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The COVID-19 pandemic has affected different parts of Australia in distinct ways across 2020 and 2021. In 2020, Melbourne was the epicentre of COVID-19. As one of the key tertiary centres caring for the patients affected by the outbreaks, the Royal Melbourne Hospital (RMH) managed the majority of the Victorian inpatient caseload.To review the demographics, management and outcomes of patients with COVID-19 cared for by the RMH services in 2020.A single health service retrospective cohort analysis of demographics, interventions and outcomes was conducted to characterise the RMH experience in 2020.From January to December 2020, 433 patients required admission more than 24 h. The demographics of affected patients and outcomes changed over the course of the study. Overall, 47% (203/433) required oxygen, most frequently (36%; 154/433) with low-flow devices (nasal prongs or hudson mask), and 11% (47/433) of patients required admission to intensive care. We recorded a 30-day mortality of 24% (104/433) mortality overall, rising to over 50% in patients aged over 80 years.The experience of this health service in 2020 demonstrated changing demographics over time, with associated differences in outcomes; notably marked mortality in older populations, frequent complications and limited inter-site transfer possible with mobilised resources.

Background and Purpose Vancomycin is one of the most common antibiotics administered in the hospital setting, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. Experimental Approach Male Sprague-Dawley rats received allometrically scaled (1) vancomycin (2) flucloxacillin, (3) vancomycin+flucloxacillin, (4) vancomycin+imipenem-cilastatin, or (5) saline for 4 days. Vancomycin was administered intravenously and flucloxacillin or imipenem-cilastatin were administered intraperitoneally. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. Key Results Urinary output increased every study day for vancomycin+flucloxacillin; whereas in the vancomycin group it was elevated after the first dose only. In the vancomycin+flucloxacillin group, urinary KIM-1/24h increased on all days compared to vancomycin. In the vancomycin+imipenem-cilastatin group, urinary KIM-1/24h was decreased on days 1 and 2 compared to vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin+flucloxacillin compared to vancomycin and vancomycin+imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1 (4-parameter Hill Slope, R2=0.7985). Conclusion and Implications Vancomycin+flucloxacillin caused more kidney injury compared to vancomycin alone and vancomycin+imipenem-cilastatin in a translational rat model as determined by multiple kidney injury biomarkers. The combination of vancomycin+imipenem-cilastatin was nephroprotective.

Importance: Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence.Objective: To construct a clinical guideline for pyogenic osteomyelitis management, with a new standard of evidence to resolve the gap between strength of recommendation and quality of evidence, through the use of a novel open access approach utilizing social media tools.Evidence Review: This consensus statement and systematic review study used a novel approach from the WikiGuidelines Group, an open access collaborative research project, to construct clinical guidelines for pyogenic osteomyelitis. In June 2021 and February 2022, authors recruited via social media conducted multiple PubMed literature searches, including all years and languages, regarding osteomyelitis management; criteria for article quality and inclusion were specified in the group's charter. The GRADE system for evaluating evidence was not used based on previously published concerns regarding the potential dissociation between strength of recommendation and quality of evidence. Instead, the charter required that clear recommendations be made only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were drafted to discuss pros and cons of care choices. Both clear recommendations and clinical reviews were planned with the intention to be regularly updated as new data become available.Findings: Sixty-three participants with diverse expertise from 8 countries developed the group's charter and its first guideline on pyogenic osteomyelitis. These participants included both nonacademic and academic physicians and pharmacists specializing in general internal medicine or hospital medicine, infectious diseases, orthopedic surgery, pharmacology, and medical microbiology. Of the 7 questions addressed in the guideline, 2 clear recommendations were offered for the use of oral antibiotic therapy and the duration of therapy. In addition, 5 clinical reviews were authored addressing diagnosis, approaches to osteomyelitis underlying a pressure ulcer, timing for the administration of empirical therapy, specific antimicrobial options (including empirical regimens, use of antimicrobials targeting resistant pathogens, the role of bone penetration, and the use of rifampin as adjunctive therapy), and the role of biomarkers and imaging to assess responses to therapy.Conclusions and Relevance: The WikiGuidelines approach offers a novel methodology for clinical guideline development that precludes recommendations based on low-quality data or opinion. The primary limitation is the need for more rigorous clinical investigations, enabling additional clear recommendations for clinical questions currently unresolved by high-quality data.

Described antimicrobial resistance mechanisms enable bacteria to avoid the direct effects of antibiotics and can be monitored by in vitro susceptibility testing and genetic methods. We have identified a new mechanism of sulfamethoxazole resistance that requires a host metabolite for activity. Using a combination of in vitro evolution and metabolic rescue experiments, we identified an energy-coupling factor (ECF) transporter S component gene (thfT) that enables Group A Streptococcus to acquire extracellular tetrahydrofolate and related compounds. ThfT likely modifies the substrate specificity of an ECF transporter to acquire the end products of folate biosynthesis. As ThfT-mediated resistance is undetectable by routine surveillance methods, our study highlights the need to understand antibiotic susceptibility during infection to reduce inappropriate antibiotic use and treatment failures.

Purpose of review An update on the latest advances in fertility preservation for transgender women, with an emphasis on the attitudes, access, and techniques. Recent findings With recent warming in perception toward transgendered individuals, fertility preservation services are becoming increasingly available. Although new multidisciplinary transgender clinics are appearing in North America, a 2018 report shows a referral rate for fertility preservation of only 13.5%. Despite interest in child rearing, uptake of fertility preservation is still low as patients are transitioning at increasingly younger ages. Sperm cryopreservation, ideally prior to hormonal therapy, continues to be the mainstay of fertility preservation in transwomen. It is used in conjunction with other assisted reproductive technologies such as intrauterine insemination or in-vitro fertilization with intracytoplasmic sperm injection depending on the quantity of sperm available. Recent research reporting successful autologous grafting of cryopreserved prepubertal testis leading to sperm production and offspring in macaques show great promise in the context of fertility preservation in prepubertal patients. Summary Despite the increasing accessibility of fertility preservation, referral rates and usage continue to be low, suggesting that barriers are still in place for these individuals. Clinicians must continue to counsel patients regarding the process of fertility preservation and advocate for reduction of financial and infrastructural barriers.

Background In Australia, the notification rate for hepatitis C is five times greater among Aboriginal and Torres Strait Islander peoples than nonIndigenous populations. Infection with Hepatitis C virus is associated with increased morbidity, mortality and health-related costs. However simple, tolerable and short-duration HCV therapies with extremely high efficacy are available. Methods Overall, this project aims to identify inequities in hepatitis C healthcare for Aboriginal and Torres Strait Islander peoples across South Australia (SA) and Northern Territory (NT). By using 19 routinely collected health administration datasets, we will evaluate hepatitis C diagnoses, treatment uptake, and treatment outcomes, with focus on identifying patterns in healthcare access among Aboriginal and Torres Strait Islander people in SA since 1992 or in NT since 1999 using probabilistic data linkage methodology in a secured online environment. Results The study population includes all hepatitis C notifications recorded in SA and NT, totaling more than 25,000 cases. Preliminary findings will be reported including incidence of hospitalisation, mortality, and morbidity by Aboriginal and Torres Strait Islander status. Conclusions Now that highly effective direct acting anti-viral treatments are available, it is crucial to ensure key affected populations, including Aboriginal and Torres Strait Islander people, have access to these novel biomedical approaches. Key messages This project is of national importance to address hepatitis C related morbidity and mortality in Australia, particularly among Aboriginal and Torres Strait Islander peoples. Findings will underpin future policy to reduce the burden of hepatitis C across SA and NT populations.

IntroductionIn Australia, the notification rate for hepatitis C is 5 times greater among Aboriginal and Torres Strait Islander peoples than non‑Indigenous populations (164 vs. 35 per 100,000). Infection with Hepatitis C virus is associated with increased morbidity, mortality and health-related costs. Recently, the use of simple, tolerable and short-duration HCV therapies with extremely high efficacy (cure rates >90%) became available through the Pharmaceutical Benefits Scheme (PBS) on 1 March 2016. Objectives and ApproachOverall, this project aims to identify inequities in hepatitis C healthcare for Aboriginal and Torres Strait Islander peoples across SA and NT. By using 19 routinely collected health administration datasets, we will evaluate hepatitis C diagnoses, treatment uptake, and treatment outcomes, with focus on identifying patterns in healthcare access among Aboriginal and Torres Strait Islander people. The study links state-based and federal datasets, including Medicare, Pharmaceutical Benefits Scheme, and National Mortality Database, to hepatitis C notifications reported in SA since 1992 or in NT since 1999 using probabilistic data linkage methodology in a secured online environment. ResultsThe study population includes all hepatitis C notifications recorded in SA and NT, totalling more than 25,000 cases. Preliminary findings will be reported including incidence of hospitalisation, mortality, and morbidity by Aboriginal and Torres Strait Islander status. Conclusion / ImplicationsThis project is of national importance to address hepatitis C related morbidity and mortality in Australia, particularly among Aboriginal and Torres Strait Islander peoples. Now that highly effective direct acting anti-viral treatments are available, it is crucial to ensure key affected populations, including Aboriginal and Torres Strait Islander people, have access to these novel biomedical approaches. Findings will underpin future policy to reduce the burden of hepatitis C across SA and NT populations.

Introduction: The artificial urinary sphincter (AUS) is the most effective treatment option for incontinence after prostate cancer treatment. However, patients with a “fragile urethra” (defined as prior radiotherapy, previous failed AUS, or previous urethroplasty) are at increased risk of AUS failure. The aim of this study was to evaluate outcomes using standard and transcorporal cuff placement in this group of patients. Methods: A retrospective review was performed on patients with a fragile urethra who underwent AUS insertion between 2004 and 2017. The primary outcome was the need for AUS revision. Secondary outcome measures included change in pad use, patient satisfaction, continence (≤1 pad/day), improvement (≥50% change in pad use) and cuff erosion rates. Results: Seventy-six patients met the criteria for inclusion, with a mean age of 71.6 years and a mean followup of 37.9 months. A total of 42.1% had prior radiotherapy, 56.6% had a history of failed AUS, and 19.7% had previous urethroplasty. Transcorporal cuff placement was performed in 31.6% (n=24). These patients had lower revision (20.8% vs. 36.5%; p=0.05) and erosion rates (8.3% vs. 17.3%; p=0.09). There was no significant difference in functional outcomes such as continence (66.7% vs. 73.1%; p=0.57), improvement (100% vs. 90.4%;p=0.17), or satisfaction (82.6% vs. 69.4%; p=0.26), nor for 90-day complications (4.2% vs. 9.6%; p=0.41). Conclusions: AUS insertion is an effective treatment option for post-prostatectomy incontinence in the setting of a fragile urethra. Transcorporal cuff placement in this subset of patients may be recommended, as it is associated with lower revision and erosion rates compared to standard cuff placement.

SARS-CoV-2 causes a spectrum of illness, ranging from asymptomatic to severe COVID-19. As the immunological basis for severity remains ill-defined, we analysed 78 SARS-CoV-2-infected individuals at acute and/or convalescent timepoints, up to 102 days post-symptom onset, quantifying 184 innate and adaptive immunological parameters. Acute COVID-19 in hospitalised patients was associated with high levels of IL-6, IL-18 and IL-10, elevated neutrophil-to-lymphocyte and neutrophil-to-T cell ratios, and high proportions of activated CD38+ neutrophils, CD38+ eosinophils, CD38+ HLA-DRlo monocytes, CD38+CD56dim NK cells, CD38+ γδ T cells, antibody-secreting cells, CD38+ICOS+ circulating T follicular helper (cTFH) cells, CD38+HLA-DR+CD4+ T cells, effector CD27-CD45RA+ and CD38+ CD8+ T cells. During convalescence, elevated seroconversion and neutralising antibodies were prominent and correlated with acute CXCR3+ cTFH cell activation. Strikingly, intensive care unit (ICU) patients with severe COVID-19 displayed higher levels of soluble IL-6R, IL-18, and hyperactivation of innate, adaptive and myeloid compartments than ward patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients during acute and convalescent phases of SARS-CoV-2 infection, and integrate key cellular pathways of complex perturbed immune networks that underpin severe COVID-19, providing important insights into potential biomarkers and immunotherapies. Funding: This work was supported by the Australian National Health and Medical Research Council (NHMRC) Leadership Investigator Grant to KK (#1173871), NHMRC Program Grant to DLD (#1132975), Research Grants Council of the Hong Kong Special Administrative Region, China (#T11-712/19-N) to KK, the Jack Ma Foundation to KK, KS, DIG and AWC, the a2 milk foundation to KS, the Victorian Government MRFF award (#2002073) to SJK, DIG and AKW, MRFF Award (#1202445) to KK, NHMRC program grant 1149990 (SJK), NHMRC project grant 1162760 (AKW), NHMRC Program Grant (#1071916) to KK and DCJ, NHMRC Program Grant (1113293) to DIG, the Merridew Foundation to NJCK. KK is supported by NHMRC Senior Research Fellowship (1102792), DLD by a NHMRC Principal Research Fellowship (#1137285), KS by an NHMRC Investigator grant (#1177174), SYCT by a NHMRC Career Development Fellowship (#1145033), DIG by an NHMRC Senior Principal Research Fellowship (#1117766) and SJK by NHMRC Senior Principal Research Fellowship (#1136322). SRL is supported by an NHMRC program grant (#1149990) and practitioner fellowship (#1135851). LH and WZ are supported by the Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS) from The University of Melbourne. XJ is supported by China Scholarship Council-University of Melbourne joint Scholarship. CES has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement (#792532). JRH and WZ are supported by the Melbourne Research Scholarship from The University of Melbourne. TMA and FM-W are International Society for Advancement of Cytometry Marylou Ingram Scholars. GHP is supported by the Australian Government Research Training Program (RTP) Scholarship. JAJ is supported by an NHMRC Early Career Fellowship (ECF) (#1123673). EBC. is supported by a NHMRC Peter Doherty Fellowship (#1091516). KK and AC were supported by the University of Melbourne Dame Kate Campbell Fellowship. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. Conflict of Interest: The authors declare no conflict of interest. Ethical Approval: The study was approved by the Alfred Hospital (#280/14), Melbourne Health (HREC/17/MH/53), Monash Health (HREC/15/MonH/64/2016.196), The University of Melbourne (#2056689, #2056761, #1442952, #1955465 and #1443389) and James Cook University (H7886) Human Research Ethics Committees.

Indigenous Australians are highly susceptible to severe influenza disease during seasonal and pandemic infections. Current antibody-based vaccines targeting humoral immunity are the most effective way to combat influenza infections but show reduced efficacy in Indigenous Australians. The underlying mechanisms are still unknown. We recruited 166 Indigenous & non-Indigenous donors to elucidate adaptive immune responses induced by the inactivated quadrivalent influenza vaccine. Participants were bled at baseline, day 7 and day 28 post-vaccination. We analysed hemagglutination inhibition titres against the vaccine and previously circulating strains, analysed IgG1 and IgG3 allotypes, evaluated total IgG glycosylation and performed Luminex assays to dissect antibody responses against viral HA, NA and NP proteins. Additionally, we assessed influenza-specific B cell responses with fluorescent HA probes, antibody-secreting cells and circulating Tfh cells. More than 15,000 datapoints were collected to compare adaptive immune responses between Indigenous and non-Indigenous donors. We found that the majority of immune readouts were comparable between the two groups. However, interestingly, we found significantly lower pre-vaccine titres and lower back-boosting to pre-pandemic H1N1 viruses in Indigenous compared to non-Indigenous donors. This might explain, at least in part, high susceptibility of Indigenous Australians to the 2009 pandemic. Our comprehensive dataset will be used to understand and improve optimal vaccine responses in Indigenous and non-Indigenous populations globally.

The 2009 influenza pandemic caused generally mild infections due, at least partially, to broadly cross-reactive pre-existing CD8+ T cell immunity. In contrast, severe disease was observed in Indigenous populations worldwide, as shown by disproportionate hospitalisation rates. Human leukocyte antigen-I (HLA-I) molecules present viral peptides to CD8+ T cells, eliciting anti-viral responses that contribute to accelerated viral clearance. We identified several HLA-I alleles which are highly prevalent in Indigenous Australians (HLA-A*11:01, A*24:02, A*34:01, B*13:01 and B*15:21) but largely understudied. Using specific HLA-allomorph expressing C1R cell lines, we identified influenza A and B immunopeptidomes by mass spectrometry. A total of 653 influenza peptides derived from various viral proteins were presented during infection by different HLA-Is. Using virus-specific PBMC expansions, we screened these peptides for their potential to reactivate influenza-specific memory CD8+ T cells. We identified on average 4.6 (2–8) immunogenic epitopes per HLA-I for influenza A and B. We defined epitope-specific CD8+ T cells ex vivo across different human tissues and determined their memory subsets, phenotype and activation in healthy donors and influenza-infected patients. Overall, our approach is effective in detection of immunogenic epitopes and understanding CD8+ T cell pools in Indigenous populations, thus providing potential vaccine targets to protect Indigenous populations globally, from severe influenza disease. This is the first study to identify hallmarks of immunogenic responses and reveal key targets of an effective CD8+ T cell vaccine in Indigenous people.

Stair climbing is a readily available form of vigorous-intensity physical activity. Evidence indicates that placing stair prompt signs at points-of-decision (e.g. near elevators and stairways) is an inexpensive, effective strategy for increasing physical activity through stair use. This article aims to share the experience of the New York City Department of Health and Mental Hygiene (NYC DOHMH) in the outreach and implementation of a population-scale stair prompt initiative, including lessons learned from process evaluations, with other public health authorities conducting a similar program. Between May 2008 and August 2012, NYC DOHMH implemented a stair prompt initiative as one strategy in a comprehensive program to increase physical activity and healthy eating through physical improvements to NYC's buildings, streets and neighborhoods, particularly targeting facilities in underserved and low-income neighborhoods. Program evaluation was conducted using program planning documents to examine the process, and data from NYC information line call center, outreach tracking database, and site and phone audits to examine process outcomes. The initiative successfully distributed more than 30,000 stair prompts to building owners/managers of over 1000 buildings. Keys to success included multi-sector partnerships between NYC's Health Department and non-health government agencies and organizations (such as architecture and real estate organizations), a designated outreach coordinator, and outreach strategies targeting building owners/managers owning/managing multiple buildings and buildings serving underserved and at risk populations. A NYC citywide initiative successfully distributed stair prompts to the wider community to promote population-level health impacts; lessons learned may assist other jurisdictions considering similar initiatives to increase physical activity., Highlights • Evaluation of a stair prompt initiative shows this evidence-based intervention can be used in a program for broad physical activity promotion. • Dedicated resources and multi-sectoral partnerships are critical in the implementation of health initiatives to improve the built environment. • Engaging building operators with large portfolios of buildings allowed widespread dissemination of stair prompts under resource constraints. • Using already available resources such as a city’'s information telephone line can also assist in inexpensive stair prompt dissemination. • Health disparities can be targeted through additional outreach focused on buildings in high-needs neighborhoods and settings.

Non-planar (3D) interconnects have an important role in the electronic packaging industry these days. These unconventional interconnects allow manufacturers to save materials and space while connecting circuit components on flexible and non-planar substrates. Among a variety of flexible boards, double-sided flexible substrates have attracted the electronic industry to effectively and compactly develop miniaturized flexible devices such as sensors-on-chips. This study reports our developmental procedure for the creation of non-planar silver interconnects on the edge of double-sided copper substrates separated by a layer of polyethylene terephthalate (PET) using laser-assisted maskless microdeposition (LAMM). The article consists of the characterization of the LAMM process to effectively deposit Ag nanoparticles for production of conductive interconnects. Several parameters, including the deposition and laser processing parameters, are optimized to achieve interconnects free of pores, cracks and delamination. For investigating the topography and microstructure of interconnects, various analytical tools, such as SEM, XRD, Profilometery, and EDS were used. Furthermore, a 3D finite element numerical model was developed to predict the laser processing of silver nanoparticles on the substrate. The model includes a coupled thermal and structural governing physics to derive the temperature history throughout the simulation as well as strain/displacement within the substrate, which is identified the major source of cark formation in Ag tracks. The SEM micrographs of the laser processed nanoparticles suggest that a minimum of 1.24 W laser power was needed for an effective nanoparticles sintering to obtain conductive 3D interconnects with minimum amount of cracks whereas a 1.7 W laser power caused PET to decompose.

A new and unique beta-titanium alloy (Ti. +. 25. mol% (Ta,Nb,V). +. (Zr,Hr,O) has interesting properties such as low elastic modulus, high strength and high elastic deformability as well as Invar a ...

Non-planar (3D) interconnects have an important role in the electronic packaging industry today. They allow manufacturers to save materials and space when connecting circuit components on flexible and non-planar substrates. Nowadays, double-sided flexible substrates have attracted the electronic industry to develop miniaturized flexible devices, such as sensors-on-chips, effectively and compactly. This study reports on our preliminary results for the creation of non-planar silver interconnects on the edge of double-sided copper substrates separated by a layer of polyethylene terephthalate (PET) using laser-assisted maskless microdeposition (LAMM). In the LAMM process, which is a laser-based direct write technology, suspensions of silver nano-particles are used in a layer-by-layer deposition followed by laser post sintering. This study includes the characterization of the LAMM process to achieve desired conductivity in the produced interconnects, which is the main indicator of performance for the electronic packages. Several parameters, including the deposition and laser processing parameters, are optimized to achieve interconnects free of pores, cracks and delamination with reasonable bonding. For investigating the topography and microstructure of the interconnects, an optical microscope and scanning electron microscope (SEM) are used.Non-planar (3D) interconnects have an important role in the electronic packaging industry today. They allow manufacturers to save materials and space when connecting circuit components on flexible and non-planar substrates. Nowadays, double-sided flexible substrates have attracted the electronic industry to develop miniaturized flexible devices, such as sensors-on-chips, effectively and compactly. This study reports on our preliminary results for the creation of non-planar silver interconnects on the edge of double-sided copper substrates separated by a layer of polyethylene terephthalate (PET) using laser-assisted maskless microdeposition (LAMM). In the LAMM process, which is a laser-based direct write technology, suspensions of silver nano-particles are used in a layer-by-layer deposition followed by laser post sintering. This study includes the characterization of the LAMM process to achieve desired conductivity in the produced interconnects, which is the main indicator of performance for the electroni...

To determine role of estrogen receptors in testicular descent, a morphometric study of the testis and structures derived from the gubernaculum was made in sexually mature male mice having an estrogen receptor disrupted gene mutation (ERKO). Macroscopic dissections and sagittal serial sections were made of the pelvis of four wild-type mice, four mice heterozygous for the ERKO mutation, and four homozygous ERKO males. By external morphological examination the testes appeared to be descended in all three genotypes. All mice had development of a cremaster sac, which is derived from the gubernaculum, but this was twice as large in wild-type mice than in both the heterozygote or homozygote ERKO groups. The cause for the smaller cremaster sac appeared to be excessive development of the cremaster muscle in ERKO mice. The thickened muscle was associated with postmortem retraction of the testes into the inguinal canal or abdomen. Spermatogenesis and testicular volume were deficient in homozygous ERKO mice at this age. This study demonstrates that estrogen has a previously unknown role in masculine sexual development of the gubernaculum and the structures derived from it, such as the cremaster muscle.