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Loss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy MYCN tumors, larger deletions correlate with MYCN amplification, indicating two tumor suppressor regions in 1p36, only one of which facilitates MYCN oncogenesis. To better define this region, we genome-edited the syntenic 1p36 locus in primary mouse neural crest cells (NCCs), a putative NBL cell of origin. In in vitro cell transformation assays, we show that Chd5 loss confers most of the MYCN -independent tumor suppressor effects of 1p36 LOH. In contrast, MYCN -driven tumorigenesis selects for NCCs with Arid1a deletions from a pool of NCCs with randomly sized 1p36 deletions, establishing Arid1a as the MYCN -associated tumor suppressor. Our findings reveal that Arid1a loss collaborates with oncogenic MYCN and better define the tumor suppressor functions of 1p36 LOH in NBL. • Larger 1p36 deletions involving Arid1a locus reduce tumor latency in Mycn -driven NBL • The latency reduction is associated with a deregulation of PRC2 and Trp53 pathways • Arid1a loss is favored over other 1p36 candidates in Mycn -driven tumors Garcia-Lopez et al. present a mouse model of high-risk neuroblastoma that includes 1p36 loss and Mycn overexpression. This study substantiates previous predictions from NBL genetic studies, which proposed that two tumor suppressor regions exist in 1p36. It further demonstrates that Mycn overexpression selects for loss of Arid1a during tumorigenesis. [ABSTRACT FROM AUTHOR]

Background In Australia, invasive meningococcal disease (IMD) incidence rapidly increased between 2014 and 2017 due to rising serogroup W (MenW) and MenY infections. We aimed to better understand the genetic diversity of IMD during 2017 and 2018 using whole genome sequencing data. Methods Whole genome sequencing data from 440 Australian IMD isolates collected during 2017 and 2018 and 1737 international MenW:CC11 isolates collected in Europe, Africa, Asia, North America, and South America between 1974 and 2020 were used in phylogenetic analyses; genetic relatedness was determined from single-nucleotide polymorphisms. Results Australian isolates were as follows: 181 MenW (41%), 144 MenB (33%), 88 MenY (20%), 16 MenC (4%), 1 MenW/Y (0.2%), and 10 nongenogroupable (2%). Eighteen clonal complexes (CCs) were identified, and 3 (CC11, CC23, CC41/44) accounted for 78% of isolates (343/440). These CCs were associated with specific serogroups: CC11 (n = 199) predominated among MenW (n = 181) and MenC (n = 15), CC23 (n = 80) among MenY (n = 78), and CC41/44 (n = 64) among MenB (n = 64). MenB isolates were highly diverse, MenY were intermediately diverse, and MenW and MenC isolates demonstrated the least genetic diversity. Thirty serogroup and CC-specific genomic clusters were identified. International CC11 comparison revealed diversification of MenW in Australia. Conclusions Whole genome sequencing comprehensively characterized Australian IMD isolates, indexed their genetic variability, provided increased within-CC resolution, and elucidated the evolution of CC11 in Australia. [ABSTRACT FROM AUTHOR]

Background: The demographic of Northern Territory prison population differs than elsewhere in Australia and the prevalence of hepatitis B and hepatitis C may therefore be somewhat different from other jurisdictions. There has been no study which has specifically described the serological results of a large proportion of prisoners in Northern Territory correctional facilities over an extended period of time.Methods: This retrospective longitudinal study reviewed serological results and testing rates for hepatitis B, and hepatitis C performed in correctional facilities in the Northern Territory of Australia between July 1st, 2003 and June 30th, 2017.Results: The proportion of positive records over 14 years for hepatitis B surface antigen (HBsAg) was 641/12,066 (5.3, 95% CI 4.9-5.7), for hepatitis B core antibody (anti-HBc) 4937/12,138 (40.1, 95%CI 39.8-41.6), for hepatitis B surface antibody (anti-HBs) 6966/13,303 (52.4, 95% CI 51.5-53.2), and for hepatitis C antibody 569/12,153 (4.7, 95% CI 4.3-5.1). The proportion of prisoners tested for hepatitis B and hepatitis C has decreased since 2015, while a high proportion of prisoners remain non-immune to hepatitis B.Conclusion: There is a relatively high proportion of positive serological markers of hepatitis B, and a lower proportion of positive hepatitis C serology in the Northern Territory's correctional facilities compared to overall Australian rates. As the proportion of prisoners tested for hepatitis B and C has decreased recently, and a high proportion of prisoners remain non-immune to hepatitis B, there are opportunities to increase testing and vaccination rates in this population. [ABSTRACT FROM AUTHOR]

This document is a list of resources and reagents used in various research studies related to cancer biology. It includes information about antibodies, cell lines, chemicals, kits, and genes that were utilized in these studies. The purpose of this list is to provide researchers with a comprehensive reference for the materials and methods used in these experiments. [Extracted from the article]

Rationale: Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects. Objective: The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A. Methods: Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018 mg/kg/injection). Once trained, cocaine (0.018 mg/kg/injection) or oxycodone (0.0056 mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1–3.2 µg/kg/injection), nalfurafine (0.0032–0.1 µg/kg/injection), triazole 1.1 (3.2–100.0 µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components. Results: Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed. Conclusions: These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the effect of target population on nonculture-based detection of markers of Neisseria gonorrhoeae antimicrobial resistance (AMR). Results indicated that the polymerase chain reaction (PCR)-based methods could be used to rapidly pinpoint incursion of resistant strains into previously unaffected populations. It concluded that for molecular N. gonorrhoeae AMR surveillance, the population under study is as important as the genetic mechanisms being targeted.

Background: This case report is of a patient with psychosis secondary to thyrotoxicosis that persisted and reemerged after definitive treatment of thyroidectomy, which is a unique occurrence in the literature. Case presentation: This patient is a male between 30 and 35 years of age with a history of Graves Disease and no past psychiatric history who was admitted to the hospital due to psychosis secondary to thyrotoxicosis. The thyrotoxicosis was treated with surgical removal, but the psychotic symptoms persisted after surgery and normalization of standard thyroid functional measures. The symptoms were of sufficient significance for inpatient psychiatric hospitalization, a rare occurrence. Ultimately after an extended stay in the psychiatric unit, the patient’s symptoms stabilized with a second-generation antipsychotic, and the patient was discharged from the psychiatric unit. Conclusion: This case is evidence that the link between psychosis and hyperthyroidism is still poorly understood due to the patient’s psychotic symptoms persisting after the definitive treatment of thyroidectomy and the fact that it required anti-psychotic medications for normalization. [ABSTRACT FROM AUTHOR]

Background Influenza circulated at historically low levels during 2020/2021 due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic travel restrictions. In Australia, international arrivals were required to undergo a 14-day hotel quarantine to limit new introduction of SARS-CoV-2. Methods We usedtesting data for travelers arriving on repatriation flights to Darwin, Australia, from 3 January 2021 to 11 October 2021 to identify importations of influenza virus into Australia. We used this information to estimate the risk of a case exiting quarantine while still infectious. Influenza-positive samples were sequenced, and cases were followed up to identify transmission clusters. Data on the number of cases and total passengers were used to infer the risk of influenza cases exiting quarantine while infectious. Results Despite very low circulation of influenza globally, 42 cases were identified among 15 026 returned travelers, of which 30 were A(H3N2), 2 were A(H1N1)pdm09, and 10 were B/Victoria. Virus sequencing data identified potential in-flight transmission, as well as independent infections prior to travel. Under the quarantine strategy in place at the time, the probability that these cases could initiate influenza outbreaks in Australia neared 0. However, this probability rose as quarantine requirements relaxed. Conclusions Detection of influenza virus infections in repatriated travelers provided a source of influenza viruses otherwise unavailable and enabled development of the A(H3N2) vaccine seed viruses included in the 2022 Southern Hemisphere influenza vaccine. Failure to test quarantined returned travelers for influenza represents a missed opportunity for enhanced surveillance to better inform public health preparedness. [ABSTRACT FROM AUTHOR]

Recent studies report that fentanyl analogs with relatively low pK a values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pK a values in terms of potency and efficacy in male and female Sprague-Dawley rats. Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. Low pK a fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pK a relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs. [Display omitted] • FF3 and NFEPP are fentanyl analogs with relatively low pKa values. • Low pKa may restrict activity to the low-pH environment of injured tissue. • FF3 and NFEPP produced analgesic, respiratory, and reinforcing effects in rats. • Efficacy, but not potency, of FF3 and NFEPP in all measures was similar to fentanyl. [ABSTRACT FROM AUTHOR]

Epidemiologic and genomic investigation of SARS-CoV-2 infections associated with 2 repatriation flights from Australia to India in April 2021 indicated that 4 passengers transmitted SARS-CoV-2 to >11 other passengers. Results suggest transmission despite mandatory mask use and predeparture testing. For subsequent flights, predeparture quarantine and expanded predeparture testing were implemented. [ABSTRACT FROM AUTHOR]

Summary: Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance. [Copyright &y& Elsevier]

The use of a novel inducible FGF signalling system in the frog Xenopus laevis is reported. We show that the lipophilic, synthetic, dimerizing agent AP20187 is able to rapidly activate signalling through an ectopically expressed mutant form of FGFR1 (iFGFR1) in Xenopus embryos. iFGFR1 lacks an extracellular ligand binding domain and contains an AP20187 binding domain fused to the intracellular domain of mouse FGFR1. Induction of signalling by AP20187 is possible until at least early neurula stages, and we demonstrate that ectopically expressed iFGFR1 protein persists until late neurula stages. We show that activation of signalling through iFGFR1 can mimic a number of previously reported FGF activities, including mesoderm induction, repression of anterior development, and neural posteriorization. We show that competence to morphological posteriorization of the anteroposterior axis by FGF signalling only extends until about stage 10.5. We demonstrate that the competence of neural tissue to express the posterior markers Hoxa7 and Xcad3, in response to FGF signalling, is lost by the end of gastrula stages. We also show that activation of FGF signalling stimulates morphogenetic movements in neural tissue until at least the end of the gastrula stage. [Copyright &y& Elsevier]

Separation from conspecifics in chicks produces an increase in distress vocalizations and a decrease in response to a noxious stimulus (stress-induced analgesia). This study questioned the relative contributions of novelty to the test chamber and social separation in mediating these stress responses. Eight-day-old chicks were tested either in isolation or in the presence of two social companions for a 3-min observation period in which distress vocalizations were recorded as well as the frequency of footlifts in response to a 50-μl injection of 0.10% formalin into the plantar surface of the footpad. In Expt. 1, chicks received six, 3-min test chamber habituation trials (vs. no habituation) one per day before testing; in Expt. 2, chicks were tested with mirrors placed in the chambers (vs. no mirrors). In both studies, isolated chicks in control groups (i.e., no habituation or no mirror) exhibited increased distress vocalizations and decreased nociceptive responses. In Expt. 1, habituation to the test chamber attenuated stress-induced analgesia but did not affect distress vocalizations. In Expt. 2, placement of mirrors in the test chamber attenuated distress vocalizations but did not affect stress-induced analgesia. These findings demonstrate a dissociation of stress behaviors in the chick social-separation-stress procedure: the stress-induced analgesia response is primarily mediated by novelty to the test apparatus while the distress vocalizations response is mediated by separation from conspecifics. [Copyright &y& Elsevier]

Rationale: Triazole 1.1 is a novel kappa-opioid receptor (KOR) agonist reported to produce antinociception without KOR-typical adverse effects. When combined with the mu-opioid receptor (MOR) agonist, oxycodone, triazole 1.1 blocks oxycodone-induced pruritis without producing sedation-like effects in nonhuman primates. However, it is unknown if triazole 1.1 can reduce the abuse-related effects or enhance the antinociceptive effects of oxycodone similarly to other KOR agonists. Objectives: The aim of the present study was to quantitatively compare the behavioral effects of triazole 1.1 to the KOR agonists, U50,488h and nalfurafine, on oxycodone self-administration and oxycodone-induced thermal antinociception when administered as mixtures with oxycodone. Methods: In the self-administration study, male Sprague–Dawley (SD) rats (n = 6) self-administered intravenous (i.v.) oxycodone alone (0.056 mg/kg/inj) or combined with U50,488 h (0.032-0.32 mg/kg/inj), nalfurafine (0.00032–0.0032 mg/kg/inj), or triazole 1.1 (0.32–1.8 mg/kg/inj) under a progressive-ratio schedule of reinforcement. In a hot plate assay, male SD rats (n = 6) received i.v. injections of oxycodone (1.0-5.6 mg/kg), U50,488h (1.0-18.0 mg/kg), nalfurafine (0.01-1.0 mg/kg), or triazole 1.1 (3.2-32.0 mg/kg) alone or in combinations of fixed proportion with oxycodone based on the relative potencies of the single drugs. Each study concluded with administration of the KOR antagonist nor-BNI and some degree of retesting of the previous conditions to verify that the behavioral effects were mediated by KOR activation. Results: All KOR agonists reduced oxycodone self-administration in a dose-dependent manner. Moreover, all single drugs and drug combinations produced dose-dependent, fully efficacious thermal antinociception. All KOR agonist:oxycodone combinations produced either additive or super-additive thermal antinociception. Finally, each KOR agonist was blocked in effect by nor-BNI in both behavioral measures. Conclusion: This study demonstrates that triazole 1.1 reduces oxycodone's reinforcing effects and enhances oxycodone-induced antinociception to degrees that are comparable to typical KOR agonists. Given triazole 1.1's mild adverse-effect profile, developing MOR-KOR agonist combinations from the triazole 1.1 series may render new pain therapeutics with reduced abuse liability. [ABSTRACT FROM AUTHOR]

An obituary for Dr. William L. Woolverton, a leading scientist and educator in behavioral pharmacology, is presented.

Rationale: Combinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive ratio (PR) schedule of reinforcement. Methods: In separate experiments, adult male rhesus monkeys (N = 4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01–0.1 mg/kg/injection) alone and combined with salvinorin A (experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (experiment 2; 0.0001–0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine's effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg; i.m.). Results: All subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (experiment 1) or to levels that were significantly lower than oxycodone alone (experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI. Conclusions: These results demonstrate that KOR agonists, including the clinically used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys and that nalfurafine's punishing effect is KOR-dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability. [ABSTRACT FROM AUTHOR]

Recent preclinical studies have investigated the atypical kappa-opioid receptor (KOR) agonist, nalfurafine, as a co-formulary with mu-opioid receptor (MOR) agonists as a potential deterrent for misuse. However, no study has investigated effects of nalfurafine combined with a MOR agonist using an oral route of administration. The objective of the current study was to measure behavioral effects of orally administered oxycodone and nalfurafine, alone and combined, in rhesus monkeys using a quantitative behavioral observation procedure. Adult male rhesus monkeys (N=5) were orally administered vehicle, oxycodone (0.56-1.8 mg/kg), nalfurafine (0.001-0.0056 mg/kg), or mixtures (1.0 mg/kg oxycodone/0.001-0.0056 mg/kg nalfurafine) in a Jell-O vehicle at multiple timepoints (10-320 min). Species-typical and drug-induced behaviors were recorded by observers blinded to conditions. Oxycodone alone significantly increased scratch and face-rub behaviors without affecting other behaviors. Nalfurafine decreased baseline levels of scratch without affecting other behaviors, and oxycodone-nalfurafine combinations resulted in reduced oxycodone-induced scratching at a dose (0.001 mg/kg) that did not produce sedation-like effects. Oxycodone combined with larger nalfurafine doses (0.0032-0.0056 mg/kg) also reduced oxycodone induced scratch that were accompanied with sedation-like effects (i.e., increased lip droop). Nalfurafine was orally active in rhesus monkeys, and it reduced oxycodone-induced pruritus at a dose that did not produce sedation-like effects that are commonly observed with prototypical KOR agonists. Combinations of low doses of nalfurafine with MOR agonists such as oxycodone may be well-tolerated by humans who are prescribed MOR agonists for the treatment of pain. • Orally administered nalfurafine-oxycodone combinations have not been evaluated. • Nalfurafine was orally active in male rhesus monkeys. • Nalfurafine reduced oxycodone-induced pruritis at a dose that did not produce sedation. • Low doses of nalfurafine combined with MOR agonists may be well-tolerated by humans. [ABSTRACT FROM AUTHOR]

Mu-opioid agonists (e.g., oxycodone) are highly effective therapeutics for pain. However, they also produce reinforcing effects that increase their likelihood of abuse. Recent strategies in drug development have focused on opioids with biased receptor-signaling profiles that favor activation of specific intracellular pathways over others with the aim of increasing therapeutic selectivity. TRV130, a mu agonist biased towards G-protein signaling, produces antinociceptive effects comparable to the mu agonist, morphine, but exhibits reduced side effects. However, in terms of abuse potential, we know of no published preclinical data investigating the effects of TRV130 as a reinforcer. In the present study, we assessed the relative reinforcing effects of TRV130 and oxycodone, a commonly-prescribed mu agonist, in rats self-administering the drugs under a progressive-ratio (PR) schedule of reinforcement. In addition, we assessed the relative potency and efficacy of TRV130 and oxycodone in rats in a test of thermal antinociception (Hot Plate). For self-administration, male Sprague-Dawley rats (n = 7) self-administered intravenous infusions of TRV130 or oxycodone (0.01-0.32 mg/kg/inj) under a PR schedule of reinforcement. For the Hot-Plate test, male rats (n = 7) received subcutaneous injections of TRV130 (0.1-3.2 mg/kg/inj) or oxycodone (0.1-5.6 mg/kg/inj), and nociceptive response latencies were measured. TRV130 and oxycodone were equi-potent and equi-effective in self-administration and thermal antinociception. This study demonstrates that TRV130 produces reinforcing and antinociceptive effects that are quantitatively similar to oxycodone, and that a biased-signaling profile does not necessarily reduce abuse potential. [ABSTRACT FROM AUTHOR]

Rationale: Nalfurafine is a G protein signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G protein signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or ß-arrestin-signaling-biased KOR agonists. Objectives: This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior. Methods: Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli). Results: Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS. Conclusions: These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus. [ABSTRACT FROM AUTHOR]

Rationale: Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. Objectives: The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats. Methods: To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. Results: Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. Conclusions: These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone. [ABSTRACT FROM AUTHOR]

Neisseria gonorrhoeae antimicrobial resistance (AMR) is a globally recognized health threat; new strategies are needed to enhance AMR surveillance. The Northern Territory of Australia is unique in that 2 different first-line therapies, based primarily on geographic location, are used for gonorrhea treatment. We tested 1,629 N. gonorrhoeae nucleic acid amplification test-positive clinical samples, collected from regions where ceftriaxone plus azithromycin or amoxicillin plus azithromycin are recommended first-line treatments, by using 8 N. gonorrhoeae AMR PCR assays. We compared results with those from routine culture-based surveillance data. PCR data confirmed an absence of ceftriaxone resistance and a low level of azithromycin resistance (0.2%), and that penicillin resistance was <5% in amoxicillin plus azithromycin regions. Rates of ciprofloxacin resistance and penicillinase-producing N. gonorrhoeae were lower when molecular methods were used. Molecular methods to detect N. gonorrhoeae AMR can increase the evidence base for treatment guidelines, particularly in settings where culture-based surveillance is limited. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to develop a real-time PCR method for specific detection of the gonococcal GyrA amino acid 91 locus directly in clinical samples so as to predict Neisseria gonorrhoeae ciprofloxacin susceptibility. Methods: The real-time PCR assay, GyrA91-PCR, was designed using two probes, one for detection of the WT S91 sequence and the other for detection of the S91F alteration. The performance of the assay was initially assessed using characterized N. gonorrhoeae isolates (n = 70), a panel of commensal Neisseria and Moraxella species (n = 55 isolates) and clinical samples providing negative results by a commercial N. gonorrhoeae nucleic acid amplification test (NAAT) method (n = 171). The GyrA91-PCR was then applied directly to N. gonorrhoeae NAAT-positive clinical samples (n = 210) from the year 2014 for which corresponding N. gonorrhoeae isolates with susceptibility results were also available. Results: The GyrA91-PCR accurately characterized the GyrA 91 locus of all 70 N. gonorrhoeae isolates (sensitivity = 100%, 95% CI = 94.9%-100%), whereas all non-gonococcal isolates and N. gonorrhoeae NAAT-negative clinical samples gave negative results by the GyrA91-PCR (specificity = 100%, 95% CI = 98.4%-100%). When applied to the 210 N. gonorrhoeae NAAT-positive clinical samples, the GyrA91-PCR successfully characterized 195 samples (92.9%, 95% CI = 88.5%-95.9%). When compared with the corresponding bacterial culture results, positivity by the GyrA91-PCR WT probe correctly predicted N. gonorrhoeae susceptibility to ciprofloxacin in 161 of 162 (99.4%, 95% CI = 96.6%-99.9%) samples. Conclusions: The use of a PCR assay for detection of mutation in gyrA applied directly to clinical samples can predict ciprofloxacin susceptibility in N. gonorrhoeae. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD) has been associated with the emergence of sleep disturbances. Although effective treatments for OUD exist, evidence suggests that these treatments also may be associated with sleep impairment. The extent to which these effects are an effect of OUD treatment or a result of chronic opioid use remains unknown. We investigated the acute effects of methadone, buprenorphine, and naltrexone on actigraphy-based sleep-like parameters in non-opioid-dependent male rhesus monkeys (Macaca mulatta, n = 5). Subjects were fitted with actigraphy monitors attached to primate collars to measure sleep-like parameters. Actigraphy recordings were conducted under baseline conditions, or following acute injections of vehicle, methadone (0.03-1.0 mg/kg, i.m.), buprenorphine (0.01-1.0 mg/kg, i.m.), or naltrexone (0.03-1.0 mg/kg, i.m.) in the morning (4 h after "lights on") or in the evening (1.5 h before "lights off"). Morning and evening treatments with methadone or buprenorphine significantly increased sleep latency and decreased sleep efficiency. The effects of buprenorphine on sleep-like measures resulted in a biphasic dose-response function, with the highest doses not disrupting actigraphy-based sleep. Buprenorphine induced a much more robust increase in sleep latency and decrease in sleep efficiency compared to methadone, particularly with evening administration, and detrimental effects of buprenorphine on sleep-like measures were observed up to 25.5 h after drug injection. Treatment with naltrexone, on the other hand, significantly improved sleep-like measures, with evening treatments improving both sleep latency and sleep efficiency. The currently available pharmacotherapies for OUD significantly alter sleep-like parameters in non-opioid-dependent monkeys, and opioid-dependent mechanisms may play a significant role in sleep-wake regulation. [ABSTRACT FROM AUTHOR]

Obesity is associated with abnormal brain reactivity in response to palatable food consumption, a factor that may contribute to non-homeostatic eating. However, little is known about how obesity interacts with the reinforcing effects of highly palatable constituents of food (e.g., fat), and if altered reinforcement processes associated with obesity generalize to non-food reinforcers. The current study compared the reinforcing effects of a fat (corn oil) and a drug of abuse (cocaine) in obese and lean Zucker rats. Specifically, obese and lean Zucker rats self-administered corn oil or intravenous cocaine in a behavioral economic demand procedure. For corn oil, maximum demand was higher and demand elasticity was lower in the obese rats compared to their lean counterparts. However, there were no differences in demand for cocaine between the obese and lean rats. These results demonstrate that a fat in the form of corn oil is a more effective reinforcer in obese Zucker rats. However, the fact that demand for cocaine was not different between the obese and lean rats suggests that differences in reward mechanisms may be reinforcer-specific and do not necessarily generalize to non-food reinforcers. [ABSTRACT FROM AUTHOR]

Examination of a drug's abuse potential at multiple levels of analysis (molecular/cellular action, whole-organism behavior, epidemiological data) is an essential component to regulating controlled substances under the Controlled Substances Act (CSA). We reviewed studies that examined several central nervous system (CNS) stimulants, focusing on those with primarily dopaminergic actions, in drug self-administration, drug discrimination, and physical dependence. For drug self-administration and drug discrimination, we distinguished between experiments conducted with rats and nonhuman primates (NHP) to highlight the common and unique attributes of each model in the assessment of abuse potential. Our review of drug self-administration studies suggests that this procedure is important in predicting abuse potential of dopaminergic compounds, but there were many false positives. We recommended that tests to determine how reinforcing a drug is relative to a known drug of abuse may be more predictive of abuse potential than tests that yield a binary, yes-or-no classification. Several false positives also occurred with drug discrimination. With this procedure, we recommended that future research follow a standard decision-tree approach that may require examining the drug being tested for abuse potential as the training stimulus. This approach would also allow several known drugs of abuse to be tested for substitution, and this may reduce false positives. Finally, we reviewed evidence of physical dependence with stimulants and discussed the feasibility of modeling these phenomena in nonhuman animals in a rational and practical fashion. This article is part of the Special Issue entitled ‘CNS Stimulants’. [ABSTRACT FROM AUTHOR]

Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01–0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.32–1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01–0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0–56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias. • Some atypical KOR agonists are purportedly biased toward G-protein signaling. • Biased KOR agonists with reduced side-effects may be useful therapeutics. • All KOR agonists reduced oxycodone-induced scratch. • U50-488H and nalfurafine produced sedative-like and motor-impairing effects. • Triazole 1.1 had a reduced side-effect profile, alone and when combined with oxycodone. [ABSTRACT FROM AUTHOR]

Rationale: G-protein biased mu-opioid receptor (MOR) agonists have been reported to exhibit superior therapeutic windows compared to prototypical MOR agonists when relating antinociception to respiratory depression. However, there is relatively little research on the abuse potential of G-protein biased MOR agonists in relation to other behavioral endpoints., Objectives: The aim of the present study was to quantitatively compare the reinforcing, antinociceptive, and respiratory-depressant effects of the prototypical MOR agonists, fentanyl and oxycodone, to the G-protein biased MOR agonists, SR14968 and SR17018, in male and female rats., Methods: In the self-administration study, four separate groups of Sprague-Dawley (SD) rats self-administered intravenous (i.v.) fentanyl, oxycodone, SR14968, and SR17018 under a progressive-ratio schedule of reinforcement. Using a within-subjects design, separate cohorts of SD rats were tested with i.v. fentanyl, oxycodone, SR14968, and SR17018 using a hot-plate assay, assays of neuropathic and inflammatory antinociception, and whole-body plethysmography., Results: All MOR agonists functioned as reinforcers, but SR14968 and SR17018 were less efficacious relative to oxycodone and fentanyl. Moreover, all MOR agonists produced dose-dependent and fully efficacious antinociception across all nociception modalities. Oxycodone and fentanyl, but not SR14968 or SR17018, produced respiratory depression in a dose-dependent manner., Conclusion: The present results indicate that the G-protein biased MOR agonists tested herein produce MOR-typical antinociception, exhibit reduced but apparent abuse potential, and do not produce respiratory effects at doses that are above the antinociceptive range. Atypical MOR agonists within the SR series should be further studied as foundational molecules for the development of safter analgesics., Competing Interests: Declarations Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: The Northern Territory (NT) has the highest rates of sexually transmitted infections (STI) in Australia; however, the local prevalence of Mycoplasma genitalium ( M. genitalium ) has not been previously determined. This study was designed to review M. genitalium detection, to determine the regional NT prevalence and macrolide resistance rates. In our study the NT background prevalence of M. genitalium is 13%, with the highest detection rates occurring in central Australia and in correctional facility inmates. Symptomatic patients attending sexual health clinics have a positivity rate of 12%, but very high macrolide resistance. The decision to screen for M. genitalium should be based on several factors, including the prevalence of the infection in the local population; the availability of effective treatments; and the potential benefits and risks of detection and therapy., (© Commonwealth of Australia CC BY-NC-ND.)

Background: We describe the recent temporal patterns of respiratory syncytial virus (RSV) and influenza virus detections in the Northern Territory (NT) of Australia, between 2020 and 2023., Methods: This retrospective analysis of patients presenting with respiratory diseases utilised a multiplex viral nucleic acid detection assay for RSV, influenza and SARS Cov2 (COVID-19) to determine the relative frequency of non-COVID-19 respiratory viral detections by age and month during the study period., Results: During this period of the NT COVID-19 epidemic, disruption of the usual annual wet season RSV outbreak patterns occurred, and the yearly influenza peak was absent for two annual cycles. Our data also reveals that 25% of RSV infections were occurring in patients greater than 40 years of age, compared to 32% of influenza infections presenting in the same period, documenting a greater burden of adult disease than previously documented in the NT., Conclusions: Loss of non-COVID-19 viral seasonality and a substantial unrecognised RSV adult burden were noted. We will continue to monitor seasonality, and the RSV burden and this will help to target the populations benefiting from recently released RSV vaccine., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Introduction: The effectiveness of antibiotics for treating gonococcal infections is compromised due to escalating antibiotic resistance; and the development of an effective gonococcal vaccine has been challenging. Emerging evidence suggests that the licensed meningococcal B (MenB) vaccine, 4CMenB is effective against gonococcal infections due to cross-reacting antibodies and 95% genetic homology between the two bacteria, Neisseria meningitidis and Neisseria gonorrhoeae, that cause the diseases. This project aims to undertake epidemiological and genomic surveillance to evaluate the long-term protection of the 4CMenB vaccine against gonococcal infections in the Northern Territory (NT) and South Australia (SA), and to determine the potential benefit of a booster vaccine doses to provide longer-term protection against gonococcal infections., Methods and Analyses: This observational study will provide long-term evaluation results of the effectiveness of the 4CMenB vaccine against gonococcal infections at 4-7 years post 4CMenB programme implementation. Routine notifiable disease notifications will be the basis for assessing the impact of the vaccine on gonococcal infections. Pathology laboratories will provide data on the number and percentage of N. gonorrhoeae positive tests relative to all tests administered and will coordinate molecular sequencing for isolates. Genome sequencing results will be provided by SA Pathology and Territory Pathology/New South Wales Health Pathology, and linked with notification data by SA Health and NT Health. There are limitations in observational studies including the potential for confounding. Confounders will be analysed separately for each outcome/comparison., Ethics and Dissemination: The protocol and all study documents have been reviewed and approved by the SA Department for Health and Well-being Human Research Ethics Committee (HREC/2022/HRE00308), and the evaluation will commence in the NT on receipt of approval from the NT Health and Menzies School of Health Research Human Research Ethics Committee. Results will be published in peer-reviewed journals and presented at scientific meetings and public forums., Competing Interests: Competing interests: HM acknowledges support from the National Health and Medical Research Council of Australia: Practitioner Fellowship (APP1155066). HM is an independent investigator on clinical trials of investigational vaccines manufactured by pharmaceutical companies including Pfizer, ILiAD Biotechnologies and Merck. The institution at which HM, BW, MM and PA are employed has received funding for investigator-led research from GlaxoSmithKline, Sanofi-Pasteur and Pfizer Vaccines. All authors receive no personal payments from the industry. There are no other conflicts of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Eclampsia, new-onset seizures in pregnancy, can complicate preeclampsia, a hypertensive pregnancy disorder. The mechanisms contributing to increased risk of seizures in preeclampsia are not fully known. One mechanism could be abnormal endocannabinoid system (ECS) activity and impaired neuromodulation. Indeed, increased placental cannabinoid receptor 1 (CB1R) expression and reduced serum anandamide, a CB1R ligand, have been reported in preeclampsia patients. We hypothesized that reduced uterine perfusion pressure (RUPP), used to mimic preeclampsia, leads to changes in hippocampal CB1R expression, and that manipulating CB1R activity will change seizure severity in RUPP mice. Pregnant mice underwent sham or RUPP surgery on gestational day (GD)13.5. On GD18.5, mice received: no drug treatment, pentylenetetrazol (PTZ, 40 mg/kg), Rimonabant (10 mg/kg) + PTZ, or 2-AG (1 mg/kg) + PTZ. Behaviors were video recorded (15 min for Rimonabant and 2-AG, followed by 30 min for PTZ), and the hippocampus was harvested. The expression of CB1R and ECS proteins was measured in hippocampal homogenates, synaptosomes, and cytosol. Hippocampal CB1R increased in homogenates and cytosolic fraction, and was unchanged in synaptosomes of RUPP mice. Increased CB1R colocalization on glutamate-releasing neurons within hippocampal CA1 was observed in RUPP mice. Rimonabant modestly increased seizure scores over time in RUPP mice. PTZ after rimonabant pretreatment increased seizure scores and duration, while reducing latency in sham mice, with little to no change in RUPP mice. Furthermore, RUPP mice had lower seizure scores over time than sham following CB1R blockade and activation. These data suggest that RUPP modifies CB1R activity prior to seizure induction, which protects mice from worse seizure outcomes., (© 2023 Wiley Periodicals LLC.)

Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a "molecular glue" that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.

Melioidosis caused by Burkholderia pseudomallei causes significant morbidity and mortality in Southeast Asia and northern Australia. Clinical manifestations remain diverse, including localized skin infection, pneumonia, and chronic abscess formation. Culture remains the gold standard of diagnosis, with serology and antigen detection tests playing a role if culture is unfeasible. Serologic diagnosis remains challenging, with limited standardization across different assays. In areas of endemicity, high rates of seropositivity have been documented. The indirect hemagglutination assay (IHA) is one of the more widely used serologic tests in these areas. In Australia, only three centers perform the test. Annually, laboratory A, laboratory B, and laboratory C perform approximately 1,000, 4,500, and 500 tests, respectively. A comparison of a total of 132 sera was analyzed from the routine quality exchange program between these centers from 2010 until 2019. Overall, 18.9% of sera tested had an interpretative discrepancy between laboratories. IMPORTANCE This study found significant discrepant results between three Australian centers offering the melioidosis indirect hemagglutination assay (IHA), despite testing the same samples. We have highlighted that the IHA is a nonstandardized test, which had different source antigens at each of the different laboratories. Melioidosis is a global disease, is associated with significant mortality, and is perhaps under recognized. It is likely to have increasing impact with changing weather patterns. The IHA has been used frequently as an adjunct to the diagnosis of clinical disease and is the mainstay of determining seroprevalence within populations. Despite its relative ease of use, especially in low resource settings, our study highlights the significant limitations of the melioidosis IHA. It has wide ranging implications, serving as an impetus for developing better diagnostic tests. This study is of interest to practitioners and researchers working in the various geographic regions affected by melioidosis.

Illicit drugs like cocaine may be uncertain in terms of the time and effort required to obtain them. Behavior maintained by variable schedules resembles excessive drug-taking compared with fixed schedules. However, no prior research has examined fixed versus variable schedules in drug versus nondrug choice. The present study evaluated cocaine versus food choice under fixed- (FR) and variable-ratio (VR) schedules. The simpler food versus food and cocaine versus cocaine arrangements also were included. Adult female ( n = 6) and male ( n = 7) rhesus monkeys chose between cocaine (0.01-0.18 mg/kg/injection) and food (4 pellets/delivery), food and food (4 pellets/delivery), or cocaine and cocaine (0.018-0.03 mg/kg/injection) under FR and VR 100 and 200 schedules. In cocaine versus food choice, cocaine's potency to maintain choice was greatest when available under a VR 100 or 200 schedule and food under an FR schedule and was lowest when cocaine was available under an FR 200 schedule and food was available under a VR 200 schedule. In food versus food choice, males chose food associated with a VR schedule more than food associated with an FR schedule. In cocaine versus cocaine choice, females and males chose cocaine associated with a VR schedule more than cocaine associated with an FR schedule, particularly under VR 200. These findings suggest that uncertainty in terms of time and effort required to obtain cocaine, or perhaps the occasional low-cost access that results from VR schedules, results in greater allocation of behavior toward drug reinforcers at the expense of more certain, nondrug alternatives. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: This study describes characteristics of the legionellosis cases occurring between 2010 and 2021 in the Northern Territory (NT), Australia., Methods: We retrospectively reviewed 53 cases of legionellosis during the defined period and documented patient and clinical characteristics, diagnostics, and seasonality of infection., Results: All cases were sporadic. The incidence rate in the NT was higher than the Australian median rate (2.1 and 1.5 per 100,000 population per year respectively). Aboriginal and Torres Strait Islander patients presented at a younger age than did non-Indigenous patients (median 41 and 60 years of age respectively), and overall there was a male preponderance. There was a higher proportion of legionellosis in the months with increased humidity, with a greater number of L. longbeachae infections detected overall (59%) than of L. pneumophila (41%). The majority of cases were diagnosed serologically (57% of L. pneumophilia and 93% of L. longbeachae )., Conclusions: Legionellosis in the NT is more common, seasonal, and may be underreported due to current reliance on serological testing for diagnosis. The higher incidence of legionellosis, and the younger age of Aboriginal and Torres Strait Islander patients of the NT, have public health implications, given that the clinical presentation of legionellosis is indistinguishable from other forms of pneumonia., (© Commonwealth of Australia CC BY-NC-ND.)