The multiplicity of analysis strategies jeopardizes replicability: lessons learned across disciplines.

For a given research question, there are usually a large variety of possible analysis strategies acceptable according to the scientific standards of the field, and there are concerns that this multiplicity of analysis strategies plays an important role in the non-replicability of research findings. Here, we define a general framework on common sources of uncertainty arising in computational analyses that lead to this multiplicity, and apply this framework within an overview of approaches proposed across disciplines to address the issue. Armed with this framework, and a set of recommendations derived therefrom, researchers will be able to recognize strategies applicable to their field and use them to generate findings more likely to be replicated in future studies, ultimately improving the credibility of the scientific process.

Storylines of combined future land use and climate scenarios and their hydrological impacts in an Alpine catchment (Brixental/Austria).

In this paper, the hydrological impacts of future socio-economic and climatic development are assessed for a regional-scale Alpine catchment (Brixental, Tyrol, Austria). Therefore, coupled storylines of future land use and climate scenarios were developed in a transdisciplinary stakeholder process by means of questionnaire analyses and interviews with local experts from various relevant societal sectors. Resulting future land use maps for each decade were used as spatial input in the hydrological model WaSiM, to which a new module for the consideration of snow-canopy interaction processes has been added. Simulation results for three developed storylines, each combined with a moderate (A1B) and an extreme (RCP8.5) climate future, show that in a warmer and dryer climate the amount of annual simulated streamflow at the gauge of the catchment undergoes a significant reduction. The (mainly natural) reforestation of the catchment - caused by abandonment of previously cultivated areas - leads to additional losses of water by enhanced interception and evapotranspiration processes. Further cultivation of the current mountain pasture areas has a certain potential to attenuate undesirable long-term impacts of climate change on the catchment water balance.

Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome.

Constitutional mismatch repair deficiency (CMMR-D) syndrome is a rare inherited childhood cancer predisposition caused by biallelic germline mutations in one of the four mismatch repair (MMR)-genes, MLH1, MSH2, MSH6 or PMS2. Owing to a wide tumor spectrum, the lack of specific clinical features and the overlap with other cancer predisposing syndromes, diagnosis of CMMR-D is often delayed in pediatric cancer patients. Here, we report of three new CMMR-D patients all of whom developed more than one malignancy. The common finding in these three patients is agenesis of the corpus callosum (ACC). Gray matter heterotopia is present in two patients. One of the 57 previously reported CMMR-D patients with brain tumors (therefore all likely had cerebral imaging) also had ACC. With the present report the prevalence of cerebral malformations is at least 4/60 (6.6%). This number is well above the population birth prevalence of 0.09-0.36 live births with these cerebral malformations, suggesting that ACC and heterotopia are features of CMMR-D. Therefore, the presence of cerebral malformations in pediatric cancer patients should alert to the possible diagnosis of CMMR-D. ACC and gray matter heterotopia are the first congenital malformations described to occur at higher frequency in CMMR-D patients than in the general population. Further systematic evaluations of CMMR-D patients are needed to identify possible other malformations associated with this syndrome.

In situ RHAMM protein expression in acute myeloid leukemia blasts suggests poor overall survival.

Treatment options for patients with high-risk acute myeloid leukemia (AML) include high-dose chemotherapy regimens in combination with allogeneic hematopoietic stem cell transplantation, which takes advantage of the donor T-cell-mediated graft-versus-leukemia effect. Together with beneficial responses observed in assays targeted at leukemia-associated antigens (LAA), this encouraged research on cancer vaccines and adoptive cellular therapies in AML. The receptor for hyaluronic acid-mediated motility (RHAMM, CD168) was identified as one of the most promising LAA in AML. Thus far, little is known about in situ expression in leukemic bone marrow blasts or the prognostic role of RHAMM and its interaction partners in AML. We immunohistochemically analyzed the expression and prognostic significance of RHAMM on trephine bone marrow biopsies from 71 AML cases that had been evaluated for cytogenetics and presence of FLT3-internal tandem duplications and NPM1 mutations. Fifty-five patients (77%) were treated with curative intent, while 16 (23%) received the most appropriate supportive care. Twenty of 71 (28%) AML cases were considered RHAMM+. Receiver operating characteristic curves showed significant discriminatory power considering overall survival (OS) in AML patients treated curatively for RHAMM (p = 0.015). Multivariable analysis revealed that expression of RHAMM in >5% of leukemic blasts identifies a subgroup of curatively treated cases with adverse OS independent of failures to achieve complete remission. RHAMM not only represents a promising LAA with specific T-cell responses in AML but, if assessed in situ on blasts, also a probable prognostic factor.