Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and dose selection in patients with primary hyperoxaluria type 1.

AIM: To characterize pharmacokinetic and pharmacodynamic profiles of nedosiran in patients with primary hyperoxaluria type 1 (PH1), identify influential covariates and confirm therapeutic doses. METHODS: A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (Uox). Simulations of dosing to achieve clinically meaningful reduction in Uox in children, adolescents and adults with PH1 were performed. RESULTS: Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and Uox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5 mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m2). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal Uox (<0.6 mmol) by week 52. CONCLUSIONS: The final POP-PKPD model characterizes observed nedosiran PK and Uox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6 years with relatively preserved kidney function.

Variable Efficacy of Tranexamic Acid in Geriatric Hip Fractures Treated With Arthroplasty Versus Cephalomedullary Nails.

INTRODUCTION: Geriatric hip fractures are associated with high rates of disability and mortality. Many of these patients require perioperative and postoperative allogeneic blood transfusions, which carry several noteworthy risks. A growing body of literature supports the efficacy of tranexamic acid (TXA) in geriatric hip fractures, without sufficient data examining which subgroups are likely to benefit the most. METHODS: In this study, we sought to evaluate whether TXA was associated with reduced blood loss and transfusions in a geriatric population undergoing hip fracture fixation at our institution during a 2-year period. The first year's data were collected in a retrospective fashion before the introduction of a quality control initiative encouraging TXA administration for all geriatric hip fractures. The second year's data were collected prospectively. A subgroup analysis was conducted for patients who underwent arthroplasties. RESULTS: Among the pooled cohort of patients undergoing surgery, TXA showed no benefit over control subjects for reducing blood loss or transfusion requirements. However, the subgroup of patients undergoing arthroplasty procedures showed a notable decrease in total blood loss and total units transfused during hospitalization. DISCUSSION: These results suggest that TXA may be most beneficial when targeted to arthroplasties performed for geriatric hip fractures.

Metabolism and excretion of [14C]mobocertinib, a selective covalent inhibitor of EGFR exon 20 insertion mutants, in healthy male subjects.

Mobocertinib (formerly known as TAK-788) is a targeted covalent tyrosine kinase inhibitor of epidermal growth factor receptor with exon 20 insertion mutations. This article describes the metabolism and excretion of mobocertinib in healthy male subjects after a single oral administration of [14C]mobocertinib. Mobocertinib related materials were highly covalently bound to plasma proteins such as human serum albumin. The mean extraction recovery of total radioactivity was only 3.9% for 6 individual Hamilton pooled plasma samples. After extraction, mobocertinib was the most abundant component accounting for 7.7% of total extracted circulating radioactivity (TECRA) in the supernatant. Each of identified metabolites accounted for <10% of TECRA. Mobocertinib underwent extensive first-pass metabolism with the fraction of the dose absorbed estimated to be approximately 91.7%. Fecal excretion of mobocertinib metabolites was the major elimination route. Mobocertinib was mainly eliminated via oxidative metabolism with a fraction of approximately 88% metabolized by CYP3A4/5. The other minor elimination pathways included cysteine conjugation, metabolism by other CYPs, and renal excretion of unchanged mobocertinib. Significance Statement This manuscript describes the metabolism and excretion of a targeted covalent inhibitor mobocertinib in humans after a single oral administration of [14C]mobocertinib. Mobocertinib was highly covalently bound to human plasma proteins. No metabolite accounted for >10% of total extracted circulating radioactivity in human plasma. Mobocertinib was mainly eliminated via CYP3A4/5 mediated oxidative metabolism followed by fecal excretion after approximately 91.7% of the dose was absorbed.

Arterial occlusion secondary to prior cardiac catheterization in a radial forearm flap-lessons learnt from an unusual case.

The radial forearm free flap (RFFF) is a workhorse flap for head and neck reconstruction. We present an unusual case of radial artery occlusion, likely from previous transradial cardiac catheterization, in a patient for whom an RFFF was raised for floor of mouth reconstruction following resection of squamous cell carcinoma. Pre-operative assessment with ultrasound Doppler and an Allen test was normal. The flap was raised uneventfully under tourniquet control. However, following flap elevation and tourniquet release, poor flap perfusion was noted, and cutback of the artery revealed a long segment of hard fibrous plaque within the lumen. Retrospective review of medical records showed a history of cardiac catheterization via the same radial artery. We discuss various measures that can prevent this occurrence, including careful pre-operative screening of previous procedures involving the radial artery, the reverse Allen test, Doppler ultrasound, and consideration of distal arterial exploration without a tourniquet.

A phase 1 study to assess the absolute bioavailability, mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib, an oral inhibitor of EGFR exon 20 insertion mutations, in healthy participants.

Mobocertinib (TAK-788) is a first-in-class oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that received accelerated approval for the treatment of patients with non-small cell lung cancer with EGFR exon 20 insertion mutations previously treated with platinum-based chemotherapy. This phase 1, 2-period, study was conducted to assess the absolute bioavailability of mobocertinib (Period 1), as well as mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib (Period 2) in healthy adult males. In Period 1, participants received a single oral capsule dose of 160 mg mobocertinib, followed by a 15-minute intravenous infusion of 50 µg (~ 2 µCi) [14C]-mobocertinib administered from 3.75 to 4 h after the capsule dose. In Period 2, a single oral dose of 160 mg (~ 100 µCi) [14C]-mobocertinib was administered as an oral solution. The geometric mean absolute bioavailability of mobocertinib was determined to be 36.7%. After oral administration of [14C]-mobocertinib, mobocertinib and its active metabolites, AP32960 and AP32914, were minor components in plasma, accounting for only 0.275% of total plasma radioactivity as the majority of mobocertinib-related material was covalently bound to plasma proteins. The geometric mean percentage of the administered radioactive dose recovered in the urine and feces was 3.57% and 76.0%, respectively. Only 0.39% of the oral dose of [14C]-mobocertinib was recovered in the urine as mobocertinib; thus, indicating that renal excretion of unchanged drug was a very minor pathway of elimination. In both treatment periods, mobocertinib was generally safe and well-tolerated as all adverse events were Grade 1 in severity. (Trial registration number ClinicalTrials.gov NCT03811834. Registration date January 22, 2019).

Radiation Biological Toximetry Using Circulating Cell-Free DNA (cfDNA) for Rapid Radiation/Nuclear Triage.

Optimal triage biodosimetry would include risk stratification within minutes, and it would provide useful triage despite heterogeneous dosimetry, cytokine therapy, mixed radiation quality, race, and age. For regulatory approval, the U.S. Food and Drug Administration (FDA) Biodosimetry Guidance requires suitability for purpose and a validated species-independent mechanism. Circulating cell-free DNA (cfDNA) concentration assays may provide such triage information. To test this hypothesis, cfDNA concentrations were measured in unprocessed monkey plasma using a branched DNA (bDNA) technique with a laboratory developed test. The cfDNA levels, along with hematopoietic parameters, were measured over a 7-day period in Rhesus macaques receiving total body radiation doses ranging from 1 to 6.5 Gy. Low-dose irradiation (0-2 Gy) was easily distinguished from high-dose whole-body exposures (5.5 and 6.5 Gy). Fold changes in cfDNA in the monkey model were comparable to those measured in a bone marrow transplant patient receiving a supralethal radiation dose, suggesting that the lethal threshold of cfDNA concentrations may be similar across species. Average cfDNA levels were 50 ± 40 ng/mL [±1 standard deviation (SD)] pre-irradiation, 120 ± 13 ng/mL at 1 Gy; 242 ± 71 ng/mL at 2 Gy; 607 ± 54 at 5.5 Gy; and 1585 ± 351 at 6.5 Gy (±1 SD). There was an exponential increase in cfDNA concentration with radiation dose. Comparison of the monkey model with the mouse model and the Guskova model, developed using Chernobyl responder data, further demonstrated correlation across species, supporting a similar mechanism of action. The test is available commercially in a Clinical Laboratory Improvement Amendments (CLIA) ready form in the U.S. and the European Union. The remaining challenges include developing methods for further simplification of specimen processing and assay evaluation, as well as more accurate calibration of the triage category with cfDNA concentration cutoffs.

Preservative-Free versus Benzalkonium Chloride-Preserved Latanoprost Ophthalmic Solution in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: A Phase 3 US Clinical Trial.

Purpose: To evaluate the safety and efficacy of a preservative-free latanoprost 0.005% formulation (T2345) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) compared to benzalkonium chloride-preserved latanoprost 0.005% (BPL) formulation in the United States (US). Patients and Methods: A prospective, randomized, multicenter, observer-masked, parallel-group study enrolled 335 patients diagnosed with POAG or OHT from 31 US sites who had adequately controlled intraocular pressure (IOP; ≤18 mm Hg) with latanoprost monotherapy. After a ≥72-hour washout period, patients were randomized to T2345 (n=165) or BPL (n=170) groups. Study drugs were dosed once-daily from Day 0 to Day 84 in one or both eyes. The study eye was the eye with lower IOP at baseline. The primary efficacy measure was the between-group comparison of the mean IOP values in the study eye at each time point (8 AM, 10 AM, and 4 PM on Days 15, 42, and 84). Safety measurements included ocular and systemic treatment-emergent adverse events (TEAEs). Results: Both T2345 and BPL adequately controlled IOP with 95% CIs within 1.5 mm Hg in the study eye at all assessed time points. The percentages of patients with diurnal IOP <18 mm Hg at Day 84 were 73.1% vs 78.7% for the T2345 and BPL groups, respectively. Adverse events were generally mild-to-moderate and primarily ocular. Fewer patients in the T2345 group experienced ocular TEAEs (13.9% vs 22.5%, respectively) and TEAEs with a suspected relationship to the study medication compared with the BPL group (5.5% vs 11.8%, respectively). The most common ocular TEAEs were instillation site pain and conjunctival hyperemia. Conclusion: In patients with POAG or OHT, both T2345 and BPL maintained IOP at or below clinically meaningful values for the duration of the study. T2345 showed a favorable safety profile, with numerically lower incidences of ocular TEAEs than BPL.

The use of natural language processing in detecting and predicting falls within the healthcare setting: a systematic review.

Falls are a common problem associated with significant morbidity, mortality, and economic costs. Current fall prevention policies in local healthcare settings are often guided by information provided by fall risk assessment tools, incident reporting, and coding data. This review was conducted with the aim of identifying studies which utilized natural language processing (NLP) for the automated detection and prediction of falls in the healthcare setting. The databases Ovid Medline, Ovid Embase, Ovid Emcare, PubMed, CINAHL, IEEE Xplore, and Ei Compendex were searched from 2012 until April 2023. Retrospective derivation, validation, and implementation studies wherein patients experienced falls within a healthcare setting were identified for inclusion. The initial search yielded 2611 publications for title and abstract screening. Full-text screening was conducted on 105 publications, resulting in 26 unique studies that underwent qualitative analyses. Studies applied NLP towards falls risk factor identification, known falls detection, future falls prediction, and falls severity stratification with reasonable success. The NLP pipeline was reviewed in detail between studies and models utilizing rule-based, machine learning (ML), deep learning (DL), and hybrid approaches were examined. With a growing literature surrounding falls prediction in both inpatient and outpatient environments, the absence of studies examining the impact of these models on patient and system outcomes highlights the need for further implementation studies. Through an exploration of the application of NLP techniques, it may be possible to develop models with higher performance in automated falls prediction and detection.

Safety, Pharmacokinetics, and Exposure-Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease.

Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure-response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30 mL/min/1.73 m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10 participants with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2 ; Group 3) received a single dose of subcutaneous nedosiran sodium 170 mg. Group 1a received nedosiran 8 hours before beginning hemodialysis, Group 1b received nedosiran 2 hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic-pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24-hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.

An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus.

Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis; however, its effects on cancer progression remain poorly understood. Here, to address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed dedicated regression-based methods to analyse ribosome profiling and alternative polyadenylation data, and identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a translational controller of a specific mRNA regulon. We found that HNRNPC is downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3' untranslated region lengthening and, subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. In addition, the reduced expression of HNRNPC and its regulon is associated with the worse prognosis in breast cancer patient cohorts.

Impact of COVID-19 on hospital screening, diagnosis and treatment activities among prostate and colorectal cancer patients in Canada.

BACKGROUND: Suspension of cancer screening and treatment programs were instituted to preserve medical resources and protect vulnerable populations. This research aims to investigate the implications of COVID-19 on cancer management and clinical outcomes for patients with prostate and colorectal cancer in Canada. METHODS: We examined hospital cancer screening, diagnosis, treatment, length of stay, and mortality data among prostate and colorectal cancer patients between April 2017 and March 2021. Baseline trends were established with data between April 2017 and March 2020 for comparison with data collected between April 2020 and March 2021. Scenario analyses were performed to assess the incremental capacity requirements needed to restore hospital cancer care capacities to the pre-pandemic levels. RESULTS: For prostate cancer, A 12% decrease in diagnoses and 5.3% decrease in treatment activities were observed during COVID-19 between April 2020 and March 2021. Similarly, a 43% reduction in colonoscopies, 11% decrease in diagnoses and 10% decrease in treatment activities were observed for colorectal cancers. An estimated 1,438 prostate and 2,494 colorectal cancer cases were undiagnosed, resulting in a total of 620 and 1,487 unperformed treatment activities for prostate and colorectal cancers, respectively, across nine provinces in Canada. To clear the backlogs of unperformed treatment procedures will require an estimated 3%-6% monthly capacity increase over the next 6 months. INTERPRETATION: A concerted effort from all stakeholders is required to immediately ameliorate the backlogs of cancer detection and treatment activities. Mitigation measures should be implemented to minimize future interruptions to cancer care in Canada.

Evaluating the utility of inflammatory markers in the diagnosis of soft tissue abscesses of the forearm and hand.

Upper extremity abscesses frequently present to the acute care setting with inconclusive physical examination and imaging findings. We sought to investigate the diagnostic accuracy of inflammatory markers including white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). A retrospective cohort study was performed to identify subjects ≥ 18  years treated with surgical debridement of upper extremity abscesses at our institution between January 2012 and December 2015. In this study, 188 patients were screened, and 72 met the inclusion criteria. A confirmed abscess as defined by culture positivity was present in 67 (93.1 %) cases. The sensitivity of WBC, ESR, or CRP individually was 0.45, 0.71, and 0.81. The specificity of WBC, ESR, or CRP individually was 0.80, 0.80, and 0.40. In combination all three markers when positive had a sensitivity of 0.26 and specificity of 1.0. These values were similar among patients with diabetes and those with obesity. With the highest sensitivity and lowest specificity, CRP exhibited the most utility as a screening test (level IV).

Spine or Hip First? Outcomes in Patients Undergoing Sequential Lumbar Spine or Hip Surgery.

BACKGROUND: Lumbar spine pathology frequently coexists in patients who have hip arthrosis. There is controversy on whether lumbar or hip pathology should be first addressed. The purpose of this study was to evaluate the outcomes of sequential lumbar spine (LSP) or hip arthroplasty (THA). METHODS: Using a large national database from 2010 to 2020, we reviewed the records of 241,279 patients who had concurrent hip arthritis and lumbar spine disease defined as spinal stenosis, lumbar radiculopathy, or degenerative disc disease. During the study period, 6,458 (2.7%) patients with concurrent hip/spine disease underwent sequential operative treatment of either the hip joint or lumbar spine within 2 years. The rates of subsequent surgery in either the hip or the spine, opioid requirements, and rates of hip dislocation were determined and analyzed using compared Chi-squared analyses. RESULTS: Patients undergoing THA first had lower risk of subsequent spinal procedure compared to patients who had spinal procedures first (5.7 versus 23.7%, P < .001). This disparity was maintained up to 5 years (P < .001). Opioid requirements at 1 year were highest in patients who underwent spinal procedures only (836 pills/patient) compared to any other group THA only (566 pills/patient), LSP and then THA (564 pills/patient), THA and LSP (586 pills/patient). Also, THA following LSP was associated with significantly higher rates of dislocation compared to patients undergoing THA first (3.2 versus 1.9%, P < .001). CONCLUSION: Total hip arthroplasty first in patients who have concurrent spine disease was associated with lower risk of subsequent surgery, opioid requirement, and risk of postoperative instability compared to patients having lumbar procedure first.