Vitamin K2 ameliorates osteoarthritis by suppressing ferroptosis and extracellular matrix degradation through activation GPX4's dual functions.

Vitamin K2 (VK2) is an effective compound for anti-ferroptosis and anti-osteoporosis, and Semen sojae praeparatum (Dandouchi in Chinese) is the main source of VK2. Chondrocyte ferroptosis and extracellular matrix (ECM) degradation playing a role in the pathogenesis of osteoarthritis (OA). Glutathione peroxidase 4 (GPX4) is the intersection of two mechanisms in regulating OA progression. But no studies have elucidated the therapeutic effects and mechanisms of VK2 on OA. This study utilized an in vivo rat OA model created via anterior cruciate ligament transection (ACLT) and an in vitro chondrocyte oxidative damage model induced by TBHP to investigate the protective effects and mechanisms of action of VK2 in OA. Knee joint pain in mice was evaluated using the Von Frey test. Micro-CT and Safranin O-Fast Green staining were employed to observe the extent of damage to the tibial cartilage and subchondral bone, while immunohistochemistry and PCR were used to examine GPX4 levels in joint cartilage. The effects of VK2 on rat chondrocyte viability were assessed using CCK-8 and flow cytometry assays, and chondrocyte morphology was observed with toluidine blue and alcian blue staining. The impact of VK2 on intracellular ferroptosis-related markers was observed using fluorescent staining and flow cytometry. Protein expression changes were detected by immunofluorescence and Western blot analysis. Furthermore, specific protein inhibitors were applied to confirm the dual-regulatory effects of VK2 on GPX4. VK2 can increase bone mass and cartilage thickness in the subchondral bone of the tibia, and reduce pain and the OARSI score induced by OA. Immunohistochemistry results indicate that VK2 exerts its anti-OA effects by regulating GPX4 to delay ECM degradation. VK2 can inhibit the activation of the MAPK/NFκB signaling pathway caused by reduced expression of intracellular GPX4, thereby decreasing ECM degradation. Additionally, VK2 can reverse the inhibitory effect of RSL3 on GPX4, increase intracellular GSH content and the GSH/GSSG ratio, reduce MDA content, and rescue chondrocyte ferroptosis. The protective mechanism of VK2 may involve its dual-target regulation of GPX4, reducing chondrocyte ferroptosis and inhibiting the MAPK/NFκB signaling pathway to decelerate the degradation of the chondrocyte extracellular matrix.

Earthquake forecasting from paleoseismic records.

Forecasting large earthquakes along active faults is of critical importance for seismic hazard assessment. Statistical models of recurrence intervals based on compilations of paleoseismic data provide a forecasting tool. Here we compare five models and use Bayesian model-averaging to produce time-dependent, probabilistic forecasts of large earthquakes along 93 fault segments worldwide. This approach allows better use of the measurement errors associated with paleoseismic records and accounts for the uncertainty around model choice. Our results indicate that although the majority of fault segments (65/93) in the catalogue favour a single best model, 28 benefit from a model-averaging approach. We provide earthquake rupture probabilities for the next 50 years and forecast the occurrence times of the next rupture for all the fault segments. Our findings suggest that there is no universal model for large earthquake recurrence, and an ensemble forecasting approach is desirable when dealing with paleoseismic records with few data points and large measurement errors.

Biochanin A abrogates osteoclastogenesis in type 2 diabetic osteoporosis via regulating ROS/MAPK signaling pathway based on integrating molecular docking and experimental validation.

BACKGROUND: There are accumulating type 2 diabetes patients who have osteoporosis simultaneously. More effective therapeutic strategies should be discovered. Biochanin A (BCA) has been indicated that can play a role in improving metabolic disorders of type 2 diabetes and preventing osteoporosis. But whether BCA can treat type 2 diabetic osteoporosis has not been studied. PURPOSE: To investigate if the BCA can protect against type 2 diabetic osteoporosis and clarify the mechanism. METHODS: Micro-CT and histology assays were performed to detect the trabecular bone and analyze the bone histomorphology effect of BCA. CCK-8 assay was performed to detect the toxicity of BCA. TRAcP staining, immunofluorescence and hydroxyapatite resorption assay were used to observe osteoclasts differentiation and resorptive activity. Molecular docking provided evidence about BCA regulating the MAPK axis via prediction by the algorithm. QRT-PCR and Western Blotting were utilized to detect the expression of osteoclastogenesis-related markers and MAPK signaling pathway. RESULTS: Accumulation of bone volume after BCA treatment could be found based on the 3D reconstruction. Besides, there were fewer osteoclasts in db/db mice treated with BCA than db/db mice treated with saline. In vitro, we found that BCA hadn't toxicity in osteoclasts precursor, but also inhibited differentiation of osteoclasts. Further, we found that BCA suppresses osteoclastogenesis via ROS/MAPK signaling pathway. CONCLUSION: BCA can prevent type 2 diabetic osteoporosis by restricting osteoclast differentiation via ROS/MAPK signaling pathway.

Combination of curcumin and catalase protects against chondrocyte injury and knee osteoarthritis progression by suppressing oxidative stress.

Knee Osteoarthritis (KOA) is an age-related progressive degenerative joint disease, which is featured with pain, joint deformity, and disability. Accumulating evidence indicated oxidative stress plays a crucial role in the occurrence and development of KOA. Curcumin is a polyphenolic compound with significant antioxidant activity among various diseases while catalase (CAT) is an enzyme degrading hydrogen peroxide in treating oxidative diseases. We previously showed that the expression of CAT was low in cartilage. However, the combination of curcumin and CAT in KOA is still elusive. In this study, we demonstrated that the combination of curcumin and CAT has the potential to inhibit the IL1ß-induced chondrocyte apoptosis without cytotoxicity in vitro. Mechanistically, we found that the synergistic application curcumin and CAT not only promotes curcumin's regulation of the NRF2/HO-1 signaling pathway to enhance antioxidant enzyme expression to remove superoxide radicals, but also CAT can further remove downstream hydrogen peroxide which enhances the ability to scavenge reactive oxygen species (ROS). In vivo, studies revealed that combination of curcumin and catalase could better inhibit oxidative stress-induced chondrocyte injury by promoting the expression of ROS scavenging enzymes. In sum, the combination of curcumin and catalase can be used to treat KOA. Thus, combination of curcumin and catalase may act as a novel therapeutic agent to manage KOA and our research gives a rationale for their combined use in the therapeutic of KOA.

Arctiin attenuates iron overload­induced osteoporosis by regulating the PI3K/Akt pathway.

Iron overload is a prevalent pathological factor observed among elderly individuals and those with specific hematological disorders, and is frequently associated with an elevated incidence of osteoporosis. Although arctiin (ARC) has been shown to possess antioxidant properties and the ability to mitigate bone degeneration, its mechanism of action in the treatment of iron overload­induced osteoporosis (IOOP) remains incompletely understood. To explore the potential molecular mechanisms underlying the effects of ARC, the MC3T3­E1 cell osteoblast cell line was used. Cell Counting Kit was used to assess MC3T3­E1 cell viability. Alkaline phosphatase staining and alizarin red staining were assessed for osteogenic differentiation. Calcein AM assay was used to assess intracellular iron concentration. In addition, intracellular levels of reactive oxygen species (ROS), lipid peroxides, mitochondrial ROS, apoptosis rate and mitochondrial membrane potential changes in MC3T3­E1 cells were examined using flow cytometry and corresponding fluorescent dyes. The relationship between ARC and the PI3K/Akt pathway was then explored by western blotting and immunofluorescence. In addition, the effects of ARC on IOOP was verified using an iron overload mouse model. Immunohistochemistry was performed to evaluate expression of osteogenesis­related proteins. Micro-CT and H&E were used to analyze bone microstructural parameters and histomorphometric indices in the bone tissue. Notably, ARC treatment reversed the decreased viability and increased apoptosis in MC3T3­E1 cells originally induced by ferric ammonium citrate, whilst promoting the formation of mineralized bone nodules in MC3T3­E1 cells. Furthermore, iron overload induced a decrease in the mitochondrial membrane potential, augmented lipid peroxidation and increased the accumulation of ROS in MC3T3­E1 cells. ARC not only positively regulated the anti­apoptotic and osteogenic capabilities of these cells via modulation of the PI3K/Akt pathway, but also exhibited antioxidant properties by reducing oxidative stress. In vivo experiments confirmed that ARC improved bone microarchitecture and biochemical parameters in a mouse model of iron overload. In conclusion, ARC exhibits potential as a therapeutic agent for IOOP by modulating the PI3K/Akt pathway, and via its anti­apoptotic, antioxidant and osteogenic properties.

Test-retest reliability of movement-evoked pain and sensitivity to movement-evoked pain in patients with rotator cuff-related shoulder pain.

BACKGROUND: The number of researchers and clinicians using movement-evoked pain and sensitivity to movement-evoked pain to assess shoulder pain has increased. However, the intrarater test-retest reliability of movement-evoked pain and sensitivity to movement-evoked pain in people with rotator cuff-related shoulder pain (RCRSP) is still unknown. OBJECTIVE: We examined the intrarater test-retest reliability of movement-evoked pain and sensitivity to movement-evoked pain in participants with RCRSP. METHODS: Seventy-four participants with RCRSP performed five trials of active shoulder abduction to elicit pain under two experimental conditions: active shoulder abduction to the onset of pain and maximum range of motion (ROM). The primary outcome measures were pain intensity and ROM. Test-retest reliability of movement-evoked pain and sensitivity to movement-evoked pain was examined using intraclass correlation coefficient (ICC3,1) and minimal detectable change (MDC90). RESULTS: The reliability of movement-evoked pain under both experimental conditions was good to excellent (ICC: 0.81 to 0.95), while the reliability of sensitivity to movement-evoked pain was poor in both conditions (ICC≤0.45). The MDC90 for pain intensity was 1.6 and 1.8 during shoulder abduction to the onset of pain and maximum ROM, respectively. The MDC90 for ROM was 17.5° and 11.2° during shoulder abduction to the onset of pain and maximum ROM condition, respectively. CONCLUSION: This study confirms movement-evoked pain testing during active shoulder abduction to the onset of pain or maximum ROM condition is reliable to assess pain associated with movement in patients with RCRSP. The minimal detectable change score of movement-evoked pain can guide clinicians and researchers on how to interpret changes in these outcomes.

Cardamonin protects against iron overload induced arthritis by attenuating ROS production and NLRP3 inflammasome activation via the SIRT1/p38MAPK signaling pathway.

Iron homeostasis plays an essential role in joint health, while iron overload can cause damage and death of cartilage cells. Cardamonin (CAR) is a substance found in the fruit of the chasteberry plant and has anti-inflammatory and anti-tumor activities. We first administered iron dextran (500 mg/kg) intraperitoneally to establish an iron overload mouse model and surgically induced osteoarthritis. The extent of OA and iron deposition were assessed using Micro-ct, Safranin-O/fast green staining, H&E staining, and Prussian Blue 10 weeks later. We administered primary chondrocytes with Ferric Ammonium Citrate (FAC) to evaluate the chondrocyte changes. Chondrocytes were identified in vitro by toluidine blue staining, and chondrocyte viability was evaluated by CCK-8. The rate of apoptosis was determined by Annexin V-FITC/PI assay. The mechanism of action of CAR was verified by adding the SIRT1 inhibitor EX527, and the expression of SIRT1 and MAPK signaling pathways was detected by Western blot. Iron overload also promoted chondrocyte apoptosis, a process that was reversed by CAR. In addition, CAR reduced NLRP3 inflammasome production via the SIRT1-MAPK pathway, and the SIRT1 inhibitor EX527 inhibited the treatment of OA by CAR.CAR inhibited cartilage degeneration induced by iron overload both in vivo and in vitro. Besides, our study showed that iron overload not only inhibited type II collagen expression but also induced MMP expression by catalyzing the generation of NLRP3 inflammasome. Our results suggest that CAR can treat KOA by promoting SIRT1 expression and inhibiting p38MAPK pathway expression to reduce the production of NLRP3 inflammasome vesicles.

Initial effect of high-volume mobilisation with movement on shoulder range of motion and pain in patients with rotator cuff-related shoulder pain: protocol for a randomised controlled trial (Evolution Trial).

INTRODUCTION: Mobilisation with movement (MWM) is commonly used for treating patients with rotator cuff-related shoulder pain (RCRSP). However, the evidence supporting MWM efficacy for improving shoulder range of motion (ROM) and pain in patients with RCRSP is limited. It is also unclear whether higher volume MWM leads to better clinical outcomes compared with lower volume MWM in patients with RCRSP. The primary aim of this study is to assess the effect of MWM on the angular onset of pain during shoulder abduction in patients with RCRSP. METHODS AND ANALYSIS: Sixty participants with RCRSP will be randomised to receive either MWM or sham MWM intervention. The primary outcome is the angular onset of pain during shoulder abduction, and secondary outcomes are pain intensity at the angular onset of pain during shoulder abduction, maximum shoulder ROM, pain intensity during maximum shoulder abduction, pressure pain threshold, mechanical temporal summation, global rating of change scale (GROC) and Brief Pain Inventory-Short Form (BPI-SF). The angular onset of pain and the pain intensity at that range will be assessed at baseline, after 1 set and 3 sets of 10 repetitions of MWM or sham MWM. The GROC will be measured immediately after receiving 3 sets of interventions and on day 3 after interventions. The BPI-SF will be measured on days 1, 3, 5 and 7 after interventions. Other secondary outcomes will be assessed at baseline and after 3 sets of interventions. A linear mixed effects model with a random intercept will be used to compare changes in the outcome measures between MWM and sham MWM interventions. ETHICS AND DISSEMINATION: This study has been approved by the University of Otago Ethics Committee (Ref. H21/117). Findings from this study will be disseminated through presentations at international and national conferences and will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN 12621001723875.

Perinatal psychotropic dispensing: A descriptive population-based study in New Zealand.

INTRODUCTION: Decisions about using psychotropics during pregnancy are complex as risks of untreated illness are balanced against risks of fetal exposure to medication. The objective was to describe perinatal psychotropic dispensing patterns in New Zealand. METHODS: Nationwide data from the New Zealand National Maternity Collection between January 1, 2011 and December 31, 2017 identified 399 715 pregnancies. These were linked with dispensing records to determine the proportion of pregnancies during which at least 1 psychotropic was dispensed. Proportions were calculated separately for each class, year, pregnancy period, and across maternal characteristics. The pattern of dispensing (including discontinuations) was also determined for the 25 841 women who were dispensed at least 1 psychotropic drug prior to pregnancy. RESULTS: From the 399 715 pregnancies in the study cohort, 6.6% were dispensed at least 1 psychotropic during pregnancy. Antidepressants (5.1%) were the most dispensed, followed by hypnotics (1.2%), anxiolytics (0.7%), and antipsychotics (0.7%). From the 25 841 pregnancies during which a psychotropic was dispensed pre-pregnancy, 91% and 90% discontinued hypnotics and anxiolytics respectively, prior to or during pregnancy. This was followed by lithium (71%), antipsychotics (66%), and antidepressants (66%). DISCUSSION: Dispensing of psychotropics during pregnancy occurs in approximately 6.6% of pregnancies in New Zealand. Two-thirds of women (66%) on antidepressants or antipsychotics discontinue dispensing before or during pregnancy. This may have implications for maternal mental health, suggesting there is a need to investigate how healthcare providers and women are making decisions about psychotropic use during pregnancy.

Metformin suppresses Oxidative Stress induced by High Glucose via Activation of the Nrf2/HO-1 Signaling Pathway in Type 2 Diabetic Osteoporosis.

BACKGROUND: Metformin (MET) is widely used as a first-line hypoglycemic agent for the treatment of type 2 diabetes mellitus (T2DM) and was also confirmed to have a therapeutic effect on type 2 diabetic osteoporosis (T2DOP). However, the potential mechanisms of MET in the treatment of T2DOP are unclear. OBJECTIVE: To clarify the effect of MET in T2DOP and to explore the potential mechanism of MET in the treatment of T2DOP. METHODS: In vitro, we used MC3T3-E1 cells to study the effects of MET on osteogenic differentiation and anti-oxidative stress injury in a high glucose (Glucose 25 mM) environment. In vivo, we directly used db/db mice as a T2DOP model and assessed the osteoprotective effects of MET by Micro CT and histological analysis. RESULTS: In vitro, we found that MET increased ALP activity in MC3T3-E1 cells in a high-glucose environment, promoted the formation of bone mineralized nodules, and upregulated the expression of the osteogenesis-related transcription factors RUNX2, Osterix, and COL1A1-related genes. In addition, MET was able to reduce high glucose-induced reactive oxygen species (ROS) production. In studies on the underlying mechanisms, we found that MET activated the Nrf2/HO-1 signaling pathway and alleviated high-glucose-induced oxidative stress injury. In vivo results showed that MET reduced bone loss and bone microarchitecture destruction in db/db mice. CONCLUSION: Our results suggest that MET can activate the Nrf2/HO-1 signaling pathway to regulate the inhibition of osteogenic differentiation induced by high glucose thereby protecting T2DOP.

Infraslow closed-loop brain training for anxiety and depression (ISAD): a protocol for a randomized, double-blind, sham-controlled pilot trial in adult females with internalizing disorders.

BACKGROUND: The core intrinsic connectivity networks (core-ICNs), encompassing the default-mode network (DMN), salience network (SN) and central executive network (CEN), have been shown to be dysfunctional in individuals with internalizing disorders (IDs, e.g. major depressive disorder, MDD; generalized anxiety disorder, GAD; social anxiety disorder, SOC). As such, source-localized, closed-loop brain training of electrophysiological signals, also known as standardized low-resolution electromagnetic tomography (sLORETA) neurofeedback (NFB), targeting key cortical nodes within these networks has the potential to reduce symptoms associated with IDs and restore normal core ICN function. We intend to conduct a randomized, double-blind (participant and assessor), sham-controlled, parallel-group (3-arm) trial of sLORETA infraslow (<0.1 Hz) fluctuation neurofeedback (sLORETA ISF-NFB) 3 times per week over 4 weeks in participants (n=60) with IDs. Our primary objectives will be to examine patient-reported outcomes (PROs) and neurophysiological measures to (1) compare the potential effects of sham ISF-NFB to either genuine 1-region ISF-NFB or genuine 2-region ISF-NFB, and (2) assess for potential associations between changes in PRO scores and modifications of electroencephalographic (EEG) activity/connectivity within/between the trained regions of interest (ROIs). As part of an exploratory analysis, we will investigate the effects of additional training sessions and the potential for the potentiation of the effects over time. METHODS: We will randomly assign participants who meet the criteria for MDD, GAD, and/or SOC per the MINI (Mini International Neuropsychiatric Interview for DSM-5) to one of three groups: (1) 12 sessions of posterior cingulate cortex (PCC) ISF-NFB up-training (n=15), (2) 12 sessions of concurrent PCC ISF up-training and dorsal anterior cingulate cortex (dACC) ISF-NFB down-training (n=15), or (3) 6 sessions of yoked-sham training followed by 6 sessions genuine ISF-NFB (n=30). Transdiagnostic PROs (Hospital Anxiety and Depression Scale, HADS; Inventory of Depression and Anxiety Symptoms - Second Version, IDAS-II; Multidimensional Emotional Disorder Inventory, MEDI; Intolerance of Uncertainty Scale - Short Form, IUS-12; Repetitive Thinking Questionnaire, RTQ-10) as well as resting-state neurophysiological measures (full-band EEG and ECG) will be collected from all subjects during two baseline sessions (approximately 1 week apart) then at post 6 sessions, post 12 sessions, and follow-up (1 month later). We will employ Bayesian methods in R and advanced source-localisation software (i.e. exact low-resolution brain electromagnetic tomography; eLORETA) in our analysis. DISCUSSION: This protocol will outline the rationale and research methodology for a clinical pilot trial of sLORETA ISF-NFB targeting key nodes within the core-ICNs in a female ID population with the primary aims being to assess its potential efficacy via transdiagnostic PROs and relevant neurophysiological measures. TRIAL REGISTRATION: Our study was prospectively registered with the Australia New Zealand Clinical Trials Registry (ANZCTR; Trial ID: ACTRN12619001428156). Registered on October 15, 2019.

Naringenin protects against iron overload-induced osteoarthritis by suppressing oxidative stress.

BACKGROUND: The traditional Chinese medicine Gusuibu, the rhizome of Rhizoma Drynariae, is used to treat rheumatism and fractures. Naringenin (NAR) is an active ingredient in Gusuibu and has significant anti-inflammatory and antioxidant effects. However, the role of naringenin in iron overload-induced osteoarthritis (IOOA) is unknown. HYPOTHESIS: NAR reduces cartilage damage in IOOA. METHODS: The effects of NAR on the viability of IOOA chondrocytes and the synthesis ability of type II collagen were evaluated using cell counting kit (CCK8) and toluidine blue assays. To determine the mechanism of action and characteristics of NAR, the intracellular iron ion content, apoptosis rate, and mitochondrial membrane potential (MMP) change, and malondialdehyde (MDA) levels, as well as the degree of reactive oxygen species (ROS) and lipid hydroperoxide (LPO) accumulation in the cells were detected in vitro and verified using western blotting and quantitative real-time PCR (qRT-PCR). To verify the role of NAR in vivo, IOOA mice were established using iron dextran and surgery-induced destabilised medial meniscus. Changes in the articular cartilage and subchondral bone were examined using Safranin O-fast Green staining (S-O), haematoxylin-eosin staining (H&E), and microcomputed tomography (µCT). RESULTS: In vitro, NAR attenuated the impairment of cell viability, apoptosis, and MMP caused by ferric ammonium citrate and interleukin-1ß co-culture, increased the levels of MDA, reduced the expression of matrix metallopeptidase (MMP)3, MMP13, and Bax, and restored the expression of type II collagen (Col II). NAR showed a slight iron accumulation-reducing effect. NAR alleviated the accumulation of ROS and LPO in IOOA chondrocytes and upregulated antioxidant genes nuclear factor E2-related factor 2 (NRF2) and haem oxygenase 1 (HO-1). When ML385, a specific NRF-2 inhibitor, was added, the protective effect of NAR was significantly inhibited. In vivo, NAR reduced synovitis and attenuated cartilage damage and subchondral bone proliferation in IOOA mice. CONCLUSIONS: NAR can reduce oxidative stress through the NRF2-HO-1 pathway, alleviate cartilage damage under iron overload, and has the potential to treat IOOA.

Staying at home: the potential cost savings related to triage advice provided by the New Zealand National Poisons Centre.

INTRODUCTION: Evidence from multiple countries suggests poisons centres create value in several ways including the provision of expert clinical advice, decreased hospital length of stay and triage of exposures enabling safe management without further medical utilisation. Data specific to the New Zealand context are lacking. Therefore, this study aimed to estimate one aspect of poison centre value, namely the potential savings to the health system related to triage advice provided by the New Zealand National Poisons Centre (NZNPC). METHODS: A prospective survey was conducted over a 2-week period where eligible NZNPC callers - who were advised their exposure did not require further medical assessment - were asked what alternative action they would have taken in the hypothetical absence of the NZNPC. The potential cost savings associated with the alternative actions respondents would have taken were calculated using publicly available information and extrapolated to the population level using annual NZNPC call numbers for 2019. RESULTS: Among 554 eligible callers, 399 were recruited to participate and 396 provided responses. The single most common alternative action was "search the Internet" (54/396, 14%). In-person medical assessment would have been sought by 25% (100/396), and 39% (154/396) would have called an alternative provider within the healthcare system. The estimated cost associated with alternative actions for the study period was NZ$25,637. When extrapolated to the 2019 year, the potential savings from avoided healthcare utilisation was NZ$1,061,551. CONCLUSION: In 2019, in the absence of NZNPC triage advice, a conservatively estimated NZ$1,061,551 would have been spent on healthcare related to poisoning exposures that were appropriate for management without further medical utilisation. It is important to note that this estimate is only one aspect of the total value created by the NZNPC and is consistent with findings of value from other poisons centres internationally.

Treatment pathways in people with type 2 diabetes mellitus: a nationwide cohort study of new users of metformin monotherapy in New Zealand.

OBJECTIVES: The aims of this study were to describe the following: (1) the time to change of therapy in patients with type 2 diabetes who had initiated metformin monotherapy as first-line treatment and (2) the sequence in which subsequent therapeutic regimens were introduced. DESIGN: Cohort study. SETTING: National study based on linked data from the New Zealand Ministry of Health's National Collections of health and pharmaceutical dispensing data. PARTICIPANTS: People with type 2 diabetes mellitus who initiated metformin monotherapy between 1 January 2006 and 30 September 2014 (n=93 874). PRIMARY OUTCOME MEASURES: Cumulative incidence curves were plotted to show the time taken to move from one regimen to another, while sunburst plots were used to illustrate the sequence in which regimens were introduced. RESULTS: About 10% and 35% of cohort members had moved to a second regimen 1 year and 5 years, respectively, after initiating metformin monotherapy; the majority received a regimen recommended by New Zealand treatment guidelines (mostly metformin and a sulphonylurea). Of those who started a recommended second regimen, 37% and 67% had moved to a third regimen after 1 and 5 years, respectively; the corresponding proportions for those who started an 'other' (not listed as recommended) second regimen were 53% and 75%. Most of those who received a third regimen after a recommended second regimen were dispensed an 'other' third regimen. Of those who moved to a third regimen from an 'other' second regimen, similar proportions received recommended and 'other' third regimens. CONCLUSIONS: Real-world type 2 diabetes treatment patterns in New Zealand are complex and not always consistent with guidelines.

A Descriptive Analysis of Transitions from Smoking to Electronic Nicotine Delivery System (ENDS) Use: A Daily Diary Investigation.

OBJECTIVES: We aimed to examine patterns in smoking and electronic nicotine delivery system (ENDS) use over an extended period of time (up to 20 weeks) in people who smoked and who had never previously made a successful quit attempt using an ENDS. DESIGN AND SETTING: We conducted a longitudinal mixed-methods study in Dunedin, New Zealand, during 2018 and 2019. PARTICIPANTS: Purposively selected participants (N = 45; age (≥18 years), gender, ethnicities, cigarettes/day) who wished to quit smoking. INTERVENTIONS: Participants were provided with a second-generation ENDS device (vape pen or starter "tank" device) at the start of their quit attempt, and asked to complete smartphone-based daily diary surveys assessing smoking and ENDS use. OUTCOME MEASURES: Sunburst plots and a sequence plot were used to describe weekly and daily patterns of smoking and ENDS use (smoking only, ENDS use only, dual use, abstinent). RESULTS: The most frequently reported movements among participants, classified according to their study week behaviour, occurred between dual use and exclusive ENDS use (and vice versa). A smaller group reported moving from dual use to exclusive smoking (and often back to dual use), and a small number reported moving between abstinence and different ENDS and smoked tobacco usage behaviours. Data visualisations focussing on those participants who had provided data during each of weeks 9-12 indicate that only a minority reported sustained dual use; instead, most participants indicated varied smoked tobacco and ENDS use, which included periods of dual use. CONCLUSIONS: The considerable variety observed within and between study participants suggests that high variability is typical rather than exceptional. Transitions from smoking to ENDS use may involve considerable periods of dual use, which is likely to be dynamic and potentially sustained over several months.

Medication risk management and health equity in New Zealand general practice: a retrospective cross-sectional study.

BACKGROUND: Despite an overt commitment to equity, health inequities are evident throughout Aotearoa New Zealand. A general practice electronic alert system was developed to notify clinicians about their patient's risk of harm due to their pre-existing medical conditions or current medication. We aimed to determine whether there were any disparities in clinician action taken on the alert based on patient ethnicity or other demographic factors. METHODS: Sixty-six New Zealand general practices from throughout New Zealand participated. Data were available for 1611 alerts detected for 1582 patients between 1 and 2018 and 1 July 2019. The primary outcome was whether action was taken following an alert or not. Logistic regression was used to assess if patients of one ethnicity group were more or less likely to have action taken. Potential confounders considered in the analyses include patient age, gender, ethnicity, socio-economic deprivation, number of long term diagnoses and number of long term medications. RESULTS: No evidence of a difference was found in the odds of having action taken amongst ethnicity groups, however the estimated odds for Maori and Pasifika patients were lower compared to the European group (Maori OR 0.88, 95 %CI 0.63-1.22; Pasifika OR 0.88, 95 %CI 0.52-1.49). Females had significantly lower odds of having action taken compared to males (OR 0.76, 95 %CI 0.59-0.96). CONCLUSIONS: This analysis of data arising from a general practice electronic alert system in New Zealand found clinicians typically took action on those alerts. However, clinicians appear to take less action for women and Maori and Pasifika patients. Use of a targeted alert system has the potential to mitigate risk from medication-related harm. Recognising clinician biases may improve the equitability of health care provision.

Medication-related harm in New Zealand general practice: a retrospective records review.

BACKGROUND: The extent of medication-related harm in general practice is unknown. AIM: To identify and describe all medication-related harm in electronic general practice records. The secondary aim was to investigate factors potentially associated with medication-related harm. DESIGN AND SETTING: Retrospective cohort records review study in 44 randomly selected New Zealand general practices for the 3 years 2011-2013. METHOD: Eight GPs reviewed 9076 randomly selected patient records. Medication-related harms were identified when the causal agent was prescribed in general practice. Harms were coded by type, preventability, and severity. The number and proportion of patients who experienced medication-related harm was calculated. Weighted logistic regression was used to identify factors associated with harm. RESULTS: In total, 976 of 9076 patients (10.8%) experienced 1762 medication-related harms over 3 years. After weighting, the incidence rate of all medication-related harms was 73.9 harms per 1000 patient-years, and the incidence of preventable, or potentially preventable, medication-related harms was 15.6 per 1000 patient-years. Most harms were minor (n = 1385/1762, 78.6%), but around one in five harms were moderate or severe (n = 373/1762, 21.2%); three patients died. Eighteen study patients were hospitalised; after weighting this correlates to a hospitalisation rate of 1.1 per 1000 patient-years. Increased age, number of consultations, and number of medications were associated with increased risk of medication-related harm. Cardiovascular medications, antineoplastic and immunomodulatory agents, and anticoagulants caused most harm by frequency and severity. CONCLUSION: Medication-related harm in general practice is common. This study adds to the evidence about the risk posed by medication in the real world. Findings can be used to inform decision making in general practice.

Using an Information Package to Reduce Patients' Risk of Renal Damage: Protocol for a Randomized Feasibility Trial.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are a common cause of renal damage, especially when taken together with angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin II receptor blockers (ARBs) plus a diuretic - a combination known as the "triple whammy." New Zealand patients are at high risk of the "triple whammy" because they can easily purchase NSAIDs without a prescription and in nonpharmacy retail settings (eg, the supermarket), there is no legal requirement to include patient information sheets with medication, and direct-to-consumer drug advertising is permitted. A patient information package has been developed for those at greatest risk of the "triple whammy," consisting of a printable PDF and an interactive online learning activity. This information package aims to inform patients about their elevated risk of harm from NSAIDS and discourage use of NSAIDs. A randomized control trial was planned to assess the effect of the information package. OBJECTIVE: This study aims to pilot the trial procedures for recruiting patients and providing patient information online and to assess the acceptability of the patient information package. METHODS: A two-armed randomized feasibility trial will be undertaken in Northland, New Zealand. We will recruit 50 patients who are at least 18 years old from those who have signed up to receive email alerts through their general practice. Patients eligible for this study have been prescribed an ACE-i or ARB plus a diuretic in the past 3 months. They will be randomly allocated to 2 study arms. The intervention arm will receive access to an information package plus usual care; the control arm will receive usual care alone. Online surveys will be used to assess NSAID knowledge and NSAID use at baseline and after 2 weeks for both arms. The intervention arm will also evaluate the information package in an additional survey based on Normalization Process Theory (NPT) concepts. We will report the number and proportion of participants who are eligible and consent to participate in the trial. Response and drop-out rates will be reported for each trial arm. The numbers of patients who interact with the education package will be reported together with the patient evaluation of it. RESULTS: Funding has been obtained from the Health Research Council of New Zealand (HRC 18-031). The University of Otago Human Research Ethics Committee (H21/016) has approved this trial. Consultation has been undertaken with The Ngai Tahu research consultation committee. The trial commenced on April 12, 2021. CONCLUSIONS: This feasibility trial will test the study processes prior to commencing a randomized controlled trial and will determine the acceptability of the patient information package. We anticipate this work will provide useful information for other researchers attempting similar work. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/29161.

Patterns of metformin monotherapy discontinuation and reinitiation in people with type 2 diabetes mellitus in New Zealand.

AIM: To describe the patterns of discontinuation and reinitiation in new users of metformin monotherapy in New Zealand, overall and according to person- and healthcare-related factors. MATERIALS AND METHODS: We created a cohort (n = 85,066) of all patients in New Zealand with type 2 diabetes mellitus who initiated metformin monotherapy between 1 January 2006 and 30 September 2014 from the national data collections, and followed them until the earlier of their death or 31 December 2015. Discontinuation was defined as a gap in possession of metformin monotherapy of ≥90 days. We explored patterns of discontinuation and reinitiation using competing risks methods. RESULTS: After 1 year of follow-up, 28% of cohort members had discontinued metformin monotherapy at least once; the corresponding figures after 2 and 5 years were 37% and 46%. The proportions who reinitiated metformin monotherapy within 1, 2, and 5 years of their first discontinuation were 23%, 49%, and 73%. Discontinuation after the first reinitiation was common (48% after 1 year). Discontinuation and reinitiation varied by age, ethnicity, and other person- and healthcare-related factors. DISCUSSION: Our findings highlight the dynamic nature of metformin monotherapy use, show that substantial periods of non-use are common, and identify priority populations for interventions to facilitate adherence.

Sanhuang Jiangtang tablet protects type 2 diabetes osteoporosis via AKT-GSK3ß-NFATc1 signaling pathway by integrating bioinformatics analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Sanhuang Jiangtang tablet (SHJTT), has been widely used to treat type 2 diabetes mellitus (T2DM). However, the potential and mechanism of SHJTT in treating type 2 diabetes osteoporosis (T2DOP) has not been reported. AIM OF THE STUDY: The aim of this work was to investigate the role and the underlying molecular mechanism of SHJTT in managing type 2 diabetes osteoporosis. MATERIALS AND METHODS: The target genes of each component consisting of SHJTT were obtained by searching the ETCM database. The target genes of osteoporosis and diabetes were individually acquired by analyzing the DisGeNET and OMIM disease databases. Then the potential therapeutic genes were obtained from the intersection of the herbal medicine targets and the disease targets which were imported into the R and STRING platform for the analysis of GO terms, KEGG pathways and PPI network. The key modules of PPI network were constructed by Cytoscape software. Finally, leptin receptor deficiency (db/db) mice were confirmed as an animal model of type 2 diabetic osteoporosis (T2DOP) through phenotype assessment and the key genes of SHJTT against T2DOP were validated by quantitative real-time PCR (qRT-PCR). RESULTS: A total of 786 target genes of SHJTT were obtained from ETCM. Simultaneously, a total of 3906 osteoporosis and type 2 diabetes associated targets were acquired from DisGeNET and OMIM databases. Then, 97 common targets were found by overlapping them. On the basis of the GO and KEGG enrichment analysis and PPI network, we found that the related pathway of SHJTT in type 2 diabetes osteoporosis was AKT-GSK3ß-NFATc1 pathway which is tightly associated with osteoclast differentiation. The expression of key genes including Akt1, Mapk3, Gsk3ß, Mmp9, Nfkb1 were significantly down-regulated by SHJTT in T2DOP mice (p < 0.05). CONCLUSIONS: SHJTT had a protective effect on T2DOP via regulating AKT-GSK3ß-NFATc1 signaling pathway. This study might provide a theoretical basis for the application of SHJTT for the treatment of type 2 diabetic osteoporosis.