Predictors of Mental Health Outcomes in a Multidisciplinary Weight Management Program for Class 3 Obesity.

This study aimed to examine the potential predictors of improvement in mental health outcomes following participation in an intensive non-surgical outpatient weight management program (WMP) in an Australian public hospital. This was a retrospective cohort study of all adults with Class 3 obesity (BMI ≥ 40 kg/m2) who enrolled in the WMP from March 2018 to June 2021. The participants completed the Eating Disorder Examination Questionnaire Short Version (EDE-QS), Kessler-10 Psychological Distress Scale, and 36-Item Short-Form Survey (SF-36) at baseline and 12-month follow-up. A total of 115 patients completed 12 months in the WMP and were included in the study, with 76.5% being female, a mean ± SD age at baseline of 51.3 ± 13.8 years, a weight of 146 ± 26 kg, and a BMI of 51.1 ± 8.6 kg/m2. The participants lost an average of 8.6 ± 0.2 kg over 12 months, and greater weight loss at follow-up was significantly associated with improved global EDE-QS scores, psychological distress, and improved mental health quality of life. However, improvements in most mental health outcomes were not predicted by weight loss alone. Notably, a lower eating disorder risk at baseline was associated with less psychological distress at follow-up and greater weight loss at follow-up. Our results also found an association between reduced psychological distress and reduced binge eating frequency. These findings support the inclusion components of obesity interventions that target the psychological correlates of obesity to support improved outcomes in people with Class 3 obesity. Future studies should aim to identify which aspects of the WMP helped improve people's psychological outcomes.

Urokinase-type plasminogen activator (uPA) regulates invasion and matrix remodelling in colorectal cancer.

Background: Cancer cells remodel their local physical environment through processes of matrix reorganisation, deposition, stiffening and degradation. Urokinase-type plasminogen activator (uPA), which is encoded by the PLAU gene, is an extracellular proteolytic enzyme known to be involved in cancer progression and tumour microenvironment (TME) remodelling. Perturbing uPA therefore has a strong potential as a mechano-based cancer therapy. This work is a bioengineering investigation to validate whether 1) uPA is involved in matrix degradation and 2) preventing matrix degradation by targeting uPA can reduce cancer cell invasion and metastasis. Methods: To this aim, we used an engineered 3D in vitro model, termed the tumouroid, that appropriately mimics the tumour's native biophysical environment (3 kPa). A CRISPR-Cas9 mediated uPA knockout was performed to introduce a loss of function mutation in the gene coding sequence. Subsequently, to validate the translational potential of blocking uPA action, we tested a pharmacological inhibitor, UK-371,801. The changes in matrix stiffness were measured by atomic force microscopy (AFM). Invasion was quantified using images of the tumouroid, obtained after 21 days of culture. Results: We showed that uPA is highly expressed in invasive breast and colorectal cancers, and these invasive cancer cells locally degrade their TME. PLAU (uPA) gene knock-out (KO) completely stopped matrix remodelling and significantly reduced cancer invasion. Many invasive cancer gene markers were also downregulated in the PLAU KO tumouroids. Pharmacological inhibition of uPA showed similarly promising results, where matrix degradation was reduced and so was the cancer invasion. Conclusion: This work supports the role of uPA in matrix degradation. It demonstrates that the invasion of cancer cells was significantly reduced when enzymatic breakdown of the TME matrix was prevented. Collectively, this provides strong evidence of the effectiveness of targeting uPA as a mechano-based cancer therapy.

Patient experiences of prescription drug monitoring programs: a qualitative analysis from an Australian pharmaceutical helpline.

BACKGROUND: Prescription Drug Monitoring Programs (PDMP) are electronic databases that are used to track and monitor the prescribing and dispensing of controlled substances, such as opioid analgesics and benzodiazepines. PDMP have been used widely throughout North America and have recently been implemented in Australia. Several unintended harms have been associated with PDMP in North America, including increased stigma, discrimination, and dismissal from care for patients prescribed these medications. AIMS: This study aimed to better understand how people who use prescription medications extramedically and their loved ones give meaning to their consumption and their treatment experiences and concerns in the context of a newly implemented real-time PDMP in Victoria, Australia. METHOD: Nineteen audio recordings of telephone calls made to the PDMP Pharmaceutical Helpline were transcribed and thematically analysed. RESULTS: Patients and their families were hopeful that PDMP would stop the extra medical use of medications. However, many were deeply concerned about how they would cope with withdrawal or life stressors without the support these medications afforded. Patients reported experiences of stigma and strained therapeutic relationships associated with PDMP implementation. CONCLUSION: PDMP have the potential to both assist and harm patients whose prescription medication use has been identified as 'risky' by the PDMP. The findings from this study suggest that clear and open communication, as well as reflection on unconscious bias and stigma may assist healthcare providers to facilitate better patient experiences and outcomes in the context of prescription medication dependence.

Exploring types of play in an adapted robotics program for children with disabilities.

PURPOSE: Play is an important occupation in a child's development. Children with disabilities often have fewer opportunities to engage in meaningful play than typically developing children. The purpose of this study was to explore the types of play (i.e., solitary, parallel and co-operative) within an adapted robotics program for children with disabilities aged 6-8 years. METHOD: This study draws on detailed observations of each of the six robotics workshops and interviews with 53 participants (21 children, 21 parents and 11 programme staff). RESULTS: Our findings showed that four children engaged in solitary play, where all but one showed signs of moving towards parallel play. Six children demonstrated parallel play during all workshops. The remainder of the children had mixed play types play (solitary, parallel and/or co-operative) throughout the robotics workshops. We observed more parallel and co-operative, and less solitary play as the programme progressed. Ten different children displayed co-operative behaviours throughout the workshops. The interviews highlighted how staff supported children's engagement in the programme. Meanwhile, parents reported on their child's development of play skills. CONCLUSIONS: An adapted LEGO® robotics program has potential to develop the play skills of children with disabilities in moving from solitary towards more parallel and co-operative play. Implications for rehabilitation Educators and clinicians working with children who have disabilities should consider the potential of LEGO® robotics programs for developing their play skills. Clinicians should consider how the extent of their involvement in prompting and facilitating children's engagement and play within a robotics program may influence their ability to interact with their peers. Educators and clinicians should incorporate both structured and unstructured free-play elements within a robotics program to facilitate children's social development.

Hippocampal GLP-1 receptors influence food intake, meal size, and effort-based responding for food through volume transmission.

Glucagon-like peptide-1 (GLP-1) is produced in the small intestines and in nucleus tractus solitarius (NTS) neurons. Activation of central GLP-1 receptors (GLP-1Rs) reduces feeding and body weight. The neural circuits mediating these effects are only partially understood. Here we investigate the inhibition of food intake and motivated responding for food in rats following GLP-1R activation in the ventral hippocampal formation (HPFv), a region only recently highlighted in food intake control. Increased HPFv GLP-1R activity following exendin-4 administration potently reduced food intake (both chow and Western diet) and body weight, whereas HPFv GLP-1R blockade increased food intake. These hypophagic effects were based on reduced meal size, and likely do not involve nausea as HPFv exendin-4 did not induce a conditioned flavor avoidance. HPFv GLP-1R activation also reduced effort-based responding for food under an operant progressive ratio reinforcement schedule, but did not affect food conditioned place preference expression. To investigate possible routes of HPFv GLP-1 signaling, immunohistochemical analysis revealed the absence of GLP-1 axon terminals in the HPFv, suggesting volume transmission as a mechanism of action. Consistent with this, the presence of active GLP-1 was detected in both the cerebrospinal fluid (CSF) and the HPFv. The source of CSF GLP-1 may be NTS GLP-1-producing neurons, as, (1) ∼30% of NTS GLP-1 neurons colocalized with the retrograde tracer fluorogold (FG) following lateral ventricle FG injection, and (2) GLP-1-immunoreactive axon terminals were observed adjacent to the ventricular ependymal layer. Collectively these findings illuminate novel neuronal and behavioral mechanisms mediating food intake reduction by GLP-1.

Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin.

Ceftobiprole, an investigational cephalosporin, is currently in phase III clinical development. Ceftobiprole is a broad-spectrum cephalosporin with demonstrated in vitro activity against Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-resistant S. epidermidis, penicillin-resistant S. pneumoniae, Enterococcus faecalis, Gram-negative bacilli including AmpC-producing Escherichia coli and Pseudomonas aeruginosa, but excluding extended-spectrum beta-lactamase-producing strains. Like cefotaxime, ceftriaxone, ceftazidime, and cefepime, ceftobiprole demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. In single-step and serial passage in vitro resistance development studies, ceftobiprole demonstrated a low propensity to select for resistant subpopulations. Ceftobiprole, like cefepime, is a weak inducer and a poor substrate for AmpC beta-lactamases.Ceftobiprole medocaril, the prodrug of ceftobiprole, is converted by plasma esterases to ceftobiprole in <30 minutes. Peak serum concentrations of ceftobiprole observed at the end of a single 30-minute infusion were 35.5 mug/mL for a 500-mg dose and 59.6 mug/mL for a 750-mg dose. The volume of distribution of ceftobiprole is 0.26 L/kg ( approximately 18 L), protein binding is 16%, and its serum half-life is approximately 3.5 hours. Ceftobiprole is renally excreted ( approximately 70% in the active form) and systemic clearance correlates with creatinine clearance, meaning that dosage adjustment is required in patients with renal dysfunction. Ceftobiprole has a modest post-antibiotic effect (PAE) of approximately 0.5 hours for MRSA and a longer PAE of approximately 2 hours for penicillin-resistant pneumococci. Ceftobiprole, when administered intravenously at 500 mg once every 8 hours (2-hour infusion), has a >90% probability of achieving f T(>MIC) (free drug concentration exceeds the minimum inhibitory concentration [MIC]) for 40% and 60%, respectively, of the dosing interval for isolates with ceftobiprole MIC < or =4 and < or =2 mg/L, respectively.Currently, only limited clinical trial data are published for ceftobiprole. In a phase III trial, 784 patients with Gram-positive skin infections were randomized to treatment with either ceftobiprole 500 mg or vancomycin 1 g, each administered twice daily for 7-14 days; 93.3% of patients were clinically cured with ceftobiprole compared with 93.5% receiving vancomycin, and the eradication rate for MRSA infections was 91.8% for ceftobiprole compared with 90% for vancomycin. A phase III, randomized, double-blind, multicenter trial compared ceftobiprole 500 mg every 8 hours with vancomycin 1 g every 12 hours plus ceftazidime 1 g every 8 hours in patients with complicated skin and skin structure infections. Of the 828 patients enrolled, 31% had diabetic foot infections, 30% had abscesses, and 22% had wounds. No difference in clinical cure was reported in the clinically evaluable, intent-to-treat and microbiologically evaluable populations with cure rates of 90.5%, 81.9%, and 90.8%, respectively, in the ceftobiprole-treated patients and 90.2%, 80.8%, and 90.5%, respectively, in the vancomycin plus ceftazidime-treated group. Microbiologic eradication of Gram-positive cocci meticillin-susceptible S. aureus (MSSA) [ceftobiprole 91% vs vancomycin plus ceftazidime 92%] and MRSA (ceftobiprole 87% vs vancomycin plus ceftazidime 80%), as well as Gram-negative bacilli, E. coli (ceftobiprole 89% vs vancomycin plus ceftazidime 92%), and P. aeruginosa (ceftobiprole 87% vs vancomycin plus ceftazidime 100%), was not significantly different between groups. Similar cures rates in the microbiologically evaluable population occurred in both groups for Panton-Valentine leukocidin (PVL)-positive MSSA and PVL-positive MRSA.Currently, ceftobiprole has completed phase III trials for complicated skin and skin structure infections due to MRSA and nosocomial pneumonia due to suspected or proven MRSA; phase III trials are also ongoing in community-acquired pneumonia. Ceftobiprole has so far demonstrated a good safety profile in preliminary studies with similar tolerability to comparators. The broad-spectrum activity of ceftobiprole may allow it to be used as monotherapy in situations where a combination of antibacterials might be required. Further clinical studies are needed to determine the efficacy and safety of ceftobiprole and to define its role in patient care.