Collateral damage of NUDT15 deficiency in cancer provides a cancer pharmacogenetic therapeutic window with thiopurines.

Genome instability is a hallmark of cancer and are driven by mutations in oncogenes and tumor suppressor genes. Despite successes seen with select targeted therapeutics, this type of personalized medicine is only beneficial for a small subpopulation of cancer patients who have one of a few actionable genetic changes. Most tumors also contain hundreds of passenger mutations that offered no fitness advantage or disadvantage during tumor evolution. Mutations in known pharmacogenetic (PGx) loci for which germline variants encode variability in drug response can cause somatically acquired drug sensitivity. The NUDT15 gene is a known PGx locus that participates in the rate-limiting metabolism of thiopurines. People with two defective germline alleles of NUDT15 are hypersensitive to the toxic effects of thiopurines. NUDT15 is located adjacent to the Retinoblastoma ( RB1 ) tumor suppressor gene, which often undergoes homozygous deletion in retinoblastomas and other epithelial cancers. We observed that RB1 undergoes homozygous deletions in 9.4% of prostate adenocarcinomas and 2.5% of ovarian cancers, and in nearly all of these cases NUDT15 is also lost. Moreover, 44% of prostate adenocarcinomas and over 60% of ovarian cancers have lost one allele of NUDT15, which predicts that a majority of all prostate and ovarian cancers have somatically acquired hypersensitivity to thiopurine treatment. We performed a retrospective analysis of >16,000 patients in the US Veterans Administration health care system and found concurrent xanthine oxidase inhibition (XOi) and thiopurine usage for non-cancer indications is significantly associated with reduced incidence of prostate cancer. The hazard ratio for the development of prostate cancer in patients treated with thiopurines and XOi was 0.562 (0.301-1.051) for the unmatched cohort and 0.389 (0.185-0.819) for the propensity score matched cohort. We experimentally depleted NUDT15 from ovarian and prostate cancer cell lines and observed a dramatic sensitization to thiopurine-induced and DNA damage-dependent toxicity. These results indicate that somatic loss of NUDT15 predicts therapeutic sensitivity to a low cost and well tolerated drug with a broad therapeutic window.

Exposure to angiotensin-converting enzyme inhibitors that cross the blood-brain barrier and the risk of dementia among patients with human immunodeficiency virus.

More than one million people in the United States and over 38 million people worldwide are living with human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) greatly improves the health of people living with HIV (PLWH); however, the increased life longevity of PLWH has revealed consequences of HIV-associated comorbidities. HIV can enter the brain and cause inflammation even in individuals with well-controlled HIV infection. The quality of life for PLWH can be compromised by cognitive deficits and memory loss, termed HIV-associated neurological disorders (HAND). HIV-associated dementia is a related but distinct diagnosis. Common causes of dementia in PLWH are similar to the general population and can affect cognition. There is an urgent need to identify treatments for the aging PWLH population. We previously developed AI-based biomedical literature mining systems to uncover a potential novel connection between HAND the renin-angiotensin system (RAAS), which is a pharmacological target for hypertension. RAAS-targeting anti-hypertensives are gaining attention for their protective benefits in several neurocognitive disorders. To our knowledge, the effect of RAAS-targeting drugs on the cognition of PLWH development of dementia has not previously been analyzed. We hypothesized that exposure to angiotensin-converting enzyme inhibitors (ACEi) that cross the blood brain barrier (BBB) reduces the risk/occurrence of dementia in PLWH. We report a retrospective cohort study of electronic health records (EHRs) to examine the proposed hypothesis using data from the United States Department of Veterans Affairs, in which a primary outcome of dementia was measured in controlled cohorts of patients exposed to BBB-penetrant ACEi versus those unexposed to BBB-penetrant ACEi. The results reveal a statistically significant reduction in dementia diagnosis for PLWH exposed to BBB-penetrant ACEi. These results suggest there is a potential protective effect of BBB ACE inhibitor exposure against dementia in PLWH that warrants further investigation.

Valgus-impacted subcapital neck of femur fractures: a systematic review, meta-analysis with cost analysis of fixation in-situ versus nonoperative management.

BACKGROUND: The management of the valgus-impacted neck of femur fracture (AO/OTA 31-B1) remains contentious. The objective of this study was to determine whether operative intervention is cost-effective. METHODS: We conducted a systematic review using electronic databases (Medline, Embase, Cochrane, Ebsco, Scholar) identifying studies published in the English language concerning valgus-impacted neck of femur fractures until June 2022. Additional studies were identified through hand searches of major orthopaedic journals, and bibliographies of major orthopaedic textbooks. MeSH terms (hip fracture and femoral neck fracture) and keywords (undisplaced, valgus-impacted, valgus, subcapital, Garden) connected by the Boolean operators "AND" and "OR" were used to identify studies. 2 reviewers independently extracted the data using standardised forms and recording spreadsheet. Methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-analysis of Statistics Assessment and Review Instrument. Meta-analysis was undertaken. Outcome measures were rate of displacement, avascular necrosis, non-union, mortality and requirement of further operative intervention. A cost utility analysis was then conducted to compare the 2 groups on the basis of the cost of initial treatment and the potential requirement of secondary intervention to hemiarthroplasty. RESULTS: 47 studies met the inclusion criteria. Meta-analysis data demonstrated a significant difference in the displacement rate of 22.8% and 2.8% between the nonoperative and internal fixation groups respectively (p = 0.05). The overall incidence of further operative intervention for each group was 23% and 10% respectively. There was no significant difference with respect to avascular necrosis, mortality or union rates. The cost utility analysis revealed nonoperative management to be approximately 60% more costly than initial internal fixation when the costs of subsequent surgery were included. CONCLUSIONS: This meta-analysis of the existing literature concludes that whilst nonoperative management is possible for valgus impacted neck of femur fractures, it is associated with higher complication rates and greater expense than management by internal fixation.

Suppression of HIV and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.

HIV-associated neurological disorder (HAND) is a serious complication of HIV infection, marked by neurotoxicity induced by viral proteins like Tat. Substance abuse exacerbates neurocognitive impairment in people living with HIV. There is an urgent need for effective therapeutic strategies to combat HAND comorbid with Cocaine Use Disorder (CUD). Our analysis of the HIV and cocaine-induced transcriptomes in primary cortical cultures revealed a significant overexpression of the macrophage-specific gene, aconitate decarboxylase 1 (Acod1), caused by the combined insults of HIV and cocaine. ACOD1 protein converts the tricarboxylic acid intermediate cis-aconitate into itaconate during the activation of inflammation. The itaconate produced facilitates cytokine production and subsequently activates anti-inflammatory transcription factors, shielding macrophages from infection-induced cell death. While the role of itaconate' in limiting inflammation has been studied in peripheral macrophages, its immunometabolic function remains unexplored in HIV and cocaine-exposed microglia. We assessed in this model system the potential of 4-octyl-itaconate (4OI), a cell-penetrable esterified form of itaconate known for its potent anti-inflammatory properties and potential therapeutic applications. We administered 4OI to primary cortical cultures exposed to Tat and cocaine. 4OI treatment increased the number of microglial cells in both untreated and Tat±Cocaine-treated cultures and also reversed the morphological altercations induced by Tat and cocaine. In the presence of 4OI, microglial cells also appeared more ramified, resembling the quiescent microglia. Consistent with these results, 4OI treatment inhibited the secretion of the proinflammatory cytokines IL-1α, IL-1ß, IL-6, and MIP1-α induced by Tat and cocaine. Transcriptome profiling further determined that Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (Nqo1), Glutathione S-transferase Pi (Gstp1), and glutamate cysteine ligase catalytic (Gclc), were most significantly activated in Tat-4OI treated cultures, relative to Tat alone. Further, genes associated with cytoskeleton dynamics in inflammatory microglia were downregulated by 4OI treatment. Together, the results strongly suggest 4-octyl-itaconate holds promise as a potential candidate for therapeutic development aimed at addressing HAND coupled with CUD comorbidities.

The use of antibiotic-loaded bone cement and systemic antibiotic prophylactic use in 2,971,357 primary total knee arthroplasties from 2010 to 2020: an international register-based observational study among countries in Africa, Europe, North America, and Oceania.

BACKGROUND AND PURPOSE: Antibiotic-loaded bone cement (ALBC) and systemic antibiotic prophylaxis (SAP) have been used to reduce periprosthetic joint infection (PJI) rates. We investigated the use of ALBC and SAP in primary total knee arthroplasty (TKA). PATIENTS AND METHODS: This observational study is based on 2,971,357 primary TKAs reported in 2010-2020 to national/regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, the Netherlands, New Zealand, Norway, Romania, South Africa, Sweden, Switzerland, the UK, and the USA. Aggregate-level data on trends and types of bone cement, antibiotic agents, and doses and duration of SAP used was extracted from participating registries. RESULTS: ALBC was used in 77% of the TKAs with variation ranging from 100% in Norway to 31% in the USA. Palacos R+G was the most common (62%) ALBC type used. The primary antibiotic used in ALBC was gentamicin (94%). Use of ALBC in combination with SAP was common practice (77%). Cefazolin was the most common (32%) SAP agent. The doses and duration of SAP used varied from one single preoperative dosage as standard practice in Bolzano, Italy (98%) to 1-day 4 doses in Norway (83% of the 40,709 TKAs reported to the Norwegian arthroplasty register). CONCLUSION: The proportion of ALBC usage in primary TKA varies internationally, with gentamicin being the most common antibiotic. ALBC in combination with SAP was common practice, with cefazolin the most common SAP agent. The type of ALBC and type, dose, and duration of SAP varied among participating countries.

Structural Basis for Variations in Polo-like Kinase 1 Conformation and Intracellular Stability Induced by ATP-Competitive and Novel Noncompetitive Abbapolin Inhibitors.

Polo-like kinase 1 (PLK1) is an essential protein kinase with multiple roles in mitotic progression. PLK1 consists of a kinase domain (KD) and a phosphopeptide-binding polobox domain (PBD), which is responsible for substrate recognition and subcellular localization. The regulation of PLK1 involves an autoinhibitory conformation in which KD and PBD interact. Our previous work identified PBD-binding molecules termed abbapolins that inhibit the cellular phosphorylation of a PLK1 substrate and induce the loss of intracellular PLK1. Here, we describe a comparison of the abbapolin activity with that of KD inhibitors to gain insight into conformational features of PLK1. As measured by a cellular thermal shift assay, abbapolins produce ligand-induced thermal stabilization of PLK1. In contrast, KD inhibitors decreased the soluble PLK1, suggesting that catalytic-site binding causes a less thermally stable PLK1 conformation. Binding measurements with full-length PLK1 and a KD inhibitor also demonstrated a conformational change. Interestingly, the cellular consequences of KD versus PBD engagement contrast as KD binding causes the accumulation of intracellular PLK1, whereas PBD binding produces a striking loss of nuclear PLK1. These data are consistent with the relief of autoinhibited PLK1 by KD binders; an explanation for these observations is presented using structures for the catalytic domain and full-length PLK1 predicted by AlphaFold. Collectively, the results highlight an underappreciated aspect of targeting PLK1, namely, conformational perturbations induced by KD versus PBD binding. In addition to their significance for PBD-binding ligands, these observations have implications for the development of ATP-competitive PLK1 inhibitors because catalytic inhibitors may conversely promote PLK1 noncatalytic functions, which may explain their lack of clinical efficacy to date.

The 45-year evolution of the Mathys RM monoblock cups: have the paradigm shifts been worthwhile?

INTRODUCTION: The Robert Mathys (RM) monoblock uncemented cup is a design less commonly used in primary total hip replacement. It's purported advantages over modular cemented cups are: (1) its modulus of elasticity approximating bone, thus mimicking load transmission and the biomechanical behaviour of the cup to better match stresses on the acetabulum, leading to bone-preservation; and (2) as a 1-piece cup there is absence of a mobile interface between a liner and shell, preventing backside wear. Since its inception in 1983 there have been 3 major design changes: the RM Classic, the RM Pressfit, and the RM Vitamys with the most modern polyethylene (vitamin E). METHODS: In a retrospective cohort study of the New Zealand Joint Registry, all designs of RM acetabular cup were reviewed. Data were included from1998 to 2018. All-cause revision rates, reasons for revision and the Oxford Hip Score (OHS) were assessed. RESULTS: In total 13,272 acetabular cups were included. The all-cause revision rates did not differ between the designs. Revision rates for aseptic loosening in the RM Vitamys were lower, but the follow-up was shorter and more larger heads were used. There was no difference in the OHS. CONCLUSION: All implant designs were safe. The use of larger heads led to a decrease in revisions due to dislocation. It has to be waited out whether the RM Vitamys performs superior in the long-term due to the highly cross-linked polyethylene.

Inhibitors of the PLK1 polo-box domain: drug design strategies and therapeutic opportunities in cancer.

INTRODUCTION: Polo Like Kinase 1 (PLK1) is a key regulator of mitosis and its overexpression is frequently observed in a wide variety of human cancers, while often being associated with poor survival rates. Therefore, it is considered a potential and attractive target for cancer therapeutic development. The Polo like kinase family is characterized by the presence of a unique C terminal polobox domain (PBD) involved in regulating kinase activity and subcellular localization. Among the two functionally essential, druggable sites with distinct properties that PLK1 offers, targeting the PBD presents an alternative approach for therapeutic development. AREAS COVERED: Significant progress has been made in progressing from the peptidic PBD inhibitors first identified, to peptidomimetic and recently drug-like small molecules. In this review, the rationale for targeting the PBD over the ATP binding site is discussed, along with recent progress, challenges, and outlook. EXPERT OPINION: The PBD has emerged as a viable alternative target for the inhibition of PLK1, and progress has been made in using compounds to elucidate mechanistic aspects of activity regulation and in determining roles of the PBD. Studies have resulted in proof of concept of in vivo efficacy suggesting promise for PBD binders in clinical development.

Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration.

Serum tyrosine levels increase during aging, neurocognitive, metabolic, and cardiovascular disorders. However, calorie restriction (CR) and sleep lower serum tyrosine levels. We previously showed that tyrosine inhibits tyrosyl-tRNA synthetase (TyrRS)-mediated activation of poly-ADP-ribose polymerase 1 (PARP1). Here, we show that histone serine-ADP-ribosylation is decreased in Alzheimer's Disease (AD) brains, and increased tyrosine levels deplete TyrRS and cause neuronal DNA damage. However, dopamine and brain-derived neurotrophic factor (BDNF) increase TyrRS and histone serine-ADP-ribosylation. Furthermore, cis-resveratrol (cis-RSV) that binds to TyrRS mimicking a 'tyrosine-free' conformation increases TyrRS, facilitates histone serine-ADP-ribosylation-dependent DNA repair, and provides neuroprotection in a TyrRS-dependent manner. Conversely, trans-RSV that binds to TyrRS mimicking a 'tyrosine-like' conformation decreases TyrRS, inhibits serine-ADP-ribosylation-dependent DNA repair, and induces neurodegeneration in rat cortical neurons. Our findings suggest that age-associated increase in serum tyrosine levels may effect neurocognitive and metabolic disorders and offer a plausible explanation for divergent results obtained in clinical trials using resveratrol.

Apex Predator Nematodes and Meso-Predator Bacteria Consume Their Basal Insect Prey through Discrete Stages of Chemical Transformations.

Microbial symbiosis drives physiological processes of higher-order systems, including the acquisition and consumption of nutrients that support symbiotic partner reproduction. Metabolic analytics provide new avenues to examine how chemical ecology, or the conversion of existing biomass to new forms, changes over a symbiotic life cycle. We applied these approaches to the nematode Steinernema carpocapsae, its mutualist bacterium, Xenorhabdus nematophila, and the insects they infect. The nematode-bacterium pair infects, kills, and reproduces in an insect until nutrients are depleted. To understand the conversion of insect biomass over time into either nematode or bacterium biomass, we integrated information from trophic, metabolomic, and gene regulation analyses. Trophic analysis established bacteria as meso-predators and primary insect consumers. Nematodes hold a trophic position of 4.6, indicative of an apex predator, consuming bacteria and likely other nematodes. Metabolic changes associated with Galleria mellonella insect bioconversion were assessed using multivariate statistical analyses of metabolomics data sets derived from sampling over an infection time course. Statistically significant, discrete phases were detected, indicating the insect chemical environment changes reproducibly during bioconversion. A novel hierarchical clustering method was designed to probe molecular abundance fluctuation patterns over time, revealing distinct metabolite clusters that exhibit similar abundance shifts across the time course. Composite data suggest bacterial tryptophan and nematode kynurenine pathways are coordinated for reciprocal exchange of tryptophan and NAD+ and for synthesis of intermediates that can have complex effects on bacterial phenotypes and nematode behaviors. Our analysis of pathways and metabolites reveals the chemistry underlying the recycling of organic material during carnivory. IMPORTANCE The processes by which organic life is consumed and reborn in a complex ecosystem were investigated through a multiomics approach applied to the tripartite Xenorhabdus bacterium-Steinernema nematode-Galleria insect symbiosis. Trophic analyses demonstrate the primary consumers of the insect are the bacteria, and the nematode in turn consumes the bacteria. This suggests the Steinernema-Xenorhabdus mutualism is a form of agriculture in which the nematode cultivates the bacterial food sources by inoculating them into insect hosts. Metabolomics analysis revealed a shift in biological material throughout progression of the life cycle: active infection, insect death, and conversion of cadaver tissues into bacterial biomass and nematode tissue. We show that each phase of the life cycle is metabolically distinct, with significant differences including those in the tricarboxylic acid cycle and amino acid pathways. Our findings demonstrate that symbiotic life cycles can be defined by reproducible stage-specific chemical signatures, enhancing our broad understanding of metabolic processes that underpin a three-way symbiosis.

Structure-activity and mechanistic studies of non-peptidic inhibitors of the PLK1 polo box domain identified through REPLACE.

Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase involved in cell cycle regulation and mitotic progression. Studies have shown that PLK1 is upregulated in many tumors and high levels are adversely related to a poor prognosis. Knocking down or inhibiting PLK1 results in synthetic lethality in PTEN deficient prostate tumors and Kras mutant colorectal tumors, further validating PLK1 as an oncotarget. Substrate recognition by PLK1 occurs through the Polo-Box Domain (PBD), which is a phospho-peptide binding site also responsible for subcellular localization. Much effort has been directed to target this kinase therapeutically through the ATP-binding site, and a few such inhibitors have advanced to clinical trials however with limited clinical efficacy. Moreover, it has been shown that a point mutation in PLK1 (C67V) confers dramatic cellular resistance to catalytic site inhibitors. An alternative approach to target PLK1 potently and selectively is through the PBD to block its protein-protein interactions. Through the REPLACE strategy, for converting peptide inhibitors into more drug-like non peptidic compounds, a PBD targeting compound series ("ABBAs"), has been identified and the key determinants of potency and selectivity elucidated through structure-activity relationship studies. In cellular experiments, the ABBAs were shown to lead to profound effects on the cell cycle, to inhibit tumor proliferation and overcome resistance of cells expressing the PLK1 C67V mutant to ATP-based inhibitors. These non-ATP competitive inhibitors of PLK1 were also used chemical biology probes to investigate the gene regulatory effects of PLK1, known to act on transcription factors such as p53.

Teleconsultation in orthopaedic surgery: A systematic review and meta-analysis of patient and physician experiences.

INTRODUCTION: The primary purpose of this review was to evaluate patient and physician preference and satisfaction for teleconsultation in orthopaedic surgery compared to traditional face-to-face consultation. In addition, we evaluated the effects of teleconsultation on patient length of visit, healthcare costs, range of motion (ROM), pain, quality of life (QOL), and ongoing management plans. METHODS: A systematic review of MEDLINE, Embase, Web of Science, and Cochrane Library was conducted according to PRISMA guidelines. Randomised control trials and case control studies comparing teleconsultation with traditional, face-to-face consultation in the management of orthopaedic conditions were included. The primary outcome measures were patient and physician preference and satisfaction. Secondary outcomes included patient length of visit, healthcare costs, ROM, pain, QOL, and ongoing management plans. RESULTS: A total of 13 articles meeting the eligibility criteria were included for systematic review and 8 for meta-analysis. There was no significant difference in patient satisfaction, length of visit, or time spent with the physician between the telemedicine and in-office control group. The mean difference of patient preference for telemedicine was significantly higher in the telemedicine group compared to the in-office visit group (OR 1.44, 95% CI 1.12-1.87, p = 0.005). DISCUSSION: Telemedicine was not inferior to face-to-face office visits in regard to patient and physician preference and satisfaction. Therefore, it would be an effective adjunct to face-to-face office visits, serving as a mechanism of triage and long-term continuity of care.

How do 3D-printed primary uncemented acetabular components compare with established uncemented acetabular cups? The experience of the New Zealand National Joint Registry.

BACKGROUND: 3D-printed or additive manufactured acetabular implants are an exciting new technology being used in hip surgery with increasing frequency especially in complex acetabular reconstructions. However, the performance of acetabular components produced by this method for primary THR is unknown. METHODS: 41,272 uncemented cups in primary THR for OA were identified in the NZJR for the purposed of this study. There were 39,080 uncemented cups in the control group (15,798 Pinnacle cups, 12,724 Trident cups and 10,558 RM Pressfit cups) compared to 2192 3D-printed uncemented implants (1397 Delta TT cups, 640 Ti Por and 155 Polymax cups). All-cause revision rates and reasons for revision were examined. Kaplan-Meier survival analysis was performed. RESULTS: 3D-printed cups were inserted into younger, fitter patients with a higher mean BMI compared to those in the control group (p < 0.001). The overall all-cause revision rate for 3D-printed cups was not significantly different to the controls: 0.77/100 cys (95% CI 0.59-1) compared to 0.55/100 cys (95% CI 0.52-0.58) in the control group (p = 0.058, Hazards ratio 1.29, 95% CI 0.992-1.678). There was no difference in aseptic cup loosening or deep infection rates between either group or indeed individual implant designs. CONCLUSIONS: 3D-printed uncemented cups provide reliable survivorship and clinical results in primary THR comparable to established designs manufactured by traditional means. The theoretical concerns of increased rates of fatigue failure or deep infection are unsubstantiated.

An age and sex matched study on the effect of obesity on the functional outcomes and complication rates in patients with adult spinal deformity undergoing primary multi-level thoracolumbar spinal fusion.

Background: The objective of this study was to determine the effect of obesity on the functional outcomes and complication rates of patients with adult spinal deformity (ASD) undergoing multi-level thoracolumbar fusion. Methods: An age and sex matched comparison of functional outcomes [Numeric Rating Scale (NRS) back and leg scores, Core Outcome Measurement Index (COMI) back scores, Scoliosis Research Society 22 (SRS22) satisfaction and total scores, Short Form 36 (SF36) general health scores, Physical Component Score (PCS), Mental Component Score (MCS), Oswestry Disability Index (ODI) (including all domains)] at 6 months, 1, 2, 3 and 4 years and the complication rates at final follow-up between obese [body mass index (BMI) >30] and normal BMI (18.5-24.9) patients undergoing more than 3 levels of thoracolumbar fusion with a minimum 2-year follow-up. Patients who had undergone any previous spinal surgery were excluded. Results: Thirty patients were included in each arm of the study. Baseline demographics, including the number of levels fused, were similar between the groups. Estimated blood loss (EBL) was higher in obese patients (1,916 vs. 1,099 mL, P=0.001), but operative time was similar (282 vs. 320 min, P=0.351). The functional outcomes and satisfaction scores were consistently poorer in the obese group at all time-points, but their satisfaction scores were similar. Obese patients had a higher complication rate (OR 3.05, P=0.038) predominantly due to dural tears and nerve root injuries, but a similar reoperation rate. Conclusions: In patients with ASD undergoing multi-level thoracolumbar fusion, obesity results in a higher blood loss, poorer sagittal correction, poorer post-operative functional scores and higher complication rates than patients with a normal BMI. However, obesity does not affect operative times, length of hospital stay or reoperation rates. Furthermore, patients with obesity have similar post-operative satisfaction scores to patients with normal BMIs.

Benchmarking total hip replacement constructs using noninferiority analysis: the New Zealand joint registry study.

BACKGROUND: The aim of this study was to compare the relative performance of total hip replacement constructs and discern if there is substantial variability in performance in currently commonly used prostheses in the New Zealand Joint Registry (NZJR) using a noninferiority analysis. METHODS: All patients who underwent a primary total hip replacement (THR) registered in the NZJR between 1st January 1999 to June 2020 were identified. Using a noninferiority analysis, the performance of hip prostheses were compared with the best performing contemporary construct. Construct failure was estimated using the 1-Kaplan Meier survival function method to estimate net failure. The difference in failure between the contemporary benchmark and other constructs was examined. RESULTS: In total 135,432 THR were recorded comprising 1035 different THR constructs. Notably 328 constructs were used just once. Forty-eight constructs (62,251 THR) had > 500 procedures at risk at 3 years post-primary of which 28 were inferior by at least 20% relative risk of which, 10 were inferior by at least 100% relative risk. Sixteen constructs were identified with > 500 procedures at risk at 10 years with 9 inferior by at least 20%, of which one was inferior by > 100% relative risk. There were fewer constructs noninferior to the best practice benchmark when we performed analysis by gender. In females at 10 years, from 5 constructs with > 500 constructs at risk, 2 were inferior at the 20% margin. In males at 10 years, there were only 2 eligible constructs of which one was inferior at the 20% margin. CONCLUSIONS: We discerned that there is substantial variability in construct performance and at most time points, just over half of constructs are inferior to the best performing construct by at least 20%. These results can facilitate informed decision-making when considering THR surgery.

Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and Target-Resistant Cells.

PLK1, polo-like kinase 1, is a central player regulating mitosis. Inhibition of the subcellular localization and kinase activity of PLK1 through the PBD, polo-box domain, is a viable alternative to ATP-competitive inhibitors, for which the development of resistance and inhibition of related PLK family members are concerns. We describe novel nonpeptidic PBD-binding inhibitors, termed abbapolins, identified through successful application of the REPLACE strategy and demonstrate their potent antiproliferative activity in prostate tumors and other cell lines. Furthermore, abbapolins show PLK1-specific binding and inhibitory activity, as measured by a cellular thermal shift assay and an ability to block phosphorylation of TCTP, a validated target of PLK1-mediated kinase activity. Additional evidence for engagement of PLK1 was obtained through the unique observation that abbapolins induce PLK1 degradation in a manner that closely matches antiproliferative activity. Moreover, abbapolins demonstrate antiproliferative activity in cells that are dramatically resistant to ATP-competitive PLK1 inhibitors.

Teleconsultation in the Management of Elective Orthopedic and Spinal Conditions During the COVID-19 Pandemic: Prospective Cohort Study of Patient Experiences.

BACKGROUND: The global adoption of teleconsultation has been expedited as a result of the COVID-19 pandemic. By allowing remote communication, teleconsultation may help limit the spread of the virus while maintaining the crucial patient-provider relationship. OBJECTIVE: The aim of this study is to evaluate the value of teleconsultation compared to in-person visits in the management of elective orthopedic and spinal procedures. METHODS: This was a prospective observational cohort study of 853 patients receiving orthopedic and spinal care at a private outpatient clinic in New Zealand. Patients were randomly divided into two groups: (1) patients receiving telephone consultation remotely, and (2) patients receiving in-person office consultations at the outpatient clinic. All patients received telephone consultations for 4 weeks during the mandated COVID-19 lockdown, followed by 4 weeks of telephone or in-person consultation. Patient preference, satisfaction, and duration of visit were recorded. Comparisons of patient preference between groups, visit type, sex, and location were performed using chi-square tests; similarly, satisfaction scores and visit durations were compared using a general linear model. RESULTS: We report that 91% (353/388) of patients in the telephone group preferred teleconsultation over in-person office visits during the COVID-19 lockdown (P<.001). A combined-group analysis showed that 55.3% (446/807) of all patients preferred teleconsultation compared to 31.2% (252/807) who preferred in-person office visits (P<.001). Patients in the telephone group reported significantly higher satisfaction scores (mean 9.95, SD 0.04, 95% CI 9.87-10.03) compared to patients in the in-person group (mean 9.53, SE 0.04, 95% CI 9.45-9.62; P<.001). Additionally, in-person consultations were significantly longer in duration compared to telephone consultations, with a mean visit time of 6.70 (SE 0.18) minutes, 95% CI 6.32-7.02, compared to 5.10 (SE 0.17) minutes, 95% CI 4.73-5.42 (P<.001). CONCLUSIONS: Patients who use telephone consultations are more likely to prefer it over traditional, in-person visits in the future. This increased preference, coupled with higher patient satisfaction scores and shorter duration of visits, suggests that teleconsultation has a role in orthopedic surgery, which may even extend beyond the COVID-19 pandemic.

Does surgical approach affect early outcomes following primary total hip replacement in obese patients?

AIM: The aim of this study was to assess whether obese patients undergoing primary total hip replacement (THR) via a posterior approach had superior revision rates and Oxford Hip Scores (OHS) compared to those via a lateral approach. PATIENTS AND METHODS: This is a retrospective cohort study using prospective data from the New Zealand Joint Registry applying STROBE and RECORD guidelines. Patients undergoing THR since 2010 were stratified by body mass index (BMI) into obese (BMI 30-39 kg/m2), and morbidly obese (BMI ⩾40 kg/m2) groups. All-cause revision rates, and 6-month OHS post-surgery were compared between groups. Multivariate analysis was performed. RESULTS: 12,109 unilateral THRs in obese patients were identified. The mean follow-up was 2.8 years (range 0.01-6.95 years). Univariate analysis in the BMI ⩾ 40 group showed the posterior approach had a significantly lower all-cause revision rate (0.99/100 observed component years (ocys); 95% CI, 0.65-1.44/100 ocys) than the lateral approach (1.71/100 ocys (95% CI, 0.98-2.77/100 ocys), p < 0.05). There was no significant difference in dislocation rates between the surgical approaches. OHS was statistically higher in the posterior approach group in BMI 30-39 patients (p < 0.001) but not clinically significant. Multivariate analysis showed femoral head size significantly influenced all-cause revision rates and mitigated against the increased risk associated with the surgical approach. CONCLUSION: The choice of surgical approach in obese patients conveys no advantage in overall revision rates in the short-term. Choosing an appropriate size of femoral head may be of greater importance than choice of surgical approach for obese patients in primary THR.

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.