Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation.

We report a novel utilization of a pH modifier as a disproportionation retardant in a tablet formulation. The drug molecule of interest has significant bioavailability challenges that require solubility enhancement. In addition to limited salt/cocrystal options, disproportionation of the potential salt(s) was identified as a substantial risk. Using a combination of Raman spectroscopy with chemometrics and quantitative X-ray diffraction in specially designed stress testing, we investigated the disproportionation phenomena. The learnings and insight drawn from crystallography drove the selection of the maleate form as the target API. Inspired by the fumarate form's unique stability and solubility characteristics, we used fumaric acid as the microenvironmental pH modulator. Proof-of-concept experiments with high-risk (HCl) and moderate-risk (maleate) scenarios confirmed the synergistic advantage of fumaric acid, which interacts with the freebase released by disproportionation to form a more soluble species. The resultant hemifumarate helps maintain the solubility at an elevated level. This work demonstrates an innovative technique to mediate the solubility drop during the "parachute" phase of drug absorption using compendial excipients, and this approach can potentially serve as an effective risk-mitigating strategy for salt disproportionation.

Predictive performance of the common red flags in emergency department headache patients: a HEAD and HEAD-Colombia study.

OBJECTIVES: Only a small proportion of patients presenting to an ED with headache have a serious cause. The SNNOOP10 criteria, which incorporates red and orange flags for serious causes, has been proposed but not well studied. This project aims to compare the proportion of patients with 10 commonly accepted red flag criteria (singly and in combination) between patients with and without a diagnosis of serious secondary headache in a large, multinational cohort of ED patients presenting with headache. METHODS: Secondary analysis of data obtained in the HEAD and HEAD-Colombia studies. The outcome of interest was serious secondary headache. The predictive performance of 10 red flag criteria from the SNNOOP10 criteria list was estimated individually and in combination. RESULTS: 5293 patients were included, of whom 6.1% (95% CI 5.5% to 6.8%) had a defined serious cause identified. New neurological deficit, history of neoplasm, older age (>50 years) and recent head trauma (2-7 days prior) were independent predictors of a serious secondary headache diagnosis. After adjusting for other predictors, sudden onset, onset during exertion, pregnancy and immune suppression were not associated with a serious headache diagnosis. The combined sensitivity of the red flag criteria overall was 96.5% (95% CI 93.2% to 98.3%) but specificity was low, 5.1% (95% CI 4.3% to 6.0%). Positive predictive value was 9.3% (95% CI 8.2% to 10.5%) with negative predictive value of 93.5% (95% CI 87.6% to 96.8%). CONCLUSION: The sensitivity and specificity of the red flag criteria in this study were lower than previously reported. Regarding clinical practice, this suggests that red flag criteria may be useful to identify patients at higher risk of a serious secondary headache cause, but their low specificity could result in increased rates of CT scanning. TRIAL REGISTRATION NUMBER: ANZCTR376695.

Enhancing pain care with the American Pain Society Patient Outcome Questionnaire for use in the emergency department (APS-POQ-RED): validating a patient-reported outcome measure.

BACKGROUND: In general, the quality of pain care in emergency departments (ED) is poor, despite up to 80% of all ED patients presenting with pain. This may be due to the lack of well-validated patient-reported outcome measures (PROMs) of pain care in the ED setting. The American Pain Society-Patient Outcome Questionnaire-Revised Edition (APS-POQ-R), with slight modification for ED patients, is a potentially useful PROM for the adult ED, however it is yet to be completely validated. METHODS: Adult patients, who had presented with moderate to severe acute pain, were recruited at two large inner-city EDs in Australia. A modified version of the APS-POQ-R was administered at the completion of their ED care. Responses were randomly split into three groups and underwent multiple rounds of exploratory and confirmatory factor analysis with testing for construct, convergent, divergent validity and internal consistency. RESULTS: A total of 646 ED patients (55.6% female), with a median age of 48.3 years, and moderate to severe pain on arrival, completed the ED-modified APS-POQ-R. Psychometric evaluation resulted in a reduced nine-question tool, which measures three constructs (pain relief and satisfaction (α=0.891), affective distress (α=0.823) and pain interference (α=0.908)) and demonstrated construct, convergent, divergent validity, and internal consistency. CONCLUSIONS: This new tool, which we refer to as the American Pain Society-Patient Outcome Questionnaire-Revised for the ED (APS-POQ-RED), should form the basis for reporting patient-reported outcomes of ED pain care in future quality improvement and research.

Developing Robust Clinical Text Deep Learning Models - A "Painless" Approach.

The success of deep learning in natural language processing relies on ample labelled training data. However, models in the health domain often face data inadequacy due to the high cost and difficulty of acquiring training data. Developing such models thus requires robustness and performance on new data. A generalised incremental multiphase framework is proposed for developing robust and performant clinical text deep learning classifiers. It incorporates incremental multiphases for training data size assessments, cross-validation setup to avoid test data bias, and robustness testing through inter/intra-model significance analysis. The framework's effectiveness and generalisation were confirmed by the task of identifying patients presenting in 'pain' to the emergency department.

Determinants of fatigue in emergency department clinicians who wear personal protective equipment.

OBJECTIVE: To determine the independent predictors for clinician fatigue and decline in cognitive function following a shift in the ED during early stages of the COVID-19 pandemic. METHODS: This was a prospective, quasi-experimental study conducted in a metropolitan adult tertiary-referral hospital ED over 20 weeks in 2021. The participants were ED doctors and nurses working clinical shifts in an ED isolation area or high-risk zone (HRZ) with stringent personal protective equipment (PPE). The participants' objective and subjective fatigue was measured by the Samn-Perelli fatigue score and a psychomotor vigilance 'smart game' score, respectively. Postural signs/symptoms and urine specific gravity (SG) were measured as markers of dehydration. RESULTS: Sixty-three participants provided data for 263 shifts. Median (interquartile range) age was 33 (28-38) years, 73% were female. Worsening fatigue score was associated with working afternoon shifts (afternoon vs day, adjusted odds ratio [aOR] 5.16 [95% confidence interval (CI) 1.32-20.02]) and in non-HRZ locations (HRZ vs non-HRZ, aOR 0.23 [95% CI 0.06-0.87]). Worsening cognitive function (game score) was associated with new onset postural symptoms (new vs no symptoms, aOR 4.14 [95% CI 1.34-12.51]) and afternoon shifts (afternoon vs day, aOR 3.13 [95% CI 1.16-8.44]). Working in the HRZ was not associated with declining cognitive function. Thirty-four (37%) of the 92 participants had an end of shift urine SG >1.030. CONCLUSION: Working afternoon shifts was associated with fatigue. There was no association between HRZ allocation and fatigue, but our study was limited by a low COVID workload and fluctuating PPE requirements in the non-HRZs. Workplace interventions that target the prevention of fatigue in ED clinicians working afternoon shifts should be prioritised.

Incidence of Discharge Against Medical Advice in Queensland Hospital Emergency Departments Among Indigenous Patients from 2016 to 2021.

BACKGROUND: The incidence of discharge against medical advice (DAMA) in emergency departments (EDs) among Indigenous people is a growing concern in Australia. This study aimed to determine the incidence of ED DAMA in public hospitals in Queensland (QLD) from 2016 to 2021 and investigate the disparities in ED DAMA between Indigenous and non-Indigenous patients. The study also assessed the impact of the COVID-19 pandemic on the incidence of ED DAMA. METHODS: A descriptive epidemiological study was conducted using aggregated data from QLD public hospital EDs. The data was retrieved from Clinical Excellence QLD, Healthcare Improvement Unit, in the QLD Health Open Data Portal for the period 1 January 2016 to 31 December 2021. Incidence rates and unadjusted odds ratios were calculated and compared using the chi-square test to identify differences between Indigenous and non-Indigenous patients. RESULTS: The annual incidence of DAMA in EDs was 7.7% among Indigenous patients, compared to 4.8% among non-Indigenous patients, with the highest rate (8.9%) reported in 2021 among Indigenous patients. The incidence of ED DAMA was higher for Indigenous patients in major cities (20.0%) than in very remote areas (7.4%). Patients in triage categories 4 (10.0%) and 3 (7.3%) accounted for the vast majority of ED DAMA events among Indigenous patients. The acute group A hospitals had the highest incidence of ED DAMA (10.9% for Indigenous patients and 6.5% for non-Indigenous patients). The COVID-19 pandemic had no impact on the incidence of ED DAMA. CONCLUSION: Indigenous patients experience a disparity in ED DAMA incidence. Addressing this issue requires collaborative efforts from healthcare providers, policymakers, and community organizations.

Developing In Situ Chemometric Models with Raman Spectroscopy for Monitoring an API Disproportionation with a Complex Polymorphic Landscape.

An in situ Raman method was developed to characterize the disproportionation of two salts involving a complex polymorphic landscape comprising up to two metastable and one stable freebase forms. Few precedents exist for Raman calibration procedures for solid form quantitation involving more than two polymorphs, while no literature examples were found for cases with multiple metastable forms. Therefore, a new Raman calibration procedure was proposed by directly using disproportionation experiments to generate multiple calibration samples encompassing a range of polymorph ratios through in-line Raman measurements complemented by off-line reference X-ray diffraction measurements. The developed Raman methods were capable of accurately quantitating each solid form in situ when solid concentration variation was incorporated into the calibration dataset. The kinetic understanding of the thermodynamically driven polymorphic conversions gained from this Raman method guided the selection of the salt best suited for the delivery of the active ingredient in the drug product. This work provided a spectroscopic and mathematical approach for simultaneously quantitating multiple polymorphs from a complex mixture of solids with the objective of real-time monitoring.

Computed tomography brain scan utilization in patients with headache presenting to emergency departments: a multinational study.

BACKGROUND AND IMPORTANCE: Recommended indications for emergency computed tomography (CT) brain scans are not only complex and evolving, but it is also unknown whether they are being followed in emergency departments (EDs). OBJECTIVE: To determine the CT utilization and diagnostic yield in the ED in patients with headaches across broad geographical regions. DESIGN: Secondary analysis of data from a multinational cross-sectional study of ED headache presentations over one month in 2019. SETTING AND PARTICIPANTS: Hospitals from 10 participating countries were divided into five geographical regions [Australia and New Zealand (ANZ); Colombia; Europe: Belgium, France, UK, and Romania; Hong Kong and Singapore (HKS); and Turkey). Adult patients with nontraumatic headache as the primary presenting complaint were included. Patients were identified from ED management systems. OUTCOME MEASURES AND ANALYSIS: The outcome measures were CT utilization and diagnostic yield. CT utilization was calculated using a multilevel binary logistic regression model to account for clustering of patients within hospitals and regions. Imaging data (CT requests and reports) were sourced from radiology management systems. MAIN RESULTS: The study included 5281 participants. Median (interquartile range) age was 40 (29-55) years, 66% were women. Overall mean CT utilization was 38.5% [95% confidence interval (CI), 30.4-47.4%]. Regional utilization was highest in Europe (46.0%) and lowest in Turkey (28.9%), with HKS (38.0%), ANZ (40.0%), and Colombia (40.8%) in between. Its distribution across hospitals was approximately symmetrical. There was greater variation in CT utilization between hospitals within a region than between regions (hospital variance 0.422, region variance 0.100). Overall mean CT diagnostic yield was 9.9% (95% CI, 8.7-11.3%). Its distribution across hospitals was positively skewed. Regional yield was lower in Europe (5.4%) than in other regions: Colombia (9.1%), HKS (9.7%), Turkey (10.6%), and ANZ (11.2%). There was a weak negative correlation between utilization and diagnostic yield ( r  = -0.248). CONCLUSION: In this international study, there was a high variation (28.9-46.6%) in CT utilization and diagnostic yield (5.4-11.2%) across broad geographic regions. Europe had the highest utilization and the lowest yield. The study findings provide a foundation to address variation in neuroimaging in ED headache presentations.

A Phase 2 Randomized, Placebo-controlled Crossover Trial to Evaluate Safety and Efficacy of Platelet-rich Plasma Injections for Peyronie's Disease: Clinical Trial Update.

Intralesional injection of platelet-rich plasma for Peyronie's disease appears to be safe according to early observations from an ongoing clinical trial. Efficacy data remain elusive until completion of the trial.

Low-intensity extracorporeal shockwave therapy for diabetic men with erectile dysfunction: A systematic scoping review.

BACKGROUND: Erectile dysfunction (ED) is a very common complication in men with diabetes mellitus (DM). Low-intensity extracorporeal shockwave therapy (Li-ESWT) offers a promising nonsurgical treatment option for ED. A systematic scoping review investigating the outcomes of Li-ESWT in diabetic men with ED has not yet been performed. OBJECTIVES: To systematically review animal and clinical studies related to the use of Li-ESWT for treatment of DM-related ED. DATA SOURCES: PubMed, Embase, The Cochrane Library, Scopus, and Web of Science were searched, unrestricted by dates or study design. MATERIALS AND METHODS: We included qualitative studies, quantitative studies, primary research studies, meta-analyses, and research letters written in English. Full text reviewing was completed in all animal and human studies discussing Li-ESWT for the treatment of ED in subjects with DM. Data extracted included the journal citation, publication year, country of origin, study design, and a summary of the pertinent findings. RESULTS: Our search yielded nine clinical studies and 10 animal studies. The results of the clinical studies suggest that Li-ESWT is a safe and effective treatment in men with well-controlled DM and moderate or better ED. However, the benefit is less durable in diabetic men than nondiabetic men. The results of the animal studies suggest that Li-ESWT can significantly improve erectile function in diabetic rat models with ED. CONCLUSIONS: The examined studies present encouraging results for the use of Li-ESWT to treat diabetic men with ED. Future studies, particularly robust randomized controlled trials, are necessary to confirm these findings and provide long-term follow-up.

Strategies to Increase Testosterone in Men Seeking Fertility.

Prevalence of testosterone deficiency is increasing in the adolescent and young adult male population. As the average paternal age rises, there is a significant population of men with hypogonadism seeking testosterone therapy wishing to achieve or maintain fertility potential. Identification of potential lifestyle modifications that may improve the testosterone deficiency is one of the initial interventions of the holistic strategy in treatment. This is followed by drug therapy; however, traditional testosterone therapy acts as a contraceptive by suppressing the hypothalamus-pituitary-gonadal (HPG) axis and therefore cannot be used as a treatment strategy. A solution has been the off-label use of selective estrogen receptor modulators, human chorionic gonadotropin (hCG), and anastrozole inhibitors to treat hypogonadal symptoms while increasing intratesticular testosterone, a necessity for spermatogenesis. Recently, a novel therapy, Natesto intranasal testosterone gel, has been shown to increase serum testosterone levels while maintaining semen parameters. This is hypothesized to be because of its short-acting properties having lesser effect on the HPG axis, in contrast to the long-acting properties of traditional testosterone therapy. It is important to differentiate hypogonadal men between those seeking to achieve or maintain fertility status because the drug therapy of choice differs. This can be accomplished by determining the levels of 17-hydroxyprogesterone (17-OHP), because it is a biomarker for intratesticular testosterone. Those with low 17-OHP may wish to initiate treatment with alternative therapies, whereas those with high 17-OHP may trial short-acting testosterone therapies. As the urologist's armamentarium continues to increase, better strategies to increase testosterone levels in men seeking fertility can be achieved.

Impact of COVID-19 pandemic on emergency department patient volume and flow: Two countries, two hospitals.

OBJECTIVES: COVID-19 greatly disrupted the provision of emergency care across the globe. ED service delivery was urgently redesigned as human and material resources were mobilised, and patients with respiratory symptoms were isolated. This study aimed to compare ED patient volume and flow metrics before and during the COVID-19 pandemic. METHODS: An observational study was conducted in two large urban EDs in Brisbane, Australia and Seoul, Republic of Korea. Patient volume and flow were quantified using ED presentation numbers and service times, respectively. Daily case numbers, waiting, treatment and admission delay times were compared between 2019 and 2020/2021 using time series plots. Outcomes were further classified by triage category and age group. Trends were examined alongside a timeline of health service and government policies. RESULTS: There were reductions in daily presentations for the least urgent triage categories during the early phase of the pandemic. The caseloads for the most urgent triage categories were unaffected. The trends were similar in both EDs. A reduction in waiting and admission delay times but not treatment times coincided with reduced presentations in Brisbane. This pattern gradually reversed as presentations returned to baseline. In Seoul, admission delay times returned to pre-pandemic levels despite a persistent reduction in presentation numbers. CONCLUSIONS: Total daily presentations varied considerably according to government mandated social restrictions and testing requirements in both EDs. The reductions in waiting and admission delay times corresponded with improvements in hospital capacity.

Effect of Radiofrequency Electromagnetic Radiation Emitted by Modern Cellphones on Sperm Motility and Viability: An In Vitro Study.

BACKGROUND: Cellphones emit radiofrequency electromagnetic radiation (RF-EMR) for transmission of data for social media communication, web browsing, and music/podcast streaming. Use of Bluetooth ear buds has probably prolonged the time during which cellphones reside in the trouser pockets of men. It has been postulated that RF-EMR increases oxidative stress and induces free radical formation. OBJECTIVE: To investigate the effect of wireless-spectrum (4G, 5G, and WiFi) RF-EMR emitted by modern smartphones on sperm motility and viability and explore whether these effects can be mitigated using a physical barrier or distance. DESIGN, SETTING, AND PARTICIPANTS: Semen samples were obtained from fertile normozoospermic men aged 25-35 yr. A current-generation smartphone in talk mode was used as the RF-EMR source. A WhatsApp voice call was made using either 4G, 5G, or WiFi wireless connectivity. We determined if exposure effects were mitigated by either a cellphone case or greater distance from the semen sample. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The semen samples were analyzed according to 2010 World Health Organization laboratory guidelines. Statistical analysis was performed using SPSS v.28. RESULTS AND LIMITATIONS: We observed decreases in sperm motility and viability with WiFi exposure but not with exposure to 4G or 5G RF-EMR. With large variability among smartphones, continued research on exposure effects is needed. CONCLUSIONS: Our exploratory study revealed that sperm motility and viability are negatively impacted by smartphones that use the WiFi spectrum for data transmission. PATIENT SUMMARY: We looked at the effect of cellphone use on sperm motility and viability. We found that cellphones using WiFi connectivity for data usage have harmful effects on semen quality in men.

A Comparative Analysis of Ergonomic Risk Utilizing the 4K-3D Exoscope Versus Standard Operating Microscope for Male Fertility Microsurgery.

OBJECTIVE: To stratify ergonomic risk in a urologic microsurgeon using the 4K-3D exoscope versus the operating microscope (OM) with wearable technology. METHODS: The surgeon was calibrated with wearable sensor inertial measurement units (IMUs) on the head and upper arms. Each inertial measurement units contained an accelerometer, magnetometer, and gyroscope to measure surgeon joint angle change during microscopic procedures for male fertility. The validated modified rapid upper limb assessment was used to determine the proportion of time spent in ranges of risk. Categories 1-4 were assigned for the head and upper extremities (4= highest ergonomic risk). Chi-squared analysis was used to analyze differences in proportions. RESULTS: A total of 500 and 479 minutes from 4K-3D exoscope and OM guided surgeries were analyzed. The 4K-3D exoscope significantly favored upper arm category 1 positioning compared to the OM (56.2% vs 37.7%; P < .0001). The OM exposed the surgeon to higher category 3 positioning (14.6% vs 1.6%; P <.0001). More time was spent with the neck "extended" using the 4K-3D exoscope (51.8% vs 19.5%; P < .0001) with 67% of neck extension between 0-10° (category 1). Overall, more time was spent with the neck in risk group 1-2 with the OM (P < .0001). CONCLUSION: The 4K-3D exoscope offers favorable ergonomic positioning for the upper extremities which may reduce work stress-related injury. More operative time was spent with the neck in mild extension with 4K-3D exoscope utilization. However, the OM favored longer operative times in low-risk neck ergonomic positions.

Patterns of chemotherapy use in muscle-invasive bladder cancer in a tertiary centre.

Objectives: Although neoadjuvant chemotherapy (NAC) has been demonstrated to have significant benefits to survival in patients with muscle-invasive bladder cancer (MIBC), the current utilization of NAC in Australia is unknown. The aim of this study was to evaluate the patterns of neoadjuvant and adjuvant chemotherapy (AC) use in patients undergoing cystectomy for MIBC at a large tertiary institution in Australia. Methods: A retrospective study was conducted using data of patients who underwent a radical cystectomy (RC) at a high-volume centre for MIBC between 2011 and 2021. Results: Of 69 patients who had a cystectomy for ≥ pT2 bladder cancer, 73.9% were eligible for NAC. However, of those eligible, only five patients received NAC (9.8%). Of the total patients who were eligible for AC, only 44.4% received postoperative chemotherapy. Common reasons for the lack of uptake were due to patients being unfit or declining treatment. There was no difference in progression-free survival or overall survival in those who received NAC and AC. Conclusions: The majority of patients undergoing RC for MIBC received AC compared to NAC, reflecting the real-world challenge of NAC uptake. This highlights the need for ongoing improvements in selection and usage of NAC and less reliance of AC utilization post RC.

Metabolic synergy in Camelina reproductive tissues for seed development.

Photosynthesis in fruits is well documented, but its contribution to seed development and yield remains largely unquantified. In oilseeds, the pods are green and elevated with direct access to sunlight. With 13C labeling in planta and through an intact pod labeling system, a unique multi-tissue comprehensive flux model mechanistically described how pods assimilate up to one-half (33 to 45%) of seed carbon by proximal photosynthesis in Camelina sativa. By capturing integrated tissue metabolism, the studies reveal the contribution of plant architecture beyond leaves, to enable seed filling and maximize the number of viable seeds. The latent capacity of the pod wall in the absence of leaves contributes approximately 79% of seed biomass, supporting greater seed sink capacity and higher theoretical yields that suggest an opportunity for crop productivity gains.

Future of Male Infertility Evaluation and Treatment: Brief Review of Emerging Technology.

Over the past few decades, there have been significant advances in male infertility, particularly in the development of novel diagnostic tools. Unfortunately, there remains a substantial number of patients that remain infertile despite these improvements. In this review, we take heed of the emerging technologies that will shape the future of male infertility diagnosis, evaluation, and treatment. Improvement in computer-assisted semen analyses and portability allow males to obtain basic semen parameters from the comfort of their home. Additionally, breakthrough ultrasound technology allows for preoperative prediction of potential areas of spermatogenesis within the testes, high-resolution optics permits better visualization during microdissection testicular sperm extraction (mTESE), and artificial intelligence improves sperm selection and identification.

Phase 2 Study of Neoadjuvant FGFR Inhibition and Androgen Deprivation Therapy Prior to Prostatectomy.

BACKGROUND: Disease recurrence is common following prostatectomy in patients with localised prostate cancer with high-risk features. Although androgen deprivation therapy increases the rates of organ-confined disease and negative surgical margins, there is no significant benefit on disease recurrence. Multiple lines of evidence suggest that (Fibroblast Growth Factor/Fibroblast Growth Factor Receptor) FGF/FGFR-signalling is important in supporting prostate epithelial cell survival in hostile conditions, including acute androgen deprivation. Given the recent availability of oral FGFR inhibitors, we investigated whether combination therapy could improve tumour response in the neo-adjuvant setting. METHODS: We conducted an open label phase II study of the combination of erdafitinib (3 months) and androgen deprivation therapy (4 months) in men with localised prostate cancer with high-risk features prior to prostatectomy using a Simon's 2 stage design. The co-primary endpoints were safety and tolerability and pathological response in the prostatectomy specimen. The effect of treatment on residual tumours was explored by global transcriptional profiling with RNA-sequencing. RESULTS: Nine patients were enrolled in the first stage of the trial. The treatment combination was poorly tolerated. Erdafitinib treatment was discontinued early in six patients, three of whom also required dose interruptions/reductions. Androgen deprivation therapy for 4 months was completed in all patients. The most common adverse events were hyperphosphataemia, taste disturbance, dry mouth and nail changes. No patients achieved a complete pathological response, although patients who tolerated erdafitinib for longer had smaller residual tumours, associated with reduced transcriptional signatures of epithelial cell proliferation. CONCLUSIONS: Although there was a possible enhanced anti-tumour effect of androgen deprivation therapy in combination with erdafitnib in treatment naïve prostate cancer, the poor tolerability in this patient population prohibits the use of this combination in this setting.