The Impact of Deprescribing Interventions on the Drug Burden Index and Other Outcomes: A Systematic Review.

OBJECTIVES: The Drug Burden Index (DBI) calculates a person's exposure to anticholinergic and sedative medications. We aimed to review randomized controlled trials (RCTs) of deprescribing interventions that reported the DBI as an outcome, their characteristics, effectiveness in reducing the DBI, and impact on other outcomes. DESIGN: Systematic review with meta-analysis. SETTING AND PARTICIPANTS: RCTs of deprescribing interventions where the DBI was measured as a primary or secondary outcome in humans within any setting were included. METHODS: Electronic databases, citation indexes, and gray literature were searched from April 1, 2007, to September 1, 2023. Quality was assessed using the Cochrane risk-of-bias tool. RESULTS: Of 1721 records identified, 9 met the inclusion criteria. Six interventions were delivered by pharmacists and 3 were delivered by pharmacists/nurses or pharmacists/geriatricians. All interventions required at least intermediate-level skills and involved multiple components and target groups. Studies were conducted in the community (n = 5), nursing homes (n = 2), and hospitals (n = 2). The mean or median age was ≥75 years and most participants were women in all studies. Most (n = 6) studies were underpowered. The follow-up period ranged from 3 to 12 months. Three studies reported a lower DBI in the intervention group compared with control: 1 pharmacist independent prescriber-delivered in nursing homes (adjusted rate ratio, 0.83; 95% CI, 0.74 to 0.92), 1 pharmacist/nurse practitioner-delivered in hospital (adjusted mean difference (MD), -0.28; 95% CI, -0.51 to -0.04), and 1 geriatrician/pharmacist-delivered in hospital (MD, -0.28; 95% CI, -0.52 to -0.04). Meta-analysis showed no difference in the change in DBI between control and intervention groups in the community including nursing homes (MD, -0.03; 95% CI, -0.08 to 0.01) or hospital setting (MD, -0.19; 95% CI, -0.45 to 0.06). Interventions had inconsistent effects on cognition and no effect on other reported outcomes. CONCLUSIONS AND IMPLICATIONS: RCTs of deprescribing interventions had no significant impact on reducing DBI or improving outcomes. Further suitably powered studies are required.

Pharmaceutical Care Network Europe definition of quality indicators for pharmaceutical care: a systematic literature review and international consensus development.

BACKGROUND: Over the past 40 years, the tasks of pharmacists have shifted from logistic services to pharmaceutical care (PhC). Despite the increasing importance of measuring quality of care, there is no general definition of Quality Indicators (QIs) to measure PhC. Recognising this, a working group in a European association of PhC researchers, the Pharmaceutical Care Network Europe (PCNE), was established in 2020. AIM: This research aimed to review existing definitions of QIs and develop a definition of QIs for PhC. METHOD: A two-step procedure was applied. Firstly, a systematic literature review was conducted to identify existing QI definitions that were summarised. Secondly, an expert panel, comprised of 17 international experts from 14 countries, participated in two surveys and a discussion using a modified Delphi technique to develop the definition of QIs for PhC. RESULTS: A total of 182 QI definitions were identified from 174 articles. Of these, 63 QI definitions (35%) cited one of five references as the source. Sixteen aspects that construct QI definitions were derived from the identified definitions. As a result of the Delphi study, the panel reached an agreement on a one-sentence definition of QIs for PhC: "quality indicators for pharmaceutical care are validated measurement tools to monitor structures, processes or outcomes in the context of care provided by pharmacists". CONCLUSION: Building upon existing definition of QIs, an international expert panel developed the PCNE definition of QIs for PhC. This definition is intended for universal use amongst researchers and healthcare providers in PhC.

Association of the Drug Burden Index (DBI) exposure with outcomes: A systematic review.

BACKGROUND: The Drug Burden Index (DBI) measures an individual's total exposure to anticholinergic and sedative medications. This systematic review aimed to investigate the association of the DBI with clinical and prescribing outcomes in observational pharmaco-epidemiological studies, and the effect of DBI exposure on functional outcomes in pre-clinical models. METHODS: A systematic search of nine electronic databases, citation indexes and gray literature was performed (April 1, 2007-December 31, 2022). Studies that reported primary data on the association of the DBI with clinical or prescribing outcomes conducted in any setting in humans aged ≥18 years or animals were included. Quality assessment was performed using the Joanna Briggs Institute critical appraisal tools and the Systematic Review Centre for Laboratory animal Experimentation risk of bias tool. RESULTS: Of 2382 studies screened, 70 met the inclusion criteria (65 in humans, five in animals). In humans, outcomes reported included function (n = 56), cognition (n = 20), falls (n = 14), frailty (n = 7), mortality (n = 9), quality of life (n = 8), hospitalization (n = 7), length of stay (n = 5), readmission (n = 1), other clinical outcomes (n = 15) and prescribing outcomes (n = 2). A higher DBI was significantly associated with increased falls (11/14, 71%), poorer function (31/56, 55%), and cognition (11/20, 55%) related outcomes. Narrative synthesis was used due to significant heterogeneity in the study population, setting, study type, definition of DBI, and outcome measures. Results could not be pooled due to heterogeneity. In animals, outcomes reported included function (n = 18), frailty (n = 2), and mortality (n = 1). In pre-clinical studies, a higher DBI caused poorer function and frailty. CONCLUSIONS: A higher DBI may be associated with an increased risk of falls and decreased function and cognition. Higher DBI was inconsistently associated with increased mortality, length of stay, frailty, hospitalization or reduced quality of life. Human observational findings with respect to functional outcomes are supported by preclinical interventional studies. The DBI may be used as a tool to identify older adults at higher risk of harm.

Development of a maturity matrix to assess organizational readiness of community pharmacies for implementation of guideline recommendations in diabetes care.

OBJECTIVES: Pharmaceutical care for people with diabetes mellitus type 2 (DMT2) has been described in professional guidelines. To apply their recommendations, organizational changes are needed. We aimed to describe, for the first time, the development of a maturity matrix for community pharmacy teams (MM-CP) to assess organizational readiness in implementing the guideline recommendations on pharmaceutical DMT2 care. METHODS: MM-CP development was conducted in a systematic consensus process with pharmacists from existing working groups. In three meetings with preparatory assignments, mutually exclusive domains were chosen for the DMT2 guideline implementation. After determining the growth steps, the resulting matrix cells were filled with examples of the organizational implementation activities. To explore the generalizability of domains and growth steps, two other working groups for "medication surveillance" and "multidose drug dispensing" guidelines were consulted. KEY FINDINGS: A five-by-five matrix was developed using the domains "personalized care," "teamwork," "information systems and data exchange," "external collaboration," and "education and research" on the horizontal axis, and the growth steps "being aware and motivated," "being able to," "performing, evaluating and improving," and "innovating" on the vertical axis. The MM-CP cells were filled with examples to implement the core recommendations of the DMT2 guideline. The matrix is to be used by pharmacy teams as a formative instrument. CONCLUSIONS: The MM-CP is ready for use by community pharmacy teams for self-assessing their organizational readiness. However, further research is required to evaluate its potential in stimulating targeted improvement during the implementation of the DMT2-guideline recommendations in community pharmacies.

Single-Leg Loading Test to Predict Time to Jog and Return to Sports after Acute Lateral Ankle Sprain in Competitive Athletes.

In a previous study, the utility of a single-leg loading (SLL) test after acute lateral ankle sprain (LAS) was reported. However, whether the severity level assessed by the SLL test is associated with the time to jog and return to sports (RTS) remains unclear. Therefore, this study aimed to examine whether the time to jog and RTS differ depending on the severity level. A total of 240 athletes after sustaining acute LAS were included in this study. The SLL test was performed at the first visit, and the patients were classified into four levels (Levels 1-4). The Steel-Dwass multiple comparison method and multiple regression analysis was performed to verify whether the SLL test can predict the time to jog and RTS. On examining the relationship between the severity levels assessed by the SLL test and time to jog and RTS, significant differences were found among almost all the severity levels. Moreover, the multiple regression analysis revealed that only the SLL test showed a significant correlation with both the time to jog and RTS. This study suggested that the time to jog and RTS can be predicted by conducting the SLL test for acute LAS and dividing the severity into four levels.

Impact of a Comprehensive Intervention Bundle Including the Drug Burden Index on Deprescribing Anticholinergic and Sedative Drugs in Older Acute Inpatients: A Non-randomised Controlled Before-and-After Pilot Study.

INTRODUCTION: Implementation of the Drug Burden Index (DBI) as a risk assessment tool in clinical practice may facilitate deprescribing. OBJECTIVE: The purpose of this study is to evaluate how a comprehensive intervention bundle using the DBI impacts (i) the proportion of older inpatients with at least one DBI-contributing medication stopped or dose reduced on discharge, compared with admission; and (ii) the changes in deprescribing of different DBI-contributing medication classes during hospitalisation. METHODS: This before-and-after study was conducted in an Australian metropolitan tertiary referral hospital. Patients aged ≥ 75 years admitted to the acute aged care service for ≥ 48 h from December 2020 to October 2021 and prescribed DBI-contributing medication were included. During the control period, usual care was provided. During the intervention, access to the intervention bundle was added, including a clinician interface displaying DBI score in the electronic medical record. In a subsequent 'stewardship' period, a stewardship pharmacist used the bundle to provide clinicians with patient-specific recommendations on deprescribing of DBI-contributing medications. RESULTS: Overall, 457 hospitalisations were included. The proportion of patients with at least one DBI-contributing medication stopped/reduced on discharge increased from 29.9% (control period) to 37.5% [intervention; adjusted risk difference (aRD) 6.5%, 95% confidence intervals (CI) -3.2 to 17.5%] and 43.1% (stewardship; aRD 12.1%, 95% CI 1.0-24.0%). The proportion of opioid prescriptions stopped/reduced rose from 17.9% during control to 45.7% during stewardship (p = 0.04). CONCLUSION: Integrating a comprehensive intervention bundle and accompanying stewardship program is a promising strategy to facilitate deprescribing of sedative and anticholinergic medications in older inpatients.

Validation of quality indicators for evaluating geriatric pharmacotherapy services in primary care: a mixed methods study.

OBJECTIVE: To assess measurement properties of 121 face and content validated quality indicators (QIs) for medication safety in geriatric pharmacotherapy in primary care. DESIGN: A mixed methods study: a 6-month observational study in primary care (July-December 2020) and in-depth semistructured online interviews with participants (February-March 2021). SETTING: Sixty community pharmacies in Japan. PARTICIPANTS: Patients aged 75 years and older who were regularly taking six or more prescription medicines for ˃4 weeks were eligible. The observational study included 457 patients. The interviews were undertaken with 26 community pharmacists, including pharmacy managers and owners. PRIMARY AND SECONDARY OUTCOME MEASURES: Five measurement properties of QIs (applicability, improvement potential, acceptability, implementation issues and sensitivity to change) were evaluated. A web application was developed for data reporting and data visualisation. RESULTS: This study showed that 53 QIs met the measurement properties of applicability, improvement potential, acceptability and implementation issues. Of 53 QIs, 17 also had a high sensitivity to change. Interviews identified eight themes (indicator characteristics, web application, policy, patient, time, competence, pharmacy administration and collaboration) in relation to the consequence of implementation of QIs. CONCLUSIONS: A set of 121 QIs for geriatric pharmacotherapy was field tested for their five measurement properties. This QI set can be used to identify patients who may benefit from clinician reviews of their medicines. These QIs may be applied at different levels within the healthcare system: patient, pharmacy, regional and national levels. Further mechanisms to automatically collect and report data should be established to facilitate sustainable quality improvement initiatives.

Influence of lateral hinge fractures on biplanar medial closing-wedge distal femoral osteotomy for valgus knee: a new classification of lateral hinge fracture.

BACKGROUND: The purpose of this study was to examine the influence of lateral hinge fractures in medial closing-wedge distal femoral osteotomy (MCWDFO) on bone union. METHODS: Twenty-one patients were followed-up for more than 1 year after MCWDFO. The incidence and type of hinge fracture, as well as the course of bone healing, were investigated. Slow healing was defined as bone union was not obtained until 3 months after surgery. RESULTS: Hinge fractures were observed in 12 cases (57%). There were three types of hinge fractures. Type 1: the lateral cortex was completely cut through (4 cases), type 2: the osteotomy line was too proximal (6 cases), and type 3: the hinge point was significantly medial (2 cases). There was a significant difference in the mean correction angles between hinge fracture and no-fracture cases, with the mean angles being 13.8 ± 4.0° and 9.6 ± 3.1°, respectively. Sixty-seven percent (8/12) of cases with hinge fractures developed slow healing. Among the hinge fracture cases, when there was no displacement of the hinge fracture and good contact with the anterior flange, 40% (2/5) of cases developed slow healing. If there was displacement of the hinge or no contact of the anterior flange, 86% (6/7) of cases developed slow healing. In contrast, only 11% (1/9) of subjects who did not have a hinge fracture, developed slow healing. In 67% (6/9) of cases with slow healing, a correction loss of 2° or greater (average: 4.3 degrees valgus) was observed. There were no cases of non-union. Clinical outcomes at 1 year showed no significant difference between the groups with and without hinge fractures. CONCLUSIONS: There is a very high risk of hinge fracture in patients undergoing MCWDFO. Hinge fractures often lead to slow healing and a loss of correction. We recommend the endpoint of the distal lateral cortex of the femur as the ideal hinge point for the prevention of hinge fractures. Bone union is obtained slowly in even all hinge fracture cases without revision surgery. Consequently, surgical results are not affected by the occurrence of hinge fracture at 1 year.

Unintentional drug-related deaths in people with mental illness in NSW Australia, 2012-2016: a retrospective cohort study.

PURPOSE: People with mental illness are a vulnerable and stigmatised group with poor health outcomes including greater premature mortality. This study aimed to investigate trends and rates of change in unintentional drug-related deaths for people with mental illness, describe types of medicines involved, and identify populations at risk in a cohort from New South Wales, Australia. METHODS: Features of unintentional drug-related deaths for people with mental illness between 2012 and 2016 were identified in a retrospective review of data from the National Coronial Information System. RESULTS: A total of 495 unintentional drug-related deaths were identified (1.6 deaths/100,000 population), showing an upward trend (p < 0.01). The most common substance involved was diazepam in both genders (males 135/319, 42%, female 76/176, 43%) and more than one contributory drug was included in 80% of cases. Between 2012 and 2016, amphetamine-related deaths showed the highest increase (3.2-fold), followed by codeine (2.5-fold) and quetiapine (2.5-fold). Males (RR 1.8, 95% CI 1.5-2.2) and people aged 35-44 (RR 1.7, CI 1.3-2.2) were more likely to die from unintentional drug-related deaths compared with the reference (females and people aged 25-34). CONCLUSION: This study found that the drugs commonly involved in deaths are also the drugs commonly used by and prescribed to people with mental illness. There were also significant differences between gender, age group, and marital status in the trend and rate of unintentional drug-related deaths for people with mental illness. A multifaceted approach encompassing both pharmaceutical prescribing and targeted public health messaging is required to inform intervention and prevention strategies.

Anteromedial plating without filling the gap in open wedge high tibial osteotomy may increase the risk of screw breakage, which can be reduced by medial plating and bone-substitute insertion.

BACKGROUND: Open wedge high tibial osteotomy (OWHTO) brings new complications such as screw breakages with or without correction loss and time-dependent increased posterior tibial slopes (PTS) due to the opening gap. For preventive purposes, we changed our OWHTO procedure from anteromedial plating without filling the gap (non-grafted group, n = 40, 2009-2012) to medial plating with bone-substitute insertion (grafted group, n = 45, 2012-2015). The objectives of this study were to evaluate the complication patterns and the effects of the modifications. METHODS: Patients undergoing OWHTO with TomoFix plates were included in this retrospective study. Demographics, clinical outcomes (flexion range and Japanese Orthopaedic Association score) and radiological outcomes (femorotibial angle) were assessed in both groups pre-operatively and 2-years postoperatively. The plate installation angle [PIA] and screw insertion depth [SID] were measured on computed tomographic slices at 6 months. PIA/SID was defined as the angle between the tibial anteroposterior axis and plate-width axis/the distance between the proximal screw tip and the proximal tibiofibular joint. The non-grafted group was further divided into complication and non-complication subgroups. Screw breakages were assessed during plate removal (1.5-2.5 years postoperatively). RESULTS: There were no differences in baseline characteristics or radiological/clinical outcomes between the non-grafted and grafted groups. There were 0 and 11 complications in the grafted and non-grafted groups, respectively. Complications included 7 screw breakages, 4 correction losses, and 5 time-dependent increased PTS with some overlaps. PIA and SID were significantly lower (p < 0.001) and higher (p < 0.001), respectively, in the grafted group and significantly lower (p = 0.018) and higher (p = 0.040), respectively, in the non-complication subgroup within the non-grafted group. The cutoff value of PIA for complications was calculated at 48.0°. CONCLUSIONS: Medial plating OWHTO (PIA<48°) using bone-substitute with deeper screw insertion reinforces the opening gap for better angular stability compared with anteromedial plating without bone-substitute.

Comparison of a multidomain frailty index from routine health data with the hospital frailty risk score in older patients in an Australian hospital.

BACKGROUND: Frailty is an important determinant of health-care needs and outcomes for people in hospital. OBJECTIVES: To compare characteristics and predictive ability of a multidomain frailty index derived from routine health data (electronic frailty index-acute hospital; eFI-AH) with the hospital frailty risk score (HFRS). METHODS: This retrospective study included 6771 patients aged ≥75 years admitted to an Australian metropolitan tertiary referral hospital between October 2019 and September 2020. The eFI-AH and the HFRS were calculated for each patient and compared with respect to characteristics, agreement, association with age and ability to predict outcomes. RESULTS: Median eFI-AH was 0.17 (range 0-0.66) whilst median HFRS was 3.2 (range 0-42.9). Moderate agreement was shown between the tools (Pearson's r 0.61). After adjusting for age and gender, both models had associations with long hospital stay, in-hospital mortality, unplanned all-cause readmission and fall-related readmission. Specifically, the eFI-AH had the strongest association with in-hospital mortality (adjusted odds ratio (aOR) 2.81, 95% confidence intervals (CI) 2.49-3.17), whilst the HFRS was most strongly associated with long hospital stay (aOR 1.20, 95% CI 1.18-1.21). Both tools predicted hospital stay >10 days with good discrimination and calibration. CONCLUSIONS: Although the eFI-AH and the HFRS did not consistently identify the same inpatients as frail, both were associated with adverse outcomes and they had comparable predictive ability for prolonged hospitalisation. These two constructs of frailty may have different implications for clinical practice and health service provision and planning.

Polypharmacy and precision medicine.

Precision medicine is an approach to maximise the effectiveness of disease treatment and prevention and minimise harm from medications by considering relevant demographic, clinical, genomic and environmental factors in making treatment decisions. Precision medicine is complex, even for decisions about single drugs for single diseases, as it requires expert consideration of multiple measurable factors that affect pharmacokinetics and pharmacodynamics, and many patient-specific variables. Given the increasing number of patients with multiple conditions and medications, there is a need to apply lessons learned from precision medicine in monotherapy and single disease management to optimise polypharmacy. However, precision medicine for optimisation of polypharmacy is particularly challenging because of the vast number of interacting factors that influence drug use and response. In this narrative review, we aim to provide and apply the latest research findings to achieve precision medicine in the context of polypharmacy. Specifically, this review aims to (1) summarise challenges in achieving precision medicine specific to polypharmacy; (2) synthesise the current approaches to precision medicine in polypharmacy; (3) provide a summary of the literature in the field of prediction of unknown drug-drug interactions (DDI) and (4) propose a novel approach to provide precision medicine for patients with polypharmacy. For our proposed model to be implemented in routine clinical practice, a comprehensive intervention bundle needs to be integrated into the electronic medical record using bioinformatic approaches on a wide range of data to predict the effects of polypharmacy regimens on an individual. In addition, clinicians need to be trained to interpret the results of data from sources including pharmacogenomic testing, DDI prediction and physiological-pharmacokinetic-pharmacodynamic modelling to inform their medication reviews. Future studies are needed to evaluate the efficacy of this model and to test generalisability so that it can be implemented at scale, aiming to improve outcomes in people with polypharmacy.

Night vision restored in days after decades of congenital blindness.

Signaling of vision to the brain starts with the retinal phototransduction cascade which converts visible light from the environment into chemical changes. Vision impairment results when mutations inactivate proteins of the phototransduction cascade. A severe monogenically inherited blindness, Leber congenital amaurosis (LCA), is caused by mutations in the GUCY2D gene, leading to a molecular defect in the production of cyclic GMP, the second messenger of phototransduction. We studied two patients with GUCY2D-LCA who were undergoing gene augmentation therapy. Both patients had large deficits in rod photoreceptor-based night vision before intervention. Within days of therapy, rod vision in both patients changed dramatically; improvements in visual function and functional vision in these hyper-responding patients reached more than 3 log10 units (1000-fold), nearing healthy rod vision. Quick activation of the complex molecular pathways from retinal photoreceptor to visual cortex and behavior is thus possible in patients even after being disabled and dormant for decades.

Comparing exposed and buried Kirschner wires in fixation for pediatric supracondylar humerus fractures: A propensity score-matched study.

PURPOSE: To thoroughly compare the outcomes between exposed and buried Kirschner wires (K-wires) in fixation for pediatric supracondylar humerus fractures. METHODS: We examined patients who underwent surgery at our institution between January 2007 and June 2021. We investigated their age, sex, fracture pattern, number of K-wires used, whether they were exposed or buried, operative time, postoperative complications, number of outpatient visits, duration from surgery to K-wire removal, total length of hospitalization, and perioperative radiographic parameters. After propensity score matching, intergroup comparisons were performed to assess the differences in postoperative complication rate, number of outpatient visits, duration from surgery to K-wire removal, total length of hospitalization, and loss of reduction. RESULTS: Propensity score matching resulted in 43 pairs in both groups. Although more patients complained of skin irritation in the buried K-wire group, there was more backing out of the K-wire in the exposed K-wire group (p < 0.01). There were no significant differences in other complications. There were more outpatient visits in the buried K-wire group (p < 0.01). The duration from surgery to K-wire removal and the total length of hospitalization were significantly longer in the buried K-wire group (p < 0.01). There was no significant difference in the loss of Baumann's angle (p = 0.61), tilting angle (p = 0.48), or the development of rotation (p > 0.99) between groups. CONCLUSION: More outpatient visits and longer lengths of hospitalization in the buried K-wire group may lead to increased costs and burden on parents.

Development and consensus testing of quality indicators for geriatric pharmacotherapy in primary care using a modified Delphi study.

Background Polypharmacy is associated with an increased risk of adverse drug events in older people. Although national guidance on geriatric pharmacotherapy exists in Japan, tools to routinely monitor the quality of care provided by community pharmacists are lacking. Aim To develop a set of quality indicators (QIs) to measure the quality of care provided by community pharmacists in improving geriatric pharmacotherapy in primary care in Japan, using a modified Delphi study. Method The development of QIs for the Japanese community pharmacy context followed a two-step process: national guidance review and consensus testing using a modified Delphi study. The latter involved two rounds of rating with a face-to-face meeting between the rounds. Ten experts in geriatric pharmacotherapy in primary care were recruited for the panel discussion. QIs were mapped to three key taxonomies and frameworks: the Anatomical Therapeutic Chemical (ATC) classification system, problems and causes of drug-related problems (DRPs) taxonomy and Donabedian's framework. Results A total of 134 QIs for geriatric pharmacotherapy were developed. This QI set included 111 medicine specific indicators, covering medicines in 243 third-level ATC classifications. QIs were classified into the problem of treatment safety (80%) and causes of drug selection (38%) based on validated classification for DRPs. In Donabedian's framework, most QIs (82%) were process indicators. There were no structure indicators. Conclusion A set of 134 QIs for geriatric pharmacotherapy was rigorously developed. Measurement properties of these QIs will be evaluated for feasibility, applicability, room for improvement, sensitivity to change, predictive validity, acceptability and implementation issues in a subsequent study.

Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children.

PURPOSE: Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. METHODS: This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. RESULTS: All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. CONCLUSION: Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

Deprescribing in the Older Patient: A Narrative Review of Challenges and Solutions.

Polypharmacy is a major challenge in healthcare for older people, and is associated with increased risks of adverse outcomes, such as delirium, falls, frailty, cognitive impairment and hospitalization. There is significant public and professional interest in the role of deprescribing in reducing medication-related harms in older people. We aim to provide a narrative review of 1) the safety and efficacy of deprescribing interventions, 2) the challenges and solutions of deprescribing research and implementation in clinical practice, and 3) the benefits of using Computerized Clinical Decision Support Systems (CCDSS) and Quality Indicators (QIs) in deprescribing research and practice. Deprescribing is an established management strategy to minimize polypharmacy and potentially inappropriate medications. There is limited clinical evidence for its efficacy on global and geriatric outcomes. Various challenges at patient, healthcare professional and healthcare system levels may impact on the success of deprescribing interventions in research and practice. Management strategies that target all levels of the healthcare system are required to overcome these challenges. Future studies may consider large multicenter prospective designs to establish the effects and sustainability of deprescribing interventions on clinical outcomes.

Doxorubicin Embedded into Nanofibrillated Bacterial Cellulose (NFBC) Produces a Promising Therapeutic Outcome for Peritoneally Metastatic Gastric Cancer in Mice Models via Intraperitoneal Direct Injection.

Natural materials such as bacterial cellulose are gaining interest for their use as drug-delivery vehicles. Herein, the utility of nanofibrillated bacterial cellulose (NFBC), which is produced by culturing a cellulose-producing bacterium (Gluconacetobacter intermedius NEDO-01) in a medium supplemented with carboxymethylcellulose (CMC) that is referred to as CM-NFBC, is described. Recently, we demonstrated that intraperitoneal administration of paclitaxel (PTX)-containing CM-NFBC efficiently suppressed tumor growth in a peritoneally disseminated cancer xenograft model. In this study, to confirm the applicability of NFBC in cancer therapy, a chemotherapeutic agent, doxorubicin (DXR), embedded into CM-NFBC, was examined for its efficiency to treat a peritoneally disseminated gastric cancer via intraperitoneal administration. DXR was efficiently embedded into CM-NFBC (DXR/CM-NFBC). In an in vitro release experiment, 79.5% of DXR was released linearly into the peritoneal wash fluid over a period of 24 h. In the peritoneally disseminated gastric cancer xenograft model, intraperitoneal administration of DXR/CM-NFBC induced superior tumor growth inhibition (TGI = 85.5%) by day 35 post-tumor inoculation, compared to free DXR (TGI = 62.4%). In addition, compared with free DXR, the severe side effects that cause body weight loss were lessened via treatment with DXR/CM-NFBC. These results support the feasibility of CM-NFBC as a drug-delivery vehicle for various anticancer agents. This approach may lead to improved therapeutic outcomes for the treatment of intraperitoneally disseminated cancers.

Quick and simple test to evaluate severity of acute lateral ankle sprain.

BACKGROUND/OBJECTIVE: For early return to sports after a lateral ankle sprain (LAS) and recurrence prevention, effective rehabilitation and gradual return to sports should be initiated while predicting the return time based on the appropriate severity evaluation immediately after injury. However, since severity evaluations performed in previous studies required large space and stairs and involved high-revel activity, their use as a test and index to evaluate severity after LAS was not appropriate considering convenience and risk of re-injury. Therefore, a quick and simple test was developed to evaluate the severity of acute LAS. This study aimed to verify the association between ankle function for severity evaluation and anterior talofibular ligament (ATFL) injury type by ultrasonography and to clarify the usefulness for acute LAS severity evaluation of the single-leg loading (SLL) test. METHODS: In total, 50 patients (34 men, 16 women) out of 58 patients who visited our sports clinic within 3 days after acute LAS and who conformed to the study criteria were included in this study. During the first visit, SLL test and objective/subjective ankle joint evaluation were performed. The SLL test consists of single-leg standing, single-leg heel raising and single-leg hopping, and patients were classified into four levels from 1 to 4 according to results. In addition, ultrasonographic evaluation was performed within 1 week after the first visit to evaluate the type of ATFL injury. Type I was defined as intact ATFL, Type II as swollen ATFL with an almost intact fibrillar pattern and Type III as ATFL appearing swollen with a disrupted fibrillar pattern. The relationship between the SLL test and each evaluation item was investigated using Spearman's correlation coefficient. RESULTS: As a result of the SLL test, 15 patients had Level 1 (30%), 19 Level 2 (38%), 5 Level 3 (10%) and 11 Level 4 (22%). With regard to correlation coefficients of the SLL test, Japanese Society for Surgery of the Foot ankle/hindfoot scale and sports activity were rs = 0.71 (p < 0.001) and rs = 0.66 (p < 0.001), respectively, showing a significant positive correlation. SLL test and the type of ATFL injury also showed a significant negative correlation (rs = -0.58, p < 0.001). CONCLUSIONS: The SLL test was a simple and useful test that can be used as an index to evaluate the severity of acute LAS.

Therapeutic efficacy of a paclitaxel-loaded nanofibrillated bacterial cellulose (PTX/NFBC) formulation in a peritoneally disseminated gastric cancer xenograft model.

Nano-fibrillated bacterial cellulose (NFBC) is a safe, biocompatible material that can be prepared by culturing a cellulose-producing bacterium in a culture supplemented with carboxymethylcellulose (CMC) or hydroxypropylcellulose (HPC). CM-NFBC and HP-NFBC, prepared using CMC or HPC, show hydrophilicity and amphiphilicity, respectively, and thus they could be useful carriers for hydrophobic anticancer agents such as paclitaxel (PTX). In the present study, we prepared novel PTX formulations for intraperitoneal administration by associating PTX with either CM-NFBC or HP-NFBC and studied their therapeutic efficacy on peritoneally disseminated gastric cancer in a xenograft nude mouse model. Freeze-dried PTX formulations (PTX/CM-NFBC and PTX/HP-NFBC) were quickly reconstituted with saline without any foaming, compared to nanoparticle albumin-bound PTX (nab-PTX, Abraxane®). Both PTX/NFBC formulations extended the mean survival times in our xenograft murine models compared with either free PTX or nab-PTX. The PTX/NFBC formulations reduced systemic side effects of free PTX relating to weight loss. In our disseminated gastric peritoneal cancer model, the PTX/NFBC formulation increased the therapeutic index for PTX by increasing the therapeutic efficacy and decreasing toxicity. NFBCs should receive consideration as improved carriers for the clinical delivery of hydrophobic anticancer drugs such as PTX in malignancies in the abdominal cavity with peritoneal metastasis and dissemination.