Improvements in Therapy Experience with Evoked Compound Action Potential Controlled, Closed-Loop Spinal Cord Stimulation - Primary Outcome of the ECHO-MAC Randomized Clinical Trial.

Spinal cord stimulation (SCS) is a well-established treatment for chronic neuropathic pain. However, over- or under-delivery of the SCS may occur because the spacing between the stimulating electrodes and the spinal cord is not fixed; spacing changes with motion and postural shifts may result in variable delivery of the SCS dose, and in turn a sub-optimal therapy experience for the patient. The evoked compound action potential (ECAP)-a measure of neural activation - may be used as a control signal to adapt SCS parameters in real-time to compensate for this variability. In this prospective, multicenter, randomized, single-blind, crossover trial, reduction in overstimulation intensity was used as a perceptual measure to evaluate a novel ECAP-controlled, closed-loop (CL) SCS algorithm relative to traditional open-loop (OL) SCS. The primary outcome used a Likert scale to assess sensation during activities of daily living with CL versus OL SCS. Of the 42 subjects in the Intent-to-Treat Analysis set, 97.6% had a reduction in sensation with CL versus OL SCS. The primary objective was met as the lower confidence limit (87.4%) exceeded the performance goal of 50% (p < 0.001). A total of 88.1% (37/42) of subjects preferred CL and 11.9% (5/42) preferred OL SCS. SCS dose consistency during CL SCS was demonstrated by the reduced variability in ECAP amplitude with CL SCS (SD: 8.72 µV) relative to OL SCS (SD: 19.95 µV). Together, these results demonstrate that the ECAP-controlled, CL algorithm reduces or eliminates unwanted sensation, and thereby provides a more preferred and consistent SCS experience. PERSPECTIVE: Patients with chronic pain need durable and dependable options for pain relief. SCS is an important therapy option, and new technology advancements could improve long-term therapy use. Closed-loop SCS offers a preferred and more consistent therapy experience for patients that could lead to increased therapy utilization and reliable therapy outcomes.

In silico gepotidacin target mining among 33 213 global Neisseria gonorrhoeae genomes from 1928 to 2023 combined with gepotidacin MIC testing of 22 gonococcal isolates with different GyrA and ParC substitutions.

OBJECTIVES: The novel dual-target triazaacenaphthylene, gepotidacin, recently showed promising results in its Phase III randomized controlled trial for the treatment of gonorrhoea. We investigated alterations in the gepotidacin GyrA and ParC targets in gonococci by in silico mining of publicly available global genomes (n = 33 213) and determined gepotidacin MICs in isolates with GyrA A92 alterations combined with other GyrA and/or ParC alterations. METHODS: We examined gonococcal gyrA and parC alleles available at the European Nucleotide Archive. MICs were determined using the agar dilution method (gepotidacin) or Etest (four antimicrobials). Models of DNA gyrase and topoisomerase IV were obtained from AlphaFold and used to model gepotidacin in the binding site. RESULTS: GyrA A92 alterations were identified in 0.24% of genomes: GyrA A92P/S/V + S91F + D95Y/A/N (0.208%), A92P + S91F (0.024%) and A92P (0.003%), but no A92T (previously associated with gepotidacin resistance) was found. ParC D86 alterations were found in 10.6% of genomes: ParC D86N/G (10.5%), D86N + S87I (0.051%), D86N + S88P (0.012%) and D86G + E91G (0.003%). One isolate had GyrA A92P + ParC D86N alterations, but remained susceptible to gepotidacin (MIC = 0.125 mg/L). No GyrA plus ParC alterations resulted in a gepotidacin MIC > 4 mg/L. Modelling of gepotidacin binding to GyrA A92/A92T/A92P suggested that gepotidacin resistance due to GyrA A92T might be linked to the formation of a new polar contact with DNA. CONCLUSIONS: In silico mining of 33 213 global gonococcal genomes (isolates from 1928 to 2023) showed that A92 is highly conserved in GyrA, while alterations in D86 of ParC are common. No GyrA plus ParC alterations caused gepotidacin resistance. MIC determination and genomic surveillance of potential antimicrobial resistance determinants are imperative.

Hotspots of kidney failure: Analysing Australian metropolitan dialysis demand for service planning.

OBJECTIVE: To locate incident hotspots of dialysis demand in Australian capital cities and measure association with prevalent dialysis demand and socioeconomic disadvantage. METHODS: A retrospective cohort study used Australia and New Zealand Dialysis and Transplant Registry data on people commencing dialysis for kidney failure (KF) resident in an Australian capital city, 1 January 2001 - 31 December 2021. Age-sex-standardised dialysis incidence was estimated by Statistical Area Level 3 (SA3) and dialysis prevalence by SA2. RESULTS: A total of 32,391 people commencing dialysis were referenced to SA3s within city metropolitan areas based on residential postcode. Incident hotspots were located in Western Sydney. The highest average annual change of standardised incidence was 8.3 per million people (false discovery rate-corrected 95% CI 1.0,15.7) in Mount Druitt, reflecting a 263% increase in absolute demand from 2001-3 to 2019-21. Incident dialysis for diabetic kidney disease contributed substantially to total growth. Incident hotspots were co-located with areas where prevalent dialysis demand was associated with socioeconomic deprivation. CONCLUSIONS: Novel spatial analyses of geo-referenced registry data located hotspots of kidney failure and associated socio-demographic and comorbid states. IMPLICATIONS FOR PUBLIC HEALTH: These analyses advance current abilities to plan dialysis capacity at a local level. Hotspots can be targeted for prevention and slowing the progression of kidney disease.

Greater haemodialysis exposure ('quotidian haemodialysis') has different mortality associations by patient age group.

Background: Worldwide, most people requiring kidney replacement therapy receive haemodialysis (HD) three times per week. Greater HD time and/or frequency may improve survival, but implementation requires understanding potential benefits across the range of patients. Methods: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we assessed whether quotidian HD (defined as >3 sessions/week and/or >5 h/session) was associated with reduced mortality in adult patients. The primary outcome of all-cause mortality was analysed by a time-varying Cox proportional hazards model with quotidian HD as the exposure of interest. Results: Of 24 138 people who received HD between 2011 and 2019, 2632 (10.9%) received quotidian HD at some stage. These patients were younger, more likely male and more likely to receive HD at home. Overall, quotidian versus standard HD was associated with a decreased risk for all-cause mortality {crude hazard ratio [HR] 0.50 [95% confidence interval (CI) 0.45-0.56]}, but an interaction between quotidian HD and age was identified (P = .005). Stratified by age groups and splitting follow-up time where proportional hazards were violated, the corresponding HR compared with standard HD was 2.43 (95% CI 1.56-3.79) for people >75 years of age in the first year of quotidian HD, 1.52 (95% CI 0.89-2.58) for 1-3 years and 0.95 (95% CI 0.51-1.78) for ≥3 years. There was no significant survival advantage in younger people. Conclusions: Although quotidian HD conferred survival benefit in crude analyses, people ≥75 years of age had greater mortality with quotidian HD than standard HD. The mortality benefit in younger people was attenuated when adjusted for known confounders.

Epigenetic age acceleration is a distinctive trait of epithelioid sarcoma with potential therapeutic implications.

Recently, DNA methylation clocks have been proven to be precise age predictors, and the application of these clocks in cancer tissue has revealed a global age acceleration in a majority of cancer subtypes when compared to normal tissue from the same individual. The polycomb repressor complex 2 plays a pivotal role in the aging process, and its targets have been shown to be enriched in CpG sites that gain methylation with age. This complex is further regulated by the chromatin remodeling complex SWItch/Sucrose Non-Fermentable and its core subunit, notably the tumor suppressor gene SMARCB1, which under physiological conditions inhibits the activity of the polycomb repressor complex 2. Hence, the loss of function of core members of the SWItch/sucrose non-fermentable complex, such as the tumor suppressor gene SMARCB1, results in increased activity of polycomb repressor complex 2 and interferes with the aging process. SMARCB1-deficient neoplasms represent a family of rare tumors, including amongst others malignant rhabdoid tumors, atypical teratoid and rhabdoid tumors, and epithelioid sarcomas. As aging pathways have recently been proposed as therapeutic targets for various cancer types, these tumors represent candidates for testing such treatments. Here, by deriving epigenetic age scores from more than 1000 tumor samples, we identified epigenetic age acceleration as a hallmark feature of epithelioid sarcoma. This observation highlights the potential of targeting aging pathways as an innovative treatment approach for patients with epithelioid sarcoma.

Calciphylaxis Episodes in the Australia and New Zealand Dialysis and Transplant Registry.

Introduction: Calciphylaxis is a rare disorder associated with significant morbidity and mortality. Data registries are an invaluable source of information for rare diseases. We reviewed cases of calciphylaxis recorded in the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and evaluated associations and outcomes of this condition. Methods: Data was obtained on all cases of calciphylaxis reported between 2019 and 2022 in Australian and New Zealand patients on kidney replacement therapy (KRT). This cohort was compared to all patients in the registry who received KRT from 2019 to 2022 without an episode of calciphylaxis. Cox proportional hazards regression including a time-varying covariate for calciphylaxis episode was conducted for mortality with models restricted to patients on dialysis only. Results: From 2019 to 2022, 333 patients had calciphylaxis episodes reported. Overall incidence rate for patients on dialysis was 4.5 (4.1-5.1) episodes per 1000 patient-years on dialysis. Median age was 63 (interquartile range [IQR]: 55-73) years, 54% were female, 66% had diabetes, 59% were obese (body mass index [BMI] ≥ 30 kg/m2) and 77% were receiving hemodialysis (HD) treatment. Compared to patients without calciphylaxis (n = 46,526), patients with calciphylaxis were more likely to be older, female, and have diabetes, greater BMI, coronary artery, and peripheral vascular disease. The median time to calciphylaxis was 3.2 (IQR: 0.9-6.7) years after KRT commencement. Half of the patients with calciphylaxis died by 12 months from diagnosis. Adjusted hazard ratio (HR) of mortality for patients on dialysis with calciphylaxis <1 year and 1 to 4 years after an episode was 5.8 (4.9-6.9) and 1.5 (1.0-2.1), respectively compared to patients on dialysis without calciphylaxis. Conclusion: Calciphylaxis is a rare but life-threatening condition in people on KRT with the greatest mortality burden within 12 months of diagnosis.

Patient Perspectives of Center-Specific Reporting in Kidney Failure Care: An Australian Qualitative Study.

Introduction: Public reporting of quality of care indicators in healthcare is intended to inform consumer decision-making; however, people may be unaware that such information exists, or it may not capture their priorities. The aim of this study was to understand the views of people with kidney disease about public reporting of dialysis and transplant center outcomes. Methods: This qualitative study involved 27 patients with lived experience of kidney disease in Australia who participated in 11 online focus groups between August and December 2022. Transcripts were analyzed thematically. Results: Patients from all Australian states and territories participated, with 22 (81%) having a functioning kidney transplant and 22 (81%) having current or previous experience of dialysis. Five themes were identified as follows: (i) surrendering to the health system, (ii) the complexity of quality, (iii) benefits for patient care and experience, (iv) concerned about risks and unintended consequences, and (v) optimizing the impact of data. Conclusion: Patients desire choice among kidney services but perceive this as rarely possible in the Australian context. Health professionals are trusted to make decisions about appropriate centers. Public reporting of center outcomes may induce fear and a loss of balanced perspective; however, it was supported by all participants and represents an opportunity for self-advocacy and informed decision-making. Strategies to mitigate potential risks include availability of trusted clinicians and community members to aid in data interpretation, providing context about centers and patients, and framing statistics to promote positivity and hope.

Antecedent Cardiac Arrest Status of Donation After Circulatory Determination of Death (DCDD) Kidney Donors and the Risk of Delayed Graft Function After Kidney Transplantation: A Cohort Study.

BACKGROUND: The number of donors from donation after circulatory determination of death (DCDD) has increased by at least 4-fold over the past decade. This study evaluated the association between the antecedent cardiac arrest status of controlled DCDD donors and the risk of delayed graft function (DGF). METHODS: Using data from the Australia and New Zealand Dialysis and Transplant, the associations between antecedent cardiac arrest status of DCDD donors before withdrawal of cardiorespiratory support, DGF, posttransplant estimated glomerular filtration rate (eGFR), and allograft loss were examined using adjusted logistic, linear mixed modeling, and cox regression, respectively. Among donors who experienced cardiac arrest, we evaluated the association between duration and unwitnessed status of arrest and DGF. RESULTS: A total of 1173 kidney transplant recipients received DCDD kidneys from 646 donors in Australia between 2014 and 2019. Of these, 335 DCDD had antecedent cardiac arrest. Compared with recipients of kidneys from donors without antecedent cardiac arrest, the adjusted odds ratio (95% confidence interval) for DGF was 0.85 (0.65-1.11) among those with kidneys from donors with cardiac arrest. There was no association between antecedent cardiac arrest and posttransplant eGFR or allograft loss. The duration of cardiac arrest and unwitnessed status were not associated with DGF. CONCLUSIONS: This focused analysis in an Australian population showed that the allograft outcomes were similar whether DCDD donors had experienced a prior cardiac arrest, with no associations between duration or unwitnessed status of arrest and risk of DGF. This study thus provides important reassurance to transplant programs and the patients they counsel, to accept kidneys from donors through the DCDD pathway irrespective of a prior cardiac arrest.

Association between diabetic status and risk of all-cause and cause-specific mortality on dialysis following first kidney allograft loss.

Background: Diabetes mellitus (DM) is associated with a greater risk of mortality in kidney transplant patients, primarily driven by a greater risk of cardiovascular disease (CVD)-related mortality. However, the associations between diabetes status at time of first allograft loss and mortality on dialysis remain unknown. Methods: All patients with failed first kidney allografts transplanted in Australia and New Zealand between 2000 and 2020 were included. The associations between diabetes status at first allograft loss, all-cause and cause-specific mortality were examined using competing risk analyses, separating patients with diabetes into those with pre-transplant DM or post-transplant diabetes mellitus (PTDM). Results: Of 3782 patients with a median (IQR) follow-up duration of 2.7 (1.1-5.4) years, 539 (14%) and 390 (10%) patients had pre-transplant DM or developed PTDM, respectively. In the follow-up period, 1336 (35%) patients died, with 424 (32%), 264 (20%) and 199 (15%) deaths attributed to CVD, dialysis withdrawal and infection, respectively. Compared to patients without DM, the adjusted subdistribution HRs (95% CI) for pre-transplant DM and PTDM for all-cause mortality on dialysis were 1.47 (1.17-1.84) and 1.47 (1.23-1.76), respectively; for CVD-related mortality were 0.81 (0.51-1.29) and 1.02 (0.70-1.47), respectively; for infection-related mortality were 1.84 (1.02-3.35) and 2.70 (1.73-4.20), respectively; and for dialysis withdrawal-related mortality were 1.71 (1.05-2.77) and 1.51 (1.02-2.22), respectively. Conclusions: Patients with diabetes at the time of kidney allograft loss have a significant survival disadvantage, with the excess mortality risk attributed to infection and dialysis withdrawal.

Ureidopenicillins Are Potent Inhibitors of Penicillin-Binding Protein 2 from Multidrug-Resistant Neisseria gonorrhoeae H041.

Effective treatment of gonorrhea is threatened by the increasing prevalence of Neisseria gonorrhoeae strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we demonstrated the promise of the third-generation cephalosporin cefoperazone as an antigonococcal agent due to its rapid second-order rate of acylation against penicillin-binding protein 2 (PBP2) from the ESC-resistant strain H041 and robust antimicrobial activity against H041. Noting the presence of a ureido moiety in cefoperazone, we evaluated a subset of structurally similar ureido ß-lactams, including piperacillin, azlocillin, and mezlocillin, for activity against PBP2 from H041 using biochemical and structural analyses. We found that the ureidopenicillin piperacillin has a second-order rate of acylation against PBP2 that is 12-fold higher than cefoperazone and 85-fold higher than ceftriaxone and a lower MIC against H041 than ceftriaxone. Surprisingly, the affinity of ureidopenicillins for PBP2 is minimal, indicating that their inhibitory potency is due to a higher rate of the acylation step of the reaction compared to cephalosporins. Enhanced acylation results from the combination of a penam scaffold with a 2,3-dioxopiperazine-containing R1 group. Crystal structures show that the ureido ß-lactams overcome the effects of resistance mutations present in PBP2 from H041 by eliciting conformational changes that are hindered when PBP2 interacts with the weaker inhibitor ceftriaxone. Overall, our results support the potential of piperacillin as a treatment for gonorrhea and provide a framework for the future design of ß-lactams with improved activity against ESC-resistant N. gonorrhoeae.