Potential and challenges of computing with molecular materials.

We are at an inflection point in computing where traditional technologies are incapable of keeping up with the demands of exploding data collection and artificial intelligence. This challenge demands a leap to a new platform as transformative as the digital silicon revolution. Over the past 30 years molecular materials for computing have generated great excitement but continually fallen short of performance and reliability requirements. However, recent reports indicate that those historical limitations may have been resolved. Here we assess the current state of computing with molecular-based materials, especially using transition metal complexes of redox active ligands, in the context of neuromorphic computing. We describe two complementary research paths necessary to determine whether molecular materials can be the basis of a new computing technology: continued exploration of the molecular electronic properties that enable computation and, equally important, the process development for on-chip integration of molecular materials.

Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Unique chemical parameters and microbial activity lead to increased archaeological preservation at the Roman frontier site of Vindolanda, UK.

Waterlogged burial conditions impact upon artefact preservation. One major determinant of preservation is presence and behaviour of microorganisms, however, unravelling the mechanisms, especially in waterlogged conditions is challenging. In this study, we analysed elemental composition, bacterial diversity and community structure from excavation trenches at the Roman Site of Vindolanda, Northumberland, UK, using pXRF and 16S rRNA gene amplicon sequencing. Excavation trenches provide information of different occupation periods. The results indicated that microbial communities were dominated by Firmicutes, Bacteroidetes and Proteobacteria at a phylum level. Samples which also had visible vivianite presence showed that there were marked increases in Methylophilus. Methylophilus might be associated with favourable preservation in these anaerobic conditions. More research is needed to clearly link the presence of Methylophilus with vivianite production. The study emphasises the need for further integration of chemical and microbiome approaches, especially in good preservation areas, to explore microbial and chemical degradation mechanisms.

Detection of cannabinoids in hair after cosmetic application of hemp oil.

The detection of cannabis constituents and metabolites in hair is an established procedure to provide evidence of exposure to cannabis. We present the first known evidence to suggest that applying hemp oil to hair, as cosmetic treatment, may result in the incorporation of Δ9-tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD) and in one instance, the metabolite 11-hydroxy-Δ9-tetrahydrocannabinol (THC-OH). 10 volunteers treated their head hair daily with commercially available hemp oil for a period of 6 weeks. Head hair samples were collected before and after the application period. Hair samples were washed with methanol and subjected to clean up via liquid/liquid and solid phase extraction procedures, and then GC-MS/MS for the analysis of THC, CBN, CBD, THC-OH and THC-COOH. Application of hemp oil to hair resulted in the incorporation of one or more cannabis constituents in 89% of volunteers, and 33% of the group tested positive for the three major constituents, THC, CBN and CBD. One volunteer showed low levels of the metabolite THC-OH. We suggest that cosmetic use of hemp oil should be recorded when sampling head hair for analysis, and that the interpretative value of cannabinoid hair measurements from people reporting application of hemp oil is treated with caution in both criminology and public health.

An observational study of the use of acute hospital care by people with intellectual disabilities in England.

INTRODUCTION: Providing safe, high-quality admitted-patient care for people with intellectual disabilities (IDs) requires consideration for their special needs particularly in relation to communication and consent. To make allowance for these special requirements, it would be helpful for hospitals to know how often they are likely to arise. This study set out to identify the amount and patterns of use of acute, non-psychiatric hospital admitted-patient care in England by people with ID. Patterns are considered in relation to clinical specialties, modes of admission (emergency or planned) and life stages (children and young people, working age and older adults). In each case, patterns for people with ID are compared with patterns for those without. METHODS: Descriptive observational study using a major general practitioner (GP) research database (Clinical Practice Research Datalink GOLD) linked to routine national statistical records of admitted-patient care. RESULTS: Overall people identified by their GP as having ID had higher rates of admitted-patient care episodes and longer durations of stay than those without. Differences varied considerably between clinical specialties with rates more elevated in medical and paediatric than surgical specialties. Admitted-patient care rates for women with ID in obstetrics and gynaecology were lower than for other women, while rates for admitted-patient dental care were much higher for both men and women with ID. In an average English health administrative area with a local population of 250 000 people, at any time, there are likely to be approximately 670 people receiving acute admitted-patient care. Approximately six of these are likely to have been identified by their GP as having ID. At 0.9% of hospital in-patients, this is just under twice the proportion in the population. CONCLUSION AND IMPLICATIONS: Our figures are likely to be an underestimate as GP identification of people with ID is known to be far from complete. However, they indicate that the number of people with ID in acute hospital settings is likely to be substantially more than a recent survey of English health services indicated they were aware of. The study is intended to help guide expectations for acute hospitals seeking to audit the completeness of their identification of people with ID and to indicate their likely distribution between clinical specialties.

Typology of Ohio, USA, tree farmers based upon forestry outreach needs.

This study differentiated groups of Ohio tree farmers through multivariate clustering of their perceived needs for forest management outreach. Tree farmers were surveyed via a mailed questionnaire. Respondents were asked to rate, on a 1-7 scale, their informational needs for 26 outreach topics, which were reduced to six factors. Based on these factors, three clusters were identified-holistic managers, environmental stewards, and pragmatic tree farmers. Cluster assignment of individuals was dependent upon a tree farmer's age, acreage owned, and number of years enrolled in the American Tree Farm System. Holistic managers showed a greater interest in the outreach topics while pragmatic tree farmers displayed an overall lesser interest. Across clusters, print media and in-person workshops were preferred over emails and webinars for receiving forest management information. In-person workshops should be no more than 1 day events, held on a weekday, during the daytime, at a cost not exceeding $35. Programming related to environmental influences, which included managing for forest insects and diseases, was concluded to have the greater potential to impact clientele among all outreach factors due to the information being applicable across demographics and/or management objectives.

Local temperature redistribution and structural transition during joule-heating-driven conductance switching in VO2.

Joule-heating induced conductance-switching is studied in VO2 , a Mott insulator. Complementary in situ techniques including optical characterization, blackbody microscopy, scanning transmission X-ray microscopy (STXM) and numerical simulations are used. Abrupt redistribution in local temperature is shown to occur upon conductance-switching along with a structural phase transition, at the same current.

Bilateral subcortical heterotopia with partial callosal agenesis in a mouse mutant.

Cognition and behavior depend on the precise placement and interconnection of complex ensembles of neurons in cerebral cortex. Mutations that disrupt migration of immature neurons from the ventricular zone to the cortical plate have provided major insight into mechanisms of brain development and disease. We have discovered a new and highly penetrant spontaneous mutation that leads to large nodular bilateral subcortical heterotopias with partial callosal agenesis. The mutant phenotype was first detected in a colony of fully inbred BXD29 mice already known to harbor a mutation in Tlr4. Neurons confined to the heterotopias are mainly born in midgestation to late gestation and would normally have migrated into layers 2-4 of overlying neocortex. Callosal cross-sectional area and fiber number are reduced up to 50% compared with coisogenic wildtype BXD29 substrain controls. Mutants have a pronounced and highly selective defect in rapid auditory processing. The segregation pattern of the mutant phenotype is most consistent with a two-locus autosomal recessive model, and selective genotyping definitively rules out the Tlr4 mutation as a cause. The discovery of a novel mutation with strong pleiotropic anatomical and behavioral effects provides an important new resource for dissecting molecular mechanisms and functional consequences of errors of neuronal migration.

A scalable neuristor built with Mott memristors.

The Hodgkin-Huxley model for action potential generation in biological axons is central for understanding the computational capability of the nervous system and emulating its functionality. Owing to the historical success of silicon complementary metal-oxide-semiconductors, spike-based computing is primarily confined to software simulations and specialized analogue metal-oxide-semiconductor field-effect transistor circuits. However, there is interest in constructing physical systems that emulate biological functionality more directly, with the goal of improving efficiency and scale. The neuristor was proposed as an electronic device with properties similar to the Hodgkin-Huxley axon, but previous implementations were not scalable. Here we demonstrate a neuristor built using two nanoscale Mott memristors, dynamical devices that exhibit transient memory and negative differential resistance arising from an insulating-to-conducting phase transition driven by Joule heating. This neuristor exhibits the important neural functions of all-or-nothing spiking with signal gain and diverse periodic spiking, using materials and structures that are amenable to extremely high-density integration with or without silicon transistors.

Wildfires, fuel treatment and risk mitigation in Australian eucalypt forests: insights from landscape-scale simulation.

Wildfires pose significant risks to people and human infrastructure worldwide. The treatment of fuel in landscapes may alter these risks but the magnitude of this effect on risk is poorly understood. Evidence from Australian Eucalyptus forests suggests that mitigation of risk using prescribed burning as a fuel treatment is partial because weather and fuel dynamics are conducive to regular high intensity fires. We further examine the response of risk to treatment in eucalypt forests using landscape simulation modelling. We model how five key measures of wildfire activity that govern risk to people and property may respond to variations in rate and spatial pattern of prescribed fire. We then model effects of predicted climate change (2050 scenarios) to determine how the response of risk to treatment is likely to be altered in the future. The results indicate that a halving of risk to people and property in these forests is likely to require treatment rates of 7-10% of the area of the landscape per annum. Projections of 2050 weather conditions under climate change further substantially diminished the effect of rate of treatment. A large increase in rates of treatment (i.e. circa. 50% over current levels) would be required to counteract these effects of climate change. Such levels of prescribed burning are unlikely to be financially feasible across eucalypt dominated vegetation in south eastern Australia. Despite policy imperatives to expand fuel treatment, a reduction rather than an elimination of risk will result. Multi-faceted strategies will therefore be required for the management of risk.

Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis.

BACKGROUND & OBJECTIVES: Pyrazinamide is an essential component of first line anti-tuberculosis regimen as well as most of the second line regimens. This drug has a unique sterilizing activity against Mycobacterium tuberculosis. Its unique role in tuberculosis treatment has lead to the search and development of its structural analogues. One such analogue is 5-chloro-pyrazinamide (5-Cl-PZA) that has been tested under in vitro conditions against M. tuberculosis. The present study was designed with an aim to assess the activity of 5-Cl-PZA, alone and in combination with first-line drugs, against murine tuberculosis. METHODS: The minimum inhibitory concentration (MIC) of 5-Cl-PZA in Middlebrook 7H9 broth (neutral pH) and the inhibitory titre of serum from mice that received a 300 mg/kg oral dose of 5-Cl-PZA 30 min before cardiac puncture were determined. To test the tolerability of orally administered 5-Cl-PZA, uninfected mice received doses up to 300 mg/kg for 2 wk. Four weeks after low-dose aerosol infection either with M. tuberculosis or M. bovis, mice were treated 5 days/wk with 5-Cl-PZA, at doses ranging from 37.5 to 150 mg/kg, either alone or in combination with isoniazid and rifampicin. Antimicrobial activity was assessed by colony-forming unit counts in lungs after 4 and 8 wk of treatment. RESULTS: The MIC of 5-Cl-PZA against M. tuberculosis was between 12.5 and 25 µg/ml and the serum inhibitory titre was 1:4. Under the same experimental conditions, the MIC of pyrazinamide was >100 µg/ml and mouse serum had no inhibitory activity after a 300 mg/kg dose; 5-Cl-PZA was well tolerated in uninfected and infected mice up to 300 and 150 mg/kg, respectively. While PZA alone and in combination exhibited its usual antimicrobial activity in mice infected with M. tuberculosis and no activity in mice infected with M. bovis, 5-Cl-PZA exhibited antimicrobial activity neither in mice infected with M. tuberculosis nor in mice infected with M. bovis. INTERPRETATION & CONCLUSION: Our findings showed that 5-Cl-PZA at doses up to 150 mg/kg was not active in chronic murine TB model. Further studies need to be done to understand the mechanism and mode of inactivation in murine model of tuberculosis.

Expanded polytetrafluoroethylene as a substrate for retinal pigment epithelial cell growth and transplantation in age-related macular degeneration.

BACKGROUND: Retinal pigment epithelial (RPE) transplantation presents a potential treatment for age-related macular degeneration (AMD). A suitable transplant membrane that can support an intact functioning RPE monolayer is required. Expanded polytetrafluoroethylene (ePTFE) possesses the physical properties required for a transplanting device; however, cells do not attach and spread on ePTFE. This study investigated the ability of surface-modified ePTFE to optimise the growth and function of healthy RPE monolayers. METHODS: ePTFE discs were modified by ammonia gas plasma treatment. ARPE-19 cells were seeded on the membranes and maintained in media supplemented with retinoic acid and reduced serum. Cell number, morphology and proliferation were analysed. RPE monolayer function was investigated through formation of cell-cell junctions and phagocytosis of photoreceptor outer segments (POS). RESULTS: Ammonia gas plasma treatment resulted in enhanced cell growth and good monolayer formation with evidence of cell-cell junctional proteins. Furthermore, RPE monolayers were able to phagocytose POS in a time-dependent manner. CONCLUSIONS: ePTFE can be surface-modified to support an intact functional monolayer of healthy RPE cells with normal morphology and the ability to perform RPE-specific functions. Following further investigation ePTFE may be considered for use in transplantation.

A high dose of monensin does not reduce methane emissions of dairy cows offered pasture supplemented with grain.

The primary objective of our research was to determine the effect of a high dose of monensin supplementation on enteric CH(4) emissions of dairy cows offered a ryegrass pasture diet supplemented with grain. An additional objective was to evaluate effects on milk production and rumen function, because a commensurate improvement in milk production could lead to adoption of monensin as a profitable strategy for methane abatement. Two experiments were conducted (grazing and respiratory chambers) and in both experiments monensin (471 mg/d) was topdressed on 4 kg (dry matter)/d of rolled barley grain offered in a feed trough twice daily at milking times. In the grazing experiment, 50 Holstein-Friesian cows were assigned randomly to 1 of 2 groups (control or monensin). Cows grazed together as a single herd on a predominantly ryegrass sward and received monensin over a 12-wk period, during which time measurements of milk production and body weight change were made. The SF(6) tracer technique was used to estimate methane production of 30 of the 50 cows (15 control cows and 15 monensin cows) for 3 consecutive days in wk 3, 5, 8, and 12 of treatment. Samples of rumen fluid were collected per fistula from 8 of the 50 cows (4 per diet) on 2 consecutive days in wk 3, 5, 8, and 12 of treatment and analyzed for volatile fatty acids and ammonia-N. In the metabolic chamber experiment, 10 pairs of lactating dairy cows (control and monensin) were used to determine the effects of monensin on methane emissions, dry matter intake, milk production, and body weight change over a 10-wk period. Methane emissions were measured by placing cows in respiration chambers for 2 d at wk 5 and 10 of treatment. Cows received fresh ryegrass pasture harvested daily. Monensin did not affect methane production in either the grazing experiment (g/d, g/kg of milk) or the chamber experiment (g/d, g/kg of dry matter intake, g/kg of milk). In both experiments, milk production did not increase with addition of monensin to the diet. Monensin had no effect on body weight changes in either experiment. Monensin did not affect volatile fatty acids or ammonia-N in rumen fluid, but the acetate to propionate ratio tended to decrease. Monensin did not improve milk production of grazing dairy cows and no effect on enteric methane emissions was observed, indicating that monensin cannot be promoted as a viable mitigation strategy for dairy cows grazing ryegrass pasture supplemented with grain.

Supplementation with whole cottonseed causes long-term reduction of methane emissions from lactating dairy cows offered a forage and cereal grain diet.

The objective of our work was to supplement a forage and cereal diet of lactating dairy cows with whole cottonseed (WCS) for 12 wk and to determine whether the expected reduction in CH(4) would persist. A secondary objective was to determine the effect of supplementing the diet with WCS on milk yield and rumen function over the 12-wk feeding period. Fifty lactating cows were randomly allocated to 1 of 2 diets (control or WCS). The 2 separate groups were each offered, on average, 4.2 kg of DM/cow per day of alfalfa hay (a.m.) and 6.6 kg of DM/cow per day of ryegrass silage (p.m.) on the ground in bare paddocks each day for 12 wk. Cows in each group were also individually offered dietary supplements for 12 wk in a feed trough at milking times of 5.4 kg of DM/cow per day of cracked wheat grain and 0.5 kg of DM/cow per day of cottonseed meal (control) or 2.8 kg of DM/cow per day of cracked wheat grain and 2.61 kg of DM/cow per day of WCS. The 2 diets were formulated to be similar in their concentrations of CP and ME, but the WCS diet was designed to have a higher fat concentration. Samples of rumen fluid were collected per fistula from the rumen approximately 4 h after grain feeding in the morning. Samples were taken from 8 cows (4 cows/diet) on 2 consecutive days in wk 2 of the covariate and wk 3, 6, 10, and 12 of treatment and analyzed for volatile fatty acids, ammonia-N, methanogens, and protozoa. The reduction in CH(4) emissions (g/d) because of WCS supplementation increased from 13% in wk 3 to 23% in wk 12 of treatment. Similarly, the reduction in CH(4) emissions (g/kg of DMI) increased from 5.1% in wk 3 to 14.5% in wk 12 of treatment. It was calculated that the average reduction in CH(4) emissions over the 12-wk period was 2.9% less CH(4) per 1% added fat, increasing from 1.5% in wk 3 to 4.4% less CH(4) in wk 12. There was no effect of WCS supplementation on rumen ammonia-N, rumen volatile fatty acids, rumen methanogens, and rumen protozoa. On average over the 12-wk period, supplementation with WCS decreased the yield of milk (10%), fat (11%), protein (14%), lactose (11%), and fat plus protein (12%) and BW gain (31%). The WCS supplementation had no effect on milk fat concentration but resulted in a decrease in concentration of protein (5%) and lactose (11%). The major finding from this study is that addition of WCS to the diet of lactating dairy cows resulted in a persistent reduction in CH(4) emissions (g of CH(4)/kg of DMI) over a 12-wk period and that these reductions in CH(4) are consistent with previous work that has studied the addition of oilseeds to ruminant diets.

Top-down fabricated silicon nanowire sensors for real-time chemical detection.

Silicon nanowire (SiNW) sensors have been developed by using top-down fabrication that is CMOS (complementary metal-oxide-semiconductor) compatible for resistive chemical detection with fast response and high sensitivity. Top-down fabrication by electron beam lithography and reactive ion etching of a silicon on insulator (SOI) substrate enables compatibility with the CMOS fabrication process, accurate alignment with other electrical components, flexible design of the nanowire geometry and good control of the electrical characteristics. The SiNW sensors showed a large operation range for pH detection (pH = 4-10) with an average sensitivity of (Delta R/R)/pH = 2.6%/pH and a rise time of 8 s. A small pH level difference (Delta pH = 0.2) near neutral pH conditions (pH = 7) could be resolved with the SiNW sensors. The sensor response to the presence of alkali metal ions and the long term drifting effects were also investigated.

The use of complementary therapy by men with prostate cancer in the UK.

The study aims were to determine the use of complementary therapies (CT) by men with prostate cancer, and to explore factors influencing CT use and attitudes toward CT use. A cross-sectional survey design was used in which a postal questionnaire was mailed to an eligible sample of 405 patients with prostate cancer receiving outpatient treatment in a London teaching hospital. The primary outcomes were the prevalence of CT use and the relationship between CT use and mental health status. Two hundred and ninety-four patients (73%) responded, of whom 25% were using CT. The most frequently used CTs were vitamins, low-fat diets, lycopene and green tea. Multivariate analyses revealed no differences in mental health scores between CT users and non-users. CT users were younger (OR 0.93, 95% CI 0.89-0.97) and were more likely to be receiving conservative management in the form of 'active surveillance' (OR 5.23, 95% CI 1.78-15.41) compared with non-users. Over half of the participants (55%) wanted to learn more about CT. Forty-three per cent of CT users had not informed any doctor about their CT use. Clinicians need to be aware of the prevalence of CT use amongst patients with prostate cancer, considering the potential harm that could be caused by interactions with conventional treatments.

Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.

A revision of the 2000 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in May 2006. Key areas in treating depression were reviewed, and the strength of evidence and clinical implications were considered. The guidelines were drawn up after extensive feedback from participants and interested parties. A literature review is provided, which identifies the quality of evidence to inform the recommendations, the strength of which are based on the level of evidence. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse, and stopping treatment.

The anti-allergic drug, N-(3',4'-dimethoxycinnamonyl) anthranilic acid, exhibits potent anti-inflammatory and analgesic properties in arthritis.

OBJECTIVES: The degradation of tryptophan by indoleamine 2,3-dioxygenase yields a number of immunomodulatory metabolites, including 3-hydroxyanthranilic acid, 3-hydroxykynurenic acid and quinolinic acid. N-(3',4'-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is a synthetic anthranilic acid derivative that has been used therapeutically in Japan for many years as an anti-allergic drug and has recently been shown to be effective in a murine model of multiple sclerosis. METHODS: In the present study, we tested the efficacy of 3,4-DAA in collagen-induced arthritis, a mouse model of rheumatoid arthritis, and analysed its mechanism of action. RESULTS: Administration of 3,4-DAA after arthritis onset reduced clinical and histological severity of arthritis and reduced pain. It completely abrogated thermal and mechanical hyperalgesia. 3,4-DAA also suppressed Th1 cell activity in lymph node cell cultures and raised serum levels of IL-10. In vitro, 3,4-DAA suppressed IFNgamma production and proliferation of both T and B lymphocytes in a manner comparable with the endogenous tryptophan metabolite, 3-hydroxyanthranilic acid, suggesting similar mechanisms of action. CONCLUSION: It is concluded that 3,4-DAA has both anti-inflammatory and analgesic properties, and may therefore be useful in filling an unmet need, in the treatment of rheumatoid and other forms of arthritis, especially in the light of its analgesic properties.

Interventions for latent autoimmune diabetes (LADA) in adults.

BACKGROUND: Latent autoimmune diabetes in Adults (LADA) is a slowly developing type 1 diabetes which presents as non-insulin dependent diabetes and progresses to insulin dependence. However, the best treatment strategy for LADA is unclear. OBJECTIVES: To compare interventions used for LADA. SEARCH STRATEGY: Studies were obtained from searches of electronic databases (including MEDLINE, EMBASE), supplemented by hand searches, conference proceedings and consultation with experts. SELECTION CRITERIA: Selection was in duplicate by two independent reviewers. RCT and controlled clinical trials evaluating interventions for LADA or type 2 diabetes with antibodies were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed study quality. Studies were summarised in a descriptive manner. MAIN RESULTS: Searches identified 8067 citations. Eight publications (seven studies) were included, involving 735 participants. All studies had high risk of bias. There were no data on use of metformin or glitazones alone. Rosiglitazone or sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone. SU alone gave either poorer (one study, mean difference in HbA1c 2.8% (95% confidence interval (CI) 0.9 to 4.7) or equivalent metabolic control compared to insulin alone (two studies). There was evidence that SU caused earlier insulin dependence (insulin treated at two years: 60% (SU) and 5% (conventional care) (P < 0.001); classified insulin dependent: 64% (SU) and 12.5% (insulin group) (P = 0.007)). No interventions influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5) and insulin with rosiglitazone was superior to insulin alone (one study) at maintaining stimulated C-peptide. A pilot study showed better metabolic control at six months with subcutaneously administered glutamic acid decarboxylase (GAD) GAD65, a major autoantigen in autoimmune diabetes, compared to placebo. There was no information regarding quality of life, mortality, complications or costs in any of the publications. Time from diagnosis varied between recruitment at diagnosis to recruitment at nine years of disease duration and there was a great deal of variation in the selection criteria for LADA patients, making it difficult to generalise findings from these studies. AUTHORS' CONCLUSIONS: There are few studies on this topic and existing studies have a high risk of bias. However, there does seem to be an indication that SU should not be a first line treatment for antibody positive type 2 diabetes. There is no significant evidence for or against other lines of treatment of LADA.