Long-term cost-effectiveness of Dexcom G6 real-time continuous glucose monitoring system in people with type 1 diabetes in Australia.

INTRODUCTION: Real-time continuous glucose monitoring (rt-CGM) allows patients with diabetes to adjust insulin dosing, potentially improving glucose control. This study aimed to compare the long-term cost-effectiveness of the Dexcom G6 rt-CGM device versus self-monitoring of blood glucose (SMBG) and flash glucose monitoring (FGM) in Australia in people with type 1 diabetes (T1D). METHODS: Long-term costs and clinical outcomes were estimated using the CORE Diabetes Model. Clinical input data for the analysis of rt-CGM versus SMBG and FGM were sourced from the DIAMOND study and a network meta-analysis, respectively. Rt-CGM and FGM were associated with quality of life (QoL) benefits due to reduced fear of hypoglycaemia (FoH) and fingerstick testing. Analyses were performed over a lifetime time horizon from an Australian healthcare payer perspective, including direct costs from published data. Future costs and clinical outcomes were discounted at 5% per annum. RESULTS: Rt-CGM was associated with an increased quality-adjusted life expectancy of 1.199 quality-adjusted life years (QALYs), increased mean total lifetime costs of AUD 21,596 and an incremental cost-effectiveness ratio (ICER) of AUD 18,020 per QALY gained compared with SMBG. Compared with FGM, rt-CGM was associated with an increased quality-adjusted life expectancy of 0.569 QALYs, increased mean total lifetime costs of AUD 11,064 and an ICER of AUD 19,455 per QALY gained. Key drivers of outcomes included HbA1c benefits and QoL benefits associated with reduced FoH and fingerstick testing. CONCLUSIONS: Due to improved clinical outcomes and QoL gains rt-CGM is highly cost-effective compared with SMBG and FGM in people with T1D in Australia.

Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties.

One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or 'binders' have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L2(Metal)3]6+ where Metal = Cu2+, Zn2+ or Mn2+) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L2Cu3]6+ and [L2Zn3]6+ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO43-, SO42- or PhOPO32-) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L2Cu3]6+ and [L2Zn3]6+ complexes but via different mechanisms.

Colorectal premalignancy is associated with consensus molecular subtypes 1 and 2.

Background: Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown. Patients and methods: We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier. Results: Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-ß activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations. Conclusions: Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.

Ruthenium-Containing Linear Helicates and Mesocates with Tuneable p53-Selective Cytotoxicity in Colorectal Cancer Cells.

The ligands L1 and L2 both form separable dinuclear double-stranded helicate and mesocate complexes with RuII . In contrast to clinically approved platinates, the helicate isomer of [Ru2 (L1 )2 ]4+ was preferentially cytotoxic to isogenic cells (HCT116 p53-/- ), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53+/+ . Other structurally similar RuII -containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be "tuned" to either genotype. In the search for compounds that can target difficult-to-treat tumours that lack the p53 tumour suppressor gene, [Ru2 (L1 )2 ]4+ is a promising compound for further development.

High temperature pyrolysis of 2-methyl furan.

The dissociation of 2-methyl furan at high temperatures has been studied in a combined experimental and theoretical approach to elucidate the details of this multi-channel unimolecular reaction. Laser schlieren densitometry studies were performed in a diaphragmless shock tube over the range 1600 < T < 2300 K and three pressures 60, 120 and 240 Torr. The theoretical study identified many reaction paths, most of which are initiated by the formation of carbenes. Of these paths, five account for 99% consumption of 2MF, and three account for 95% consumption. Simulations of the experimental results with a model that incorporated the theoretical predictions of reaction paths failed to reproduce the experimental data. This was resolved by increasing the rate of loss of an H-atom from the methyl group in 2-methyl furan by a factor of 2-4. The resulting model provides good simulations of the complete set of experimental data. The branching fractions for the three key reactions are both temperature and pressure dependent.

'Maybe I will give some help . maybe not to help the eyes but different help': an analysis of care and support of children with visual impairment in community settings in Malawi.

BACKGROUND: Visual impairment in children is common in low and middle-income settings. Whilst visual impairment (VI) can impact on the development of children, many reach full potential with appropriate early intervention programmes. Although there is increased emphasis on early child development globally, it is not yet clear how to provide specific programmes for children with VI in low and middle-income settings. This study aims to identify facilitators and barriers to the provision of a developmental stimulation programme for children with VI in rural and urban Malawi. METHODS: We undertook 6 focus groups, 10 home observations and 20 in-depth interviews with carers of children with VI under 6 years in urban and rural Southern Malawi. We utilised topic guides relating to care, play, communication and feeding. Qualitative data were subject to thematic analysis that included placing themes within Bronfenbrenner's ecological framework. We established authenticity of themes through feedback from participants. RESULTS: We identified themes within Bronfenbrenner's framework at five levels: (1) blindness acting as a barrier to stimulation and communication, health and complex needs all affecting the individual child; (2) understanding of VI, ability to be responsive at the microsystem level of the carer; (3) support from other carers at microsystem level within a mesosystem; (4) support from other professionals (knowledge of, identification and management of children with VI, responsibilities and gender roles, environmental safety and prejudice, stigma and child protection all at the level of the exosystem. DISCUSSION: This study has revealed the requirements needed in order to produce meaningful and appropriate programmes to support nutrition, care and early stimulation for children with VI in this and similar African settings. This includes supporting carers to understand their child's developmental needs, how to better communicate with, feed and stimulate their child; offering advice sensitive to carers' responsibilities and professional training to better support carers and challenge community stigma.

Optimization of Water Content for the Cryopreservation Of Allium sativum In Vitro Cultures by Encapsulation-Dehydration.

BACKGROUND: There is a general requirement to determine and correlate water content to viability for the standardization of conservation protocols to facilitate effective cryostorage of plant germplasm. OBJECTIVE: This study examined water content as a critical factor to optimize the cryostorage of Allium sativum. MATERIALS AND METHODS: Stem discs were excised from post-harvest, stored bulbs prior to cryopreservation by encapsulation-dehydration and water content was determined gravimetrically. RESULTS: Survival of cryopreserved stem discs was 42.5 %, with 22.5 % exhibiting shoot regrowth following 6 h desiccation. Gravimetric data demonstrated a correlation between water content corresponding with survival / regrowth from desiccated, cryopreserved stem discs. For encapsulated stem discs a 25 % residual moisture and corresponding water content of 0.36 g H2O g-1 d.wt correlated with maximal survival following ~6.5 h of desiccation. CONCLUSION: The data concurs with the literature suggesting the formation of a stable vitrified state and a 'window' for optimal survival and regrowth that is between 6 - 10 h desiccation. Further studies using differential scanning calorimetry (DSC) are suggested to substantiate these findings.

Note: An improved solenoid driver valve for miniature shock tubes.

A solenoid driver valve has been built to improve the operating performance of diaphragmless shock tubes, which are used for high pressure, high temperature chemical kinetics, and fluid mechanics studies. For shock tube driver application, the most important characteristics are those of sealing, strength, and quality of the generated shock waves and repeatability of opening characteristics and therefore subsequent post-shock conditions. The main features of the new driver valve are a face o-ring sealing design of the valve, the large internal volume, and through inserts near the solenoid core: adjustable opening characteristics of the valve.

Statistical power to detect change in a mangrove shoreline fish community adjacent to a nuclear power plant.

An expansion is underway of a nuclear power plant on the shoreline of Biscayne Bay, Florida, USA. While the precise effects of its construction and operation are unknown, impacts on surrounding marine habitats and biota are considered by experts to be likely. The objective of the present study was to determine the adequacy of an ongoing monitoring survey of fish communities associated with mangrove habitats directly adjacent to the power plant to detect fish community changes, should they occur, at three spatial scales. Using seasonally resolved data recorded during 532 fish surveys over an 8-year period, power analyses were performed for four mangrove fish metrics (fish diversity, fish density, and the occurrence of two ecologically important fish species: gray snapper (Lutjanus griseus) and goldspotted killifish (Floridichthys carpio). Results indicated that the monitoring program at current sampling intensity allows for detection of <33% changes in fish density and diversity metrics in both the wet and the dry season in the two larger study areas. Sampling effort was found to be insufficient in either season to detect changes at this level (<33%) in species-specific occurrence metrics for the two fish species examined. The option of supplementing ongoing, biological monitoring programs for improved, focused change detection deserves consideration from both ecological and cost-benefit perspectives.

Screening adherence and cancer risk perceptions in colorectal cancer survivors with Lynch-like syndrome.

Cancer screening recommendations for patients with Lynch-like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Thirty-four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Most participants (76%) believed they should undergo colonoscopy every 1-2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper gastrointestinal endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer (EC) and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for EC and only one-third advised relatives to have genetic counseling. Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of nondiagnostic germline mutation testing among patients with LLS.

Is the 2003 ISSVD terminology and classification of vulvodynia up-to-date? A neurobiological perspective.

This paper aims to determine if the 2003 International Society for the Study of Vulvovaginal Disease (ISSVD) terminology and classification of vulval pain is up-to-date, according to a current and widely accepted neurobiological pain classification, which divides pain into nociceptive, inflammatory and pathological pain with the latter subdivided into neuropathic and dysfunctional pain. Nociceptive pain is protective, adaptive, high-threshold pain provoked by noxious stimuli. Inflammatory pain is protective, adaptive, low-threshold pain associated with peripheral tissue damage and inflammation. Pathological pain is non-protective, maladaptive, low-threshold pain caused by structural damage to the nervous system (neuropathic pain) or by its abnormal function (dysfunctional pain). The 2003 ISSVD vulval pain classification should be revised in terms of current neurobiological pain information. Inflammatory vulval pain occurs as a result of specific infectious, inflammatory and neoplastic disorders. Neuropathic vulval pain arises following a specific neurological disorder, responsible for structural damage to the nervous system. Vulvodynia is dysfunctional vulval pain, caused by abnormal function of the nervous system itself.

Cryopreservation of quince (Cydonia oblonga Mill.).

BACKGROUND: Quince (Cydonia oblonga Mill.) has great potential for utilisation in pharmaceutical and food industries. OBJECTIVE: The study was to develop an efficient cryopreservation approach for quince. METHODS: Factors on the survival and regrowth such as cold acclimation, explant type and recovery media composition were assessed. The effectiveness of the resultant protocols for a number of quince cultivars was determined. RESULTS AND CONCLUSION: Quince shoot tips and nodal sections are successfully cryopreserved. Sustained regrowth of quince Angers A was observed after encapsulation-osmoprotection/dehydration, encapsulation-dehydration and PVS2 vitrification. The highest regrowth rate (80%) was obtained from explants excised from cold hardened shoots and cryopreserved using encapsulation-osmoprotection/dehydration and vitrification protocols. The optimised vitrification protocol in combination with shoot cold hardening and a MS recovery medium without activated charcoal and auxin resulted in satisfactory regrowth of shoots from six quince cultivars. The morphology of acclimatised plants derived from cryopreserved shoots was comparable with non-cryopreserved plants.

Provoked vestibulodynia: inflammatory, neuropathic or dysfunctional pain? A neurobiological perspective.

This paper aims to clarify the nature of the pain in provoked vestibulodynia (PV). It reviews published data about the nature of the pain in PV, employing a recent pain classification, which divides pain from a neurobiological perspective, into nociceptive, inflammatory and pathological pain, with the latter subdivided into neuropathic and dysfunctional pain. Nociceptive pain is high-threshold pain provoked by noxious stimuli; inflammatory pain is adaptive, low-threshold pain associated with peripheral tissue inflammation; pathological pain is maladaptive, low-threshold pain caused by structural damage to the nervous system (neuropathic) or by its abnormal function (dysfunctional). Most of the published data show that in PV, there is no active peripheral tissue inflammation. Similarly, no neural damage has been demonstrated. It is reasonable to consider PV as dysfunctional pain induced by exposure to acute physical or psychological precipitating events in the presence of an individual predisposition to produce or maintain abnormal central sensitisation.

Gynecologic cancer screening and communication with health care providers in women with Lynch syndrome.

We evaluated knowledge of gynecologic cancer screening recommendations, screening behaviors, and communication with providers among women with Lynch syndrome (LS). Women aged ≥25 years who were at risk for LS-associated cancers completed a semi-structured interview and a questionnaire. Of 74 participants (mean age 40 years), 61% knew the appropriate age to begin screening, 75-80% correctly identified the recommended screening frequency, and 84% reported no previous screening endometrial biopsy. Women initiated discussions with their providers about their LS cancer risks, but many used nonspecific terms or relied on family history. Most were not offered high-risk screening options. While many women were aware of risk-appropriate LS screening guidelines, adherence was suboptimal. Improving communication between women and their providers regarding LS-related gynecologic cancer risk and screening options may help improve adherence.

Communication and technology in genetic counseling for familial cancer.

When a cancer predisposing germline mutation is detected in an index case, the presence of the underlying syndrome is confirmed and the potential for predictive testing of at-risk relatives is established. However, the reporting of a positive family history does not routinely lead to communication of information about risk to close, much less distant relatives. This review summarizes information technology utilized to address penetration or 'reach' of knowledge of risk within extended families, including the use of telephone and video counseling to reach distant patients, and anticipate novel internet-based processes for communication between investigators and relatives.

A miniature high repetition rate shock tube.

A miniature high repetition rate shock tube with excellent reproducibility has been constructed to facilitate high temperature, high pressure, gas phase experiments at facilities such as synchrotron light sources where space is limited and many experiments need to be averaged to obtain adequate signal levels. The shock tube is designed to generate reaction conditions of T > 600 K, P < 100 bars at a cycle rate of up to 4 Hz. The design of the apparatus is discussed in detail, and data are presented to demonstrate that well-formed shock waves with predictable characteristics are created, repeatably. Two synchrotron-based experiments using this apparatus are also briefly described here, demonstrating the potential of the shock tube for research at synchrotron light sources.