Sex as a Critical Variable in Basic and Pre-Clinical Studies of Fibrodysplasia Ossificans Progressiva.

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and pre-clinical studies of FOP.

Palliative care for persons with late-stage Alzheimer's and related dementias and their caregivers: protocol for a randomized clinical trial.

BACKGROUND: Limited access to specialized palliative care exposes persons with late-stage Alzheimer's disease and related dementias (ADRD) to burdensome treatment and unnecessary hospitalization and their caregivers to avoidable strain and financial burden. Addressing this unmet need, the purpose of this study was to conduct a randomized clinical trial (RCT) of the ADRD-Palliative Care (ADRD-PC) program. METHODS: The study will use a multisite, RCT design and will be set in five geographically diverse US hospitals. Lead investigators and outcome assessors will be masked. The study will use 1:1 randomization of patient-caregiver dyads, and sites will enroll N = 424 dyads of hospitalized patients with late-stage ADRD with their family caregivers. Intervention dyads will receive the ADRD-PC program of (1) dementia-specific palliative care, (2) standardized caregiver education, and (3) transitional care. Control dyads will receive publicly available educational material on dementia caregiving. Outcomes will be measured at 30 days (interim) and 60 days post-discharge. The primary outcome will be 60-day hospital transfers, defined as visits to an emergency department or hospitalization ascertained from health record reviews and caregiver interviews (aim 1). Secondary patient-centered outcomes, ascertained from 30- and 60-day health record reviews and caregiver telephone interviews, will be symptom treatment, symptom control, use of community palliative care or hospice, and new nursing home transitions (aim 2). Secondary caregiver-centered outcomes will be communication about prognosis and goals of care, shared decision-making about hospitalization and other treatments, and caregiver distress (aim 3). Analyses will use intention-to-treat, and pre-specified exploratory analyses will examine the effects of sex as a biologic variable and the GDS stage. DISCUSSION: The study results will determine the efficacy of an intervention that addresses the extraordinary public health impact of late-stage ADRD and suffering due to symptom distress, burdensome treatments, and caregiver strain. While many caregivers prioritize comfort in late-stage ADRD, shared decision-making is rare. Hospitalization creates an opportunity for dementia-specific palliative care, and the study findings will inform care redesign to advance comprehensive dementia-specific palliative care plus transitional care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04948866. Registered on July 2, 2021.

The impact of CFTR modulator triple therapy on type 2 inflammatory response in patients with cystic fibrosis.

BACKGROUND: Treatment of cystic fibrosis (CF) has been revolutionized by the use of cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) triple therapy. Prior studies support a role for type 2 (T2) inflammation in many people with CF (PwCF) and CF-asthma overlap syndrome (CFAOS) is considered a separate clinical entity. It is unknown whether initiation of ETI therapy impacts T2 inflammation in PwCF. We hypothesized that ETI initiation decreases T2 inflammation in PwCF. METHODS: A single center retrospective chart review was conducted for adult PwCF. As markers of T2 inflammation, absolute eosinophil count (AEC) and total immunoglobulin E (IgE) data were collected longitudinally 12 months prior to ETI therapy initiation and 12 months following therapy initiation. Multivariable analyses adjusted for the age, gender, CFTR mutation, disease severity, inhaled steroid use, and microbiological colonization. RESULTS: There was a statistically significant reduction (20.10%, p < 0.001) in 12-month mean total IgE following ETI initiation; this change remained statistically significant in the multivariate model. The longitudinal analysis demonstrated no change in AEC following therapy initiation. CONCLUSION: This study demonstrates that there is a statistically significant percent reduction in mean total IgE but no change in AEC following ETI initiation. ETI may lead to decreased antigen and superantigen load in the airway as a result of improved mucociliary clearance and these changes may drive the decline in total IgE, without influencing the epigenetic drivers of eosinophilic inflammation. Further studies are warranted to determine the underlying mechanism of ETI impact on T2 inflammation and possible role for asthma immunomodulator therapy post ETI initiation in CFAOS.

Transitional care from skilled nursing facilities to home: study protocol for a stepped wedge cluster randomized trial.

BACKGROUND: Skilled nursing facility (SNF) patients are medically complex with multiple, advanced chronic conditions. They are dependent on caregivers and have experienced recent acute illnesses. Among SNF patients, the rate of mortality or acute care use is over 50% within 90 days of discharge, yet these patients and their caregivers often do not receive the quality of transitional care that prepares them to manage serious illnesses at home. METHODS: The study will test the efficacy of Connect-Home, a successfully piloted transitional care intervention targeting seriously ill SNF patients discharged to home and their caregivers. The study setting will be SNFs in North Carolina, USA, and, following discharge, in patients' home. Using a stepped wedge cluster randomized trial design, six SNFs will transition at randomly assigned intervals from standard discharge planning to the Connect-Home intervention. The SNFs will contribute data for patients (N = 360) and their caregivers (N = 360), during both the standard discharge planning and Connect-Home time periods. Connect-Home is a two-step intervention: (a) SNF staff create an individualized Transition Plan of Care to manage the patient's illness at home; and (b) a Connect-Home Activation RN visits the patient's home to implement the written Transition Plan of Care. A key feature of the trial includes training of the SNF and Home Care Agency staff to complete the transition plan rather than using study interventionists. The primary outcomes will be patient preparedness for discharge and caregiver preparedness for caregiving role. With the proposed sample and using a two-sided test at the 5% significance level, we have 80% power to detect a 18% increase in the patient's preparedness for discharge score. We will employ linear mixed models to compare observations between intervention and usual care periods to assess primary outcomes. Secondary outcomes include (a) patients' quality of life, functional status, and days of acute care use and (b) caregivers' burden and distress. DISCUSSION: Study results will determine the efficacy of an intervention using existing clinical staff to (a) improve transitional care for seriously ill SNF patients and their caregivers, (b) prevent avoidable days of acute care use in a population with persistent risks from chronic conditions, and (c) advance the science of transitional care within end-of-life and palliative care trajectories of SNF patients and their caregivers. While this study protocol was being implemented, the COVID-19 pandemic occurred and this protocol was revised to mitigate COVID-related risks of patients, their caregivers, SNF staff, and the study team. Thus, this paper includes additional material describing these modifications. TRIAL REGISTRATION: ClinicalTrials.gov NCT03810534 . Registered on January 18, 2019.

Densities and inhibitory phenotypes among indigenous Streptomyces spp. vary across native and agricultural habitats.

Streptomyces spp. perform vital roles in natural and agricultural soil ecosystems including in decomposition and nutrient cycling, promotion of plant growth and fitness, and plant disease suppression. Streptomyces densities can vary across the landscape, and inhibitory phenotypes are often a result of selection mediated by microbial competitive interactions in soil communities. Diverse environmental factors, including those specific to habitat, are likely to determine microbial densities in the soil and the outcomes of microbial species interactions. Here, we characterized indigenous Streptomyces densities and inhibitory phenotypes from soil samples (n = 82) collected in 6 distinct habitats across the Cedar Creek Ecosystem Science Reserve (CCESR; agricultural, prairie, savanna, wetland, wet-woodland, and forest). Significant variation in Streptomyces density and the frequency of antagonistic Streptomyces were observed among habitats. There was also significant variation in soil chemical properties among habitats, including percent carbon, percent nitrogen, available phosphorus, extractable potassium, and pH. Density and frequency of antagonists were significantly correlated with one or more environmental parameters across all habitats, though relationships with some parameters differed among habitats. In addition, we found that habitat rather than spatial proximity was a better predictor of variation in Streptomyces density and inhibitory phenotypes. Moreover, habitats least conducive for Streptomyces growth and proliferation, as determined by population density, had increased frequencies of inhibitory phenotypes. Identifying environmental parameters that structure variation in density and frequency of antagonistic Streptomyces can provide insight for determining factors that mediate selection for inhibitory phenotypes across the landscape.

Fungicide Sensitivity Monitoring of Alternaria spp. Causing Leaf Spot of Sugarbeet (Beta vulgaris) in the Upper Great Lakes.

Alternaria leaf spot (ALS), caused by Alternaria spp., can occur wherever sugarbeet is grown. Infection by Alternaria spp. and disease management has historically been considered a minor issue in sugarbeet production in the United States. An increase of both incidence and severity in 2016 of ALS high enough to cause yield loss has been observed in Michigan. With a renewed need to consider potential management of this disease, the sensitivity was determined for populations of Alternaria spp. to three classes of fungicides currently labeled for management of leaf spot on sugarbeet, including demethylase inhibitor (DMI), quinone outside inhibitor (QoI), and organo-tin fungicides. Leaves with symptoms of ALS were sampled from sugarbeet fields in east-central Michigan and southwestern Ontario, Canada. Monoconidial isolates were obtained to determine sensitivity to each fungicide class above. A spiral gradient dilution method was used to estimate the fungicide effective concentration (in milligrams per liter) that caused a 50% inhibition of fungal growth in vitro for all isolates. Significant temporal shifts were detected in the frequencies of sensitivity phenotypes to DMI and QoI but not organo-tin fungicides from 2016 through 2017. Individual isolates of Alternaria spp. were recovered with cross-resistance to DMI and multiple resistance to DMI, QoI, and triphenyltin hydroxide fungicides. To our knowledge, this is the first report of a fungus other than Cercospora beticola with resistance to organo-tin fungicides. Fungicide sensitivity monitoring indicates that an effective integrated disease management approach combining fungicide efficacy trials and monitoring pathogen biology is essential for developing effective resistance management recommendations.

Intranasal deferoxamine affects memory loss, oxidation, and the insulin pathway in the streptozotocin rat model of Alzheimer's disease.

Accumulation of metal and the accompanying increase in oxidative stress and inflammation plays an important role in neurodegenerative disease. Deferoxamine (DFO) is a metal chelator found to be beneficial in several animal models of neurodegenerative disease and insult including Alzheimer's disease, Parkinson's disease, stroke, and subarachnoid hemorrhage. In this study, we determine whether intranasally (IN) administered DFO is beneficial in the intracerebroventricular streptozotocin (ICV STZ) rat model of sporadic Alzheimer's disease, which is different from previous models in that it exhibits dysregulation of insulin metabolism as well as oxidative stress and inflammation. Surgical induction of the model included ICV injections of either STZ or citrate buffer (sham in rats), which were treated IN with either saline or DFO (n=10-15/group). Treatment started either before or after injection of STZ to induce the model, and continued throughout the study. IN treatment continued three times per week for three weeks before behavior tests started followed by eventual euthanasia with tissue collection. Spatial memory tests with the Morris water maze showed that STZ rats treated with IN DFO both before and after model induction had significantly shorter escape latencies. Pre-treatment with IN DFO also significantly decreased footslips on the tapered balance beam test. Brain tissue analyses showed DFO treatment decreased oxidation as measured by oxyblot and increased insulin receptor expression. These results further support the potential of IN DFO for use as a treatment for Alzheimer's disease, and show benefit in a non-amyloid/tau rodent model.

Associations between systemic pro-inflammatory markers, cognitive function and cognitive complaints in a population-based sample of working adults.

BACKGROUND: The knowledge is limited regarding the relation between systemic inflammatory biomarkers and subjective and objective cognitive functioning in population-based samples of healthy adults across the adult age-span. Thus, the aim of this study was to study a selection of four pro-inflammatory biomarkers (IL-6, MCP-1, TNF-α, CRP) in relation to executive cognitive functioning, episodic memory and subjective cognitive complaints (SCC) in a population-based sample of 215 working adults (age 25-67). RESULTS: Higher levels of MCP-1 were associated with poorer executive cognitive functioning, even after adjustments for demographical factors, health status/conditions, SCC and depressive symptoms. IL-6 and CRP were associated with poorer executive cognitive functioning, but these associations covaried with age especially and were not present after adjustment for demographical factors. MCP-1 was associated with poorer episodic memory, but this association also covaried with age especially and was not present after adjustment for demographical factors, and CRP was associated with episodic memory only among participants without reported health conditions. Higher MCP-1 levels were also associated with more SCC and this association covaried with depressive symptoms, while higher levels of TNF-α were associated with less SCC. CONCLUSION: Low grade inflammatory processes in terms of higher systemic levels of pro-inflammatory biomarkers (MCP-1, IL-6 & CRP) were associated with poorer executive functioning in this sample of working adults, and MCP-1 was so after extensive adjustments. Support for associations between these biomarkers and episodic memory and SCC were more limited. Future research should address the causality of associations between low grade inflammatory processes and cognitive functioning.

Body mass index as a predictor of healthy and disease-free life expectancy between ages 50 and 75: a multicohort study.

BACKGROUND: While many studies have shown associations between obesity and increased risk of morbidity and mortality, little comparable information is available on how body mass index (BMI) impacts health expectancy. We examined associations of BMI with healthy and chronic disease-free life expectancy in four European cohort studies. METHODS: Data were drawn from repeated waves of cohort studies in England, Finland, France and Sweden. BMI was categorized into four groups from normal weight (18.5-24.9 kg m-2) to obesity class II (⩾35 kg m-2). Health expectancy was estimated with two health indicators: sub-optimal self-rated health and having a chronic disease (cardiovascular disease, cancer, respiratory disease and diabetes). Multistate life table models were used to estimate sex-specific healthy life expectancy and chronic disease-free life expectancy from ages 50 to 75 years for each BMI category. RESULTS: The proportion of life spent in good perceived health between ages 50 and 75 progressively decreased with increasing BMI from 81% in normal weight men and women to 53% in men and women with class II obesity which corresponds to an average 7-year difference in absolute terms. The proportion of life between ages 50 and 75 years without chronic diseases decreased from 62 and 65% in normal weight men and women and to 29 and 36% in men and women with class II obesity, respectively. This corresponds to an average 9 more years without chronic diseases in normal weight men and 7 more years in normal weight women between ages 50 and 75 years compared to class II obese men and women. No consistent differences were observed between cohorts. CONCLUSIONS: Excess BMI is associated with substantially shorter healthy and chronic disease-free life expectancy, suggesting that tackling obesity would increase years lived in good health in populations.

Job strain as a risk factor for clinical depression: systematic review and meta-analysis with additional individual participant data.

BACKGROUND: Adverse psychosocial working environments characterized by job strain (the combination of high demands and low control at work) are associated with an increased risk of depressive symptoms among employees, but evidence on clinically diagnosed depression is scarce. We examined job strain as a risk factor for clinical depression. METHOD: We identified published cohort studies from a systematic literature search in PubMed and PsycNET and obtained 14 cohort studies with unpublished individual-level data from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium. Summary estimates of the association were obtained using random-effects models. Individual-level data analyses were based on a pre-published study protocol. RESULTS: We included six published studies with a total of 27 461 individuals and 914 incident cases of clinical depression. From unpublished datasets we included 120 221 individuals and 982 first episodes of hospital-treated clinical depression. Job strain was associated with an increased risk of clinical depression in both published [relative risk (RR) = 1.77, 95% confidence interval (CI) 1.47-2.13] and unpublished datasets (RR = 1.27, 95% CI 1.04-1.55). Further individual participant analyses showed a similar association across sociodemographic subgroups and after excluding individuals with baseline somatic disease. The association was unchanged when excluding individuals with baseline depressive symptoms (RR = 1.25, 95% CI 0.94-1.65), but attenuated on adjustment for a continuous depressive symptoms score (RR = 1.03, 95% CI 0.81-1.32). CONCLUSIONS: Job strain may precipitate clinical depression among employees. Future intervention studies should test whether job strain is a modifiable risk factor for depression.

Effect of a treat-to-target strategy based on methotrexate and intra-articular betamethasone with or without additional cyclosporin on MRI-assessed synovitis, osteitis, tenosynovitis, bone erosion, and joint space narrowing in early rheumatoid arthritis: results from a 2-year randomized double-blind placebo-controlled trial (CIMESTRA).

OBJECTIVES: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect. METHOD: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods. RESULTS: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, -3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups. CONCLUSIONS: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated.

Pilot Randomized Trial of Tacrolimus/Everolimus vs Tacrolimus/Enteric-Coated Mycophenolate Sodium in Adult, Primary Kidney Transplant Recipients at a Single Center.

BACKGROUND: Recent studies suggest that the combination of tacrolimus (TAC) and everolimus (EVL) could become a viable option for use as standard maintenance immunosuppression in non-highly sensitized kidney transplant recipients. METHODS: We conducted a single-center, open-label, randomized pilot trial comparing two maintenance immunosuppression regimens in non-highly sensitized, adult, primary kidney transplant recipients: (TAC/EVL, Group A) vs our standard maintenance regimen of TAC plus enteric-coated mycophenolate mofetil (TAC/EC-MPS, Group B). In both treatment arms, dual induction therapy consisting of anti-thymocyte globulin (Thymoglobulin) and basiliximab was given. Early corticosteroid withdrawal (by 7-10 days posttransplantation) was also planned in both arms. There were 30 study participants, 15 per treatment arm. Results during the first 12 months posttransplantation are reported here. RESULTS: Between 1 month and 12 months posttransplantation, mean TAC trough levels ranged between 5 and 8 ng/mL in both arms. Mean trough EVL level in Group A ranged between 4 and 6 ng/mL, and mean EC-MPS dose in Group B ranged from 1440 mg at 1 month to 945 mg at 12 months. One patient in Group A vs three patients in Group B experienced a first biopsy-proven acute rejection during the first 12 months posttransplantation (P = .32). Four patients in each group experienced biopsy-proven chronic allograft injury (interstitial fibrosis/tubular atrophy) (P = .99). There was a slight trend toward more favorable renal function in Group A at months 1-3 posttransplantation (P = .06, .10, and .18 for estimated glomerular filtration rate, respectively). No graft failures or deaths were observed in either group during the first 12 months posttransplantation. Four patients in each group developed an infection during the first 12 months posttransplantation. Two patients in Group A developed new-onset diabetes after transplant during the 12-month follow-up period, vs no patients in Group B (P = .13). CONCLUSION: TAC/EVL may be a viable alternative to TAC/EC-MPS for use as standard maintenance immunosuppression in non-highly sensitized kidney transplant recipients and should be given further consideration.

Variable selection and regression analysis for the prediction of mortality rates associated with foodborne diseases.

The purpose of this study was to apply a novel statistical method for variable selection and a model-based approach for filling data gaps in mortality rates associated with foodborne diseases using the WHO Vital Registration mortality dataset. Correlation analysis and elastic net regularization methods were applied to drop redundant variables and to select the most meaningful subset of predictors. Whenever predictor data were missing, multiple imputation was used to fill in plausible values. Cluster analysis was applied to identify similar groups of countries based on the values of the predictors. Finally, a Bayesian hierarchical regression model was fit to the final dataset for predicting mortality rates. From 113 potential predictors, 32 were retained after correlation analysis. Out of these 32 predictors, eight with non-zero coefficients were selected using the elastic net regularization method. Based on the values of these variables, four clusters of countries were identified. The uncertainty of predictions was large for countries within clusters lacking mortality rates, and it was low for a cluster that had mortality rate information. Our results demonstrated that, using Bayesian hierarchical regression models, a data-driven clustering of countries and a meaningful subset of predictors can be used to fill data gaps in foodborne disease mortality.

Regional brain volumes, diffusivity, and metabolite changes after electroconvulsive therapy for severe depression.

OBJECTIVE: To investigate the role of hippocampal plasticity in the antidepressant effect of electroconvulsive therapy (ECT). METHOD: We used magnetic resonance (MR) imaging including diffusion tensor imaging (DTI) and proton MR spectroscopy (1 H-MRS) to investigate hippocampal volume, diffusivity, and metabolite changes in 19 patients receiving ECT for severe depression. Other regions of interest included the amygdala, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex, and hypothalamus. Patients received a 3T MR scan before ECT (TP1), 1 week (TP2), and 4 weeks (TP3) after ECT. RESULTS: Hippocampal and amygdala volume increased significantly at TP2 and continued to be increased at TP3. DLPFC exhibited a transient volume reduction at TP2. DTI revealed a reduced anisotropy and diffusivity of the hippocampus at TP2. We found no significant post-ECT changes in brain metabolite concentrations, and we were unable to identify a spectral signature at ≈1.30 ppm previously suggested to reflect neurogenesis induced by ECT. None of the brain imaging measures correlated to the clinical response. CONCLUSION: Our findings show that ECT causes a remodeling of brain structures involved in affective regulation, but due to their lack of correlation with the antidepressant effect, this remodeling does not appear to be directly underlying the antidepressant action of ECT.

Is there a role for survivorship care plans in advanced cancer?

PURPOSE: The Institute of Medicine (2006) has recommended that cancer survivors completing treatment receive a survivorship care plan (SCP). The survivorship needs in advanced cancer have been overlooked and understudied. The potential role of SCPs for survivors with advanced or metastatic cancer is unknown and was explored in this study. METHODS: We conducted two focus groups of survivors with advanced or metastatic cancer. Participants reviewed a sample JourneyForward™ SCP modified for advanced cancer. Sessions were audiotaped and transcribed; transcripts and field notes were evaluated using inductive content analysis. RESULTS: Sixteen survivors with metastatic cancer participated: 12 (75 %) were female, 15 (94 %) were white, and median age was 66 (range 55-80); 9 participants had breast cancer, 4 colon, 2 prostate, and 1 ovarian cancer. Participants believed that an SCP would be most helpful after initial diagnosis and treatment, but not as helpful once the cancer progressed. They thought a "cancer care plan" focusing solely on the current management would be better to concisely summarize the treatment plan and time frame for the next segment of care for those with advanced cancer. Most participants endorsed the need to have written information to reinforce verbal information received during medical visits since it was difficult to remember information provided. Participants expected their oncologist to assume primary responsibility for coordination of the care plan, but anticipated an important supportive role for primary care providers. To this end, they emphasized the need for better communication between providers. CONCLUSIONS: A cancer care plan developed by the oncologist, similar to an SCP but more focused on current management, may be more useful for survivors with advanced cancer. Exploring this topic in larger groups of more diverse survivors with advanced cancer will help to elucidate the details a written plan of care should contain, and how to promote effective coordination between oncology and primary care providers. IMPLICATIONS FOR CANCER SURVIVORS: There are many transitions of care along the cancer journey. A written plan of care, similar to an SCP, may be useful for survivors with advanced cancer.

Use of PCR-RFLP Analysis to Monitor Fungicide Resistance in Cercospora beticola Populations from Sugarbeet (Beta vulgaris) in Michigan, United States.

Genetic resistance to Quinone outside inhibitor (QoI) and benzimidazole fungicides may be responsible for a recent decline in efficacy of chemical control management strategies for Cercospora leaf spot (CLS) caused by Cercospora beticola in Michigan sugarbeet (Beta vulgaris) fields. The target genes and fungicide resistance mutations are known for these two fungicides. Based on this, two standard polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays were developed to detect the G143A and E198A point mutations in the fungal mitochondrial cytochrome b and the ß-tubulin genes, respectively. These mutations confer a high level of resistance to either QoI or benzimidazole fungicides. The presence of the G143A and E198A mutations was monitored within C. beticola populations recovered from Michigan sugarbeet production fields collected in 2012. Both the QoI-resistant cytochrome b allele and the benzimidazole-resistant ß-tubulin allele were detected directly from leaf tissue following a PCR-RFLP assay. Using either detection assay, the G143A and E198A mutations were detected in over 90% of the 118 field samples originating from Michigan sugarbeet production under fungicide management programs for CLS control. Monitoring of the G143A and E198A mutations in fields located in 9 counties and 58 townships indicated that the mutations were widespread in Michigan sugarbeet production areas. The PCR-based assays used and developed in this study were effective in detecting the presence of the G143A and E198A mutations in C. beticola field populations from Michigan.

Intranasally-administered deferoxamine mitigates toxicity of 6-OHDA in a rat model of Parkinson׳s disease.

Deferoxamine (DFO) has shown therapeutic promise for the treatment of Parkinson׳s disease (PD) as it has reduced both behavioral and biochemical deficits when injected into the brain of rodent models of PD. Intranasally administered DFO targets the brain directly but non-invasively and has been effective in animal models of stroke and Alzheimer׳s disease. In this study we sought to determine whether intranasal (IN) DFO could be neuroprotective for PD in a rat model. PD was induced with a unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, while sham surgery rats received saline injections. Rats were pre-treated three times with either IN DFO or saline (starting 4 days before 6-OHDA), and post-treated twice/wk for one month before behavioral tests. In the apomorphine-induced rotational test, IN DFO significantly decreased the number of contralateral turns after injection of apomorphine HCl (p<0.05). Also, IN DFO significantly decreased limb asymmetry in the rearing tube as measured with contralateral limb touches (p<0.05). The IN DFO treatment yielded a trend towards decreased contralateral foot-slips on the tapered balance beam, though the difference was not significant. Finally, IN DFO-treated rats had increased preservation of tyrosine hydroxylase immunoreactive neurons in the substantia nigra (p<0.05). These results confirm that DFO is beneficial in a 6-OHDA model and demonstrate improvement in motor deficits and dopaminergic neuronal survival with non-invasive intranasal delivery, making this an attractive potential treatment for PD.

First Report of Fusarium proliferatum Causing Dry Rot in Michigan Commercial Potato (Solanum tuberosum) Production.

Fusarium dry rot of potato (Solanum tuberosum L.) is a postharvest disease caused by several Fusarium spp. Thirteen Fusarium spp. have been implicated in dry rot of potatoes worldwide. Among them, 11 species have been reported causing potato dry rot of seed tubers in the northern United States (1). Historically, Fusarium sambucinum was the predominant species in Michigan potato production (3). Dry rot symptomatic tubers (n = 972) were collected from Michigan commercial potato storage facilities in 2011 and 2012 to determine the composition of Fusarium spp. Sections were cut from the margins of necrotic tissue with a sterile scalpel and surface disinfested in 0.6% sodium hypochlorite for 10 s, rinsed twice in sterile distilled water, and dried on sterile filter paper. The tissue sections were plated on half-strength potato dextrose agar (PDA) amended with 0.5 g/liter of streptomycin sulfate. Dishes were incubated at 23°C in the dark for 7 days. Putative Fusarium isolates were transferred onto water agar and hyphal tips from the margin of actively growing cultures were removed with a sterile scalpel and plated to carnation leaf agar (CLA) and half-strength PDA to generate pure cultures. Seven hundred and thirty Fusarium isolates were collected using these techniques. Preliminary identification of the 730 isolates was based on colony and conidial morphology on PDA and CLA, respectively. While F. oxysporum and F. sambucinum were isolated as expected from prior reports (3), three isolates of F. proliferatum were also identified. On CLA, macroconidia of F. proliferatum were sparse, slender, and mostly straight, with three to five septae (4). Microconidia were abundant, usually single celled, oval or club-shaped in short chains or false heads on monophialides and polyphialides (4), and chlamydospores were absent. On PDA, abundant white mycelium was produced and turned violet with age. Koch's postulates were confirmed through pathogenicity testing on disease-free potato tubers cvs. Atlantic and Russet Norkotah. Tubers were surface disinfested for 10 min in 0.6% sodium hypochlorite and rinsed twice in distilled water. Three tubers of each cultivar per isolate were wounded at the apical end of the tuber to a depth of 4 to 10 mm with a 4 mm diameter cork-borer. Tubers were inoculated by inserting a mycelial plug from a 7-day-old culture grown on PDA into the wound and incubating the tubers at 20°C for 21 days. All Fusarium isolates were tested. Control tubers were inoculated by inserting a water agar plug. Pathogenicity and virulence testing were replicated three times and repeated. Tubers inoculated with F. proliferatum developed typical potato dry rot symptoms but no dry rot symptoms were observed on control tubers. Fusarium proliferatum was re-isolated from symptomatic tubers, confirming Koch's postulates. To our knowledge, this is the first report of F. proliferatum causing potato dry rot in Michigan. References: (1) E. Gachango et al. Plant Dis. 96:1767. (2) D. Geiser et al. Eur. J. Plant Pathol. 110:473, 2004. (3) M. L. Lacy and R. Hammerschmidt. Fusarium dry rot. Extension Bulletin. Retrieved from http://web1.msue.msu.edu/msue/iac/onlinepubs/pubs/E/E2448POT, 23 May 2010. (4) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Wiley-Blackwell, Hoboken, NJ, 2006.