Endovascular Embolization of Aneurysmal Renal Arteriovenous Malformation.

Renal arteriovenous malformations (AVM) represent an uncommon vascular condition characterized by an abnormal direct communication between an intrarenal artery and vein. Though asymptomatic in many individuals, treatment is often indicated if the AVM causes flank pain, hematuria, or medically refractory hypertension, or if there is an associated renal artery aneurysm. We present a case of a large right renal AVM with associated renal artery aneurysm and large varix which was incidentally found on magnetic resonance imaging of the spine. Endovascular and open surgical options were considered, including ex-vivo renal vascular reconstruction and nephrectomy. The patient was successfully treated with endovascular embolization of the AVM with coil packing of the arterial aneurysm and inflow artery. The patient recovered uneventfully with well-maintained renal function and blood pressure control. We review and discuss the literature on the etiology and treatment options for renal AVM.

Therapeutic inertia in obesity management among people living with obesity from the perspective of general/family practitioners in Canada: A mixed-methods study.

This mixed-methods study aimed to explore factors contributing to therapeutic inertia among people living with obesity in Canada from the perspective of general/family practitioners (GP/FPs). One-on-one interviews and online surveys guided by the Theoretical Domains Framework were conducted. A total of 20 general/family practitioners were interviewed and 200 general/family practitioners were surveyed. Key findings from interviews were used to guide the development of the survey. Spearman's correlation analysis evaluated the association between general/family practitioners theme domain scores and their familiarity with the 2020 Canadian Adult Obesity Clinical Practice Guidelines. The 200 general/family practitioners surveyed provided representation across Canada, with diversity in age, background, and gender. The most prominent domains related to therapeutic inertia that were positively influenced by familiarity with Clinical Practice Guidelines were Beliefs about Capabilities (rs = .27; p < .01), Skills (rs = .23; p < .01), Behavioural Regulation (rs = .24; p < .01) and Emotions (rs = .23; p < .01). Irrespective of their familiarity with Clinical Practice Guidelines, most general/family practitioners reported that environmental and contextual barriers impact obesity management. Particularly, while financial barriers were reported by participants regardless of Clinical Practice Guidelines familiarity, general/family practitioners familiar with Clinical Practice Guidelines more often reported having time to discuss obesity management with patients. This study identified perceptions, resource and training considerations that contribute to healthcare decision-making and therapeutic inertia in obesity management among general/family practitioners and highlighted key areas to target with interventions in primary care to facilitate obesity management, which should be multi-faceted, with a focus on incorporating obesity education into healthcare providers training programs and improving systemic and financial support.

Bow Hunter Phenomenon From Advanced Cerebrovascular Disease Treated With Subclavian Artery Stenting and Carotid Endarterectomy.

Bow Hunter syndrome (BHS) is a rare disorder characterized by mechanical occlusion of the vertebral artery (VA) during neck rotation, resulting in symptomatic, transient, and positional vertebrobasilar insufficiency. We describe a case of a 76-year-old female who presented with dizziness and right ear tinnitus triggered by right head rotation. Her symptoms would immediately resolve upon returning her head to the neutral position. CT angiogram showed 80% stenosis of the left subclavian artery origin, 50%-70% stenosis of the proximal right internal carotid artery (ICA), and near occlusive stenoses of the origins of the bilateral VAs. After failing conservative management, the patient was treated with left subclavian artery stenting, followed by a right carotid endarterectomy (CEA) 6 weeks later. Follow-up at 1 month showed resolution of paroxysmal symptoms and no neurological sequelae. To our knowledge, there have not yet been reported cases of patients with concurrent BHS, subclavian artery stenosis, and carotid artery stenosis. We suggest that global revascularization via subclavian artery stenting and CEA may be considered as treatment for patients with BHS complicated by other cerebrovascular disease secondary to stenoses of the ICA and subclavian artery. This approach obviates the need for more complex surgery or endovascular intervention of the VA.

The Effects of the Connecting All Generations Through the Gerontech (CARETech) Program on Motivating Young People to Enter the Elderly Care Sector.

PURPOSE: This study aims to organize an intergenerational program to provide unemployed young people with operational skills related to gerontechnology and the experience required to deliver digital outreach rehabilitation services to community-dwelling older people. METHODS: A quasi-experimental research design was adopted. The young participants received a 12-session training program on the management of common chronic diseases, communication with older people, the functions and use of interactive games, and techniques to teach and match interactive games with older people. The perception of elderly outcomes (i.e., knowledge and attitude toward elderly care, willingness to care for the elderly), personal outcomes (i.e., life satisfaction, self-efficacy), and desired vocational outcomes (i.e., hours worked in the nongovernmental organization's center, hours spent with older people) were evaluated preprogram and postprogram. RESULTS: Fifty-one young people joined the program. A statistically significant improvement was seen from preprogram to postprogram in their willingness to care for the elderly (p = .016) and life satisfaction (p = .005), as well as in the number of hours that they spent in the community center volunteering or engaged in social services for older people. DISCUSSION: The findings proved that the program could improve the willingness of young people to care for older people, as well as improve their own life satisfaction. Using gerontechnology can serve to bridge the intergenerational gap and bring benefits to both young adults and older people. It may provide policy makers with a way to address the manpower shortage in elderly care services and help frail older people to age in place.

Efficacy and safety of once-weekly semaglutide 2·4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial.

BACKGROUND: There are currently limited data regarding the effect of semaglutide 2·4 mg in individuals with obesity and prediabetes in clinical trials. We aimed to assess the efficacy and safety of semaglutide 2·4 mg for weight management and glycaemic control in participants with obesity and prediabetes. METHODS: STEP 10 was a randomised, double-blind, parallel-group, phase 3 trial done across 30 trial sites in Canada, Denmark, Finland, Spain, and the UK and included participants aged 18 years or older with a BMI of 30 kg/m2 or higher and prediabetes according to UK National Institute for Health and Care Excellence criteria (defined as having at least one of the following at screening: HbA1c of 6·0-6·4% [42-47 mmol/mol] or fasting plasma glucose [FPG] of 5·5-6·9 mmol/L). Participants were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo with diet and physical activity counselling for 52 weeks, followed by a 28-week off-treatment period. Primary endpoints were percentage change in bodyweight and proportion of participants reverting to normoglycaemia (HbA1c <6·0% [<42 mmol/mol] and FPG <5·5 mmol/L) at week 52 (assessed in all randomly assigned participants by intention to treat). Selective safety data were collected for participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05040971, and is complete. FINDINGS: Between Sept 16 and Dec 29, 2021, 138 participants were randomly assigned to semaglutide 2·4 mg and 69 to placebo. 147 (71%) were female and 60 (29%) were male; 183 (88%) were White. All randomly assigned participants received at least one dose of study drug. Baseline mean age was 53 years (SD 11), bodyweight 111·6 kg (22·2), BMI 40·1 kg/m2 (6·9), waist circumference 120·1 cm (14·7), HbA1c 5·9% (0·3; 41·3 mmol/mol [3·0]), and FPG 5·9 mmol/L (0·6). There was a significantly greater reduction in bodyweight with semaglutide 2·4 mg than with placebo at week 52 (-13·9% [SD 0·7] vs -2·7% [0·6]; estimated treatment difference -11·2% [95% CI -13·0 to -9·4]; p<0·0001). Greater proportions of participants reverted to normoglycaemia at week 52 with semaglutide 2·4 mg than with placebo (103 [81%] of 127 vs nine [14%] of 64; odds ratio 19·8 [95% CI 8·7 to 45·2]; p<0·0001). Serious adverse events occurred in 12 (9%) participants receiving semaglutide 2·4 mg versus six (9%) receiving placebo. Adverse events leading to treatment discontinuation occurred in eight (6%) participants in the semaglutide 2·4 mg group versus one (1%) participant in the placebo group. No new safety signals were reported. INTERPRETATION: Semaglutide 2·4 mg provided superior reduction in bodyweight and reversion to normoglycaemia versus placebo in participants with obesity and prediabetes. The safety and tolerability profile was consistent with previous studies and with the GLP-1 receptor agonist class. These findings support the potential use of semaglutide 2·4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia. FUNDING: Novo Nordisk. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Acute and chronic complication profiles among patients with chronic kidney disease in Alberta, Canada: a retrospective observational study.

BACKGROUND: Chronic kidney disease (CKD) poses a substantial burden to individuals, caregivers, and healthcare systems. CKD is associated with higher risk for adverse events, including renal failure, cardiovascular disease, and death. This study aims to describe comorbidities and complications in patients with CKD. METHODS: We conducted a retrospective observational study linking administrative health databases in Alberta, Canada. Adults with CKD were identified (April 1, 2010 and March 31, 2019) and indexed on the first diagnostic code or laboratory test date meeting the CKD algorithm criteria. Cardiovascular, renal, diabetic, and other comorbidities were described in the two years before index; complications were described for events after index date. Complications were stratified by CKD stage, atherosclerotic cardiovascular disease (ASCVD), and type 2 diabetes mellitus (T2DM) status at index. RESULTS: The cohort included 588,170 patients. Common chronic comorbidities were hypertension (36.9%) and T2DM (24.1%), while 11.4% and 2.6% had ASCVD and chronic heart failure, respectively. Common acute complications were infection (58.2%) and cardiovascular hospitalization (24.4%), with rates (95% confidence interval [CI]) of 29.4 (29.3-29.5) and 8.37 (8.32-8.42) per 100 person-years, respectively. Common chronic complications were dyslipidemia (17.3%), anemia (14.7%), and hypertension (11.1%), with rates (95% CI) of 11.9 (11.7-12.1), 4.76 (4.69-4.83), and 13.0 (12.8-13.3) per 100 person-years, respectively. Patients with more advanced CKD, ASCVD, and T2DM at index exhibited higher complication rates. CONCLUSIONS: Over two-thirds of patients with CKD experienced complications, with higher rates observed in those with cardio-renal-metabolic comorbidities. Strategies to mitigate risk factors and complications can reduce patient burden.

3D documentation and classification of incense tree Aquilaria sinensis (Lour.) Spreng. wounds by photogrammetry and its potential conservation applications.

In recent years, illegal felling of and damage to the incense tree Aquilaria sinensis (Lour.) Spreng. have been reported in Hong Kong. Their native populations are under increasingly severe threat. Therefore, the development of a standard and efficient method to classify and document wounds on vulnerable trees is urgently needed for conservation purposes. In this study, photogrammetry was used to document wounds in A. sinensis through 3D modeling. A total of 752 wound records from 484 individual A. sinensis trees from Hong Kong were included to establish a new wound classification system. Our major findings include a novel standardized procedure for photogrammetric documentation and a wound classification system. The results of this study will facilitate A. sinensis conservation, by enhancing wound documentation and information transfer to law enforcement and education.

Venous Stasis Ulceration due to Massive Splenomegaly Causing Iliac Vein Compression From Secondary Myelofibrosis.

Venous stasis ulcers are nonhealing lesions due to venous hypertension secondary to valvular dysfunction or deep venous outflow obstruction. We describe a case of a 71-year-old male with a history of polycythemia vera, secondary myelofibrosis, and massive splenomegaly up to 38 cm who presented with chronic, perimalleolar venous stasis ulcers and pain on the left lower extremity. CT showed significant compression of the left common iliac vein due to mass effect from the spleen. He was managed medically while being evaluated for partial splenic artery embolization but expired due to other chronic conditions before any intervention could be performed. Partial splenic artery embolization may be considered as a treatment option for patients with symptomatic iliac vein compression due to massive splenomegaly secondary to myelofibrosis, as long as extramedullary hematopoiesis is not compromised.

Clinical Developments and Challenges in Treating FGFR2-Driven Gastric Cancer.

Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement in survival outcomes; however, metastatic GC remains a lethal malignancy and amongst the leading causes of cancer-related mortality worldwide. Importantly, the ongoing molecular characterisation of GCs continues to uncover potentially actionable molecular targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs in approximately 3-11% of GCs. However, whilst several inhibitors of FGFR have been clinically tested to-date, there are currently no approved FGFR-directed therapies for GC. In this review, we summarise the significance of FGFR2 as an actionable therapeutic target in GC, examine the recent pre-clinical and clinical data supporting the use of small-molecule inhibitors, antibody-based therapies, as well as novel approaches such as proteolysis-targeting chimeras (PROTACs) for targeting FGFR2 in these tumours, and discuss the ongoing challenges and opportunities associated with their clinical development.

A systematic approach for authentication of medicinal Patrinia species using an integration of morphological, chemical and molecular methods.

Four common Patrinia species, including P. heterophylla, P. monandra, P. scabiosifolia and P. villosa, have been documented as herbal medicines with various clinical applications, such as anti-cancer, anti-diarrhea and sedative. However, the authentication of medicinal Patrinia species poses a problem, particularly with the processed herbal materials. This study aimed to systematically authenticate the four medicinal Patrinia species in the market using morphological and chemical characterization, as well as DNA markers. We found the species identity authenticated by traditional morphologies were in good agreement with both chemical and molecular results. The four species showed species-specific patterns in chromatographic profiles with distinct chemical markers. We also revealed the power of complete chloroplast genomes in species authentication. The sequences of targeted loci, namely atpB, petA, rpl2-rpl23 and psaI-ycf4, contained informative nucleotides for the species differentiation. Our results also facilitate authentication of medicinal Patrinia species using new DNA barcoding markers. To the best of our knowledge, this is the first report on the application of morphology, chemical fingerprinting, complete chloroplast genomes and species-specific Insertion-Deletions (InDels) in differentiating Patrinia species. This study reported on the power of a systematic, multidisciplinary approach in authenticating medicinal Patrinia species.

Cost-effectiveness of weight-management pharmacotherapies in Canada: a societal perspective.

OBJECTIVES: This study aimed to assess the cost-effectiveness of weight-management pharmacotherapies approved by Canada Health, i.e., orlistat, naltrexone 32 mg/bupropion 360 mg (NB-32), liraglutide 3.0 mg and semaglutide 2.4 mg as compared to the current standard of care (SoC). METHODS: Analyses were conducted using a cohort with a mean starting age 50 years, body mass index (BMI) 37.5 kg/m2, and 27.6% having type 2 diabetes. Using treatment-specific changes in surrogate endpoints from the STEP trials (BMI, glycemic, blood pressure, lipids), besides a network meta-analysis, the occurrence of weight-related complications, costs, and quality-adjusted life-years (QALYs) were projected over lifetime. RESULTS: From a societal perspective, at a willingness-to-pay (WTP) threshold of CAD 50 000 per QALY, semaglutide 2.4 mg was the most cost-effective treatment, at an incremental cost-utility ratio (ICUR) of CAD 31 243 and CAD 29 014 per QALY gained versus the next best alternative, i.e., orlistat, and SoC, respectively. Semaglutide 2.4 mg extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg and remained cost-effective both under a public and private payer perspective. Results were robust to sensitivity analyses varying post-treatment catch-up rates, longer treatment durations and using real-world cohort characteristics. Semaglutide 2.4 mg was the preferred intervention, with a likelihood of 70% at a WTP threshold of CAD 50 000 per QALY gained. However, when the modeled benefits of weight-loss on cancer, mortality, cardiovascular disease (CVD) or osteoarthritis surgeries were removed simultaneously, orlistat emerged as the best value for money compared with SoC, with an ICUR of CAD 35 723 per QALY gained. CONCLUSION: Semaglutide 2.4 mg was the most cost-effective treatment alternative compared with D&E or orlistat alone, and extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg. Results were sensitive to the inclusion of the combined benefits of mortality, cancer, CVD, and knee osteoarthritis.

Obesity management from the perspectives of people living with obesity in Canada: A mixed-methods study.

AIMS: To identify and better understand themes related to why people living with obesity (PwO) in Canada may not use professional support and to explore potential strategies to address the challenges. METHODS: One-on-one interviews and online surveys, informed by the Theoretical Domains Framework, were conducted. A total of 20 PwO were interviewed and a separate group of 200 PwO were surveyed. Results from the interviews guided the development of the survey. Spearman's correlation analysis was performed to investigate the association between the theme domain scores of the PwO and their prior experience with obesity management strategies. RESULTS: The 200 PwO surveyed provided representation across Canada and were diverse in age, background and gender. The most prominent domains associated with use of professional support by PwO were: Intention (rs = -0.25; p < 0.01); Social/Professional Role and Identity (rs = -0.15; p < 0.05); and Optimism (rs = -0.15; p < 0.05). For example, PwO without professional support less often reported being transparent in obesity discussions, perceived obesity to be part of their identity, and expected to manage the illness long term. Many PwO hesitated to use various adjunctive therapies due to concerns about affordability, long-term effectiveness, and side effects. CONCLUSION: This study identified contextual, perception and resource considerations that contribute to healthcare decision-making and the use by PwO of professional support to manage obesity, and highlighted key areas to target with interventions to facilitate obesity management. Strategies such as consistent access to healthcare support and educational resources, as well as improved financial support may help PwO to feel more comfortable with exploring new strategies and take control of their healthcare.

Genetic and immune landscape evolution in MMR-deficient colorectal cancer.

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/ß-catenin, mitogen-activated protein kinase, and TGF-ß receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Role of gut microbiota on regulation potential of Dendrobium officinale Kimura & Migo in metabolic syndrome: In-vitro fermentation screening and in-vivo verification in db/db mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium officinale Kimura & Migo (DEN) is a traditional medicine in China since Han dynasty. Decoction of its stem is often used in the treatment of Type-II diabetes (T2D), which is a typical metabolic disease accompanied with the impaired metabolic function of blood glucose and lipid. AIM OF THE STUDY: Our study aimed to investigate the role of gut microbiota in differentiating DEN from different sources and its related pathway in the alleviation of metabolic syndromes induced by T2D. MATERIALS AND METHODS: The aqueous extracts of four commercially available Dendrobium (DEN-1∼4) were prepared and screened through an in-vitro fermentation system. Based on their alterations in monosaccharide composition and short chain fatty acids (SCFA) formation during fermentation with db/db faecal fluid, one DEN extract was selected for further in vivo verification. The selected Dendrobium (DEN-4) was orally administered to db/db mice for 16 days once daily at the dosage of 200 mg/kg followed by evaluating its effect on blood glucose level, liver function and intestinal microenvironment including alterations of intestinal integrity and gut microbiota composition. In addition, liver metabolomics analysis was employed to reveal the related metabolic pathways. RESULTS: Different extent of SCFA formation and utilization of monosaccharides were observed for the extracts of four DEN from different sources with a negative correlation between SCFA level and the ratio of Utilized glucose/Utilized mannose observed in the in-vitro fermentation system with db/db faecal fluid. DEN-4 with the highest SCFA formation during the in-vitro fermentation was selected and exhibited significantly hypoglycaemic effect in db/db mice with the alleviation of hepatic steatosis and impaired lipid homeostasis. Further mechanistic studies revealed that orally administered DEN-4 could improve the intestinal integrity of db/db mice via elevating their tight junction protein (ZO-1 and Occludin) expression in the colon and improve the diversity of gut microbiota with enhanced formation of SCFA. Moreover, metabolomics and KEGG pathway analysis of liver tissues suggested that the alleviated metabolic syndrome in db/db mice by DEN-4 might possibly be achieved through activation of PPAR pathway. CONCLUSION: Our current study not only revealed the potential of gut microbiota in differentiating DEN from different sources, but also demonstrated that DEN exhibited its beneficial effect on the T2D induced metabolic syndrome possibly through enhancement of intestinal integrity and activation of PPAR pathway via gut-liver axis in db/db mice.

Prevalence of Adult Type 2 Diabetes Mellitus and Related Complications in Alberta, Canada: A Retrospective, Observational Study Using Administrative Data.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a prevalent chronic disease and a leading cause of morbidity/mortality in Canada. We evaluated the burden of T2DM in Alberta, Canada, by estimating the 5-year period prevalence of T2DM and rates of comorbidities and complications/conditions after T2DM. METHODS: We conducted a population-based, retrospective study linking administrative health databases. Individuals with T2DM (≥18 years of age) were identified between 2008-2009 and 2018-2019 using a published algorithm, with follow-up data to March 2020. The 5-year period prevalence was estimated for 2014-2015 to 2018-2019. Individuals with newly identified T2DM, ascertained between 2010-2011 and 2017-2018 with a lookback period between 2008-2009 and 2009-2010 and a minimum 1 year of follow-up data, were evaluated for subsequent cardiovascular, diabetic, renal, and other complication/condition frequencies (%) and rates (per 100 person-years). Complications/conditions were stratified by atherosclerotic cardiovascular disease (ASCVD) status at index and age. RESULTS: The 5-year period prevalence of T2DM was 11,051 per 100,000 persons, with the highest prevalence in men 65 to <75 years of age. There were 195,102 individuals included in the cohort (mean age 56.7±14.7 years). The most frequently reported complications/conditions (rates per 100 person-years) were acute infection (23.10, 95% confidence interval [CI] 23.00 to 23.30), hypertension (17.30, 95% CI 16.80 to 17.70), and dyslipidemia (12.20, 95% CI 11.90 to 12.40). Individuals who had an ASCVD event/procedure and those ≥75 years of age had higher rates of complications/conditions. CONCLUSIONS: We found that over half of the individuals had hypertension or infection after T2DM. Also, those with ASCVD had higher rates of complications/conditions. Strategies to mitigate complications/conditions after T2DM are required to reduce the burden of this disease on individuals and health-care systems.

Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease.

Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. Therefore, we examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls. We found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression. Striatal overexpression of Activin A in vivo improved motor learning on the rotarod task, and normalized striatal neuronal eNMDAR-mediated currents, membrane capacitance and spontaneous excitatory postsynaptic current frequency in the YAC128 mice. These results support the therapeutic potential of Activin A signaling and targeting eNMDARs to restore striatal neuronal health and ameliorate behavioral deficits in HD.

Outcomes of de-prescribing proton pump inhibitors during acute admissions in a general medical unit: a pilot study.

The study describes the feasibility and short-to-medium-term efficacy of an evidence-based proton pump inhibitor (PPI) de-prescribing initiative undertaken as part of routine clinical care during acute admissions in a general medical unit. Of the 44 (median (IQR) age 75.5 (13.75) years; females 25 (57%)) who participated in the study, de-prescription was maintained in 29 (66%) and 27 (61%) patients at 12 and 26 weeks respectively.

The Complete Chloroplast Genomes of Nine Smilacaceae Species from Hong Kong: Inferring Infra- and Inter-Familial Phylogeny.

The Smilacaceae is a cosmopolitan family consisting of 200-370 described species. The family includes two widely accepted genera, namely Smilax and Heterosmilax. Among them, the taxonomical status of Heterosmilax has been continuously challenged. Seven Smilax and two Heterosmilax species can be found in Hong Kong, with most of them having medicinal importance. This study aims to revisit the infra-familial and inter-familial relationships of the Smilacaceae using complete chloroplast genomes. The chloroplast genomes of the nine Smilacaceae species from Hong Kong were assembled and annotated, which had sizes of 157,885 bp to 159,007 bp; each of them was identically annotated for 132 genes, including 86 protein-coding genes, 38 transfer RNA genes, and 8 ribosomal RNA genes. The generic status of Heterosmilax was not supported because it was nested within the Smilax clade in the phylogenetic trees, echoing previous molecular and morphological studies. We suggest delimitating the genus Heterosmilax as a section under the genus Smilax. The results of phylogenomic analysis support the monophyly of Smilacaceae and the exclusion of Ripogonum from the family. This study contributes to the systematics and taxonomy of monocotyledons, authentication of medicinal Smilacaceae, and conservation of plant diversity.

Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. METHODS: Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25-50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. RESULTS: Between 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5-75%) for DPYD heterozygous carriers and 93.2% (42.9-100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924). CONCLUSIONS: Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.