Aged care service use by Aboriginal and Torres Strait Islander people after aged care eligibility assessments, 2017-2019: a population-based retrospective cohort study.

OBJECTIVE: To characterise the socio-demographic characteristics, aged and health care needs, and aged care services used by older Aboriginal and Torres Strait Islander people assessed for aged care service eligibility. STUDY DESIGN: Population-based retrospective cohort study; analysis of Registry of Senior Australians (ROSA) National Historical Cohort data. SETTING, PARTICIPANTS: Aboriginal and Torres Strait Islander people aged 50 years or older who were first assessed for aged care service eligibility (permanent residential aged care, home care package, respite care, or transition care) during 1 January 2017 - 31 December 2019. MAJOR OUTCOME MEASURES: Socio-demographic and aged care assessment characteristics; health conditions and functional limitations recorded at the time of the assessment; subsequent aged care service use. RESULTS: The median age of the 6209 people assessed for aged care service eligibility was 67 years (interquartile range [IQR], 60-75 years), 3626 were women (58.4%), and 4043 lived in regional to very remote areas of Australia (65.1%). Aboriginal health workers were involved in 655 eligibility assessments (10.5%). The median number of health conditions was six (IQR, 4-8); 6013 (96.9%) had two or more health conditions, and 2592 (41.8%) had seven or more. Comorbidity was most frequent among people with mental health conditions: 597 of 1136 people with anxiety (52.5%) and 1170 of 2416 people with depression (48.5%) had seven or more other medical conditions. Geriatric syndromes were recorded for 2265 people (36.5%); assistance with at least one functional activity was required by 6190 people (99.7%). A total of 6114 people (98.5%) were approved for at least one aged care service, 3218 of whom (52.6%) subsequently used these services; the first services used were most frequently home care packages (1660 people, 51.6%). CONCLUSION: Despite the high care needs of older Aboriginal and Torres Strait Islander people, only 52% used aged care services for which they were eligible. It is likely that the health and aged care needs of older Aboriginal and Torres Strait Islander people are not being adequately met.

Development and validation of a frailty index based on Australian Aged Care Assessment Program data.

OBJECTIVES: To develop and validate a frailty index, derived from aged care eligibility assessment data. DESIGN: Retrospective cohort study; analysis of the historical national cohort of the Registry of Senior Australians (ROSA). PARTICIPANTS: 903 996 non-Indigenous Australians aged 65 years or more, living in the community and assessed for subsidised aged care eligibility during 2003-2013. MAIN OUTCOME MEASURES: 44-item frailty index; summary statistics for frailty index score distribution; predictive validity with respect to mortality and entry into permanent residential aged care during the five years after assessment. RESULTS: The mean frailty index score during 2003-2013 was 0.20 (SD, 0.07; range, 0-0.41); the proportion of assessed older people with scores exceeding 0.20 increased from 32.1% in 2003-2005 to 75.0% in 2012-2013. The risks of death and entry into permanent residential aged care at one, three and five years increased with frailty index score level (at one year, high [over 0.35] v low scores [under 0.05]: hazard ratio for death, 5.99; 95% CI, 5.69-6.31; for entry into permanent residential aged care, 8.70; 95% CI, 8.32-9.11). The predictive validity (area under the receiver operating characteristic curve) of Cox proportional hazard models including age, sex, and frailty index score was 0.64 (95% CI, 0.63-0.64) for death and 0.63 (95% CI, 0.62-0.63) for entry into permanent residential aged care within one year of assessment. CONCLUSIONS: We used Australian aged care eligibility assessment program data to construct and validate a frailty index. It can be employed in aged care research in Australia, but its application to aged care planning requires further investigation.

The dispensing of psychotropic medicines to older people before and after they enter residential aged care.

OBJECTIVE: To examine the prevalence of psychotropic medicine dispensing before and after older people enter residential care. DESIGN: Retrospective national cohort study; analysis of Registry of Senior Australians (ROSA) data. SETTING, PARTICIPANTS: All concession card-holding residents of government-subsidised residential aged care facilities in Australia who entered residential care for at least three months between 1 April 2008 and 30 June 2015. MAIN OUTCOME MEASURES: Proportions of residents dispensed antipsychotic, benzodiazepine, or antidepressant medicines during the year preceding and the year after commencing residential care, by quarter. RESULTS: Of 322 120 included aged care residents, 68 483 received at least one antipsychotic (21.3%; 95% CI, 21.1-21.4%), 98 315 at least one benzodiazepine (30.5%; 95% CI, 30.4-30.7%), and 122 224 residents at least one antidepressant (37.9%; 95% CI, 37.8-38.1%) during their first three months of residential care; 31 326 of those dispensed antipsychotics (45.7%), 38 529 of those dispensed benzodiazepines (39.2%), and 25 259 residents dispensed antidepressants (19.8%) had not received them in the year preceding their entry into care. During the first three months of residential care, the prevalence of antipsychotic (prevalence ratio [PR], 3.37; 95% CI, 3.31-3.43) and antidepressant dispensing (PR, 1.05; 95% CI, 1.04-1.07) were each higher for residents with than for those without dementia; benzodiazepine dispensing was similar for both groups (PR, 1.01; 95% CI, 0.99-1.02). CONCLUSIONS: Dispensing of psychotropic medicines to older Australians is high before they enter residential care but increases markedly soon after entry into care. Non-pharmacological behavioural management strategies are important for limiting the prescribing of psychotropic medicines for older people in the community or in residential care.

Burkholderia lata Infections from Intrinsically Contaminated Chlorhexidine Mouthwash, Australia, 2016.

Burkholderia lata was isolated from 8 intensive care patients at 2 tertiary hospitals in Australia. Whole-genome sequencing demonstrated that clinical and environmental isolates originated from a batch of contaminated commercial chlorhexidine mouthwash. Genomic analysis identified efflux pump-encoding genes as potential facilitators of bacterial persistence within this biocide.

CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity.

CD4-binding site (CD4bs) alterations in gp120 contribute to different pathophysiological phenotypes of CCR5-using (R5) HIV-1 strains, but the potential structural basis is unknown. Here, we characterized functionally diverse R5 envelope (Env) clones (n=16) to elucidate potential structural alterations within the gp120 CD4bs that influence Env function. Initially, we showed that the magnitude of gp120-CD4-binding correlates with increased fusogenicity and reduced CD4 dependence. Analysis of three-dimensional gp120 structural models revealed two CD4bs variants, D279 and N362, that were associated with reduced CD4 dependence. Further structural analysis showed that a wider aperture of the predicted CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop, was associated with amino acid alterations within V5 and correlated with increased gp120-CD4 binding and increased fusogenicity. Our results provide evidence that the gp120 V5 loop may alter CD4bs conformation and contribute to increased gp120-CD4 interactions and Env fusogenicity.

Genetic and functional heterogeneity of CNS-derived tat alleles from patients with HIV-associated dementia.

Human immunodeficiency virus type 1 (HIV-1) demonstrates a high degree of viral diversity which has an impact on viral fitness. Genetic compartmentalization of HIV-1 proteins between central nervous system (CNS) and lymphoid tissues is well established and reflects altered requirements for HIV-1 replication in macrophages/microglia, brain-specific immune selection pressures and possibly the timing of virus invasion of the CNS. Tat-encoding mRNA has been detected in the CNS of HIV-1 infected individuals and its neurotoxic effects in the CNS are well documented. However, while CNS-derived tat sequences have demonstrated significant diversity, the effect of this molecular diversity on transcriptional regulation and its impact on the pathogenesis of HIV-associated dementia (HAD) remains unclear. In this study, we cloned and characterised 44 unique tat alleles from brain, cerebral spinal fluid, spinal cord and blood/lymphoid tissue-derived HIV-1 isolates from five subjects with HAD. While phylogenetic analyses revealed tissue-specific compartmentalization of Tat variants for two patients, broad compartmentalization across the panel of tissue-derived viruses was not observed. Despite the lack of consistent tissue-specific compartmentalization, sequence variations within patients segregated CNS and non-CNS tat alleles. These amino acid alterations predominated within the transactivation domain of Tat and could account for alterations in the ability of particular Tat proteins to transactivate the LTR. Although a subset of patients demonstrated reduced transactivation capacity among CNS-derived Tat proteins compared to those from matched lymphoid tissues, overall Tat proteins from the CNS to lymphoid compartments maintained similar levels of transactivation function. Together, these data suggest that despite the observed heterogeneity in tat alleles isolated from matched lymphoid to CNS compartments, Tat function is maintained, highlighting the importance of Tat function in HIV-1 neuropathogenesis.

CD4 and MHC class 1 down-modulation activities of nef alleles from brain- and lymphoid tissue-derived primary HIV-1 isolates.

Human immunodeficiency virus type 1 (HIV-1) nef undergoes adaptive evolution in the central nervous system (CNS), reflecting altered requirements for HIV-1 replication in macrophages/microglia and brain-specific immune selection pressures. The role of Nef in HIV-1 neurotropism and pathogenesis of HIV-associated dementia (HAD) is unclear. In this study, we characterized 82 nef alleles cloned from brain, cerebral spinal fluid, spinal cord, and blood/lymphoid tissue-derived HIV-1 isolates from seven subjects with HAD. CNS isolate-derived nef alleles were genetically compartmentalized and had reduced sequence diversity compared to those from lymphoid tissue isolates. Defective nef alleles predominated in a brain-derived isolate from one of the seven subjects (MACS2-br). The ability of Nef to down-modulate CD4 and MHC class 1 (MHC-1) was generally conserved among nef alleles from both CNS and lymphoid tissues. However, the potency of CD4 and MHC-1 down-modulation was variable, which was associated with sequence alterations known to influence these Nef functions. These results suggest that CD4 and MHC-1 down-modulations are highly conserved functions among nef alleles from CNS- and lymphoid tissue-derived HIV-1 isolates that may contribute to viral replication and escape from immune surveillance in the CNS.

An altered and more efficient mechanism of CCR5 engagement contributes to macrophage tropism of CCR5-using HIV-1 envelopes.

While CCR5 is the principal coreceptor used by macrophage (M)-tropic HIV-1, not all primary CCR5-using (R5) viruses enter macrophages efficiently. Here, we used functionally-diverse R5 envelope (Env) clones to characterize virus-cell interactions important for efficient CCR5-mediated macrophage entry. The magnitude of macrophage entry by Env-pseudotyped reporter viruses correlated with increased immunoreactivity of CD4-induced gp120 epitopes, increased ability to scavenge low levels of cell-surface CCR5, reduced sensitivity to the CCR5 inhibitor maraviroc, and increased dependence on specific residues in the CCR5 ECL2 region. These results are consistent with an altered and more efficient mechanism of CCR5 engagement. Structural studies revealed potential alterations within the gp120 V3 loop, the gp41 interaction sites at the gp120 C- and N-termini, and within the gp120 CD4 binding site which may directly or indirectly lead to more efficient CCR5-usage. Thus, enhanced gp120-CCR5 interactions may contribute to M-tropism of R5 HIV-1 strains through different structural mechanisms.

Ubisol-Aqua: coenzyme Q10 prevents antiretroviral toxic neuropathy in an in vitro model.

BACKGROUND: Peripheral neuropathy is the dose-limiting toxicity of stavudine and didanosine (nucleoside analogs used in HIV treatment) and is attributed to mitochondrial toxicity from these drugs. Acetyl L-carnitine (ALC) and co-enzyme Q(10) are proposed as neuropathy treatments, but evidence to support these is limited. METHODS: We examined ALC and a water-soluble formulation of co-enzyme Q(10) (H(Q)O) for the prevention of d4T and ddI neurotoxicity using cultured fetal rat DRG as an in vitro model. RESULTS: DdI (33microM) and d4T (50microM) caused clear toxicity (impaired neurite growth) by day 8 of DRG culture. H(Q)O at concentrations 1-100microM completely prevented the toxicity of 33microM ddI in vitro and ALC at concentrations 1-100 microM substantially (but incompletely) prevented ddI toxicity in this model. In contrast, ALC was ineffective at all concentrations tested for preventing the toxicity of 50microM d4T. H(Q)O showed dose-dependent efficacy for preventing d4T toxicity. H(Q)O (1microM) partially prevented d4T toxicity while 10 and 100microM H(Q)O completely prevented d4T toxicity in this model. CONCLUSIONS: We find H(Q)O is superior to ALC for preventing the neurotoxicity of d4T (the HIV treatment most associated with neuropathy) and ddI in vitro. Further study is needed to clarify any clinical role for co-enzyme Q(10) co-administration with d4T and ddI and to assess whether this compound may have a role in treating established cases of neuropathy.

Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia.

Astrocyte infection with human immunodeficiency virus (HIV) is considered rare, so astrocytes are thought to play a secondary role in HIV neuropathogenesis. By combining double immunohistochemistry, laser capture microdissection, and highly sensitive multiplexed polymerase chain reaction to detect HIV DNA in single astrocytes in vivo, we showed that astrocyte infection is extensive in subjects with HIV-associated dementia, occurring in up to 19% of GFAP+ cells. In addition, astrocyte infection frequency correlated with the severity of neuropathological changes and proximity to perivascular macrophages. Our data indicate that astrocytes can be extensively infected with HIV, and suggest an important role for HIV-infected astrocytes in HIV neuropathogenesis.

The widening gap between clinical, teaching and research work.

Demand for medical education is increasing, and clinicians are struggling to maintain involvement in teaching and research activities. The settings of clinical training are changing and diversifying. The traditional model of medical education and the sustainability of academic medicine are under strain. Better support is required to ensure continued integration of research and education with clinical activities. Better coordination is required to overcome fragmentation within the medical education system, to ensure appropriate recognition for teaching and research across all clinical settings.

Cell-specific temporal infection of the brain in a simian immunodeficiency virus model of human immunodeficiency virus encephalitis.

Increasing evidence supports early brain infection by human immunodeficiency virus (HIV). Definitive temporal studies determining when and within which brain cells viral DNA is present are lacking. This study utilized simian immunodeficiency virus (SIV)-infected macaques sacrificed at days 10, 21, 56, and 84 post inoculation. Laser-microdissection isolated pure perivascular macrophage, parenchymal microglia, and astrocyte populations. Nested polymerase chain reaction (PCR) and sequencing determined the presence and characteristics of SIV V3 and V1 env DNA from each population. At day 10, SIV DNA was detected in perivascular macrophage and astrocytes but not parenchymal microglia. gp41 expression was restricted to perivascular macrophage. At day 21, SIV DNA was not detected in any cell type. At day 56, SIV DNA was detectable in perivascular macrophage from one of two macaques, with no gp41 expression detected. At day 84 (morphologic and clinical encephalitis), SIV DNA was detected in all cell types, gp41 was only detected in perivascular macrophage and parenchymal microglia. The neurovirulent molecular clone, SIV/17E-Fr, was the only genotype identified in the brain cell populations. Early, productive brain SIV infection was transient and restricted to trafficking perivascular macrophage. During the nonencephalitic stage, there was a period of time when no SIV DNA could be detected in the brain cell populations. SIV was then seen to reenter the brain via infected perivascular macrophage, leading to productive infection of brain parenchymal macrophage/microglia with a terminal phase of encephalitis. These data challenge current notions of a HIV reservoir within latently infected, semipermanent brain cells and has significant implications for the timing and design of therapies to prevent HIV encephalitis (HIVE).

Bacterial antigen expression is an important component in inducing an immune response to orally administered Salmonella-delivered DNA vaccines.

BACKGROUND: The use of Salmonella to deliver heterologous antigens from DNA vaccines is a well-accepted extension of the success of oral Salmonella vaccines in animal models. Attenuated S. typhimurium and S. typhi strains are safe and efficacious, and their use to deliver DNA vaccines combines the advantages of both vaccine approaches, while complementing the limitations of each technology. An important aspect of the basic biology of the Salmonella/DNA vaccine platform is the relative contributions of prokaryotic and eukaryotic expression in production of the vaccine antigen. Gene expression in DNA vaccines is commonly under the control of the eukaryotic cytomegalovirus (CMV) promoter. The aim of this study was to identify and disable putative bacterial promoters within the CMV promoter and evaluate the immunogenicity of the resulting DNA vaccine delivered orally by S. typhimurium. METHODOLOGY/PRINCIPAL FINDINGS: The results reported here clearly demonstrate the presence of bacterial promoters within the CMV promoter. These promoters have homology to the bacterial consensus sequence and functional activity. To disable prokaryotic expression from the CMV promoter a series of genetic manipulations were performed to remove the two major bacterial promoters and add a bacteria transcription terminator downstream of the CMV promoter. S. typhimurium was used to immunise BALB/c mice orally with a DNA vaccine encoding the C-fragment of tetanus toxin (TT) under control of the original or the modified CMV promoter. Although both promoters functioned equally well in eukaryotic cells, as indicated by equivalent immune responses following intramuscular delivery, only the original CMV promoter was able to induce an anti-TT specific response following oral delivery by S. typhimurium. CONCLUSIONS: These findings suggest that prokaryotic expression of the antigen and co-delivery of this protein by Salmonella are at least partially responsible for the successful oral delivery of C-fragment DNA vaccines containing the CMV promoter by S. typhimurium.

Measuring and monitoring apoptosis and drug toxicity in HIV patients by ligation-mediated polymerase chain reaction.

Apoptosis has a critical role in normal physiology while its dysregulation has causal links with certain pathologies. A biochemical hallmark of apoptosis, internucleosomal genomic DNA fragmentation, is detectable by ligation-mediated polymerase chain reaction (LM-PCR). Here we converted LM-PCR into a new apoptosis quantifier by dividing trace quantities of 600 bp apoptotic amplicons into those of a single copy house-keeping gene, generating the LM-PCR 'value'. Dynamic range was approximately 17-fold correlating with a approximately 200-fold difference in degree of apoptotic fragmentation. Inter- and intra-gel reliability were both excellent, supporting LM-PCR's utility with large sample sets. Validation experiments comprising cell exposure to staurosporine over time revealed LM-PCR is as sensitive as caspase-3/ELISA and more sensitive than terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling/flourescence-activated cell sorting (TUNEL/FACS) for distinguishing low degrees of apoptosis (the spectrum most relevant in vivo). The LM-PCR profile mirrored that of caspase-3/ELISA but not TUNEL/FACS. We then applied this molecular tool to clinical investigation. Increased apoptosis is implicated in lipoatrophy (subcutaneous fat wasting), a serious, persistent toxicity of some nucleoside analogue reverse transcriptase inhibitors (NRTIs) used in anti-HIV highly active antiretroviral therapy (HAART). We demonstrated in 105 peripheral blood mononuclear cell samples that elevated LM-PCR values are seen during therapy with stavudine (d4T), a particularly toxic NRTI (P< 0.0001 versus no HAART, unpaired t-test). Elevated values were also independently associated with clinical evidence of lipoatrophy (P= 0.007, multiple logistic regression modelling) but not with patient age, CD4 T-cell count nor HIV viral load (P> 0.8 for each). Together these data demonstrate that LM-PCR is a robust and reliable quantifier of apoptosis with potential for basic science and clinical investigation.

Impact of prior immunological exposure on vaccine delivery by Salmonella enterica serovar Typhimurium.

Recombinant Salmonella have been employed as vaccine vectors to deliver DNA and protein vaccines of viral, bacterial and parasitic origin. However, the effectiveness of Salmonella delivery may be hampered by prior immunological exposure to Salmonella. We investigated the effects of prior exposure to the Salmonella typhimurium aroAD strain BRD509 on its ability to deliver the non-toxic C fragment of tetanus toxin (TT). BALB/c mice were orally immunised with BRD509 containing the C fragment expression plasmid pTETtac4, C fragment DNA vaccine pAT153/Cfrag or BRD509 alone and, along with age matched un-vaccinated controls, were immunised again 6 months later with BRD509 (pTETtac4). Prior exposure to Salmonella was found to significantly reduce the ability of the bacteria to colonise the Peyer's patches and mesenteric lymph nodes, spread systemically to the liver and spleen and significantly impair antibody responses to Salmonella LPS and TT. Results show that prior exposure to Salmonella significantly compromises its efficacy as a vaccine vector and these negative effects do not diminish with time. In addition, findings suggest Salmonella vaccine vectors cannot be employed to deliver multiple doses of a vaccine antigen.

Targeting subcapsular antigens for prevention of Klebsiella pneumoniae infections.

Vaccination strategies against Klebsiella pneumoniae have largely focussed on the polysaccharide capsule. However, the large number and high prevalence of individual capsular serotypes limits the widespread applicability of capsule-based vaccines. This study establishes that immunization with purified LPS can protect mice against lethal challenge with K. pneumoniae, and that subcapsular antibodies directed against purified LPS can be used to treat and/or prevent experimental K. pneumoniae infection in mice. This approach offers potential for prophylaxis and/or therapy against drug-resistant strains of K. pneumoniae.

A report on the effect of commencing enfuvirtide on peripheral neuropathy.

Enfuvirtide is the first fusion inhibitor approved for use in HIV treatment and is a useful therapeutic option for highly treatment experienced individuals. Passive reporting has associated increased neuropathy rates with enfuvirtide use in some early studies but not others. The aim of this study was to describe any functional or clinical changes consistent with neuropathy among enfuvirtide users. A prospective cohort study of patients commencing or continuing enfuvirtide at a state HIV referral service, including clinical and sensory threshold monitoring, was conducted. A total of 14 patients were studied. All had advanced HIV disease and 13 (93%) had symptoms and/or signs consistent with neuropathy at baseline. Patients who entered the study on enfuvirtide-based therapy remained neurologically stable throughout follow-up. Eleven patients were assessed preand postenfuvirtide. No evidence was found for any clear effect of enfuvirtide on neuropathic symptoms, neuropathic signs, or sensory thresholds at a cohort level (p > 0.3 for all, Wilcoxon signed rank test). However, three (21%) patients experienced worsening of existing neuropathy symptoms (transient in two cases) and two (14%) patients' symptoms improved with enfuvirtide commencement. Breakthrough HIV viremia was associated with worsening symptoms in two patients at 5 and 18 months of enfuvirtide use. This study found no clear effect on peripheral nerves from enfuvirtide. Although limited by a small sample size, this study involved patients who would have been particularly vulnerable to a neurotoxin, with advanced HIV disease and a high rate of baseline neurological abnormalities. We observed no clear evidence of neurotoxicity from enfuvirtide in this population.