Patients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.

Post hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal <6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).

Of the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).

In this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.

AbbVie

Deficits in visuospatial attention, known as neglect, are common following brain injury, but underdiagnosed and poorly treated, resulting in long-term cognitive disability. In clinical settings, neglect is often assessed using simple pen-and-paper tests. While convenient, these cannot characterise the full spectrum of neglect. This protocol reports a research programme that compares traditional neglect assessments with a novel virtual reality attention assessment platform: The Attention Atlas (AA).

The AA was codesigned by researchers and clinicians to meet the clinical need for improved neglect assessment. The AA uses a visual search paradigm to map the attended space in three dimensions and seeks to identify the optimal parameters that best distinguish neglect from non-neglect, and the spectrum of neglect, by providing near-time feedback to clinicians on system-level behavioural performance. A series of experiments will address procedural, scientific, patient, and clinical feasibility domains.

Analyses focuses on descriptive measures of reaction time, accuracy data for target localisation, and histogram-based raycast attentional mapping analysis; which measures the individual’s orientation in space, and inter- and intra-individual variation of visuospatial attention. We will compare neglect and control data using parametric between-subjects analyses. We present example individual-level results produced in near-time during visual search.

The development and validation of the AA is part of a new generation of translational neuroscience that exploits the latest advances in technology and brain science, including technology repurposed from the consumer gaming market. This approach to rehabilitation has the potential for highly accurate, highly engaging, personalised care.

Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.

To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.

This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.

The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.

Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Although rare, coronary artery anomalies can have significant clinical implications. Total anomalous origin of the coronary arteries from the pulmonary artery (TCAPA) represents a rare subtype of coronary artery anomaly for which little is known. The aim of this review was to characterise the presentation, utilised diagnostic modalities, associated cardiac lesions, and treatment strategies in patients with TCAPA.

A systematic review was performed for cases of TCAPA using PubMed, Embase, and Web of Science. Keywords searched included “total anomalous origin of the coronary arteries from the pulmonary artery,” “single ostium anomalous coronary artery from the pulmonary artery,” and “anomalous origin of both coronary arteries from the pulmonary artery.”

Fifty-seven cases of TCAPA were identified in 50 manuscripts. Fifty-eight per cent of patients were male and the median age at presentation was 10 days (mean 1.71 ± 6.6 years, range 0 days–39 years). Most patients were symptomatic at the time of presentation; cyanosis (n = 22) and respiratory distress (n = 14) were the most common symptoms. Cases were most commonly diagnosed at autopsy (n = 26, 45.6%), but operative intervention was pursued in 22 cases (45.6%); aortic re-implantation (n = 14) and a Takeuchi-type repair (n = 7) were the most common routes of repair.

The clinical presentation of patients with TCAPA was found to be variable, likely related to the presence of associated cardiac lesions. TCAPA should be considered in patients with suspected anomalous origin of the left coronary artery from the pulmonary artery for the serious consequences that can occur if not promptly corrected.

Vaginal cancer is a rare malignancy that poses a challenge to treat and cure, as surgical excision requires life-changing procedures because of the proximity and involvement of rectum, bladder and anus. We report in this case study the successful delivery of stereotactic ablative radiotherapy (SABR) for a patient with vaginal cancer after previous radiotherapy.

A 71-year-old white female who presented with dyspareunia and irritative urinary symptoms proven by biopsy was our candidate patient. Subsequent PET/CT revealed a hypermetabolic 3 cm lesion at the 12–1 o’clock position in the distal vagina involving the clitoris. The patient was initially treated with volumetric-modulated arc therapy (VMAT) with simultaneous integrated boost technique to the involved nodes, and later upon recurrence treated with SABR using 30 Gy in six fractions.

To our knowledge, this is the first report of a vaginal cylinder used to physically distance organs at risk from the treatment target and also as a localising device with image guidance for the delivery of SABR using an external beam.

Personal protective equipment (PPE) is worn by prehospital providers (PHPs) for protection from hazardous exposures. Evidence regarding the ability of PHPs to perform resuscitation procedures has been described in adult but not pediatric models. This study examined the effects of PPE on the ability of PHPs to perform resuscitation procedures on pediatric patients.

This prospective study was conducted at a US simulation center. Paramedics wore normal attire at the baseline session and donned full Level B PPE for the second session. During each session, they performed timed sets of psychomotor tasks simulating clinical care of a critically ill pediatric patient. The difference in time to completion between baseline and PPE sessions per task was examined using Wilcoxon signed-rank tests.

A total of 50 paramedics completed both sessions. Median times for task completion at the PPE sessions increased significantly from baseline for several procedures: tracheal intubation (+4.5 s; P = 0.01), automated external defibrillator (AED) placement (+9.5 s; P = 0.01), intraosseous line insertion (+7 s; P < 0.0001), tourniquet (+8.5 s; P < 0.0001), intramuscular injection (+21-23 s, P < 0.0001), and pulse oximetry (+4 s; P < 0.0001). There was no significant increase in completion time for bag-mask ventilation or autoinjector use.

PPE did not have a significant impact on PHPs performing critical tasks while caring for a pediatric patient with a highly infectious or chemical exposure. This information may guide PHPs faced with the situation of resuscitating children while wearing Level B PPE.

Preference-based measures of health-related quality of life play a key role in the calculation of Quality-Adjusted Life Years (QALYs) for Health Technology Assessment (HTA). The Child Health Utility 9D (CHU9D) is a new preference-based instrument designed specifically for application in children and adolescents (aged 7 to 17 years). This study aimed to compare Chinese and Australian adolescent population preferences for CHU9D health states using profile case best worst scaling (BWS) methods.

Fifty CHU9D health states (blocked into five survey versions) were generated for valuation using a fractional factorial design. Study participants were recruited through an online panel company in Australia, and through primary and secondary schools in China. A latent class modelling framework was adopted for econometric analysis.

A total of 1,982 respondents (51 percent female) in Australia and 902 respondents (43 percent female) in China provided useable survey responses. Latent class analysis indicated the existence of preference heterogeneity for both population groups. In the Australian sample, respondents in Class I placed the most importance on the mental health dimensions of the CHU9D (for example, Worried and Annoyed) and the least importance on daily activities (for example, Activities, Daily routine, Sleep), whilst respondents in Class II placed equal weights on all attributes. In the Chinese sample, respondents in Class I placed the most importance on the Activities dimension of the CHU9D and the least importance on the Annoyed dimension, whist Class II placed the most importance on the Schoolwork dimension and the least importance on Pain.

This study has provided important cross-country insights into the use of profile case BWS methods to elicit health state preferences with young people for application in HTA in children and adolescents. The differential latent classes identified between Australia and China highlights the necessity to derive country-specific adolescent scoring algorithms for the CHU9D instrument for application in HTA.

Little is known about the experience of family caregivers of adults with cystic fibrosis (CF). This information is important for the identification of caregivers at risk for burden.

This was a longitudinal analysis of survey data obtained from caregivers of adult CF patients participating in an early intervention palliative care trial. Caregivers completed the validated Brief Assessment Scale for Caregivers (BASC) repeatedly over a 28-month period. Mixed-effects modeling evaluated multivariate associations with positive and negative caregiver perceptions over time.

Of the 54 caregivers, 47.9% were spouses. The mean age was 50.9 years (SD = 13.2); 72.2% were women; 75.9% were married; and 63.0% were employed. At baseline, the BASC revealed large variations in positive and negative perceptions of caregiving. Although average scores over time were unchanging, variation was greater across caregivers than within caregivers (0.49 vs. 0.27, respectively). At baseline, the positive impact of caregiving in the sample was higher than the negative impact. Multivariate analysis revealed that patients' baseline pulmonary function and their full-time employment status predicted caregiver burden over time.

Caregivers of CF patients varied in their positive and negative caregiving experiences, although burden levels in individual caregivers were stable over time. When the disease was advanced, caregivers of CF patients experienced more overall burden but also more positive impact. This suggests that the role of caregivers may become more meaningful as disease severity worsens. In addition, full-time patient employment was associated with lower caregiver burden regardless of disease severity. This suggests that burden in CF caregivers may be predicted by financial strain or benefits conferred by patient employment. These associations require further investigation to determine whether highly burdened caregivers can be identified and assisted using tailored interventions.