Clinical Global Impression ofChange (CGI-TD) as an anchor comparison, AIMS total score changes from baseline to Week 6 were summarized for all study participants (pooled valbenazine and placebo groups) with a “minimal” CGI-TD score of ≤3 (minimally improved or better) or “robust” ≤2 (much improved or better) at Week 6.
In the pooled population (N=373), 72% and 29% of all participants had CGI-TD scores of ≤3 and ≤2, respectively. The median (maximum, minimum) change from baseline in AIMS total score at Week 6 was -2 (-13, 8) in participants with CGI-TD score ≤3 and -3 ( 13, 8) in participants with a score ≤2.
Pooled data from 3 randomized, double-blind, placebo-controlled trials suggest that a 2 point decrease in AIMS total score may represent the minimal clinically meaningful improvement. Larger AIMS score improvements were associated with “much improved” or “very much improved” CGI TD assessments.
This study was funded by Neurocrine Biosciences, Inc.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
In-spiraling supermassive black holes should emit gravitational waves, which would produce characteristic distortions in the time of arrival residuals from millisecond pulsars. Multiple national and regional consortia have constructed pulsar timing arrays by precise timing of different sets of millisecond pulsars. An essential aspect of precision timing is the transfer of the times of arrival to a (quasi-)inertial frame, conventionally the solar system barycenter. The barycenter is determined from the knowledge of the planetary masses and orbits, which has been refined over the past 50 years by multiple spacecraft. Within the North American Nanohertz Observatory for Gravitational Waves (NANOGrav), uncertainties on the solar system barycenter are emerging as an important element of the NANOGrav noise budget. We describe what is known about the solar system barycenter, touch upon how uncertainties in it affect gravitational wave studies with pulsar timing arrays, and consider future trends in spacecraft navigation.
Successful treatment of pediatric disorders has necessitated the development of alternative medication formulations, as children may prefer alternative dosage forms to tablets or capsules. This is especially true for attention-deficit/hyperactivity disorder (ADHD), which is one of the most common chronic pediatric conditions and often involves children with a variety of overlapping physical, psychological, or neurodevelopmental disorders. A special challenge for developing alternative dosage forms for ADHD treatment is the incorporation of a once-daily long-acting formulation. Traditional ADHD medication formulations have been limited, and issues surrounding prescribed dosing regimens—including poor medication adherence, difficulty swallowing, and the lack of dosing titration options—persist in ADHD treatment. In other disease areas, the development of alternative formulations has provided options for patients who have issues with consuming solid dosage forms, particularly children and individuals with developmental disorders. In the light of these new developments, several alternative formulations for ADHD medications are under development or have recently become available. This article reviews the various strategies for developing alternative dosage forms in other disease areas and discusses the application of these strategies in ADHD treatment. Alternative dosage forms may increase medication adherence, compliance, and patient preference and, therefore, improve the overall treatment for ADHD.
Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints.
Patients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression–Improvement (CGI-I) scale score, was also analyzed.
Of 622 patients who were randomized, 596 had ≥1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92–94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (p<0.001) improved by Day 85 with both AL doses, with significantly lower scores starting from Day 8 in most instances. Treatment response rates were significantly (p<0.001) greater with both doses of AL vs placebo.
AL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety.
Cariprazine, a dopamine D3/D2 partial agonist atypical antipsychotic with preferential binding to D3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of cariprazine was established in three randomized, double-blind, placebo-controlled, 6-week trials in patients with acute exacerbation of schizophrenia. This 53-week study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia.
This was a multicenter, open-label, flexible-dose study of cariprazine 3–9 mg/d in adults with schizophrenia. Participants included new patients and patients who had completed one of two phase III lead-in studies (NCT01104766, NCT01104779). Eligible patients entered a no-drug screening period of up to 1 week followed by 48 weeks of flexibly dosed, open-label cariprazine treatment (3–9 mg/d) and 4 weeks of safety follow-up.
A total of 586 patients received open-label cariprazine treatment, ~39% of whom completed the study. No unexpected safety issues or deaths were reported. The most common (≥10%) adverse events (AEs) observed were akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73 (12.5%) patients discontinued the study due to AEs during open-label treatment. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. Mean body weight increased by 1.5 kg during the study, prolactin levels decreased slightly, and measures of efficacy remained stable.
Long-term cariprazine treatment at doses up to 9 mg/d appeared to be generally safe and well tolerated in patients with schizophrenia.
Salmonella is a leading cause of bacterial foodborne illness. We report the collaborative investigative efforts of US and Canadian public health officials during the 2013–2014 international outbreak of multiple Salmonella serotype infections linked to sprouted chia seed powder. The investigation included open-ended interviews of ill persons, traceback, product testing, facility inspections, and trace forward. Ninety-four persons infected with outbreak strains from 16 states and four provinces were identified; 21% were hospitalized and none died. Fifty-four (96%) of 56 persons who consumed chia seed powder, reported 13 different brands that traced back to a single Canadian firm, distributed by four US and eight Canadian companies. Laboratory testing yielded outbreak strains from leftover and intact product. Contaminated product was recalled. Although chia seed powder is a novel outbreak vehicle, sprouted seeds are recognized as an important cause of foodborne illness; firms should follow available guidance to reduce the risk of bacterial contamination during sprouting.