Determining the future role of clinical practice guidelines: The experience of Australia and New Zealand.

There has been recent discussion in Australia and New Zealand concerning the utility of Clinical Practice Guidelines (CPGs) and the role of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) in their development. The College Board therefore established a Steering Group (SG) to oversee an exploration of options and produce recommendations about contemporary approaches to the development of high-quality evidence-based clinical practice guidance for psychiatry. This paper outlines the SG's conclusions and recommendations, as well as the underlying methods and reasoning. In particular, we discuss best practice and recent developments in the synthesis of research evidence. Account has been taken of the opportunities offered by digital technologies, the proliferation of clinical evidence and awareness of the gains to be made by increased inclusion of lived-experience perspectives. It is recommended that the broader concept of best practice resources (BPRs) as now emphasised in so many fields of service is the most appropriate starting point for the College's role in this area especially as the expertise of the College and its fellows lends itself to the development of a range of BPRs. In conclusion, contemporary guidance needs to be tailored to the requirements of the practitioners seeking it, to articulate the real-world needs and experiences of patients, and to be delivered in a contemporary format that is responsive to rapidly emerging evidence. The experience in Australia and New Zealand may have implications elsewhere for the development of CPGs and BPRs more broadly.

A practical evidence-based approach to management of type 2 diabetes in children and young people (CYP): UK consensus.

BACKGROUND: Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes. METHODS: Multidisciplinary professionals from The Association of Children's Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. RESULTS AND DISCUSSION: Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events. CONCLUSIONS: This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.

COVID-19 pandemic impact on adolescent mental health: a reassessment accounting for development.

Current prospective reports suggest a pandemic-related increase in adolescent mental health problems. We examine whether age-related change over 11-14 years accounts for this increase. Mothers and adolescents in a UK-based birth cohort (Wirral Child Health and Development Study; WCHADS; N = 737) reported on adolescent depression and behavioural problems pre-pandemic (December 2019-March 2020), mid-pandemic (June 2020-March 2021) and late pandemic (July 2021-March 2022). Analysis used repeated measures models for over-dispersed Poisson counts with an adolescent-specific intercept with age as a time-varying covariate. Maturational curves for girls, but not for boys, showed a significant increase in self-reported depression symptoms over ages 11-14 years. Behavioural problems decreased for both. After adjusting for age-related change, girls' depression increased by only 13% at mid-pandemic and returned to near pre-pandemic level at late pandemic (mid versus late - 12%), whereas boys' depression increased by 31% and remained elevated (mid versus late 1%). Age-adjusted behavioural problems increased for both (girls 40%, boys 41%) and worsened from mid- to late pandemic (girls 33%, boys 18%). Initial reports of a pandemic-related increase in depression in young adolescent girls could be explained by a natural maturational rise. In contrast, maturational decreases in boys' depression and both boys' and girls' behavioural problems may mask an effect of the pandemic.

Should we abandon hormonal therapy in endometrial cancer? Outcomes of recurrent and metastatic endometrial cancer treated with systemic progestins.

PURPOSE: The objective of this study is to determine primary survival endpoints in women with recurrent and metastatic endometrial carcinoma (RMEC) treated with progestins. METHODS: A retrospective chart review was conducted at The Ottawa Hospital using electronic medical records. Inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥one line of progestin treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Of 2342 cases reviewed, 74 met inclusion criteria. Sixty-six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of tumors by grade was: 1: 25 (33.3%), 2: 30 (40.0%), and 3: 20 (26.7%). The PFS and OS for the entire study sample was 14.3 months (95% CI 6.2-17.9) and 23.3 months (14.8-36.8), respectively. The PFS for patients with Grade 1-2 RMEC was 15.7 months (8.0, 19.5), compared to 5.0 months (3.0, 23.0) with Grade 3 disease. The OS for patients with Grade 1-2 versus Grade 3, was 25.9 months (15.3, 40.3) versus 12.5 months (5.7, 35.9), respectively. Thirty-four (45.9%) and 40 (54.1%) patients were treated with 0 and ≥1 line of chemotherapy. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed. CONCLUSIONS: This real-world data on RMEC suggests there is a role for progestins in select subgroups of women. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed.

A longitudinal comparison of emotional, behavioral and attention problems in autistic and typically developing children.

BACKGROUND: Mental health problems are elevated in autistic individuals but there is limited evidence on the developmental course of problems across childhood. We compare the level and growth of anxious-depressed, behavioral and attention problems in an autistic and typically developing (TD) cohort. METHODS: Latent growth curve models were applied to repeated parent-report Child Behavior Checklist data from age 2-10 years in an inception cohort of autistic children (Pathways, N = 397; 84% boys) and a general population TD cohort (Wirral Child Health and Development Study; WCHADS; N = 884, 49% boys). Percentile plots were generated to quantify the differences between autistic and TD children. RESULTS: Autistic children showed elevated levels of mental health problems, but this was substantially reduced by accounting for IQ and sex differences between the autistic and TD samples. There was small differences in growth patterns; anxious-depressed problems were particularly elevated at preschool and attention problems at late childhood. Higher family income predicted lower base-level on all three dimensions, but steeper increase of anxious-depressed problems. Higher IQ predicted lower level of attention problems and faster decline over childhood. Female sex predicted higher level of anxious-depressed and faster decline in behavioral problems. Social-affect autism symptom severity predicted elevated level of attention problems. Autistic girls' problems were particularly elevated relative to their same-sex non-autistic peers. CONCLUSIONS: Autistic children, and especially girls, show elevated mental health problems compared to TD children and there are some differences in predictors. Assessment of mental health should be integrated into clinical practice for autistic children.

A practical approach to continuous glucose monitoring (rtCGM) and FreeStyle Libre systems (isCGM) in children and young people with Type 1 diabetes.

Real-time continuous glucose monitoring (rtCGM) and FreeStyle Libre glucose monitoring systems (isCGM) are new evolving technologies used in the management of Type 1 diabetes. They offer potential to improve diabetes control and reduce hypoglycaemia. rtCGM can be linked to insulin pump providing hybrid closed loop therapy. Families of children and young people are keen to have the benefit from these technologies. These are relatively expensive so it is important that health care professionals, families of children and young people (CYP) with diabetes are adequately trained in the use of these devices. Health care professionals need to be able to make patient selection based on individual needs and preferences to achieve maximum benefit. Association of Children's Diabetes Clinicians (ACDC) developed a comprehensive guideline in 2017 to help identify which patients may be most likely to benefit and how these technologies may be practically implemented. Since then new technologies have been introduced and the use of GCM has expanded in routine clinical practice. This article, aims to provide a practical approach and help identify which patients may be most likely to benefit and how the technology may be implemented in order to maximise the clinical benefits.

Synergy between callous-unemotional traits and aggression in preschool children: Cross-informant and cross-cultural replication in the UK Wirral Child Health and Development Study, and the Colombian La Sabana Parent-Child Study.

Incremental prediction of aggression from callous-unemotional (CU) traits is well established, but cross-cultural replication and studies of young children are needed. Little is understood about the contribution of CU traits in children who are already aggressive. We addressed these issues in prospective studies in the United Kingdom and Colombia. In a UK epidemiological cohort, CU traits and aggression were assessed at age 3.5 years, and aggression at 5.0 years by mothers (N = 687) and partners (N = 397). In a Colombian general population sample, CU traits were assessed at age 3.5 years and aggression at 3.5 and 5.0 years by mother report (N = 220). Analyses consistently showed prediction of age-5.0 aggression by age-3.5 CU traits controlling for age-3.5 aggression. Associations between age-3.5 CU traits and age-5.0 aggression were moderated by aggression at 3.5 years, with UK interaction terms, same informant, ß = .07 p = .014 cross-informant, ß = .14 p = .002, and in Colombia, ß = .09 p = .128. The interactions arose from stronger associations between CU traits and later aggression in those already aggressive. Our findings with preschoolers replicated across culturally diverse settings imply a major role for CU traits in the maintenance and amplification of already established aggression, and cast doubt on their contribution to its origins.

Failure to meet extubation criteria in the setting of suspected buffalo chest physiology.

We report the case of a patient who failed to meet tracheal extubation criteria due to low tidal volumes from suspected buffalo chest, which is a single pleural space physiology. This presentation followed the resection of a large pleural mass in a 59-year-old woman with a history of exercise-induced asthma, hypertension and tumour-related chronic respiratory failure. Creation of a pleuro-pleural communication during the resection of this large, unilateral pleural mass led to bilateral pneumothoraces and contributed to patients inability to generate negative inspiratory force leading to failure to meet extubation criteria. Buffalo chest may be more prevalent than suspected and should be a differential diagnosis for low tidal volumes with spontaneous ventilation following thoracic surgery. It can be differentiated from other causes of decreased tidal volume using clinical examination, ultrasound and radiography. Bilateral chest tube placement can be considered to expedite pneumothorax resolution and tracheal extubation.

The evolution of pulmonary function in childhood onset Mucopolysaccharidosis type I.

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.

Factors associated with the contemplative stage of readiness to initiate osteoporosis treatment.

We investigated the factors associated with readiness for initiating osteoporosis treatment in women at high risk of fracture. We found that women in the contemplative stage were more likely to report previously being told having osteoporosis or osteopenia, acknowledge concern about osteoporosis, and disclose prior osteoporosis treatment. INTRODUCTION: Understanding factors associated with reaching the contemplative stage of readiness to initiate osteoporosis treatment may inform the design of behavioral interventions to improve osteoporosis treatment uptake in women at high risk for fracture. METHODS: We measured readiness to initiate osteoporosis treatment using a modified form of the Weinstein Precaution Adoption Process Model (PAPM) among 2684 women at high risk of fracture from the Activating Patients at Risk for OsteoPOroSis (APROPOS) clinical trial. Pre-contemplative participants were those who self-classified in the unaware and unengaged stages of PAPM (stages 1 and 2). Contemplative participants were those in the undecided, decided not to act, or decided to act stages of PAPM (stages 3, 4, and 5). Using multivariable logistic regression, we evaluated participant characteristics associated with levels of readiness to initiate osteoporosis treatment. RESULTS: Overall, 24% (N = 412) self-classified in the contemplative stage of readiness to initiate osteoporosis treatment. After adjusting for age, race, education, health literacy, and major osteoporotic fracture in the past 12 months, contemplative women were more likely to report previously being told they had osteoporosis or osteopenia (adjusted odds ratio [aOR] (95% CI) 11.8 (7.8-17.9) and 3.8 (2.5-5.6), respectively), acknowledge concern about osteoporosis (aOR 3.5 (2.5-4.9)), and disclose prior osteoporosis treatment (aOR 4.5 (3.3-6.3)) than women who self-classified as pre-contemplative. CONCLUSIONS: For women at high risk for future fractures, ensuring women's recognition of their diagnosis of osteoporosis/osteopenia and addressing their concerns about osteoporosis are critical components to consider when attempting to influence stage of behavior transitions in osteoporosis treatment.

Severe hypokalaemia in diabetic ketoacidosis: a contributor to central pontine myelinolysis?

Summary: Hypokalaemia at presentation of diabetic ketoacidosis is uncommon as insulin deficiency and metabolic acidosis shifts potassium extracellularly. However, hypokalaemia is a recognised complication of the management of diabetic ketoacidosis as insulin administration and correction of metabolic acidosis shifts potassium intracellularly. We describe the case of a 9-year-old girl with newly diagnosed type 1 diabetes mellitus presenting in diabetic ketoacidosis, with severe hypokalaemia at presentation due to severe and prolonged emesis. After commencing management for her diabetic ketoacidosis, her serum sodium and osmolality increased rapidly. However, despite maximal potassium concentrations running through peripheral access, and multiple intravenous potassium 'corrections', her hypokalaemia persisted. Seventy two hours after presentation, she became drowsy and confused, with imaging demonstrating central pontine myelinolysis ­ a rare entity seldom seen in diabetic ketoacidosis management in children despite rapid shifts in serum sodium and osmolality. We review the literature associating central pontine myelinolysis with hypokalaemia and hypothesise as to how the hypokalaemia may have contributed to the development of central pontine myelinolysis. We also recommend an approach to the management of a child in diabetic ketoacidosis with hypokalaemia at presentation. Learning Points: Hypokalaemia is a recognised complication of treatment of paediatric diabetic ketoacidosis that should be aggressively managed to prevent acute complications. Central pontine myelinolysis is rare in children, and usually observed in the presence of rapid correction of hyponatraemia. However, there is observational evidence of an association between hypokalaemia and central pontine myelinolysis, potentially by priming the endothelial cell membrane to injury by lesser fluctuations in osmotic pressure. Consider central pontine myelinolysis as a complication of the management of paediatric diabetic ketoacidosis in the presence of relevant symptoms with profound hypokalaemia and/or fluctuations in serum sodium levels. We have suggested an approach to the management strategies of hypokalaemia in paediatric diabetic ketoacidosis which includes oral potassium supplements if tolerated, minimising the duration and the rate of insulin infusion and increasing the concentration of potassium intravenously (via central line if necessary).

TRAIL responses are enhanced by nuclear export inhibition in osteosarcoma.

Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-tumour agent that induces apoptosis of malignant cells through activation of death receptors. Death receptor agonistic antibodies are in clinical trials as TRAIL-mimetics, however, along with TRAIL monotherapy, there is limited efficacy due to the rapid emergence of TRAIL resistance, or due to existing TRAIL-insensitive disease. TRAIL-sensitisers, which enhance TRAIL activity or overcome TRAIL resistance, may facilitate death receptor agonists as viable anti-tumour strategies. In this study we demonstrate that the nuclear export inhibitor Leptomycin B, is a potent in vitro TRAIL-sensitiser in osteosarcoma cell lines. Leptomycin B works synergistically with both TRAIL and death receptor 5 agonistic antibodies to induce apoptosis in TRAIL sensitive cell lines. Further, Leptomycin B sensitises TRAIL-insensitive cell lines to TRAIL and death receptor agonistic antibody mediated apoptosis. We also confirmed that aldehyde dehydrogenase (ALDH) positive cells are not resistant to the apoptotic effects of TRAIL and Leptomycin B, an important observation since ALDH positive cells can have enhanced tumorigenicity and are implicated in disease recurrence and metastasis. The nuclear export pathway in combination with death receptor agonists, is a potential therapeutic strategy in osteosarcoma and warrants further research on clinically relevant selective inhibitors of nuclear export.

Offering HCV treatment to prisoners is an important opportunity: key principles based on policy and practice assessment in Europe.

BACKGROUND: Prisoners have a high prevalence of hepatitis C virus (HCV) infection but may find it difficult to access healthcare services. This may be related to risk behaviour including history of injecting drugs and marginalisation related to problem drug use/ opioid use disorder (OUD). Direct-acting antiviral products with superior efficacy and safety compared to interferon-based regimens offer HCV cure. Many citizens in Europe have been treated, although few received therapy in prisons. METHODS: Analysis of prisoner HCV treatment need and policy determinants of clinical practice was completed for 5 EU countries. Evidence was collected from national statistical sources and peer-reviewed publications to describe prison populations and HCV prevalence, to map national prison/ HCV health policy or guidance. A consensus of important principles for prisoner HCV care was developed. RESULTS: Data from published sources describing prisoner HCV prevalence is limited. Prisoner population requiring HCV treatment is not known; estimated numbers based on analysis of evidence: England and Wales, 9000, France, 8000, Spain, 6000, Italy, 6000, Germany, 6000. Treatment access: national law defines right to equivalent care in all countries implying access to HCV therapy in prison similar to community; useful prisoner HCV guidance facilitating treatment decisions present in: 4 of 5 national/ regional HCV policy documents, 4 of 5 national prison healthcare policies. Four of five had practical prison HCV clinical guidelines. Despite existence of policy, implementation of guidance, and so HCV treatment, is suboptimal in many locations. CONCLUSIONS: Prison is an important location to detect, address and treat HCV infection in people who may be underserved for healthcare and find it difficult to navigate community treatment pathways. This is often related to problems with OUD and resulting social inequity. HCV management in prisons must be improved. Policy and clinical practice guidance must be set to promote treatment, and practical steps to make treatment easy should be followed including education to promote engagement, set-up of optimal screening and work up processes with modern tools to reduce time needed/ achieve efficiency; programs to make it easier to get specialists' input include remote working and nurse-led services.

Correction to: Hip fracture trends in the United States, 2002 to 2015.

The name of the first author, E.M. Lewiecki, was rendered incorrectly in the original publication. The publisher regrets any inconvenience and is pleased to correct the error here.

Outcomes from 18 years of cervical spine surgery in MPS IVA: a single centre's experience.

PURPOSE: This study examines the long-term outcomes of paediatric Morquio (MPS IVA) patients undergoing cervical spine surgery and evaluates the factors that impacting this. METHODS: A retrospective review was performed on all MPS IVA patients undergoing cervical spine surgery, since the introduction of standardised neuroradiological screening. The impact of preoperative neurological status, growth, genotype and radiological status on outcome is assessed, whilst long-term surgical, radiological and neurological outcomes are documented. RESULTS: Twenty-six of the eighty-two MPS IVA patients (31%) reviewed underwent cervical spine surgery at a median age of 6.1 years (range, 1.45 to 15.24). Preoperatively, cord signal change was seen in 11 patients with 5 being myelopathic; however, 6 clinically manifesting patients had no overt cord signal change. Postoperatively, none of the 14 preoperatively clinically asymptomatic patients followed long term progressed neurologically during a median follow-up of 77.5 months (range = 18-161). Of the ten preoperatively clinically symptomatic patients who were followed up for the same duration, seven continued to deteriorate, two initially improved and one remained stable. Radiological follow-up performed for a median duration of 7 years (range = 0.5-16) has shown a degree of stenosis at the level immediately caudal to the termination of the graft in 76% of patients, though only one has become clinically symptomatic and required revision. CONCLUSIONS: Once clinically elicitable neurological signs become evident in patients with MPS IVA, they tend to progress despite surgical intervention. Referring clinicians should also not be falsely reassured by the lack of T2 spinal cord signal change but should consider surgical intervention in the face of new clinical symptomology or radiological signs of progressive canal stenosis or instability.

Does human endometrial LGR5 gene expression suggest the existence of another hormonally regulated epithelial stem cell niche?

STUDY QUESTION: Is human endometrial leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) gene expression limited to the postulated epithelial stem cell niche, stratum basalis glands, and is it hormonally regulated? SUMMARY ANSWER: LGR5 expressing cells are not limited to the postulated stem cell niche but LGR5 expression is hormonally regulated. WHAT IS KNOWN ALREADY: The human endometrium is a highly regenerative tissue; however, endometrial epithelial stem cell markers are yet to be confirmed. LGR5 is a marker of stem cells in various epithelia. STUDY DESIGN, SIZE, DURATION: The study was conducted at a University Research Institute. Endometrial samples from 50 healthy women undergoing benign gynaecological surgery with no endometrial pathology at the Liverpool Women's hospital were included and analysed in the following six sub-categories; proliferative, secretory phases of menstrual cycle, postmenopausal, those using oral and local progestagens and samples for in vitro explant culture. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, we used the gold standard method, in situ hybridisation (ISH) along with qPCR and a systems biology approach to study the location of LGR5 gene expression in full thickness human endometrium and Fallopian tubes. The progesterone regulation of endometrial LGR5 was examined in vivo and in short-term cultured endometrial tissue explants in vitro. LGR5 expression was correlated with epithelial proliferation (Ki67), and expression of previously reported epithelia progenitor markers (SOX9 and SSEA-1) immunohistochemistry (IHC). MAIN RESULTS AND THE ROLE OF CHANCE: LGR5 gene expression was significantly higher in the endometrial luminal epithelium than in all other epithelial compartments in the healthy human endometrium, including the endometrial stratum basalis (P < 0.05). The strongest SSEA-1 and SOX9 staining was observed in the stratum basalis glands, but the general trend of SOX9 and SSEA-1 expression followed the same cyclical pattern of expression as LGR5. Stratum functionalis epithelial Ki67-LI and LGR5 expression levels correlated significantly (r = 0.74, P = 0.01), however, they did not correlate in luminal and stratum basalis epithelium (r = 0.5 and 0.13, respectively). Endometrial LGR5 demonstrates a dynamic spatiotemporal expression pattern, suggesting hormonal regulation. Oral and local progestogens significantly reduced endometrial LGR5 mRNA levels compared with women not on hormonal treatment (P < 0.01). Our data were in agreement with in silico analysis of published endometrial microarrays. LARGE SCALE DATA: We did not generate our own large scale data but interrogated publically available large scale data sets. LIMITATIONS, REASONS FOR CAUTION: In the absence of reliable antibodies for human LGR5 protein and validated lineage markers for the various epithelial populations that potentially exist within the endometrium, our study does not formally characterise or examine the functional ability of the resident LGR5+ cells as multipotent. WIDER IMPLICATIONS OF THE FINDINGS: These data will facilitate future lineage tracing studies in the human endometrial epithelium; to identify the location of stem cells and further complement the in vitro functional studies, to confirm if the LGR5 expressing epithelial cells indeed represent the epithelial stem cell population. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by funding from the Wellbeing of Women project grant (RTF510) and Cancer Research UK (A14895). None of the authors have any conflicts of interest to disclose.

Manuka honey and methylglyoxal increase the sensitivity of Staphylococcus aureus to linezolid.

The continued emergence and global spread of bacterial antibiotic resistance has fuelled the search for novel antimicrobial agents and resistance-modifying compounds. Manuka honey has both antimicrobial properties and the ability to increase the efficacy of FDA-approved antibiotic drugs. Compared to other types of honey, manuka honey contains elevated levels of methylglyoxal (MGO), a small molecule that contributes to its antibacterial activity. Manuka honey has shown particular promise for the treatment of antibiotic-resistant Gram-positive organisms such as methicillin-resistant Staphylococcus aureus. Linezolid is an oxazolidinone antibiotic used in the treatment of infections caused by a range of Gram-positive pathogens. Here, we demonstrate that manuka honey, as well as MGO in isolation, increases the sensitivity of S. aureus to linezolid in both agar diffusion and broth microdilution assays. This synergistic interaction is mediated in part by increased intracellular accumulation of linezolid in the presence of MGO. SIGNIFICANCE AND IMPACT OF THE STUDY: Manuka honey is widely recognized for its antimicrobial activity. Our study adds to the growing body of evidence that manuka honey and its active ingredient, methylglyoxal (MGO), can also function as antibiotic adjuvants. In this study, we provide the first report of synergy between MGO and linezolid against Staphylococcus aureus. Both manuka honey and purified MGO significantly increased the sensitivity of S. aureus to linezolid.

The epidemiology of wrist fractures in older men: the Osteoporotic Fractures in Men (MrOS) study.

There is limited wrist fracture information on men. Our goal was to calculate frequency and identify risk factors for wrist fracture in the Osteoporotic Fractures in Men (MrOS) study. We confirmed that fracture history and certain medications are predictors, and identified novel predictors including markers of kidney function and physical performance. INTRODUCTION: To calculate the incidence of wrist fractures and their risk factors in older community-dwelling men from the US Osteoporotic Fractures in Men (MrOS) study. METHODS: Using triannual postcards, we identified incident wrist fractures (centrally confirmed by radiology) in men aged ≥ 65. Potential risk factors included the following: demographics, lifestyle, bone mineral density (BMD), selected medications, biomarkers, and physical function and performance measures. Both baseline and time-varying models were adjusted for age, race/ethnicity, MrOS geographic location, and competing mortality risks. RESULTS: We observed 97 incident wrist fractures among 5875 men followed for an average of 10.8 years. The incidence of wrist fracture was 1.6 per 1000 person-years overall and ranged from 1.0 among men aged 65-69 to 2.4 among men age ≥ 80. Significant predictors included the following: fracture history after age 50 [hazard ratio (95% CI): 2.48 (1.65, 3.73)], high serum phosphate [1.25 (1.02, 1.53)], use of selective serotonin receptor inhibitor (SSRI) [3.60 (1.96, 6.63), decreased right arm BMD [0.49 (0.37, 0.65) per SD increase], and inability to perform the grip strength test [3.38 (1.24, 9.25)]. We did not find associations with factors commonly associated with wrist and other osteoporosis fractures like falls, diabetes, calcium and vitamin D intake, and alcohol intake. CONCLUSIONS: Among these older, community-dwelling men, we confirmed that fracture history is a strong predictor of wrist fractures in men. Medications such as SSRIs and corticosteroids also play a role in wrist fracture risk. We identified novel risk factors including kidney function and the inability to perform the grip strength test.