Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low-intensity chemotherapy in acute myeloid leukaemia.

Based on promising results in older adults with acute myeloid leukaemia (AML), we treated patients with NPM1mut measurable residual disease (MRD) using off-label venetoclax in combination with low-dose cytarabine or azacitidine. Twelve consecutive patients were retrospectively identified, including five with molecular persistence and seven with molecular relapse/progression. All patients with molecular persistence achieved durable molecular complete remission (CRMRD- ) without transplantation. Six of seven patients with molecular relapse/progression achieved CRMRD- after 1-2 cycles of venetoclax. This paper highlights the promising efficacy of venetoclax-based therapy to reduce the relapse risk in patients with persistent or rising NPM1mut MRD.

Lactarius deliciosus and Pinus radiata in New Zealand: towards the development of innovative gourmet mushroom orchards.

The cultivation of Lactarius deliciosus (saffron milk cap) in New Zealand began in 2002 when fruiting bodies were produced in an Otago plantation of Pinus radiata seedlings artificially mycorrhized by L. deliciosus. In 2007, 42 P. radiata seedlings mycorrhized by L. deliciosus under controlled conditions were planted in a grass field at Plant and Food Research (Lincoln, Canterbury). The effects of pine bark mulch application and initial degree of mycorrhization of seedlings were examined to determine their influence on tree growth, development of mycorrhizae (i.e. their multiplication on the root system and their degree of branching) and fruiting body production. Mulch application increased tree growth significantly over 4 years. High initial mycorrhization slightly stimulated tree growth over 2 years. The initial degree of mycorrhization was positively, but not strongly, related to the persistence and development of L. deliciosus mycorrhizae and rhizomorphs based on root sample analyses 2 years after planting. However, mulching strongly reduced the proportion of highly branched L. deliciosus mycorrhizae compared with poorly ramified ones. A positive correlation was observed between the fruiting of L. deliciosus and the development of mycorrhizae. Mulching delayed the onset of fruiting body production. In 2010, fruiting bodies were produced only from non-mulched trees with eight of these (38 %) producing a total of 12 fruiting bodies. In 2011, 19 non-mulched trees (90 %) and 9 mulched trees (45 %) produced 143 and 47 fruiting bodies, respectively, totalling 190 fruiting bodies. By 2012, 19 non-mulched trees (90 %) and 13 mulched trees (65 %) produced 333 and 236 fruiting bodies, respectively, totalling 569 fruiting bodies (c. 30 kg). This study presents new information on factors influencing the onset of fruiting and the development of yields in a plantation of P. radiata mycorrhized by L. deliciosus. Projected yields as high as c. 300 kg/ha from the third year of production reiterate the feasibility of farming saffron milk cap in P. radiata plantations in New Zealand. Continued monitoring of this site and development of similar trials will provide important knowledge for the optimisation of yields in commercial saffron milk cap orchards.

Detection of the edible ectomycorrhizal fungus Lyophyllum shimeji colonising seedlings of cultivated conifer species in New Zealand.

Lyophyllum shimeji is an edible ectomycorrhizal fungus that is widely distributed in East Asia and also present in the northern regions of Europe. In Japan, L. shimeji is a culinary delicacy, considered amongst all edible mushrooms to have the best taste and to be second only to Tricholoma matsutake in price. Traditionally, fruiting bodies of L. shimeji have been collected from the wild but fruiting of L. shimeji is now relatively uncommon and cannot keep up with increasing consumer demand. As a result, methods for its cultivation are being developed for commercial production in Japan and other countries. In this work, techniques were developed to cultivate L. shimeji on coniferous seedlings using a pure culture inoculum. They resulted in successful mycorrhization of Pinus pinaster and Picea abies in only 8 to 10 months. As ectomycorrhizae of L. shimeji are difficult to identify morphologically, mycorrhization was confirmed using an L. shimeji-specific PCR diagnostic, which was designed following a phylogenetic analysis of the Lyophyllum section Difformia using DNA sequences of the internal transcribed spacer (ITS), intergenic spacer (IGS) and elongation factor 1-α (EF1-α) gene. L. shimeji is a member of the Lyophyllum decastes complex in section Difformia, which also includes Lyophyllum fumosum and L. decastes. This analysis confirmed the separation of L. shimeji from closely related Lyophyllum spp. and enabled its unambiguous detection using an IGS-based PCR diagnostic. This is the first report of successful mycorrhization of L. shimeji on P. pinaster and P. abies and provides an opportunity for its commercial cultivation on conifers in New Zealand.

Mycorrhiza analyses in New Zealand truffières reveal frequent but variable persistence of Tuber melanosporum in co-existence with other truffle species.

This study compiles the results from an examination of mycorrhizae on root samples from Tuber melanosporum truffières in New Zealand. Samples were taken over 5 years from 328 trees in 43 truffières established with nursery-inoculated trees. Mycorrhizae were analysed using a combination of morphological and molecular techniques, focusing on the identification of Tuber species. Results show that 49% of the trees, and nearly 90% of the truffières, retained T. melanosporum mycorrhizae up to 21 years after planting. Tuber mycorrhizae with spiky cystidia were found on 26.9% of the tested trees: Tuber brumale (5.5%), Tuber maculatum (10.7%), and unidentified Tuber species (10.7%), and were detected in 67% of the truffières tested. T. brumale was found in 28% and T. maculatum in 35% of the truffières. In 56% of the truffières, T. melanosporum was found to occur with spiky Tuber species. The existence of T. brumale and T. maculatum in the same truffière was recorded only once. Forty-four percent of trees examined had Scleroderma-like (SCL) mycorrhizae and 50% of trees hosted other ectomycorrhizal species (OE). For all categories of mycorrhizal species examined, the variation between truffières was greater than variation within each truffière. Overall results indicate that Corylus avellana tends to be more receptive to mycorrhizae of Tuber species than Quercus robur but is not necessarily more productive. In productive truffières, Q. robur appears to host SCL mycorrhizae more often than C. avellana. This is the first study of its scale to analyse the mycorrhizal species associated with T. melanosporum truffières in the Southern Hemisphere.

Peripheral Blood CD34 Donor Chimerism has Greater Clinical Utility Than CD3 for Detecting Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia or Myelodysplastic Syndrome.

Monitoring of donor chimerism (DC) may detect early relapse following allogeneic hematopoietic stem cell transplantation (allo-SCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Most centers use unfractionated peripheral blood or T-cells to monitor DC, although CD34+ DC may be more predictive. The limited adoption of CD34+ DC may be due to the lack of detailed, comparative studies. To address this knowledge gap, we compared peripheral blood CD34+ and CD3+ DC in 134 patients who underwent allo-SCT for AML or MDS. In July 2011, the Alfred Hospital Bone Marrow Transplantation Service adopted routine monitoring of DC in the lineage-specific CD34+ and CD3+ cell subsets from peripheral blood at 1, 2, 3, 4, 6, 9, and 12 months post-transplantation for AML or MDS. Immunologic interventions, including rapid withdrawal of immunosuppression, azacitidine, and donor lymphocyte infusion, were prespecified for CD34+ DC ≤80%. Overall, CD34+ DC ≤80% detected 32 of 40 relapses (positive predictive value [PPV], 68%; negative predictive value [NPV], 91%), compared with 13 of 40 relapses for CD3+ DC ≤80% (PPV, 52%; NPV, 75%). Receiver operating characteristic analysis showed the superiority of CD34+ DC, with the greatest value at day 120 post-transplantation. CD3+ DC provided additional value in only 3 cases, preceding CD34+ DC ≤80% by 1 month. We further show that the CD34+ DC sample can be used to detect NPM1mut, with the combination of CD34+ DC ≤80% and NPM1mut identifying the highest risk of relapse. Among the 24 patients in morphologic remission at the time of CD34+ DC ≤80%, 15 (62.5%) responded to immunologic interventions (rapid withdrawal of immunosuppression, azacitidine, or donor lymphocyte infusion) with recovery of CD34+ DC >80%, and 11 of these patients remained in complete remission for a median of 34 months (range, 28 to 97 months). In contrast, the other 9 patients did not respond to the clinical intervention and relapsed within a median of 59 days after detecting CD34+ DC ≤80%. The CD34+ DC was significantly higher in responders than in nonresponders (median, 72% versus 56%; P = .015, Mann-Whitney U test). Overall, monitoring of CD34+ DC was considered clinically useful (early diagnosis of relapse enabling preemptive therapy or predicting low risk of relapse) in 107 of 125 evaluable patients (86%). Our findings show that peripheral blood CD34+ DC is feasible and superior to CD3+ DC for predicting relapse. It also provides a source of DNA for measurable residual disease testing, which may further stratify the risk of relapse. If validated by an independent cohort, our results suggest that CD34+ should be used in preference to CD3+ DC for detecting early relapse and guiding immunologic interventions following allo-SCT for AML or MDS.

Association of entomopathogenic fungi with exotic bark beetles in New Zealand pine plantations.

Hylastes ater and Hylurgus ligniperda are introduced pests of re-established Pinus radiata in New Zealand. Both species breed under the bark of stumps in recently harvested areas. Adult maturation feeding on pine seedlings planted in adjacent areas can significantly impact seedling growth, and in severe cases seedlings will die. Entomopathogenic fungi are important natural mortality factors in bark beetle populations, and Beauveria spp. are predominant. Here, we report on the isolation of other fungal species from H. ater in New Zealand. Based on morphological characteristics and sequencing data, two species, Metarhizium flavoviride var. pemphigi and Hirsutella guignardii, were recovered from H. ater. Both are new records for New Zealand and appear to be the first records of these species from bark beetles worldwide.

The financial dimension of integrated behavioral/primary care.

There are two reasons why mental health, now more appropriately termed behavioral healthcare, is declining: (a) a lack of understanding among psychotherapists of healthcare economics, particularly the intricacies of medical cost offset, and (b) our failure as a profession to see the importance of behavioral interventions as an integral part of the healthcare system inasmuch as the nation pays for healthcare, not psychosocial care. This paper will briefly describe the rapid changes in the economics of healthcare during the past 75 years, including the post World War II enthusiastic espousal of psychotherapy by the American public which was followed by a precipitous decline as our outcomes research in behavioral care remained ignorant of financial outcomes, leaving it to the government and managed care to arbitrarily curtail escalating mental health costs. At the present time psychology is on the cusp of becoming part of the healthcare system through integrated behavioral/primary care, renewing the primacy of financial considerations such as return on investment (ROI) and medical cost offset, as well as an urgency that we avoid the mistakes that are emerging in some flawed implementations of integrated care.

The unmet educational agenda in integrated care.

One of the reasons integrated care has not become a dominant service delivery model is the unmet training agenda. This article argues that the typical mental health professional is not trained to adequately address the challenges of integrated care. To insure competency both a macro and clinical training agenda are needed. At the macro-level, mental health professionals need to understand healthcare economics and basic business principles as any integrated care service delivery system is embedded and driven by economic forces. Integrated care practitioners also need some basic business skills to understand these forces and to create and manage a financially viable system, given the future flux of the system. Traditional mental health professionals also do not have the clinical skills to implement integrated care. Integrated care is not simply placing a traditionally trained mental health professional and letting them practice specialty mental health in a medical setting. Thus, the special skills needed in integrated care are enumerated and discussed. Finally, a new degree program is described as it is time given the huge need and advantages of integrated care to develop specialty training in integrated care.

Opioid prescribing rates from the emergency department: Down but not out.

INTRODUCTION: To examine opioid prescribing rates following emergency department (ED) discharge stratified by patient's clinical and demographic characteristics over an 11-year period. MATERIAL AND METHODS: We used 3.9 million ED visits from commercially insured enrollees and 15.2 million ED visits from Medicaid enrollees aged 12 to 64 over 2005-2016 from the IBM® MarketScan® Research Databases. We calculated rates of opioid prescribing at discharge from the ED and the average number of pills per opioid prescription filled. RESULTS: Approximately 15-20% of ED visits resulted in opioid prescriptions filled. Rates increased from 2005 into late 2009 and 2010 and then declined steadily through 2016. Prescribing rates were similar for commercially insured and Medicaid enrollees. Being aged 25-54 years was associated with the highest rates of opioid prescriptions being filled. Hydrocodone was the most commonly prescribed opioid, but rates for hydrocodone prescription filling also fell the most. Rates for oxycodone were stable, and rates for tramadol increased. The average number of pills dispensed from prescriptions filled remained steady over the study period at 18-20. DISCUSSION: Opioid prescribing rates from the ED have declined steadily since 2010 in reversal of earlier trends; however, about 15% of ED patients still received opioid prescriptions in 2016 amidst a national opioid crisis. CONCLUSIONS: Efforts to reduce opioid prescribing could consider focusing on the pain types, age groups, and regions with high prescription rates identified in this study.

Biosynthesis of spiro-mamakone A, a structurally unprecedented fungal metabolite.

Biosynthetic studies on spiro-mamakone A (1), a potently cytotoxic and antimicrobial compound from an endophytic fungus isolated from the New Zealand native tree Knightia excelsa (rewarewa), confirm the polyketide origins of this unique compound belonging to the spirobisnaphthalene class of compounds. The biosynthesis proceeds via an unprecedented symmetric enedione with the two halves of the molecule being formed from two separate pentaketide units connected by oxidative coupling.

Concordance of somatic mutational profile in multiple primary melanomas.

This study aimed to determine the frequency and concordance of BRAF and NRAS mutation in tumours arising in patients with multiple primary melanoma (MPM). Patients with MPM managed at one of three tertiary referral centres in Melbourne, Australia, from 2010 to 2015 were included. Incident and subsequent melanomas underwent mutation testing. Cohen's kappa (κ) coefficient assessed agreement between incident and subsequent primary melanomas for both BRAF and NRAS mutation status (mutant versus wild-type). Mutation testing of at least two primary tumours from 64 patients was conducted. There was poor agreement for both BRAF and NRAS mutation status between incident and subsequent melanomas (κ = 0.10, 95% CI -0.10 to 0.42; κ = 0.06, 95% CI -0.10 to 0.57, respectively). In view of the low concordance in BRAF mutation status between incident and subsequent melanomas, mutational analysis of metastatic tissue, rather than of a primary melanoma, in patients with MPM should be used to guide targeted therapy.

Off-Label Prescribing of Psychotropic Medication, 2005-2013: An Examination of Potential Influences.

OBJECTIVE: This study examined rates of psychotropic prescriptions for various on- and off-label uses in 2005 and 2013 in the context of changes in labeled indications. METHODS: The National Disease and Therapeutic Index, a survey of nationally representative office-based physicians that identifies the diagnosis attached to each prescription, was used to capture the number of psychiatric medications prescribed for a particular diagnosis in 2005 (N=4,120) and 2013 (N=4,140). Labeled indications for each year were abstracted, and the association of prescribing patterns and changes in labeled indications was evaluated. RESULTS: Expanded labeling was associated with increased use of antidepressants for anxiety (an increase of 3.4 percentage points); antipsychotics for depression (8.3), bipolar disorder (3.4), and tic disorders, autism, and related disorders (1.5); and anxiolytics for anxiety disorders (5.5). Use of antidepressants for depression decreased, by 5.6 percentage points, as did use of antipsychotics (4.6) and anxiolytics (.7) for dementia-related disorders and of antipsychotics for attention-deficit and related disorders (2.7), likely reflecting black box warnings and evidence of side effects. Off-label use of antidepressants for attention deficit and related disorders and anxiolytics for bipolar disorders increased by 1.1 and 1.3 percentage points, respectively. CONCLUSIONS: FDA labeling plays an important but imperfect role in influencing how providers select medications. Prescribing increases for medications with new indications. Conversely, black box warnings of potentially dangerous side effects result in decreased prescribing. However, labeled indications often lag the science, and prescribing patterns should be tracked to inform the need for more education, research, and labeling changes.

The Impact Of Medicare ACOs On Improving Integration And Coordination Of Physical And Behavioral Health Care.

The accountable care organization (ACO) model holds the promise of reducing costs and improving the quality of care by realigning payment incentives to focus on health outcomes instead of service volume. One key to managing the total cost of care is improving care coordination for and treatment of people with behavioral health disorders. We examined qualitative data from ninety organizations participating in Medicare ACO demonstration programs from 2012 through 2015 to determine whether and how they focused on behavioral health care. These ACOs had mixed degrees of engagement in improving behavioral health care for their populations. The biggest challenges included a lack of behavioral health care providers, data availability, and sustainable financing models. Nonetheless, we found substantial interest in integrating behavioral health care into primary care across a majority of the ACOs.

Isolation and Mass Production of Trichoderma.

Members of the genus Trichoderma comprise the majority of commercial fungal biocontrol agents of plant diseases. As such, there is a wealth of information available on the analysis of their biocontrol potential and the mechanisms behind their superior abilities. This chapter aims to summarize the most common methods utilized within a Trichoderma biocontrol program for the isolation, identification, and mass propagation of individual strains.

Potential of the beneficial fungus Trichoderma to enhance ecosystem-service provision in the biofuel grass Miscanthus x giganteus in agriculture.

The sterile hybrid grass Miscanthus x giganteus (Mxg) can produce more than 30 t dry matter/ha/year. This biomass has a range of uses, including animal bedding and a source of heating fuel. The grass provides a wide range of other ecosystem services (ES), including shelter for crops and livestock, a refuge for beneficial arthropods, reptiles and earthworms and is an ideal cellulosic feedstock for liquid biofuels such as renewable (drop-in) diesel. In this study, the effects of different strains of the beneficial fungus Trichoderma on above- and below-ground biomass of Mxg were evaluated in glasshouse and field experiments, the latter on a commercial dairy farm over two years. Other ES benefits of Trichoderma measured in this study included enhanced leaf chlorophyll content as well as increased digestibility of the dried material for livestock. This study shows, for the first time for a biofuel feedstock plant, how Trichoderma can enhance productivity of such plants and complements other recent work on the wide-ranging provision of ES by this plant species.

Molecular genetics of fructan metabolism in perennial ryegrass.

Fructans are the main storage carbohydrates of temperate grasses, sustaining regrowth immediately after defoliation, as well as contributing to the nutritive value of feed. Fructan metabolism is based on the substrate sucrose and involves fructosyltransferases (FTs) for biosynthesis and fructan exohydrolases (FEHs) for degradation. Sucrose is also utilized by invertases (INVs), which hydrolyse it into its constituent monosaccharides for use in metabolism. The isolation, molecular characterization, functional analysis, and phylogenetic relationships of genes encoding FTs, FEHs, and INVs from temperate grasses are reviewed, with an emphasis on perennial ryegrass (Lolium perenne L.). The roles these enzymes play in fructan accumulation and remobilization, and future biotechnological applications in molecular plant breeding are discussed.

Isolation and characterisation of an invertase cDNA from perennial ryegrass (Lolium perenne).

An invertase (LpFT2) cDNA from perennial ryegrass was isolated and sequenced. Nucleotide sequence analysis revealed an ORF of 2016 bp encoding a protein of 671 amino acids. LpFT2 is 76% identical to sugarcane soluble acid invertase, and contains invertase and fructosyltransferase functional domains. LpFT2 is present as a single copy gene and maps to the distal region of LG6 in perennial ryegrass. The expression pattern analysis of LpFT2 revealed transcript accumulation in seedlings and in mature leaf sheaths. The LpFT2 recombinant protein expressed in yeast showed invertase and fructan exohydrolase-like activities with complete breakdown of sucrose, 1-kestose (DP3), 1,1-kestotetraose (DP4) and 1,1,1-kestopentaose (DP5) into glucose and fructose.

Herbert Dorken (1926-2012).

Herbert Dorken was born in Montreal, Canada, on July 7, 1926, and died in Grass Valley, California, on February 18, 2012, at the age of 85. Dorken was a prolific writer, with nearly 100 publications to his credit. He was particularly adept at taking raw health care data that the government had assembled with no apparent interpretation and translating it so that its meaning and implications for health care practice were clear. He strongly believed that the health care system in America, and particularly its mental health system, was in need of extensive reform. At the invitation in the mid- 1980s of the National Academies of Practice, he designed a model health care system that was heralded by many health economists, but it went nowhere because it was not in keeping with either of the two most prominent prevailing political health biases. In his later years, and after his daughter almost died of Lyme disease, Dorken became an advocate of the then neglected victims of this condition, the effects of which may persist for years after initial infection.

Cladobotric acids A-F: new cytotoxic polyketides from a New Zealand Cladobotryum sp.

[reaction: see text] Cladobotric acids A-F (1-6), fungal-derived polyketides, were isolated from the fermentation broth of a New Zealand Cladobotryum species. Structures were determined by extensive spectral analysis and X-ray crystallography, and the polyketide origin of 1-6 was concluded from feeding experiments with (13)C-labeled precursors. The observed folding pattern for the polyketide chain is unusual for fungi. Cladobotric acids A-F (1-6) exhibited notable cytotoxicity against the murine P388 leukemia cell line and were also active against Bacillus subtilis and Candida albicans.