A Call to Restore Your Calling: Self-Care of the Emergency Physician in the Face of Life-Changing Stress-Part 3 of 6: Physician Illness and Impairment.

Physicians suffer from most medical conditions at the same rate as their lay peers. However, physicians' self-care is often sacrificed for patient care. This third article in our series examines physician and trainee illness and impairment. Presenteeism, physician impairment, and substance use disorder (SUD) are defined. We call attention to the potential for harm of dated cultural norms, which often fuel physicians' neglect of their own health and development of ill-advised coping skills.Although any medical condition may become a functional impairment, the primary cause of physician impairment is SUD. Alcohol and prescription opioids top the list of substances used in excess by physicians. Although SUD is less prevalent in residency, we focus on the rise of marijuana and alcohol use in emergency medicine trainees. A nonpunitive model for the prevention and treatment of SUD in residency is described.Physicians are ethically and legally mandated to report any concern for impairment to either a state physician health program or a state medical board. However, recognizing physician SUD is challenging. We describe its clinical presentation, voluntary and mandated treatment tracks, provisions for protecting reporters from civil liability, prognosis for return to practice, and prevention efforts. We underscore the need to model healthy coping strategies and assist trainees in adopting them.In closing, we offer our colleagues and trainees today's to-do list for beginning the journey of reclaiming your health. We also provide resources focused on the practical support of ill and/or impaired physicians.

A Call to Restore Your Calling: Self-care of the Emergency Physician in the Face of Life-Changing Stress-Part 1 of 6.

Few practicing emergency physicians will avoid life-changing stressors such as a medical error, personal illness, malpractice litigation, or death of a patient. Many will be unprepared for the toll they will take on their lives. Some may ultimately experience burnout, post-traumatic stress disorder, and suicidal ideation. Medical education, continuing education, and maintenance of certification programs do not teach physicians to recognize helplessness, moral distress, or maladaptive coping mechanisms in themselves. Academic physicians receive little instruction on how to teach trainees and medical students the art of thriving through life-changing stressors in their career paths. Most importantly, handling a life-changing stressor is that much more overwhelming today, as physicians struggle to meet the daily challenge of providing the best patient care in a business-modeled health care environment where profit-driven performance measures (eg, productivity tracking, patient reviews) can conflict with the quality of medical care they wish to provide.Using personal vignettes and with a focus on the emergency department setting, this 6-article series examines the impact life-changing stressors have on physicians, trainees, and medical students. The authors identify internal constraints that inhibit healthy coping and tools for individuals, training programs, and health care organizations to consider adopting, as they seek to increase physician satisfaction and retention. The reader will learn to recognize physician distress and acquire strategies for self-care and peer support. The series will highlight the concept that professional fulfillment requires ongoing attention and is a work in progress.

Systemic Treatment with a miR-146a Mimic Suppresses Endotoxin Sensitivity and Partially Protects Mice from the Progression of Acute Graft-versus-Host Disease.

Acute GVHD (aGVHD) is driven by interactions between the allogenic T cell response, inflammation, tissue injury and microbial products that enter the circulation when protective barriers such as the intestinal epithelium become compromised. Mice with aGVHD become hypersensitive to LPS, secreting large quantities of inflammatory mediators that exacerbate tissue injury. We hypothesized that microRNA (miR) modulators could be used in vivo to mitigate LPS hypersensitivity, altering the course of aGVHD. Using the C57BL/6 → (C57BL/6 × DBA/2)F1 -hybrid model of aGVHD, we measured intestinal permeability over time and used a qPCR array to detect concomitant changes in the expression levels of certain microRNAs (miRs) in the intestine. Large increases in permeability were seen on day 15, when endotoxemia becomes detectable and GVHD-associated histopathological lesions develop. Amongst the miRs with altered expression levels were some that regulate sensitivity to endotoxin. We chose to focus on miR-146a and treated recipient mice systemically with a miR-146a mimic early in the GVH reaction. This led to a reduction in the burst of IFNγ that likely plays a priming role in the mechanism underlying heightened sensitivity to endotoxin. LPS-induced TNFα release and GVHD-associated weight loss were also diminished and survival was prolonged. In summary, systemic treatment with a miR-146a mimic dampens the heightened sensitivity to LPS that occurs concomitantly with increased intestinal permeability and provides partial protection from the progression of acute GVHD.

Diagnostic and prognostic value of in vivo proton MR spectroscopy for Zellweger syndrome spectrum patients.

Defects in the biogenesis of peroxisomes cause a clinically and genetically heterogeneous group of neurometabolic disorders, the Zellweger syndrome spectrum (ZSS). Diagnosis predominantly is based on characteristic clinical symptoms, a typical biochemical profile, as well as on identification of the molecular defect in any of the 12 known human PEX genes. The diagnostic workup can be hindered if the typical clinical symptoms are missing and predicting the clinical course of a given patient is almost unfeasible. As a safe and noninvasive method to analyze specific chemical compounds in localized brain regions, in vivo proton magnetic resonance spectroscopy (MRS) can provide an indication in this diagnostic process and may help predict the clinical course. However, to date, there are very few reports on this topic. In this study, we performed localized in vivo proton MRS without confounding contributions from T1- and T2-relaxation effects at 2 Tesla in a comparably large group of seven ZSS patients. Patients' absolute metabolite concentrations in cortical gray matter, white matter, and basal ganglia were assessed and compared with age-matched control values. Our results confirm and extend knowledge about in vivo MRS findings in ZSS patients. Besides affirmation of nonspecific reduction of N-acetylaspartate + N-acetylaspartylglutamate (tNAA) in combination with lipid accumulation as a diagnostic hint for this disease group, the amount of tNAA loss seems to reflect disease burden and may prove to be of prognostic value regarding the clinical course of an already diagnosed patient.

[State of integration of palliative care at Comprehensive Cancer Centers funded by German Cancer Aid]. / Integration der Palliativmedizin in die von der Deutschen Krebshilfe e. V. geförderten onkologischen Spitzenzentren.

BACKGROUND: Similarities and differences of integration of palliative care in clinical care, research and education structures at German Comprehensive Cancer Centers (CCC) are not known in detail. OBJECTIVE: Provide an overview of availability and the way of integration of specialized palliative care at CCCs funded by the German Cancer Aid (Deutsche Krebshilfe, DKH). METHOD: We conducted structured interviews from May to August 2014 with heads of palliative care departments (personally or by telephone). The interviews included a quantitative and a qualitative part. Other stakeholders of CCCs were asked the questions of the qualitative part. We evaluated the qualitative data using the content analysis by Mayring and MAXQDA 11.0. SPSS 21.0 was used for quantitative analysis. RESULTS: 26 interviews were realized in 13 CCCs with 14 sites, which received funding, by DKH till August 2014 (one CCC had two university hospitals). Of these, 12 sites had a palliative care unit (86%), 11 sites had palliative care consulting services available (79%). Participation of palliative care specialists in tumor boards is not provided in 3 institutions (21%) and is often not feasible on regular basis in the other institutions, due to staffing shortage. In 7 sites (50%) defined criteria to integrate palliative care into CCCs were available. In the last 5 years specialized palliative care of 4 sites received an invitation for a research project by another department within the CCC (29%). 10 sites (71%) had started own palliative care research projects. Chairs in palliative care were available in 4 CCCs (29%). CONCLUSION: The extent and depth of palliative care integration in the 14 CCC sites is heterogeneous.

Obtaining a genetic diagnosis in a child with disability: impact on parental quality of life.

Recent progress in genetic testing has facilitated obtaining an etiologic diagnosis in children with developmental delay/intellectual disability (DD/ID) or multiple congenital anomalies (MCA) or both. Little is known about the benefits of diagnostic elucidation for affected families. We studied the impact of a genetic diagnosis on parental quality of life (QoL) using a validated semiquantitative questionnaire in families with a disabled child investigated by array-based comparative genomic hybridization (aCGH). We received completed questionnaires from 95 mothers and 76 fathers of 99 families. We used multivariate analysis for adjustment of potential confounders. Taken all 99 families together, maternal QoL score (percentile rank scale 51.05) was significantly lower than fathers' QoL (61.83, p = 0.01). Maternal QoL score was 20.17 [95% CI (5.49; 34.82)] percentile rank scales higher in mothers of children with diagnostic (n = 34) aCGH as opposed to mothers of children with inconclusive (n = 65) aCGH (Hedges' g = 0.71). Comparison of these QoL scores with retrospectively recalled QoL before aCGH revealed an increase of maternal QoL after diagnostic clarification. Our results indicate a benefit for maternal QoL if a genetic test, here aCGH, succeeds to clarify the etiologic diagnosis in a disabled child.

Multiple sclerosis in children and adolescents: incidence and clinical picture - new insights from the nationwide German surveillance (2009-2011).

BACKGROUND AND PURPOSE: Pediatric multiple sclerosis (MS) clinical and incidence data have been reported for several countries but valid age dependent incidence data are not yet available. The true incidence of pediatric MS in Germany was estimated and the clinical characteristics at diagnosis according to the 2005 McDonald criteria are described. METHODS: Between 2009 and 2011 active prospective nationwide surveillance for MS in children and adolescents ≤15 years included all pediatric hospitals, MS centers and private practices specialized in MS. Data were adjusted for under-reporting by capture-recapture from an independent second source. RESULTS: The estimated incidence of pediatric MS was 0.64 per 100,000 person-years with clear increase from age group ≤10 (0.09/100,000) to 2.64 per 100,000 in age group 14-15 years. All had relapsing-remitting disease with polysymptomatic onset in half of the cases. Spinal MRI with positive findings in two-thirds of patients contributed to diagnosis. CONCLUSION: Using an active prospective surveillance system and the McDonald criteria for first MS diagnosis the age-related incidence of pediatric MS in Germany was uncovered and is more common than in previous estimates. Thorough application of McDonald criteria and inclusion of spinal MRI data allowed for early diagnosis in almost 90% of cases.

A Novel SLC6A8 Mutation in a Large Family with X-Linked Intellectual Disability: Clinical and Proton Magnetic Resonance Spectroscopy Data of Both Hemizygous Males and Heterozygous Females.

X-linked creatine transport (CRTR) deficiency, caused by mutations in the SLC6A8 gene, leads to intellectual disability, speech delay, epilepsy, and autistic behavior in hemizygous males. Additional diagnostic features are depleted brain creatine levels and increased creatine/creatinine ratio (cr/crn) in urine. In heterozygous females the phenotype is highly variable and diagnostic hallmarks might be inconclusive. This survey aims to explore the intrafamilial variability of clinical and brain proton Magnetic Resonance Spectroscopy (MRS) findings in males and females with CRTR deficiency. X-chromosome exome sequencing identified a novel missense mutation in the SLC6A8 gene (p.G351R) in a large family with X-linked intellectual disability. Detailed clinical investigations including neuropsychological assessment, measurement of in vivo brain creatine concentrations using quantitative MRS, and analyses of creatine metabolites in urine were performed in five clinically affected family members including three heterozygous females and one hemizygous male confirming the diagnosis of CRTR deficiency. The severe phenotype of the hemizygous male was accompanied by most distinct aberrations of brain creatine concentrations (-83% in gray and -79% in white matter of age-matched normal controls) and urinary creatine/creatinine ratio. In contrast, the heterozygous females showed varying albeit generally milder phenotypes with less severe brain creatine (-50% to -33% in gray and -45% to none in white matter) and biochemical urine abnormalities. An intrafamilial correlation between female phenotype, brain creatine depletion, and urinary creatine abnormalities was observed. The combination of powerful new technologies like exome-next-generation sequencing with thorough systematic evaluation of patients will further expand the clinical spectrum of neurometabolic diseases.

Clinical presentation of pediatric multiple sclerosis before puberty.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) onset before puberty is extremely rare and establishment of diagnosis is often difficult due to atypical presentation. The study aims to identify the typical presentation of MS in this age group. METHODS: Pediatric MS patients were identified from the database of the Center for Multiple Sclerosis in Childhood and Adolescence at the University Medical Center Göttingen, Germany. Inclusion criteria were a relapsing-remitting initial disease course and minimum disease duration of 4 years. RESULTS: Forty-seven pre-pubertal (<11 years) and 41 post-pubertal (14-16 years) MS patients were compared. Before puberty an even gender ratio was found. The pre-pubertal patients were more likely to have a polysymptomatic severe first attack with motor and brainstem involvement, sphincter dysfunction, cognitive disturbances and milder residual neurological sequelae after the first episode whilst the post-pubertal patients predominantly presented with optic neuritis and sensory symptoms. The initial symptom pattern prevailed over the first 2 years of disease. Presentation of pre-pubertal boys and girls did not differ significantly. CONCLUSIONS: To facilitate early diagnosis it is important to recognize that pre-pubertal MS presents with a specific pattern of symptoms that is maintained over the first two disease years.

Lack of functional TSLP receptors mitigates Th2 polarization and the establishment and growth of 4T1 primary breast tumours but has different effects on tumour quantities in the lung and brain.

The 4T1 mammary carcinoma cell line produces TSLP. We had hypothesized that TSLP promotes the development of a permissive environment for the growth and metastasis of primary tumour and that this is associated with a Th2-polarized antitumour immune response. We found that, in Tslpr(-/-) mice, the mean tumour diameters were smaller from days 27 to 40, and relatively fewer tumour cells were present in the lung, compared with wild-type mice. Polarization of the Th2 cytokine profile was also diminished in Tslpr(-/-) mice. These findings confirmed those reported previously by others. Here, we further show that primary tumours are established less often in Tslpr(-/-) mice and that, unexpectedly, the relative number of tumour cells in the brain is greater in Tslpr(-/-) mice compared with wild-type mice. Findings from our cytotoxicity assays show that 4T1-directed lysis is undetectable in both WT and Tslpr(-/-) mice, ruling out the possibility that altered cytotoxic responses in Tslpr(-/-) mice are responsible for the differences we observed. In a human tissue microarray, positive staining for TSLP was seen in tumour cells from breast cancer tissue, but it was also seen in normal glandular epithelial cells from normal breast tissue, which has not been shown before. Thus, our findings provide new insight into the effects of TSLP in metastatic breast cancer.

Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?

Array comparative genomic hybridization (array CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Our study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants (CNVs) as well as delineating clinical criteria, which may help separating patients with pathogenic CNVs from those without pathogenic CNVs. We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. The phenotypic features of patients with clinically significant CNV were compared with those without pathogenic CNVs. Array CGH detected pathogenic CNVs in 13.2% of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with pathogenic CNVs compared with children with normal array CGH results. Thus, we assume that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.

Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency.

Cerebral folate transport deficiency is an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 gene coding for folate receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral folate transport deficiency.

[Pain management in international curricula for undergraduate education in palliative medicine. A palliative education assessment tool (PEAT) analysis]. / Schmerztherapeutische Inhalte internationaler Curricula für die studentische Lehre in der Palliativmedizin. Eine PEAT-basierte Analyse.

BACKGROUND: In the context of undergraduate medical education, there is the question of overlap between palliative medicine and pain management. International curricula for palliative medicine were analyzed with regard to the content concerning pain management. METHODS: Available international curricula were sought through general search engines (Google, Medline/Pubmed) in the German and English languages. The palliative care education assessment tool (PEAT), a validated instrument for curricula mapping, was used for detection of pain management content. The PEAT comprises 7 domains and 83 objectives. Domain II (pain) contains 12 items (15%). Additional pain management content was analyzed qualitatively. RESULTS: Between 1993 and 2011 16 international curricula for undergraduate education in palliative medicine were identified and every curriculum contained PEAT-domain II (pain). Altogether, 2-65 out of 83 PEAT objectives and 0-11 specific pain-related PEAT objectives were included as learning content. Hence, the latter define 0-21% of the contents of the analyzed curricula. The only additional topic was "breakthrough pain" which was mentioned in 4 out of 16 curricula. CONCLUSIONS: Pain-related objectives are regularly mentioned in international undergraduate palliative medicine curricula. The extent is limited and therefore the concordance to general pain management is low.

Immunomodulatory effects of palifermin (recombinant human keratinocyte growth factor) in an SLE-like model of chronic graft-versus-host disease.

Keratinocyte growth factor (KGF) promotes epithelial cell proliferation and survival. Recombinant human KGF, also known as palifermin, protects epithelial cells from injury induced by chemicals, irradiation and acute murine graft-versus-host disease (GVHD). Findings from our studies and others have shown that palifermin also has immunomodulatory properties. In a model of acute GVHD, we showed that it shifts the immune response from one in which Th1 cytokines dominate to mixed Th1 and Th2 cytokine profile. Using the DBA/2→(C57BL/6 × DBA/2)F(1)-hybrid model of chronic, systemic lupus erythematosus-like GVHD, we showed that palifermin treatment is associated with higher levels of Th2 cytokines, the production of anti-nuclear antibodies, cryoglobulinemia and the development of more severe pathological changes in the kidney. The aim of our current study was to gain a better understanding of the immunobiology of KGF by further characterizing the palifermin-mediated effects in this model of chronic GVHD. Because the pathological changes we observed resemble those seen in thymic stromal lymphopoietin (TSLP) transgenic mice, we had originally hypothesized that palifermin might augment TSLP levels. Surprisingly, we did not observe an increase in thymic TSLP mRNA expression in palifermin-treated recipients. We did, however, observe some differences in the percentages of CD4(+) CD25(+) Foxp3(+) regulatory T cells in the spleen at some time points in palifermin-treated recipients. Most importantly, we found that TGFß levels were higher in palifermin-treated recipients early in the GVH reaction, raising the possibility that KGF might indirectly induce the development of fibrosis and glomerulonephritis through a pathway involving TGFß.

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis.

OBJECTIVE: To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. METHODS: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. RESULTS: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. CONCLUSIONS: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

[Oncology and palliative medicine]. / Onkologie und Palliativmedizin.

Approximately one half of patients who receive the diagnosis of cancer still die as the result of their disease. To be able to adequately meet the patients and their families needs, it is essential that oncologists and palliative care physicians cooperate closely. How the recommendations of international institutions are concerning the cooperation between the fields of oncology and palliative care medicine can be approached is exemplified by the concepts developed in the Center for Integrated Oncology (CIO Cologne/Bonn) at the University Hospital in Cologne and discussed critically.

Intrathecal IgM synthesis in pediatric MS is not a negative prognostic marker of disease progression: quantitative versus qualitative IgM analysis.

BACKGROUND: Intrathecal IgM synthesis is reported to be associated with a worse prognosis in adults with multiple sclerosis (MS). OBJECTIVE: To study the predictive value of intrathecal IgM synthesis for the clinical course of pediatric MS. METHODS: Seventy children with onset of MS before the age of 16 years and followed for a median period of 10.4 years (range: 0.4-22.8 years) were studied. The two subgroups with (n=44) or without (n=26) intrathecal IgM synthesis were distinguished by a new, very sensitive, evaluation of quantitative analysis in cerebrospinal fluid (CSF)/serum quotient diagrams (Reibergrams). The clinical course and EDSS (Expanded Disability Status Scale) scores at five and ten years were compared with IgM frequencies between both groups with a new statistics program for CSF data. RESULTS: The cohort of children without intrathecal IgM production had higher numbers of attacks in the first two years and shorter time intervals between first and second attack, although this was not statistically significant (p=0.04, p=0.15 respectively). In addition there was also a trend for girls without intrathecal IgM synthesis to have a higher EDSS score after 10 years compared with the group with IgM synthesis. CONCLUSION: Intrathecal IgM synthesis is not associated with a more rapid progression of disability in pediatric MS. Reevaluation of data from previous reports about the negative predictive value of intrathecal IgM synthesis in adult MS with a CSF statistics tool show that the apparent contradiction is due to a methodological bias in the qualitative detection of 'oligoclonal' IgM or linear IgM index.

Neuromyelitis optica and NMO-IgG in European pediatric patients.

OBJECTIVE: Neuromyelitis optica (NMO) is currently considered a severe relapsing CNS demyelinating disorder that is associated with aquaporin-4 immunoglobulin G (NMO-IgG) while in earlier reports of NMO in childhood it has been described as a benign and monophasic disorder. This study was performed to analyze the prevalence and the clinical course of NMO in a European pediatric cohort of patients with demyelinating CNS disorders. METHODS: A cohort study was performed evaluating 118 pediatric patients presenting at the Center for Multiple Sclerosis in Childhood and Adolescents, Göttingen, Germany, with demyelinating CNS disorders between 2000 and 2009. In all patients, NMO-IgG status was determined. RESULTS: The majority of patients (94%) were diagnosed with remitting recurrent multiple sclerosis. Six patients fulfilled the clinical criteria for NMO but only 1 was seropositive for NMO-IgG. This patient had a severe relapsing course in contrast to the seronegative patients who showed a mild and in the majority of cases monophasic course. CONCLUSIONS: The diagnostic criteria clearly distinguished the patients with NMO from patients with other demyelinating CNS disorders. In the European pediatric population, NMO is very rare and in the majority of patients not associated with NMO-IgG. These seronegative cases have a benign and predominantly monophasic course and therefore do not need the immunosuppressant therapy that is recommended for NMO in the recent literature.