Mediastinal melioidosis: A case series from far North Queensland.

Melioidosis is the clinical disease caused by the Gram-negative bacillus Burkholderia pseudomallei and is endemic to Northern Australia and Southeast Asia. It is commonly referred to as the 'great mimicker' because of its wide range of clinical presentations, often making diagnosis challenging. Isolated mediastinal lymphadenopathy as the presenting feature of melioidosis is rare and can be indistinguishable from tuberculosis or malignancy. Endobronchial ultrasound (EBUS) is the preferred technique for evaluating undifferentiated mediastinal lymphadenopathy but its role in the diagnosis of mediastinal melioidosis remains sparsely reported in the literature. In this case series, we present four cases of mediastinal melioidosis, and the role that EBUS guided fine needle aspiration (FNA) played in the diagnosis and management.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2019: the Influenza Complications Alert Network (FluCAN).

Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2019 influenza season. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Cases were defined as patients hospitalised at any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data were also collected on a frequency matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 1 April to 31 October 2019 (the 2019 influenza season), there were 4,154 patients admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 44% were elderly (≥ 65 years), 21% were children (< 16 years), 7.7% were Aboriginal and Torres Strait Islander peoples, 1.7% were pregnant and 73% had chronic comorbidities. Most admissions were due to influenza A infection (85%). Estimated vaccine coverage was 75% in the elderly, 49% in non-elderly adults with medical comorbidities, and 27% in young children (< 5 years). The estimated vaccine effectiveness in the target adult population was 42% (95% confidence interval [95% CI]: 36%, 49%). There were a larger number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2019 than in 2018.

Surveillance for severe influenza and COVID-19 in patients admitted to sentinel Australian hospitals in 2020: the Influenza Complications Alert Network (FluCAN).

Introduction: Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. Methods: The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Influenza and COVID-19 cases were defined as patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. Results: There were 448 patients with COVID-19 admitted between 16 March and 31 December 2020, and only 20 patients with influenza admitted between 1 April and 30 November 2020, to one of 22 FluCAN hospitals. Of the COVID-19 cases, 173 (39%) were > 65 years of age, 36 (8%) were children (< 16 years), 6 (1%) were Aboriginal and Torres Strait Islander peoples, 4 (1%) were pregnant and 289 (65%) had chronic comorbidities. COVID-19 hospital admissions peaked between weeks 13 and 15 (first wave) nationally, and again between weeks 31 and 35 (Victoria), with most admissions represented by those above 40 years of age. Discussion: There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.

Conservative management of traumatic pneumothoraces: A retrospective cohort study.

OBJECTIVE: Traumatic pneumothoraces (T-PTXs) are traditionally managed with an intercostal catheter (ICC), despite little evidence for this. Success with conservative management of primary spontaneous PTX has been demonstrated, and our ED has adopted a conservative approach where safe for all PTX. METHODS: We reviewed all T-PTXs at our institution over a 7-year period to assess outcomes of those conservatively managed and compare with those who received an ICC. A total of 144 cases were identified, 65 managed conservatively and 79 invasively. Each was individually reviewed and variables including demographics, aetiology, smoking/lung disease history, T-PTX size (apical interpleural distance and hemithorax percentage), length of stay, Revised Trauma Score, Injury Severity Score and delayed intervention/complications were recorded. Chi-squared, Z-score, Mann-Whitney U and t-tests were used for analysis. RESULTS: The mean apical interpleural distance was 26.8 mm (95% confidence interval [CI] 22.1-29.7 mm) in the conservative group and 49.1 mm (95% CI 41.2-57.0 mm) in the ICC group (P < 0.05 for difference between groups). Mean T-PTX percentage 25.9% (95% CI 22.1-29.7%) in the conservative group versus 45.9% (95% CI 39.7-50.5%) in the ICC group (P < 0.05 for difference between two groups) and mean Revised Trauma Score 7.4 (conservative) versus 6.8 (invasive) (P < 0.05). No conservatively managed patient required a delayed intervention for their T-PTX, and 2 of 79 (3%) patients in the ICC group had a complication (one infection, one haemothorax). CONCLUSION: Our data support conservative management of selected T-PTXs and shows a need for a prospective randomised trial to further examine this intervention.

A randomised, double-blind study investigating the relationship between early childhood trauma and the rewarding effects of morphine.

Experiences of childhood trauma (abuse and neglect) are disproportionately higher in those with opioid use disorder (OUD). Childhood trauma may affect the reinforcing and rewarding properties of opioid drugs and responses to pain, potentially via developmental changes to the endogenous opioid system. This has been supported by preclinical research, yet this has not been investigated in non-addicted humans. Physically healthy participants with either a history of severe childhood trauma or no previous history of childhood trauma attended two sessions where they received either an intramuscular active dose of morphine (0.15 mg/kg) or a very low dose control (0.01 mg/kg) in a randomised, double-blind crossover design. Sessions were held 1 week apart. Participants' physical pain threshold and tolerance were measured pre- and post-drug administration using the cold water pressor test, alongside acute subjective and behavioural responses over 2.5 h. The trauma group reported liking the effects of morphine, feeling more euphoric and wanting more of the drug over the session, as well as feeling less nauseous, dizzy, and dislike of the effects of morphine compared to the non-trauma comparison group. Morphine increased pain threshold and tolerance, yet this did not differ between the groups. Childhood trauma may therefore sensitise individuals to the pleasurable and motivational effects of opioids and reduce sensitivity to the negative effects, providing compelling evidence for individual differences in opioid reward sensitivity. This may explain the link between childhood trauma and vulnerability to OUD, with consequent implications on interventions for OUD, the prescribing of opioids, and reducing stigmas surrounding OUD.

Conservative versus invasive management of secondary spontaneous pneumothorax: a retrospective cohort study.

AIM: Hospitalization, often with intervention, is the recommended management algorithm by multiple international respiratory societies for management of a secondary spontaneous pneumothorax (SSP). Over recent years we adopted a conservative approach to SSPs. We undertook a retrospective cohort study of SSP to establish the safety profile of a conservative approach for these previously unstudied patients. METHODS: We reviewed all cases of SSP presenting to our institution from 2012 to 2019 using the 2010 British Thoracic Society definition of an SSP. Age, gender, smoking status, underlying lung disease, pneumothorax size estimate (using the Collins method), nature of intervention, inpatient duration, and any additional complications were recorded. The χ2-test and Mann-Whitney U-test were used for comparison of categorical variables and categorical/continuous variables, respectively. RESULTS: Eighty-two cases were included in the final analysis. Of them, 64 had an interpleural distance at the hilum of 1cm or greater, meeting British Thoracic Society criteria for a pleural intervention. Of these 64 patients, 25 (39%) were managed conservatively. No patient managed conservatively required a subsequent intervention. When stratified for conservative or invasive management, there was no significant difference in age, gender, smoking status, or presence of underlying lung disease between the groups. There was a significant difference in size of the pneumothorax with conservative management having smaller pneumothoraces (37% versus 54%, P < 0.001) and a shorter inpatient stay (conservative, 7.9 days; intercostal catheter, 9 days; P = 0.004). CONCLUSION: We have demonstrated success with conservative management of SSPs where a significant proportion of them met accepted criteria for a pleural intervention.

In Vivo Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders.

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.

Dysfunctional breathing treated with continuous positive airway pressure in newly diagnosed obstructive sleep apnoea: a prospective cohort study.

A prospective cohort study investigating patients with obstructive sleep apnoea (OSA) was conducted to determine the prevalence of dysfunctional breathing and if continuous positive airway pressure (CPAP) therapy improves associated symptoms. Almost half of newly diagnosed patients with OSA had dysfunctional breathing and CPAP was not an effective treatment. Dysfunctional breathing is common in patients with OSA.

Conservative versus Interventional Treatment for Spontaneous Pneumothorax.

BACKGROUND: Whether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown. METHODS: In this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks. RESULTS: A total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservative-management group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, -4.1 percentage points; 95% confidence interval [CI], -8.6 to 0.5; P = 0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of -9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of -11.0 percentage points (95% CI, -18.4 to -3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurrence than interventional management. CONCLUSIONS: Although the primary outcome was not statistically robust to conservative assumptions about missing data, the trial provides modest evidence that conservative management of primary spontaneous pneumothorax was noninferior to interventional management, with a lower risk of serious adverse events. (Funded by the Emergency Medicine Foundation and others; PSP Australian New Zealand Clinical Trials Registry number, ACTRN12611000184976.).

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2018: the Influenza Complications Alert Network (FluCAN).

The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2018 influenza season. In this observational surveillance system, cases were defined as patients admitted to any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data were also collected on a frequency-matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 3 April to 31 October 2018 (the 2018 influenza season), 769 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 30% were elderly (≥65 years), 28% were children (<16 years), 6.4% were Aboriginal and Torres Strait Islander peoples, 2.2% were pregnant and 66% had chronic comorbidities. A small proportion of FluCAN admissions were due to influenza B (13%). Estimated vaccine coverage was 77% in the elderly (≥65 years), 45% in non-elderly adults with medical comorbidities and 26% in children (<16 years) with medical comorbidities. The estimated vaccine effectiveness (VE) in the target population was 52% (95% CI: 37%, 63%). There were a smaller number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2018 than in 2017, with the demographic profile reflecting the change in circulating subtype from A/H3N2 to A/H1N1.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2017: the Influenza Complications Alert Network (FluCAN).

The Influenza Complications Alert Network (FluCAN) is a sentinel-hospital-based surveillance program that operates at sites in all jurisdictions in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2017 influenza season. In this observational surveillance system, cases were defined as patients admitted to any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data are also collected on a frequency-matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 3 April to 31 October 2017 (the 2017 influenza season), 4,359 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 52% were elderly (≥65 years), 14% were children (<16 years), 6.5% were Aboriginal and Torres Strait Islander peoples, 1.6% were pregnant and 78% had chronic comorbidities. A significant proportion were due to influenza B (31%). Estimated vaccine coverage was 72% in the elderly (≥65 years), 50% in non-elderly adults with medical comorbidities and 24% in children (<16 years) with medical comorbidities. The estimated vaccine effectiveness (VE) in the target population was 23% (95% CI: 7%, 36%). There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2017, with case numbers more than twice that reported in 2016.

Cerebral arterial gas embolism in a scuba diver with a primary lung bulla.

Primary lung bullae have been reported to cause pulmonary barotrauma and lead to cerebral arterial gas embolism (CAGE) in the context of diving; however, a lack of symptoms and often minimal radiographic findings often preclude a diagnosis of lung bullae prior to undertaking diving activity. We present the case of a healthy 27-year-old Caucasian male who presented following the second of two introductory resort dives with neurological symptoms attributable to CAGE. Investigations revealed a previously undiagnosed large primary lung bulla. This case highlights the clinical sequelae of primary lung bullae in the context of pulmonary barotrauma related to recreational diving activity.

DNA-Encoded Macrocyclic Peptide Library.

DNA-encoded library technology (ELT) is a cutting-edge enabling technology platform for drug discovery. Here we describe how to design and synthesize a macrocyclic DNA-encoded library; how to perform selection, sequencing, and data analysis to identify potential active peptides; and how to synthesize off-DNA peptides to confirm activity. This approach provides an effective tool for pharmaceutical research based on peptides.

Phase 1 trial of intrapleural LTI-01; single chain urokinase in complicated parapneumonic effusions or empyema.

BACKGROUND: Current dosing of intrapleural fibrinolytic therapy (IPFT) in adults with complicated parapneumonic effusion (CPE) / empyema is empiric, as dose-escalation trials have not previously been conducted. We hypothesized that LTI-01 (scuPA), which is relatively resistant to PA inhibitor-1 (PAI-1), would be well-tolerated. METHODS: This was an open-label, dose-escalation trial of LTI-01 IPFT at 50,000-800,000 IU daily for up to 3 days in adults with loculated CPE/empyema and failed pleural drainage. The primary objective was to evaluate safety and tolerability, and secondary objectives included assessments of processing and bioactivity of scuPA in blood and pleural fluid (PF), and early efficacy. RESULTS: LTI-01 was well tolerated with no bleeding, treatment-emergent adverse events or surgical referrals (n=14 subjects). uPA antigen increased in PFs at 3 hours after LTI-01 (p<0.01) but not in plasma. PF saturated active PAI-1, generated PAI-1-resistant bioactive complexes, increased PA and fibrinolytic activities and D-dimers. There was no systemic fibrinogenolysis, nor increments in plasma D-dimer. Decreased pleural opacities occurred in all but one subject. Both subjects receiving 800,000 IU required two doses to relieve pleural sepsis, with two other subjects similarly responding at lower doses. CONCLUSION: LTI-01 IPFT was well-tolerated at these doses with no safety concerns. Bioactivity of LTI-01 IPFT was confirmed, limited to PFs where its processing simulated that previously reported in preclinical studies. Preliminary efficacy signals including reduction of pleural opacity were observed.

Cross-Border Movement of Highly Drug-Resistant Mycobacterium tuberculosis from Papua New Guinea to Australia through Torres Strait Protected Zone, 2010-2015.

In this retrospective study, we used whole-genome sequencing (WGS) to delineate transmission dynamics, characterize drug-resistance markers, and identify risk factors of transmission among Papua New Guinea residents of the Torres Strait Protected Zone (TSPZ) who had tuberculosis diagnoses during 2010-2015. Of 117 isolates collected, we could acquire WGS data for 100; 79 were Beijing sublineage 2.2.1.1, which was associated with active transmission (odds ratio 6.190, 95% CI 2.221-18.077). Strains were distributed widely throughout the TSPZ. Clustering occurred more often within than between villages (p = 0.0013). Including 4 multidrug-resistant tuberculosis isolates from Australia citizens epidemiologically linked to the TSPZ into the transmission network analysis revealed 2 probable cross-border transmission events. All multidrug-resistant isolates (33/104) belonged to Beijing sublineage 2.2.1.1 and had high-level isoniazid and ethionamide co-resistance; 2 isolates were extensively drug resistant. Including WGS in regional surveillance could improve tuberculosis transmission tracking and control strategies within the TSPZ.

Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies.

Abelson kinase (c-Abl) is a ubiquitously expressed, nonreceptor tyrosine kinase which plays a key role in cell differentiation and survival. It was hypothesized that transient activation of c-Abl kinase via displacement of the N-terminal autoinhibitory "myristoyl latch", may lead to an increased hematopoietic stem cell differentiation. This would increase the numbers of circulating neutrophils and so be an effective treatment for chemotherapy-induced neutropenia. This paper describes the discovery and optimization of a thiazole series of novel small molecule c-Abl activators, initially identified by a high throughput screening. Subsequently, a scaffold-hop, which exploited the improved physicochemical properties of a dihydropyrazole analogue, identified through fragment screening, delivered potent, soluble, cell-active c-Abl activators, which demonstrated the intracellular activation of c-Abl in vivo.

Tuberculosis in Far North Queensland, Australia: a retrospective clinical audit.

BACKGROUND: Compared with global numbers, Australia has enjoyed relatively good tuberculosis control over the past 30 years, with an annual incidence of 5.7 per 100 000 population. Thanks to its unique geography and proximity to high-burden countries, such as Papua New Guinea (PNG), Far North Queensland (FNQ) has previously been shown to have higher rates of tuberculosis compared with both the state and national average. AIMS: To document tuberculosis epidemiology in FNQ compared to two previous audits of the region. METHODS: Retrospective clinical audit of all cases of tuberculosis reported to the Cairns Tuberculosis Control Unit between 2006 and 2016. RESULTS: A total of 453 cases were identified, 374 with microbiological/histological confirmation. There were 312 cases of pulmonary tuberculosis, 155 extrapulmonary and 21 disseminated. Three-quarters (327/453) were identified in the overseas-born population. Of the remaining 126 cases, 40 were Torres Strait Islander and 19 Aboriginal Australians. Where drug susceptibility was known, two-thirds (247/368) were fully sensitive, 42 mono-resistant, 78 multidrug resistant and 1 extensively drug resistant. Rates of human immunodeficiency virus co-infection were less than 3% (10/362). CONCLUSION: Tuberculosis remains a significant problem in FNQ. Case numbers have increased threefold since the 1990s. Much of the increase comes from the overseas-born population. Although PNG accounts for the majority, the number of positive notifications among those born abroad has increased fivefold since 2010. Tuberculosis among Aboriginal Australians has decreased following policy changes in response to previous audits. However, tuberculosis in Torres Strait residents has increased from 12 cases (1993-2002) to 40 cases (2006-2016).