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.).

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.

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.

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.

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.

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).

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2016: the Influenza Complications Alert Network (FluCAN).

During the period 1 April to 30 October 2016 (the 2016 influenza season), 1,952 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 46% were elderly (e65 years), 18% were children (<16 years), 5% were Aboriginal and Torres Strait Islander peoples, 3% were pregnant and 76% had chronic co-morbidities.

Influenza epidemiology, vaccine coverage and vaccine effectiveness in children admitted to sentinel Australian hospitals in 2014: the Influenza Complications Alert Network (FluCAN).

The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance programme operating in all states and territories in Australia. We summarise the epidemiology of children hospitalised with laboratory-confirmed influenza in 2014 and reports on the effectiveness of inactivated trivalent inactivated vaccine (TIV) in children. In this observational study, cases were defined as children admitted with acute respiratory illness (ARI) with influenza confirmed by PCR. Controls were hospitalised children with ARI testing negative for influenza. Vaccine effectiveness (VE) was estimated as 1 minus the odds ratio of vaccination in influenza positive cases compared with test-negative controls using conditional logistic regression models. From April until October 2014, 402 children were admitted with PCR-confirmed influenza. Of these, 28% were aged < 1 year, 16% were Indigenous, and 39% had underlying conditions predisposing to severe influenza. Influenza A was detected in 90% of cases of influenza; influenza A(H1N1)pdm09 was the most frequent subtype (109/141 of subtyped cases) followed by A(H3N2) (32/141). Only 15% of children with influenza received antiviral therapy. The adjusted VE of one or more doses of TIV for preventing hospitalised influenza was estimated at 55.5% (95% confidence intervals (CI): 11.6-77.6%). Effectiveness against influenza A(H1N1)pdm09 was high (91.6% , 95% CI: 36.0-98.9%) yet appeared poor against H3N2. In summary, the 2014 southern hemisphere TIV was moderately effective against severe influenza in children. Significant VE was observed against influenza A(H1N1)pdm09.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2015: the Influenza Complications Alert Network.

The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2015 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals with an acute respiratory illness with influenza confirmed by nucleic acid detection. During the period 1 April to 30 October 2015 (the 2015 influenza season), 2,070 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 46% were elderly (≥ 65 years), 15% were children (< 16 years), 5% were Indigenous Australians, 2.1% were pregnant and 75% had chronic co-morbidities. A high proportion were due to influenza B (51%). There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2015 with case numbers similar to that reported in 2014. The national immunisation program is estimated to avert 46% of admissions from confirmed influenza across all at-risk groups, but more complete vaccination coverage in target groups could further reduce influenza admissions by as much as 14%.

Improving the passive permeability of macrocyclic peptides: Balancing permeability with other physicochemical properties.

A number of methods to improve the passive permeability of a set of cyclic peptides have been investigated using 6- and 7-mer macrocyclic templates. In many cases the peptides were designed by molecular dynamics calculations to evaluate the methods. The aim of this study was not only to improve passive permeability, but also to balance permeability with other physicochemical properties with the goal of understanding and applying the knowledge to develop active cyclic peptides into drug candidates. Evaluation of the methods herein suggest that increasing passive permeability often occurs at the expense of solubility and lipophilicity. Computational methods can be useful when attempting to predict and design features to balance these properties, though limitations were observed.

Intracellular drug concentration and disposition--the missing link?

Improved understanding of the concentration of a potential drug molecule at the site of action in physiologically relevant cells or tissues has emerged as a key challenge in the early stages of drug discovery. Improved ability to carry out such studies with label-free methodology has the potential to improve understanding of drug uptake and trafficking and thus contribute to the reduction of rates of attrition in drug discovery.

Influenza epidemiology in adults admitted to sentinel Australian hospitals in 2014: 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 states and territories in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2014 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals with an acute respiratory illness with influenza confirmed by nucleic acid detection. During the period 3 April to 31 October 2014 (the 2014 influenza season), 1,692 adult patients (>16 years) were admitted with confirmed influenza to one of 15 of 17 FluCAN sentinel hospitals (excluding 2 paediatric hospitals). Of these, 47% were over 65 years of age, 10% were Indigenous Australians, 3.3% were pregnant and 85% had chronic co-morbidities. The majority of cases were due to influenza A. Influenza B was detected in 7% of patients. There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2014. These are estimated to represent a national annual burden of around 15,000 admissions and almost 100,000 bed-days nationally.

Structure-guided optimization of small molecule c-Abl activators.

c-Abl kinase is maintained in its normal inactive state in the cell through an assembled, compact conformation. We describe two chemical series that bind to the myristoyl site of the c-Abl kinase domain and stimulate c-Abl activation. We hypothesize that these molecules activate c-Abl either by blocking the C-terminal helix from adopting a bent conformation that is critical for the formation of the autoinhibited conformation or by simply providing no stabilizing interactions to the bent conformation of this helix. Structure-based molecular modeling guided the optimization of binding and activation of c-Abl of these two chemical series and led to the discovery of c-Abl activators with nanomolar potency. The small molecule c-Abl activators reported herein could be used as molecular tools to investigate the biological functions of c-Abl and therapeutic implications of its activation.

Influenza epidemiology, vaccine coverage and vaccine effectiveness in sentinel Australian hospitals in 2013: the Influenza Complications Alert Network.

The National Influenza Program aims to reduce serious morbidity and mortality from influenza by providing public funding for vaccination to at-risk groups. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at 14 sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with confirmed influenza, estimates vaccine coverage and influenza vaccine protection against hospitalisation with influenza during the 2013 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals, with influenza confirmed by nucleic acid testing. Controls were patients who had acute respiratory illnesses who were test-negative for influenza. Vaccine effectiveness was estimated as 1 minus the odds ratio of vaccination in case patients compared with control patients, after adjusting for known confounders. During the period 5 April to 31 October 2012, 631 patients were admitted with confirmed influenza at the 14 FluCAN sentinel hospitals. Of these, 31% were more than 65 years of age, 9.5% were Indigenous Australians, 4.3% were pregnant and 77% had chronic co-morbidities. Influenza B was detected in 30% of patients. Vaccination coverage was estimated at 81% in patients more than 65 years of age but only 49% in patients aged less than 65 years with chronic comorbidities. Vaccination effectiveness against hospitalisation with influenza was estimated at 50% (95% confidence interval: 33%, 63%, P<0.001). We detected a significant number of hospital admissions with confirmed influenza in a national observational study. Vaccine coverage was incomplete in at-risk groups, particularly non-elderly patients with medical comorbidities. Our results suggest that the seasonal influenza vaccine was moderately protective against hospitalisation with influenza in the 2013 season.

Influenza epidemiology, vaccine coverage and vaccine effectiveness in sentinel Australian hospitals in 2012: the Influenza Complications Alert Network (FluCAN).

Influenza is mostly a mild, self-limiting infection and severe infection requiring hospitalisation is uncommon. Immunisation aims to reduce serious morbidity and mortality. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at 15 sites across all states and territories in Australia. This study reports on the epidemiology of hospitalisation with confirmed influenza, estimate vaccine coverage and influenza vaccine protection against hospitalisation with influenza during the 2012 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals with influenza confirmed by nucleic acid detection. Controls were patients who had acute respiratory illnesses who were test-negative for influenza. Vaccine effectiveness was estimated as 1 minus the odds ratio of vaccination in case patients compared with control patients, after adjusting for known confounders. During the period 9 April to 31 October 2012, 1,231 patients were admitted with confirmed influenza at the 15 FluCAN sentinel hospitals. Of these, 47% were more than 65 years of age, 8% were Indigenous Australians, 3% were pregnant and 76% had chronic co-morbidities. Influenza A was detected in 83% of patients. Vaccination coverage was calculated from the vaccination status of 1,216 test negative controls and was estimated at 77% in patients 65 years or over and 61% in patients with chronic comorbidities. Vaccination effectiveness was estimated at 41% (95% CI: 28%, 51%, P<0.001). Vaccine coverage was incomplete in at-risk groups, particularly non-elderly patients with medical comorbidities. The study results suggest that the seasonal influenza vaccine was moderately protective against hospitalisation with influenza during the 2012 season.

Switching the stereochemical outcome of 6-endo-trig cyclizations; synthesis of 2,6-cis-6-substituted 4-oxopipecolic acids.

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6-substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-l-pipecolic acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed.