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Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson’s disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients’ quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. Methods: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. Results: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. Conclusions: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.

An optogenetic, spatial self-stimulation task in mice reveals how information carried by distinct inputs to the nucleus accumbens shell is potentially integrated to drive behavioural responses.

Neurological disorders and type 2 diabetes mellitus (T2DM) are deeply intertwined. For example, autonomic neuropathy contributes to the development of T2DM and continued unmanaged T2DM causes further progression of nerve damage. Increasing glycemic control has been shown to prevent the onset and progression of diabetic autonomic neuropathies. Neuromodulation consisting of combined stimulation of celiac vagal fibers innervating the pancreas with concurrent electrical blockade of neuronal hepatic vagal fibers innervating the liver has been shown to increase glycemic control in animal models of T2DM. The present study demonstrated that the neuromodulation reversed glucose intolerance in alloxan-treated swine in both pre- and overt stages of T2DM. This was demonstrated by improved performance on oral glucose tolerance tests (OGTTs), as assessed by area under the curve (AUC). In prediabetic swine (fasting plasma glucose (FPG) range: 101–119 mg/dL) the median AUC decreased from 31.9 AUs (IQR = 28.6, 35.5) to 15.9 AUs (IQR = 15.1, 18.3) p = 0.004. In diabetic swine (FPG range: 133–207 mg/dL) the median AUC decreased from 54.2 AUs (IQR = 41.5, 56.6) to 16.0 AUs (IQR = 15.4, 21.5) p = 0.003. This neuromodulation technique may offer a new treatment for T2DM and reverse glycemic dysregulation at multiple states of T2DM involved in diabetic neuropathy including at its development and during progression.

Lichen heaths are declining in abundance in alpine and Arctic areas partly due to an increasing competition with shrubs. This shift in vegetation types might have important consequences for the microclimate and climate on a larger scale. The aim of our study is to measure the difference in microclimatic conditions between lichen heaths and shrub vegetation during the growing season. With a paired plot design, we measured the net radiation, soil heat flux, soil temperature and soil moisture on an alpine mountain area in southern Norway during the summer of 2018 and 2019. We determined that the daily net radiation of lichens was on average 3.15 MJ (26 %) lower than for shrubs during the growing season. This was mainly due to a higher albedo of the lichen heaths but also due to a larger longwave radiation loss. Subsequently, we estimate that a shift from a lichen heath to shrub vegetation leads to an average increase in atmospheric heating of 3.35 MJ d−1 during the growing season. Surprisingly, the soil heat flux and soil temperature were higher below lichens than below shrubs during days with high air temperatures. This implies that the relatively high albedo of lichens does not lead to a cooler soil compared to shrubs during the growing season. We predict that the thicker litter layer, the presence of soil shading and a higher evapotranspiration rate at shrub vegetation are far more important factors in explaining the variation in soil temperature between lichens and shrubs. Our study shows that a shift from lichen heaths to shrub vegetation in alpine and Arctic areas will lead to atmospheric heating, but it has a cooling effect on the subsurface during the growing season, especially when air temperatures are relatively high.

The study was carried out in Kuusamo (66°15'N, 29°05'E) and Inari (68°30'N, 28°15'E), northern Finland, where 24 and 22 Scots pine stands were studied respectively. Clear-cutting (logging residue) caused a decline in lichen biomass for some few years, but otherwise the age of the stand had no effect upon lichen biomass. Instead, a positive correlation was found between litter/logging residue and the mean height of lichens; in Kuusamo, logging residue decreased significantly with the age of the stand. Grazing pressure in terms of fecal group density increased with the age of the stand. The preference of old forests came visible also as a lower mean height of lichens, which eliminates the possibility that the preference of old forests is associated only to the use of arboreal lichens. In Inari, grazing pressure sharply increased after the stand had reached the age of 100 years despite scarce litter/logging residue and fair lichen ranges in younger forests; there prevailed a negative correlation between stand density and grazing pressure. It has been suggested that there might be three main reasons for reindeers preferring old forests: 1) hardening of the snow (because of winds) on clear-cut areas, 2) logging residue preventing digging for the food beneath the snow, and 3) poor visibility in young pine stands (Inari) which might increase predation risk.

The growth rate of Cladonia rangiferina and C. mitis was studied in Kuusamo, northeastern Finland, where they share more than 90 percent of the total lichen biomass. The material was collected from 5 pine forests of different ages in Calluna-Cladina heaths. The length growth rate of C. rangiferina varied by site from 3.9 to 4.3 mmyr -' and that of C. mitis from 3.0 to 3.5 mmyr-1 C. rangiferina achieved the fastest growth in a younger (60 years) shadowy forest; growth was slowest in a clear-felled area and in an old (180 years), already thinned forest. C. mitis grew fastest in a site with young (10 years old) pine plants and slowest in a younger shadowy site. The results do not support suggestions that clear-felling itself might negatively influence the growth of lichens. However, it is important also from the point of view of range management to create a new forest as soon as possible, since both species studied here grew faster in young forests than in clear-felled areas. Harmaaporonjakalan ja mietoporonjakalan kasvunopeus eri-ikaisissa metsissa. Abstract in Finnish / Yhteenveto: Harmaaporonjakalan (Cladonia rangiferina) ja mietoporonjakalan (Cladonia mitis) kasvunopeutta tutkittiin Kuusamossa. Aineisto kerattiin 5 puustoltaan eri-ikaiselti jakalakankaalta. Harmaaporonjakala kasvoi pituutta keskimaarin 3.9 - 4.3 mm/v ja mietoporonjakala 3.0 - 3.5 mm/v kasvupaikasta riippuen. Harmaaporonjakalan kasvu oli nopeinta nuorehkossa (60 v) tiheassa metsassa, hitainta paljaaksihakkuulla ja vanhassa (180 v), jo harventuneessa metsassa. Mietoporonjakala kasvoi nopeimmin 90 cm:n taimikossa ja hitaimmin varjoisimmalla kasvupaikalla. Tulosten perusteella on vaikea yhtya kasitykseen, etta paljaaksihakkuu sinansa vahentaa poronjakalien kasvunopeutta. Myos poronhoidon kannalta on kuitenkin tarkeaa, etta uusi metsa saadaan aikaan mahdollisimman nopeasti, silla molemmat lajit kasvavat nopeimmin eri-ikaisissa nuorissa metsissa.

Size-related changes in body condition of free-ranging male calves of semi-domesticated reindeer were studied in northern Finland from October 1983 to February 1984. In October-November, back fat depth or muscle fat percent correlated positively with the body size (=back length). In January, the highest means especially for muscle fat percent were found among medium-sized calves. Carcass weight and weight/back length ratio correlated positively with size, excluding February sample, where correlation for carcass weight was non-significant and for weight/back length ratio negative. Weight in the autumn correlated negatively with weight in February. Therefore, normalizing selection for body size (working against small and large phenotypes) is expected to occur in late winter. Small calves may be at greater mortality risk because of lower initial body reserves. Large calves commonly disperse during the rutting season and they may suffer most from increased food competition later in winter. Using of medium-sized calves for breeding might be the safest policy on ranges characterized by short food supply and difficult snow conditions. Koon vaikutus poron urosvasojen talviseen kuntoon. Abstract in Finnish / Tiivistelmä: Koon vaikutusta vapaana laiduntavien poron urosvasojen kuntoon tutkittiin Pohjois-Suomessa loka-helmikuussa talvella 1983-84. Loka-marraskuussa selkärasvan paksuus tai lihaksen rasvaprosentti riippui vasan koosta ( = selän pituus). Tammikuussa sen sijaan lihaksen rasvaprosentti oli korkein keskikokoisilla vasoilla. Ruhopaino sekä ruhopaino/selän pituus oli yleensa riippuvainen koosta. Helmikuussa ruhopainon riippuvuus koosta ei ollut enää tilastollisesti merkitsevä, ja koon ja ruhopainon/selänpituuden välinen korrelaatio oli negatiivinen. Eniten painoa menettivät (%) loka-helmikuun välillä suurikokoisimmat vasat. Havainnot viittaavat siihen, että talvella esiintyvä kuolleisuus on normalisoivaa koon suhteen (karsii pieniä ja suuria fenotyyppejä). Pienten vasojen kuolleisuusriski on suuri alunperinkin vähäisen varastoravinnon vuoksi. Suuret vasat puolestaan erkaantuvat usein emistään jo rykimäaikana, ja joutuvat kärsimään eniten talven mittaan kiristyvästä ravintokilpailusta. Niukoilla laitumilla siitokseen on turvallisinta säästää keskikokoisia vasoja. Sammenhengen mellom størrelse og vinterkondisjon hos hankalver av reinsdyr. Abstract in Norwegian / Sammendrag: Størrelses-relaterte forandringer i kroppskondisjon hos fritt beitende han-kalver av semidomestiserte rein er studert i Nord-Finland fra oktober 1983 til februar 1984. I oktober - november korrelerte tykkelsen av ryggfettet eller muskelfett-prosenten positivt med kroppsstørrelsen (= rygglengden). I januar ble de høyeste middelverdier, særlig for muskelfett-prosenten, funnet hos kalver av middels størrelse. Skrott-vekter og vekt/rygglengde-forholdet korrelerte positivt med kroppsstørrelse bortsett fra februar-prøvene, der korrellasjonen for skrott-vekt var ikke-signifikant og for vekt/rygglengde-forholdet var negativt. Vekt om høsten korrelerte negativt med vekt i februar. Derfor ventes et normaliserende utvalg for kroppsvekt (som arbeider mot små og store fenotyper) å skje på senvinteren. Små kalver er utsatt for større dødsrisiko på grunn av lavere kroppsreserver. Store kalver streifer vanligvis under brunsttiden og kan komme til å lide under økt næringskonkurranse på senvinteren. Bruk av middels store kalver i avlen kan være den sikreste metode på beiter som karakteriseres av dårlige næringstilgang og vanskelige snøforhold.

Modern techniques for estimating basal levels of electroactive neurotransmitters rely on the measurement of oxidative charges. This requires time integration of oxidation currents at certain intervals. Unfortunately, the selection of integration intervals relies on ad-hoc visual identification of peaks on the oxidation currents, which introduces sources of error and precludes the development of automated procedures necessary for analysis and quantification of neurotransmitter levels in large data sets. In an effort to improve charge quantification techniques, here we present novel methods for automatic selection of integration boundaries. Our results show that these methods allow quantification of oxidation reactions both in vitro and in vivo and of multiple analytes in vitro.

Introduction: A clean and functional microscope is necessary for accurate diagnosis of infectious diseases. In tropical climates, high humidity levels and improper storage conditions allow for the accumulation of debris and fungus on the optical components of diagnostic equipment, such as microscopes. Objective: Our objective was to develop and implement a low-cost, sustainable, easy to manage, low-maintenance, passive humidity control chamber to both reduce debris accumulation and microbial growth onto the optical components of microscopes. Methods: Constructed from easily-sourced and locally available materials, the cost of each humidity control chamber is approximately $2.35 USD. Relative humidity levels were recorded every 30 minutes over a period of 10 weeks from two chambers deployed at the Belize Vector and Ecology Center and the University of Belize. Results: The humidity control chamber deployed at the University of Belize maintained internal relative humidity at an average of 35.3% (SD = 4.2%) over 10 weeks, while the average external relative humidity was 86.4% (SD = 12.4%). The humidity control chamber deployed at the Belize Vector and Ecology Center effectively maintained internal relative humidity to an average of 54.5% (SD = 9.4%) over 10 weeks, while the average external relative humidity was 86.9% (SD = 12.9%). Conclusions: Control of relative humidity is paramount for the sustainability of medical equipment in tropical climates. The humidity control chambers reduced relative humidity to levels that were not conducive for fungal growth while reducing microscope contamination from external sources. This will likely extend the service life of the microscopes while taking advantage of low-cost, locally sourced components.

Implantable devices to measure neurochemical or electrical activity from the brain are mainstays of neuroscience research and have become increasingly utilized as enabling components of clinical therapies. In order to increase the number of recording channels on these devices while minimizing the immune response, flexible electrodes under 10 µm in diameter have been proposed as ideal next-generation neural interfaces. However, the representation of motion artifact during neurochemical or electrophysiological recordings using ultra-small, flexible electrodes remains unexplored. In this short communication, we characterize motion artifact generated by the movement of 7 µm diameter carbon fiber electrodes during electrophysiological recordings and fast-scan cyclic voltammetry (FSCV) measurements of electroactive neurochemicals. Through in vitro and in vivo experiments, we demonstrate that artifact induced by motion can be problematic to distinguish from the characteristic signals associated with recorded action potentials or neurochemical measurements. These results underscore that new electrode materials and recording paradigms can alter the representation of common sources of artifact in vivo and therefore must be carefully characterized.

Objective: Cell-free DNA (cfDNA) is used as a biomarker after transplantation to detect graft injury, relying on the donor fraction (DF). We have established a PCR-based approach allowing us to separately quantify absolute values of dd-cfDNA and recipient-derived cfDNA (rd-cfDNA). We aimed to present typical clinical scenarios after heart transplantation (HTx) to illustrate the advantages of absolute cfDNA values over DF., Methods: We used the cfDNA results of our cohort (509 samples of 52 patients followed during the first year after HTx) as background and determined the trajectories of cfDNA in specific clinical situations. We profiled an uncomplicated clinical course, viral and bacterial infections, acute and chronic rejection, and false-negative and false-positive rejections in six patients (five adults, one child)., Results: There was a substantial discrepancy between relative (DF) and absolute cfDNA-levels in several clinical situations. Rd- and dd-cfDNA were independently elevated during episodes of rejection and infection and were better suited to depict treatment response than DF alone., Conclusions: Absolute quantification of cfDNA may offer clinically relevant information additive to DF in various situations after HTx and could be helpful for more accurate monitoring of diagnosis and treatment of rejection., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Background: Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal morbidity and mortality. If women at high risk for developing complications could be identified early, level of care could be triaged, limited resources could be correctly allocated and targeted interventions to prevent complications could be implemented., Methods: We updated a systematic review and meta-analysis and added single outcomes. Women with hypertensive disorders of pregnancy were included. Exposures were tests predicting adverse maternal and/or perinatal outcomes. We searched Medline, Embase, CINAHL, and Cochrane library from January 2016-February 2024. We included studies identified from the previous review. We calculated effect measures. For similar predictive tests and outcomes, area under the receiver-operating-characteristic curve (AUROC) were pooled. This study was registered by PROSPERO: CRD42022336368., Findings: Of the 2898 studies identified, 80 were included. Thirty were added from the previous review resulting in 110 included studies with 506,178 women. Despite more than 1500 tests being performed, most outcomes could not be pooled due to heterogeneity in populations, tests, and outcome definitions. For maternal outcomes, only studies reporting on the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) model could be pooled. For the composite outcome within 48-h the AUROC was 0.78 (95% CI 0.71-0.86, N = 8). There was significant heterogeneity ( I 2  = 95.7%). For perinatal outcomes, data were pooled for pulsatility index in the umbilical artery and soluble FMS-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio. Biomarkers like the sFlt-1/PlGF ratio showed promising predictive performance for some outcomes but were not externally validated., Interpretation: Despite including over 100 studies with more than 1500 predictors, we were unable to pool any single maternal outcomes and only a few individual perinatal outcomes. The fullPIERS model was externally validated, showing moderate accuracy which varied across studies and should be validated in each new population. Angiogenic biomarkers showed promise but need validation. Future studies should use standardized outcome measures and validate promising tests., Funding: VB is supported by the Swedish Research Council, Grant number 2020-01481. University of Gothenburg., Competing Interests: We declare no competing interests., (© 2024 The Author(s).)

In this prospective study we investigated a cohort after heart transplantation with a novel PCR-based approach with focus on treated rejection. Blood samples were collected coincidentally to biopsies, and both absolute levels of dd-cfDNA and donor fraction were reported using digital PCR. 52 patients (11 children and 41 adults) were enrolled (NCT03477383, clinicaltrials.gov), and 557 plasma samples were analyzed. 13 treated rejection episodes >14 days after transplantation were observed in 7 patients. Donor fraction showed a median of 0.08% in the cohort and was significantly elevated during rejection (median 0.19%, p < 0.0001), using a cut-off of 0.1%, the sensitivity/specificity were 92%/56% (AUC ROC-curve: 0.78). Absolute levels of dd-cfDNA showed a median of 8.8 copies/mL and were significantly elevated during rejection (median 23, p = 0.0001). Using a cut-off of 7.5 copies/mL, the sensitivity/specificity were 92%/43% for donor fraction (AUC ROC-curve: 0.75). The results support the feasibility of this approach in analyzing dd-cfDNA after heart transplantation. The obtained values are well aligned with results from other trials. The possibility to quantify absolute levels adds important value to the differentiation between ongoing graft damage and quiescent situations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Böhmer, Wasslavik, Andersson, Ståhlberg, Jonsson, Wåhlander, Karason, Sunnegårdh, Nilsson, Asp, Dellgren and Ricksten.)

Introduction: Myeloproliferative neoplasm (MPN) is a heterogenous group of hematological malignancies including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). JAK2 V617F is the most frequent driver mutation in all three entities, but in PMF and ET mutations in CALR and MPL are also frequent. Mutations seen in additional genes are also often the same regardless of subtype of MPN. The aim of this study was to analyze a population based MPN cohort for genetic variants with prognostic value that can guide clinical decisions., Methods: MPN patients from Western Sweden diagnosed between 2008-2013 (n=248) were screened for mutations in 54 genes associated with myeloid malignancy., Results: Mutations in the genes SRSF2 and U2AF1 correlated significantly with impaired overall survival but did not correlate to increased risk for vascular events, neither before nor after diagnosis. Rather, mutations in these genes showed an association with disease transformation. Several recurrent gene variants with allele frequency close to 50% were confirmed to be germline. However, none of these variants was found to have an earlier onset of MPN., Discussion: In conclusion, we identified gene mutations to be independent markers of impaired survival in MPN. This indicates the need for more individualized assessment and treatment of MPN patients and a wider gene mutation screening already at diagnosis. This could ensure the identification of patients with high-risk mutations early on. In addition, several genetic variants were also identified as germline in this study but gave no obvious clinical relevance. To avoid conclusions from non-informative genetic variants, a simultaneous analysis of normal cell DNA from patients at diagnosis should be considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pettersson, Adamsson, Johansson, Nilsson, Palmqvist, Andréasson and Asp.)

Introduction: Alcohol consumption during pregnancy is related to severe birth complications such as low birthweight, preterm birth and birth defects. During the last decade, the Alcohol Use Disorders Identification Test (AUDIT) has been used as a screening tool in Swedish maternal healthcare units to identify hazardous, pre-pregnancy alcohol use. However, evaluation of the screening with AUDIT, as well as adverse maternal or neonatal outcomes, has not been assessed at a national level., Material and Methods: This was a population-based cohort study of 530 458 births from 2013 to 2018 using demographic, reproductive and maternal health data from the Swedish Pregnancy Register. Self-reported alcohol consumption in the year before pregnancy, measured as AUDIT scores, was categorized into moderate (6-13 points) and high-risk (14-40 points) consumption, with low-risk (0-5 points) consumption as the reference group. Associations with pregnancy- and birth outcomes were explored with logistic regressions using generalized estimating equation models, adjusting for maternal and socioeconomic characteristics. Estimates are presented as adjusted odds ratios (aORs) with 95% confidence intervals (CIs)., Results: High-risk and moderate pre-pregnancy alcohol consumption was associated with preeclampsia, preterm birth and birth of an infant small for gestational age (SGA), but these associations were nonsignificant after adjustments. Prior moderate-risk (aOR 1.29, 95% CI 1.17-1.42) and high-risk consumption (aOR 1.62, 95% CI 1.17-2.25) increased the likelihood of intrapartum and neonatal infections., Conclusions: Apart from identifying hazardous alcohol consumption prior to pregnancy and the offer of counseling, screening with the AUDIT in early pregnancy indicates a high risk of inflammatory-/placenta-mediated pregnancy and birth outcomes. For most outcomes, AUDIT was not an independent contributor when adjusting for confounding factors. Hazardous alcohol use prior to pregnancy was independently linked to intrapartum and neonatal infections; conditions associated with morbidity and long-term sequalae. These associations may be explained by alcohol-induced changes in the maternal or fetal immune system in early pregnancy or persistent alcohol intake during pregnancy, or may depend on unidentified confounding factors., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Acute myeloid leukemia (AML) results from aberrant hematopoietic processes and these changes are frequently initiated by chromosomal translocations. One particular subtype, AML with translocation t(7;12)(q36;p13), is found in children diagnosed before 2 years of age. The mechanisms for leukemogenesis induced by t(7;12) is not understood, in part because of the lack of efficient methods to reconstruct the leukemia-associated genetic aberration with correct genomic architecture and regulatory elements. We therefore created induced pluripotent stem cell (iPSC) lines that carry the translocation t(7;12) using CRISPR/Cas9. These t(7;12) iPSC showed propensity to differentiate into all three germ layers, confirming retained stem cell properties. The potential for differentiation into hematopoietic stem and progenitor cells (HSPC) was shown by expression of CD34, CD43 and CD45. Compared with the parental iPSC line, a significant decrease in cells expressing CD235a and CD41a was seen in the t(7;12) iPSC-derived HSPC (iHSPC), suggesting a block in differentiation. Moreover, colony formation assay showed an accumulation of cells at the erythroid and myeloid progenitor stages. Gene expression analysis revealed significant down-regulation of genes associated with megakaryocyte differentiation and up-regulation of genes associated with myeloid pathways but also genes typically seen in AML cases with t(7;12). Thus, this iPSC t(7;12) leukemia model of the t(7;12) AML subtype constitutes a valuable tool for further studies of the mechanisms for leukemia development and to find new treatment options., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

This paper investigates least squares spectral analysis as a tool to analyze non-stationary signals from pass-by noise measurements in water. The spectral analysis involves successive least squares fitting of a finite Fourier series to approximate the observation in a piecewise manner. The least squares spectral analysis is used to search the signals for first- and second-order periodicity as well as the presence of fundamental periodicity. A first-order analysis reveals line components in the signals, whereas a second-order analysis reveals periodic amplitude modulations. Analysis with a higher-order finite Fourier series reveals harmonic structures in the signals. The main contribution of this paper is the model of a magnitude-squared cosine wave which can be used to analyze second-order periodicity. The developed short-time least squares spectral analysis is illustrated on noise radiated from a rigid inflatable boat in shallow water.

Introduction: Reverse transcriptase quantitative PCR (RT-qPCR) is considered the method of choice for measurable residual disease (MRD) assessment in NPM1-mutated acute myeloid leukemia (AML). MRD can also be determined with DNA-based methods offering certain advantages. We here compared the DNA-based methods quantitative PCR (qPCR), droplet digital PCR (ddPCR), and targeted deep sequencing (deep seq) with RT-qPCR., Methods: Of 110 follow-up samples from 30 patients with NPM1-mutated AML were analyzed by qPCR, ddPCR, deep seq, and RT-qPCR. To select DNA MRD cutoffs for bone marrow, we performed receiver operating characteristic analyses for each DNA method using prognostically relevant RT-qPCR cutoffs., Results: The DNA-based methods showed strong intermethod correlation, but were less sensitive than RT-qPCR. A bone marrow cutoff at 0.1% leukemic DNA for qPCR or 0.05% variant allele frequency for ddPCR and deep seq offered optimal sensitivity and specificity with respect to 3 log 10 reduction of NPM1 transcripts and/or 2% mutant NPM1/ABL. With these cutoffs, MRD results agreed in 95% (191/201) of the analyses. Although more sensitive, RT-qPCR failed to detect leukemic signals in 10% of samples with detectable leukemic DNA., Conclusion: DNA-based MRD techniques may complement RT-qPCR for assessment of residual leukemia. DNA-based methods offer high positive and negative predictive values with respect to residual leukemic NPM1 transcripts at levels of importance for response to treatment. However, moving to DNA-based MRD methods will miss a proportion of patients with residual leukemic RNA, but on the other hand some MRD samples with detectable leukemic DNA can be devoid of measurable leukemic RNA., (© 2021 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Polycythaemia vera (PV) patients have an overall comparatively favourable prognosis, but disease progression is very heterogeneous and life-threatening thrombosis and bleedings are frequent complications in untreated disease. Moreover, transformation to more severe secondary myelofibrosis and acute myeloid leukaemia can occur. The aim of this study was to identify gene mutations that could be used together with clinical data as prognostic markers to guide treatment decisions in PV patients. A well-characterized WHO-defined cohort of PV patients was used. Clinical data and blood values were evaluated and a myeloid sequencing panel was used to screen for additional mutations other than the diagnostic JAK2 V617F and JAK2 exon 12 mutations. In 78% of the PV patients, at least one mutation additional to JAK2 V617F was detected. Additional mutations in genes coding for epigenetic modifiers, like TET2, DNMT3A and ASXL1, were most frequent. When correlated to overall survival, mutations in ASXL1 were significantly associated with inferior survival. In an attempt to obtain prognostic guidance in a larger number of patients, the presence of ASXL1 mutations was combined with age and vascular complications prior to diagnosis. Based on these data we were able to define three risk groups that predicted survival., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Protons and heavy ions are considered to be ideal particles for use in external beam radiotherapy due to the superior properties of the dose distribution. While a photon (x-ray) beam delivers considerable dose to healthy tissues around the tumor, a proton beam that is delivered with sufficient energies has: a low entrance dose (the dose in front of the tumor); a high-dose region within the tumor, known as the Bragg peak; and, no exit dose beyond the tumor. Proton therapy is the next major step in advancing radiotherapy treatment. The purpose of this project was to adapt an existing radioisotope production cyclotron, a General Electric (GE) PETtrace, to enable radiobiological studies using proton beams. During routine use the PETtrace delivers 16.5 MeV protons to target with beam currents in the range of 10-100 µA resulting in dose rates in the order of kGy/s. To achieve the aim of the project the dose rate had to be reduced to the Gy/min range, without attenuating the proton energy below 5 MeV. This paper covers the design, construction and validation of the beam port., Methods: Monte Carlo simulations were performed, using GEANT4, SRIM and PACE4 to design the beam port and optimize its components. Once the beam port was fabricated, validation experiments were performed using EBT3 and HD-V2 Gafchromic™ films, and a Keithley 6485 picoampere meter., Results and Conclusion: The external beam port was successfully modeled, designed and fabricated. By using a 0.25 mm thick gold foil and a brass pin-hole collimator the beam was spread from a narrow full beam diameter of 10 mm to a wide beam with a 5% flatness area in the center of the beam that had a diameter of ~20 mm. In using this system the dose rate was reduced from kGy/s to ~30 Gy/min., (© 2019 American Association of Physicists in Medicine.)

Transcriptional studies of the human heart provide insight into physiological and pathophysiological mechanisms, essential for understanding the fundamental mechanisms of normal cardiac function and how they are altered by disease. To improve the understanding of why men and women may respond differently to the same therapeutic treatment it is crucial to learn more about sex-specific transcriptional differences. In this study the transcriptome of right atrium and left ventricle was compared across sex and regional location. Paired biopsies from five male and five female patients undergoing aortic valve replacement or coronary artery bypass grafting were included. Gene expression analysis identified 620 differentially expressed transcripts in atrial and ventricular tissue in men and 471 differentially expressed transcripts in women. In total 339 of these transcripts overlapped across sex but notably, 281 were unique in the male tissue and 162 in the female tissue, displaying marked sex differences in the transcriptional machinery. The transcriptional activity was significantly higher in atrias than in ventricles as 70% of the differentially expressed genes were upregulated in the atrial tissue. Furthermore, pathway- and functional annotation analyses performed on the differentially expressed genes showed enrichment for a more heterogeneous composition of biological processes in atrial compared with the ventricular tissue, and a dominance of differentially expressed genes associated with infection disease was observed. The results reported here provide increased insights about transcriptional differences between the cardiac atrium and ventricle but also reveal transcriptional differences in the human heart that can be attributed to sex.