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Background: The combination of an inhaled corticosteroid (ICS) and long-acting β-agonist (LABA) (ICS/LABA) has shown superiority in improving lung function (FEV1) compared with an ICS alone. The clinical effect of a ICS/LABA combination depends on the fine-particle fraction and the pulmonary deposition. Objective: We sought to compare the efficacy of 2 combinations of an ICS and LABA, namely, fluticasone propionate (FP) and formoterol (FORM) (FP/FORM) and fluticasone furoate (FF) and vilanterol (VI) (FF/VI), in asthmatic adolescents with chronic bronchial obstruction. Methods: FP/FORM (125 μg/5 μg, 2 doses twice daily via the k-haler [Mundipharma, Cambridge, UK]) and FF/VI (92 μg/22 μg, once daily via the Ellipta inhaler [GlaxoSmithKline]) were administered to adolescents aged 12 to 17 years who required regular antiasthmatic medication and had a ratio of FEV1 to forced vital capacity (FEV1/FVC) less than –1.65 SD in a 2-sequence, 16-week crossover trial. The primary efficacy end point was change in FEV1 compared with baseline. Secondary end points were FEV1/FVC ratio, maximal expiratory flow at 50% of the FVC, impulse oscillometry indices respiratory resistance at 5 Hz (R5), difference between R5 and respiratory resistance at 20 Hz (R20), area of reactance, and Asthma Control Test score. Results: Both ICS/LABA combinations resulted in a significant improvement in FEV1 and maximal expiratory flow at 50% of the FVC z scores without any significant difference between FP/FORM and FF/VI, with 40% of patients with either treatment achieving a normal prebronchodilator FEV1/FVC z score. Neither area of reactance nor difference between R5 and R20 improved significantly with either treatment. Conclusion: Both ICS/LABA combinations demonstrated significant improvements in FEV1 z score. More than one-third of the asthmatic adolescents with prolonged bronchial obstruction achieved a normal prebronchodilator FEV1/FVC ratio.

Consumption of certain probiotic strains may be beneficial for reducing the risk of acute upper respiratory tract infections (URTIs), however, underlying immunological mechanisms are elusive. Bifidobacterium lactis Bl-04™ has been reported in humans to significantly reduce the risk of URTIs, affect the innate immunity in the nasal mucosa, and reduce nasal lavage virus titer after a rhinovirus (RV) challenge. To study the immunological mechanisms, we investigated the effect of Bl-04 on cytokine production and transcriptomes of human monocyte-derived macrophages (Mfs) and dendritic cells (DCs), and further on RV replication and cytokine production in MRC-5 fibroblasts. The results showed that Bl-04 modulates antiviral immune responses and potentiates cytokine production during viral challenge mimic in immune cells. However, effect of Bl-04 on RV replication and cytokine production in fibroblasts was negligible. Overall, the findings suggest that Bl-04 mildly stimulates antiviral immunity in Mfs and DCs, and potentially influences viral replication in fibroblasts that however warrants further investigations.

Background: Total hip arthroplasty is one of the most successful operations medicine can offer. As more patients undergo total hip arthroplasty the revision burden increases proportionately. This is a cohort study of the Arcos Modular Femoral Revision System. Methods: The primary outcome was rerevision of the femoral component. Secondary outcomes include complications and radiological and clinical outcomes over 5 years. Results: A total of 74 patients were recruited, and the femoral survival rate was 100% at 5 years with 12 censorships. A total of 31 patients were given Proprosky 3/4 preoperatively. Eleven patients underwent further procedures; however, no femoral components were revised. Kaplan-Meier analysis was performed by a biostatistician. Patients demonstrated a consistent and sustained improvement in Harris hip score, Oxford hip score, and EQ-5D. Radiological review revealed minimal and stable lysis around the femoral components. Conculsion: The ARCOS Modular Femoral Revision System was designed to offer a range of options to allow femoral bone stock preservation and avoiding conversion to an endoprosthetic and seems to be effective in the medium term.

Silver nanoparticles deposits were produced with liquid flame spray (LFS) on glass and TiO2 substrates to study their optical response and photocatalytic enhancement. The correlation between extinction spectrum of the nanoparticle coating and the LFS process parameters was studied. The spectra consisted of two partly overlapping peaks: one centered in the UV region and the other in the visible light region. The visible light peak redshifted as either the silver mass concentration in the precursor solution or the precursor solution feed rate was increased, which also correlated with growing primary particle size. However, simultaneous correlation with photocatalytic activity of the decorated TiO2 surfaces was not observed, which was attributed to particle sintering on the surface. Instead, the photocatalytic activity was seen to change as the surface coverage of silver nanoparticles was varied. When the surface coverage was raised from ∼10 % to roughly 30 %, the activity, and then decreased as the loading was further raised. The increase was assumed to originate from plasmonic activation, and the decrease was attributed to the excessive amount of silver either blocking reactive area of the TiO2 or absorbing/scattering too much of the incoming light, which hindered the photocatalytic activity.

Wood-degrading white-rot fungi can efficiently degrade all plant biomass components, but the molecular mechanisms behind the degradation of plant polysaccharides remain poorly understood. For example, the gene sets and expression levels induced by the plant polysaccharide-derived monosaccharides in white-rot fungi do not reflect those induced by crude plant biomass substrates. To explore the molecular response of the white-rot fungus Dichomitus squalens to plant-derived oligo- and polysaccharides, we investigated the transcriptomes from mono- and dikaryotic strains of the fungus on 10 substrates and compared the expression of carbohydrate-active enzyme-encoding genes to that previously reported for different monosaccharides and cellobiose. Our results revealed that in D. squalens, a robust response to cellulose leads to its effective depolymerization, with an orthologue of the ascomycete Trichoderma reesei ACE3 likely acting as a central transcriptional regulator. The conserved response between cellulose and cellobiose further confirms cellobiose as the main cellulase inducer in D. squalens. Surprisingly, despite low abundance of pectin in the natural wood substrate of D. squalens, we identified polygalacturonic acid as a major inducer of a broad-targeted pectinolytic response including pectinase, pectin-related sugar transporter and catabolism genes, and four fungal specific transcription factors. This indicates that D. squalens has not only maintained its ability to degrade minor polysaccharide components in its biotope, but also a regulatory system spanning from extracellular degradation to metabolic conversion. Our study contributes to a deeper understanding of the molecular mechanisms behind white-rot fungal plant polysaccharide degradation and provides leads for functional studies of potential transcriptional regulators in basidiomycetes.

Traditional design of experiments and response surface methodology are widely used in engineering and process development. Bayesian optimization is an alternative machine learning approach that adaptively selects successive experimental conditions based on a predefined performance measure. Here we compared the two approaches using simulations and empirical experiments on alkaline wood delignification to identify important benefits and drawbacks of Bayesian optimization in the context of design of experiments. The simulations showed that the selection of initial experiments and measurement noise influenced the convergence of the Bayesian optimization algorithm to known optimal conditions. Both methods, however, showed comparable pilot-scale results on optimal digestion conditions, where high cellulose yields were combined with acceptable kappa numbers and pulp viscosities. Bayesian optimization did not enable a decrease in the number of experiments required for reaching these conditions but provided a more accurate model in the vicinity of the optimum based on additional modelling and cross-validation. These results shed light on the practical differences between the two methodologies for process development and are an important contribution to the chemometrics and machine learning communities.

Summary: Probiotics have been suggested as one solution to counter detrimental health effects by SARS-CoV-2; however, data so far is scarce. We tested the effect of two probiotic consortia, OL-1 and OL-2, against SARS-CoV-2 in ferrets and assessed their effect on cytokine production and transcriptome in a human monocyte-derived macrophage (Mf) and dendritic cell (DC) model. The results showed that the consortia significantly reduced the viral load, modulated immune response, and regulated viral receptor expression in ferrets compared to placebo. In the human Mf and DC model, OL-1 and OL-2-induced cytokine production and genes related to SARS-CoV-2 antiviral immunity. The study results indicate that probiotic stimulation of the ferret immune system leads to improved antiviral immunity against SARS-COV-2, and the genes and cytokines associated with anti-SARS-CoV-2 immunity are stimulated in human immune cells in vitro. The effect of the consortia against SARS-CoV-2 warrants further investigations in human clinical trials.

Summary: Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.

Objective: To explore the relationship between axon loss and measured cross-sectional areas of the median nerve (MN) in severe carpal tunnel syndrome (CTS). Methods: In this retrospective study of 158 examined wrists, we compared axon loss to the ultrasound parameters MN cross-sectional area at the wrist (wCSA), MN cross-sectional area at the forearm (fCSA) and wrist-to-forearm ratio (WFR), in patients with moderate to extreme CTS. Axon loss was evaluated by needle electromyography (EMG) of the abductor pollicis brevis muscle (spontaneous activity and reduction of interference pattern). Results: Both the spontaneous activity and interference pattern reduction correlated negatively to fCSA (r = −0.189, p = 0.035; r = −0.210, p = 0.019; respectively). In moderate CTS, both the spontaneous activity and interference pattern reduction correlated positively to WFR (r = 0.231, p = 0.048; r = 0.232, p = 0.047; respectively). The WFR was highest when slight spontaneous activity was detected. Neither wCSA nor WFR correlated with axon loss in severe and extreme CTS. Conclusions: The fCSA is smaller when axon loss in CTS is more prominent. The WFR is highest when CTS is associated with slight axon loss of the MN. Significance: CTS might cause retrograde axonal atrophy detected as small fCSA. Prominent axon loss in CTS may reduce the diagnostic value of WFR.

Epithelial–myoepithelial carcinoma (EMC) is a rare subtype of salivary gland neoplasms. Since the initial description of the cancer, just over 300 cases have been reported. EMCs occupy a biphasic cellular differentiation-state defined by the constitution of two cell types representing epithelial and myoepithelial lineages, yet the functional consequence of the differentiation-state heterogeneity with respect to therapy resistance of the tumors remains unclear. The reported local recurrence rate of the cases is approximately 30%, and while distant metastases are rare, a significant fraction of these cases are reported to receive no survival benefit from radio- or chemotherapy given in addition to surgery. Moreover, no targeted therapies have been reported for these neoplasms. We report here the first use and application of ex vivo drug screening together with next generation sequencing to assess targeted treatment strategies for a rare metastatic epithelial–myoepithelial carcinoma. Results of the ex vivo drug screen demonstrate significant differential therapeutic sensitivity between the epithelial and myoepithelial intra-tumor cell lineages suggesting that differentiation-state heterogeneity within epithelial–myoepithelial carcinomas may present an outlet to partial therapeutic responses to targeted therapies including MEK and mTOR inhibitors. These results suggest that the intra-tumor lineage composition of EMC could be an important factor to be assessed when novel treatments are being evaluated for management of metastatic EMC.

Therapy options for patients with metastatic melanoma (MM) have considerably improved over the past decade. However, many patients still need effective therapy after unsuccessful immunotherapy, especially patients with BRAF-negative tumors who lack the option of targeted treatment second line. Therefore, the elucidation of efficient and personalized therapy options for these patients is required. In this study, three patient-derived cancer cells (PDCs) were established from NRAS Q61-positive MM patients. The response of PDCs and five established melanoma cell lines (two NRAS-positive, one wild type, and two BRAF V600-positive) was evaluated toward a panel of 527 oncology drugs using high-throughput drug sensitivity and resistance testing. The PDCs and cell lines displayed strong responses to MAPK inhibitors, as expected. Additionally, the PDCs and cell lines were responsive to PI3K/mTOR, mTOR, and PLK1 inhibitors among other effective drugs currently undergoing clinical trials. Combinations with a MEK inhibitor were tested with other targeted agents to identify effective synergies. MEK inhibitor showed synergy with multikinase inhibitor ponatinib, ABL inhibitor nilotinib, PI3K/mTOR inhibitor pictilisib, and pan-RAF inhibitor LY3009120. The application of the patients’ cancer cells for functional drug testing ex vivo is one step further in the process of identifying potential agents and agent combinations to personalize treatment for patients with MM. Our preliminary study results suggest that this approach has the potential for larger-scale drug testing and personalized treatment applications in our expansion trial. Our results show that drug sensitivity and resistance testing may be implementable in the treatment planning of patients with MM.

Summary: Xyloglucan is a prominent matrix heteropolysaccharide binding to cellulose microfibrils in primary plant cell walls. Hence, the hydrolysis of xyloglucan facilitates the overall lignocellulosic biomass degradation. Xyloglucanases (XEGs) are key enzymes classified in several glycoside hydrolase (GH) families. So far, family GH44 has been shown to contain bacterial XEGs only. Detailed genome analysis revealed GH44 members in fungal species from the phylum Basidiomycota, but not in other fungi, which we hypothesized to also be XEGs. Two GH44 enzymes from Dichomitus squalens and Pleurotus ostreatus were heterologously produced and characterized. They exhibited XEG activity and displayed a hydrolytic cleavage pattern different from that observed in fungal XEGs from other GH families. Specifically, the fungal GH44 XEGs were not hindered by substitution of neighboring glucosyl units and generated various “XXXG-type,” “GXXX(G)-type,” and “XXX-type” oligosaccharides. Overall, these fungal GH44 XEGs represent a novel class of enzymes for plant biomass conversion and valorization.

Study region: The Nordic-Baltic region has experienced numerous flooding episodes resulting from heavy rainfall. Such events are costly and may potentially threaten the safety of the population. In this paper we present a temporally long and spatially dense dataset of annual maximum daily precipitation and their date of occurrence measured in a large region covering Fennoscandia and the Baltics (Dyrrdal et al., 2021, doi:10.11582/2021.00015). Study focus: We analyse the long-term (1901–2020) changes at 138 stations and short-term (1969–2020) changes at 724 stations for both annual maxima and their date of occurrence. Further, we assess the climatology of heavy precipitation including record evens, as well as changes in design values. New hydrological insight for the region: Results show a majority of positive trends in daily annual maxima and the 5-year return level, with hotspots in southeast of Norway, southern Sweden and southwest of Finland. Generally, annual maximum precipitation events occur somewhat later in the year now compared to the beginning of the last century. The 5-year return level is relatively homogeneous across the Nordic-Baltic region, with values between 30 and 50 mm, except for a few lower values in Finland and high values mainly exceeding 70 mm at the west coast of Norway.

Carbon catabolite repression enables fungi to utilize the most favourable carbon source in the environment, and is mediated by a key regulator, CreA, in most fungi. CreA-mediated regulation has mainly been studied at high monosaccharide concentrations, an uncommon situation in most natural biotopes. In nature, many fungi rely on plant biomass as their major carbon source by producing enzymes to degrade plant cell wall polysaccharides into metabolizable sugars. To determine the role of CreA when fungi grow in more natural conditions and in particular with respect to degradation and conversion of plant cell walls, we compared transcriptomes of a creA deletion and reference strain of the ascomycete Aspergillus niger during growth on sugar beet pulp and wheat bran. Transcriptomics, extracellular sugar concentrations and growth profiling of A. niger on a variety of carbon sources, revealed that also under conditions with low concentrations of free monosaccharides, CreA has a major effect on gene expression in a strong time and substrate composition dependent manner. In addition, we compared the CreA regulon from five fungi during their growth on crude plant biomass or cellulose. It showed that CreA commonly regulated genes related to carbon metabolism, sugar transport and plant cell wall degrading enzymes across different species. We therefore conclude that CreA has a crucial role for fungi also in adapting to low sugar concentrations as occurring in their natural biotopes, which is supported by the presence of CreA orthologs in nearly all fungi.

Introduction: Puumala hantavirus (PUUV) causes a mild type of hemorrhagic fever with renal syndrome characterized by acute kidney injury (AKI), increased capillary leakage, and thrombocytopenia. Albuminuria and hematuria in dipstick urine test at hospital admission are known to predict the severity of upcoming AKI. Methods: We analyzed dipstick urine glucose in 195 patients with acute PUUV infection at hospital admission, and divided them into 2 categories according to the presence or absence of glucose in the dipstick urine test. Determinants of disease severity were analyzed in glucosuric and nonglucosuric patients. Results: Altogether, 24 of 195 patients (12%) had glucosuria. The patients with glucosuria had more severe AKI than patients without glucosuria (median maximum creatinine concentration 459 μmol/l, range 78–1041 μmol/l vs. 166 μmol/l, range 51–1499 μmol/l; P < 0.001). The glucosuric patients had more severe thrombocytopenia (median minimum platelet count 41 × 109/l, range 5–102 × 109/l vs. 62 × 109/l, range 3–249 × 109/l; P = 0.006), and more pronounced signs of increased capillary leakage (change in weight, maximum plasma hematocrit, minimum plasma albumin). The glucosuric patients were more often in clinical shock at admission (20.8% vs. 1.2%; P < 0.001) and the length of hospital stay was longer (median 7.5 days, range 4–22 days vs. 6 days, range 2–30 days; P = 0.009). Conclusion: Glucosuria is relatively rare, but when present it predicts a more severe disease course in patients with acute PUUV infection. Keywords: acute kidney injury, glucosuria, hantavirus, Puumala virus, thrombocytopenia

Summary: The circadian clock and the hypoxia-signaling pathway are regulated by an integrated interplay of positive and negative feedback limbs that incorporate energy homeostasis and carcinogenesis. We show that the negative circadian regulator CRY1 is also a negative regulator of hypoxia-inducible factor (HIF). Mechanistically, CRY1 interacts with the basic-helix-loop-helix domain of HIF-1α via its tail region. Subsequently, CRY1 reduces HIF-1α half-life and binding of HIFs to target gene promoters. This appeared to be CRY1 specific because genetic disruption of CRY1, but not CRY2, affected the hypoxia response. Furthermore, CRY1 deficiency could induce cellular HIF levels, proliferation, and migration, which could be reversed by CRISPR/Cas9- or short hairpin RNA-mediated HIF knockout. Altogether, our study provides a mechanistic explanation for genetic association studies linking a disruption of the circadian clock with hypoxia-associated processes such as carcinogenesis. : Biological Sciences; Biochemistry; Molecular Biology; Cell Biology Subject Areas: Biological Sciences, Biochemistry, Molecular Biology, Cell Biology

Aim and scope: A Gradient Echo Plural Contrast Imaging technique (GEPCI) is a post-processing method, which can be used to obtain quantitative T2* values and generate multiple synthetic contrasts from a single acquisition. However, scan duration and image reconstruction from k-space data present challenges in a clinical workflow. This study aimed at optimizing image reconstruction and acquisition duration to facilitate a post-processing method for synthetic image contrast creation in clinical settings. Materials and methods: This study consists of tests using the American College of Radiology (ACR) image quality phantom, two healthy volunteers, four mild traumatic brain injury patients and four small vessel disease patients. The measurements were carried out on a 3.0 T scanner with multiple echo times. Reconstruction from k-space data and DICOM data with two different coil-channel combination modes were investigated. Partial Fourier techniques were tested to optimize the scanning time. Conclusions: Sum of squares coil-channel combination produced artifacts in phase images, but images created with adaptive combination were artifact-free. The voxel-wise median signed difference of T2* between the vendor’s adaptive channel combination and k-space reconstruction modes was 2.9 ± 0.7 ms for white matter and 4.5 ± 0.6 ms for gray matter. Relative white matter/gray matter contrast of all synthetic images and contrast-to-noise ratio of synthetic T1-weighted images were almost equal between reconstruction modes. Our results indicate that synthetic contrasts can be generated from the vendor’s DICOM data with the adaptive combination mode without affecting the quantitative T2* values or white matter/gray matter contrast. Keywords: Magnetic resonance imaging, Image quality, Quantitative MRI, MRI reconstruction, T2* mapping, Synthetic contrasts

Objectives: Long-term paired associative stimulation (PAS) is a non-invasive combination of transcranial magnetic stimulation and peripheral nerve stimulation and leads to improved hand motor function in individuals with incomplete traumatic tetraplegia. Spinal cord injuries (SCIs) can also be induced by neurological diseases. We tested a similar long-term PAS approach in patients with non-traumatic neurological SCI. Methods: In this case series, five patients with non-traumatic tetraplegia received PAS to the weaker upper limb 3 to 5 times per week for 6 weeks. Patients were evaluated by manual muscle testing (MMT) before and immediately after the therapy and at the 1- and 6-month follow-ups. Patients were also evaluated for spasticity, hand mechanical and digital dynamometry, pinch test and Box and Block test. Results: MMT values of all patients improved at all post-PAS evaluations. The mean ± standard error MMT increase was 1.44 ± 0.37 points (p = 0.043) immediately after PAS, 1.57 ± 0.4 points (p = 0.043) at the 1-month follow-up and 1.71 ± 0.47 points (p = 0.043) at the 6-month follow-up. The pinch test, digital dynamometry and Box and Block test results also improved in all patients. Conclusions: Long-term PAS may be a safe and effective treatment for improving hand function in patients with non-traumatic tetraplegia. Significance: This is the first report demonstrating the therapeutic potential of PAS for neurological SCI. Keywords: TMS, Rehabilitation, Plasticity, Spinal Cord, Paired Associative Stimulation, Spinal cord injury

Purpose: To determine the effect of patient’s vertical off-centering and scout direction on the function of automatic tube voltage selection (ATVS) and tube current modulation (TCM) in chest computed tomography (CT). Methods: Chest phantom was scanned with Siemens and GE CT systems using three clinical chest CT protocols exploiting ATVS and a fixed 120 kVp chest protocol. The scans were performed at five vertical positions of the phantom (−6 to +6 cm from the scanner isocenter). The effects of scout direction (posterior-to-anterior, anterior-to-posterior, and lateral) and vertical off-centering on the function of ATVS and TCM were studied by examining changes in selected voltage, radiation dose (volume CT dose index, CTDIvol), and image noise and contrast. Results: Both scout direction and vertical off-centering affected ATVS. The effect differed between the vendors for the studied geometry, demonstrating differences in technical approaches. The greatest observed increase in CTDIvol due to off-centering was 91%. Anterior-to-posterior scout produced highest doses at the uppermost table position, whereas posterior-to-anterior scout produced highest doses at the lowermost table position. Dose varied least using lateral scouts. Vertical off-centering impacted image noise and contrast due to the combined effect of ATVS, TCM, structural noise, and bowtie filters. Conclusions: Patient vertical off-centering and scout direction affected substantially the CTDIvol and image quality in chest CT examinations. Vertical off-centering caused variation also in the selected tube voltage. The function of ATVS and TCM methods differ significantly between the CT vendors, resulting in differences in CTDIvol and image noise characteristics. Keywords: Automatic tube voltage selection, Image quality, Patient centering, Tube current modulation

Poor neural speech discrimination has been connected to dyslexia, and may represent phonological processing deficits that are hypothesized to be the main cause for reading impairments. Thus far, neural speech discrimination impairments have rarely been investigated in adult dyslexics, and even less by examining sources of neuromagnetic responses. We compared neuromagnetic speech discrimination in dyslexic and typical readers with mismatch fields (MMF) and determined the associations between MMFs and reading-related skills. We expected weak and atypically lateralized MMFs in dyslexic readers, and positive associations between reading-related skills and MMF strength. MMFs were recorded to a repeating pseudoword /ta-ta/ with occasional changes in vowel identity, duration, or syllable frequency from 43 adults, 21 with confirmed dyslexia. Phonetic (vowel and duration) changes elicited left-lateralized MMFs in the auditory cortices. Contrary to our hypothesis, MMF source strengths or lateralization did not differ between groups. However, better verbal working memory was associated with stronger left-hemispheric MMFs to duration changes across groups, and better reading was associated with stronger right-hemispheric late MMFs across speech-sound changes in dyslexic readers. This suggests a link between neural speech processing and reading-related skills, in line with previous work. Furthermore, our findings suggest a right-hemispheric compensatory mechanism for language processing in dyslexia. The results obtained promote the use of MMFs in investigating reading-related brain processes.

Sustained spermatogenesis in adult males and fertility recovery following germ cell depletion are dependent on undifferentiated spermatogonia. We previously demonstrated a key role for the transcription factor SALL4 in spermatogonial differentiation. However, whether SALL4 has broader roles within spermatogonia remains unclear despite its ability to co-regulate genes with PLZF, a transcription factor required for undifferentiated cell maintenance. Through development of inducible knockout models, we show that short-term integrity of differentiating but not undifferentiated populations requires SALL4. However, SALL4 loss was associated with long-term functional decline of undifferentiated spermatogonia and disrupted stem cell-driven regeneration. Mechanistically, SALL4 associated with the NuRD co-repressor and repressed expression of the tumor suppressor genes Foxl1 and Dusp4. Aberrant Foxl1 activation inhibited undifferentiated cell growth and survival, while DUSP4 suppressed self-renewal pathways. We therefore uncover an essential role for SALL4 in maintenance of undifferentiated spermatogonial activity and identify regulatory pathways critical for germline stem cell function.

During a conversation or when listening to music, auditory and visual information are combined automatically into audiovisual objects. However, it is still poorly understood how specific type of visual information shapes neural processing of sounds in lifelike stimulus environments. Here we applied multi-voxel pattern analysis to investigate how naturally matching visual input modulates supratemporal cortex activity during processing of naturalistic acoustic speech, singing and instrumental music. Bayesian logistic regression classifiers with sparsity-promoting priors were trained to predict whether the stimulus was audiovisual or auditory, and whether it contained piano playing, speech, or singing. The predictive performances of the classifiers were tested by leaving one participant at a time for testing and training the model using the remaining 15 participants. The signature patterns associated with unimodal auditory stimuli encompassed distributed locations mostly in the middle and superior temporal gyrus (STG/MTG). A pattern regression analysis, based on a continuous acoustic model, revealed that activity in some of these MTG and STG areas were associated with acoustic features present in speech and music stimuli. Concurrent visual stimulus modulated activity in bilateral MTG (speech), lateral aspect of right anterior STG (singing), and bilateral parietal opercular cortex (piano). Our results suggest that specific supratemporal brain areas are involved in processing complex natural speech, singing, and piano playing, and other brain areas located in anterior (facial speech) and posterior (music-related hand actions) supratemporal cortex are influenced by related visual information. Those anterior and posterior supratemporal areas have been linked to stimulus identification and sensory-motor integration, respectively.

Dynamic building energy simulations need hourly weather data as input. The same high temporal resolution is required for assessments of future heating and cooling energy demand. The data presented in this article concern current typical values and estimated future changes in outdoor air temperature, wind speed, relative humidity and global, diffuse and normal solar radiation components. Simulated annual and seasonal delivered energy consumptions for heating of spaces, heating of ventilation supply air and cooling of spaces in the current and future climatic conditions are also presented for an example house, with district heating and a mechanical space cooling system. We provide details on how the synthetic future weather files were created and utilised as input data for dynamic building energy simulations by the IDA Indoor Climate and Energy program and also for calculations of heating and cooling degree-day sums. The information supplied here is related to the research article titled “Energy demand for the heating and cooling of residential houses in Finland in a changing climate” [1].

Synaptic disruption is an early pathological sign of the neurodegeneration of Dementia of the Alzheimer's type (DAT). The changes in network synchronization are evident in patients with Mild Cognitive Impairment (MCI) at the group level, but there are very few Magnetoencephalography (MEG) studies regarding discrimination at the individual level. In an international multicenter study, we used MEG and functional connectivity metrics to discriminate MCI from normal aging at the individual person level. A labeled sample of features (links) that distinguished MCI patients from controls in a training dataset was used to classify MCI subjects in two testing datasets from four other MEG centers. We identified a pattern of neuronal hypersynchronization in MCI, in which the features that best discriminated MCI were fronto-parietal and interhemispheric links. The hypersynchronization pattern found in the MCI patients was stable across the five different centers, and may be considered an early sign of synaptic disruption and a possible preclinical biomarker for MCI/DAT.

A large number of breast cancers are characterized by amplification and overexpression of the chromosome segment surrounding the HER2 (ERBB2) oncogene. As the HER2 amplicon at 17q12 contains multiple genes, we have systematically explored the role of the HER2 co-amplified genes in breast cancer cell growth and their relation to trastuzumab resistance. We integrated array comparative genomic hybridization (aCGH) data of the HER2 amplicon from 71 HER2 positive breast tumors and 10 cell lines with systematic functional RNA interference analysis of 23 core amplicon genes with several phenotypic endpoints in a panel of trastuzumab responding and non-responding HER2 positive breast cancer cells. In this Data in Brief we give a detailed description of the experimental procedures and the data analysis methods used in the study (1).

Expression of fibroblast growth factor 8 (FGF-8) is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG) mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelialmorphology progressing fromatypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN) lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.

Background: A detailed understanding of the non-perfused volume (NPV) evolution after prostate ablation therapy is lacking. The impact of different diseased prostate tissues on NPV evolution post-ablation is unknown. Purpose: To characterize the NPV evolution for three treatment groups undergoing heat-based prostate ablation therapy, including benign prostatic hyperplasia (BPH), primary prostate cancer (PCa), and radiorecurrent PCa. Materials and methods: Study design and data analysis were performed retrospectively. All patients received MRI-guided transurethral ultrasound ablation (TULSA). 21 BPH, 28 radiorecurrent PCa and 40 primary PCa patients were included. Using the T1-weighted contrast-enhanced MR image, the NPV was manually contoured by an experienced radiologist. All patients received an MRI immediately following the ablation. Follow-up included MRI at 3- and 12 months for BPH and radiorecurrent PCa patients and at 6- and 12 months for primary PCa patients. Results: A significant difference between BPH and radiorecurrent PCa patients was observed at three months (p

Background: The COVID-19 pandemic has revealed the fragility of the global food system, sending shockwaves across countries' societies and economy. This has presented formidable challenges to sustaining a healthy and resilient lifestyle. The objective of this study is to examine the food consumption patterns and assess diet diversity indicators, primarily focusing on the food consumption score (FCS), among households in 38 countries both before and during the first wave of the COVID-19 pandemic. Methods: A cross-sectional study with 37 207 participants (mean age: 36.70 ± 14.79, with 77 % women) was conducted in 38 countries through an online survey administered between April and June 2020. The study utilized a pre-tested food frequency questionnaire to explore food consumption patterns both before and during the COVID-19 periods. Additionally, the study computed Food Consumption Score (FCS) as a proxy indicator for assessing the dietary diversity of households. Findings: This quantification of global, regional and national dietary diversity across 38 countries showed an increment in the consumption of all food groups but a drop in the intake of vegetables and in the dietary diversity. The household's food consumption scores indicating dietary diversity varied across regions. It decreased in the Middle East and North Africa (MENA) countries, including Lebanon (p

Several bacteria causing infections can remain infectious on surfaces from hours to several days and weeks. Antibacterial properties of wood are poorly understood in terms of dry contamination via hands, as large majority of previous research has been carried out by using liquid inoculation methods. The effects of wood surface treatments on antimicrobial activity require more investigation. Here, antimicrobial properties of surfaces of 18 different every-day indoor materials, i.e., non-treated wooden surfaces, wood with surface and other treatments, and other solid indoor materials were examined. This study is unique, as the materials that were exposed to human contact in public space were also investigated in controlled conditions for their antibacterial properties. First, bacterial loads of different material surfaces were quantified in a real-life public setting by contact plate method. Secondly, in a controlled exposure chamber trial, bacterial viability of Staphylococcus epidermidis and Bacillus aerius/licheniformis was followed as a function of time after spreading bacterial aerosols on samples. In the public exposure, non-wood coatings/materials (tile, laminate, vinyl cork, lacquer coated wood) with non-porous surfaces had the lowest number of bacterial colonies forming units (cfu). Differences in cfu were also observed between the wood species: the lowest accounts were recorded from white oak, and black walnut. In the exposure chamber trial, the viability of S. epidermidis decreased on almost all study materials, with the lowest viability detected from non-treated white oak. Instead, B. aerius/licheniformis remained stable on most material surfaces. The differences in results in wood antibacterial properties between the dry and moist contamination may be explained by the fact that moist aerosol inoculum faces both passive and active antimicrobial mechanisms of non-treated wood; porous wood structure dries bacteria, and wood chemical constituents possess bacteriostatic efficacies. In dry conditions via hand contamination, instead, microbes may adhere more on porous surfaces than on non-porous ones.

Lacticaseibacillus paracasei Lpc-37 (Lpc-37) has previously shown to reduce perceived stress in healthy adults. The ChillEx study investigated whether Lpc-37 reduces stress in a model of chronic examination stress in healthy students. One hundred ninety university students (18–40 y) were randomized to take 1.56 × 1010 colony-forming units of Lpc-37 or placebo (1:1) each day for 10 weeks, in a triple-blind, parallel, multicenter clinical trial consisting of six visits: two screening visits, a baseline visit, and visits at 4, 8, and 10 weeks after baseline. The primary objective was to demonstrate that Lpc-37 reduces stress, as measured by the change in state anxiety from baseline to just before the first examination, after 8 weeks using the State Trait Anxiety Inventory (STAI-state). Secondary objectives aimed to demonstrate that Lpc-37 modulates psychological stress-induced symptoms and biomarkers related to mood and sleep. An exploratory analysis of fecal microbiota composition was also conducted. There was no difference between Lpc-37 and placebo groups in the change of STAI-state score (estimate 1.03; 95% confidence interval [CI]: -1.62, 3.67; p = 0.446). None of the secondary outcomes resulted in significant results when corrected for multiplicity, but exploratory results were notable. Results showed an improvement in sleep-disturbance scores (odds ratio 0.30; 95% CI: 0.11, 0.82; p = 0.020) and reduction in duration of sleep (odds ratio 3.52; 95% CI: 1.46, 8.54; p = 0.005) on the Pittsburgh Sleep Quality Index questionnaire after 8 weeks in the Lpc-37 group compared to placebo. A reduction in Bond Lader VAS-alertness was also demonstrated in the Lpc-37 group compared to placebo (estimate −3.97; 95% CI: -7.78, −0.15; p = 0.042) just prior to the examination. Analysis of fecal microbiota found no differences between study groups for alpha and beta diversity or microbiota abundance. Adverse events were similar between groups. Vital signs, safety-related laboratory measures, and gastrointestinal parameters were stable during the trial. In conclusion, probiotic Lpc-37 was safe but had no effect on stress, mood, or anxiety in healthy university students in this model of chronic academic stress. ClinicalTrials.gov: NCT04125810.

Objective: Primary objective was to retrospectively examine the effects of patient age and carpal tunnel syndrome (CTS) related axon loss on median nerve (MN) high resolution ultrasound (HRUS) in younger and older patients. HRUS parameters evaluated in this study were MN cross sectional area at the wrist (CSA) and wrist-to-forearm ratio (WFR). Methods: The material comprised 467 wrists of 329 patients. The patients were categorized into younger (

Early-onset, persistent atopic dermatitis (AD) is proposed as a distinct subgroup that may have specific genotypic features. FLG gene loss-of-function variants are the best known genetic factors contributing to epidermal barrier impairment and eczema severity. In a cohort of 140 Finnish children with early-onset moderate-to-severe AD, we investigated the effect of coding variation in FLG and 13 other genes with epidermal barrier or immune function through the use of targeted amplicon sequencing and genotyping. A FLG loss-of-function variant (Arg501Ter, Ser761fs, Arg2447Ter, or Ser3247Ter) was identified in 20 of 140 patients showing higher transepidermal water loss values than patients without these variants. Total FLG loss-of-function variant frequency (7.14%) was significantly higher than in the general Finnish population (2.34%). When tested separately, only Arg2447Ter showed a significant association with AD (P = 0.003104). In addition, a modest association with moderate-to-severe pediatric AD was seen for rs12730241 and rs6587667 (FLG2:Gly137Glu). Loss-of-function variants, previously reported pathogenic variants, or statistically significant enrichment of nonsynonymous coding region variants were not found in the 13 candidate genes studied by amplicon sequencing. However, higher IgE and eosinophil counts were found in carriers of potentially pathogenic DOCK8 missense variants, suggesting that the role of DOCK8 variation in AD should be further investigated in larger cohorts.

Objective: To assess pain relief and overall birth experience in induced vs. spontaneous-onset labours and to clarify variables among induced parturients determining satisfaction and dissatisfaction. Study design: A prospective study of 2042 women. 575 women with induced and 1467 with spontaneous-onset labour answered multiple questions in a questionnaire regarding the experience of birth giving. Satisfaction was numerically assessed via a visual analogue scale (VAS 0–10). Results: Induction of labour (IOL) did not worsen the average experience of pain relief, but the proportion of women dissatisfied with pain relief was slightly higher after IOL compared with spontaneous-onset labour (SOL). IOL was associated with lower satisfaction with overall birth experience compared with SOL (VAS 8.0 vs. 8.4; p

An inhomogeneous chemical distribution can be problematic in many biomaterial applications, including wood impregnation. Since wood is a hierarchically structured material, the chemical distribution must be considered on different length scales. Here, a combination of imaging methods revealed the distribution of phenol–formaldehyde resin in impregnation-treated European beech wood within the scale of several millimeters or larger (macroscopic) and the micron scale (cellular level). The macroscopic resin distribution was quantified by hyperspectral near-infrared (NIR) image regression. A partial least square regression model accurately predicted the resin content in the range of 0–30 % with average prediction errors of ≤0.93 % for calibration and the test set. The cellular resin distribution was investigated by mapping the UV absorbance in selected regions of interest at high lateral resolution using UV microspectrophotometry (UMSP). The application of both imaging techniques to board sections revealed a process-dependent resin distribution. NIR image regression quantified the drying-induced migration of resin toward the board surfaces. UMSP measurements in selected regions revealed that this resin migration also affected the resin distribution across cell walls. Overall, the results demonstrate the potential of combining chemical imaging techniques to quantify process-dependent heterogeneity and to develop efficient treatments for wood and other biomaterials.

Background: The Baby-Friendly Hospital Initiative aims to improve breastfeeding by implementing the Ten Steps to Successful Breastfeeding (Ten Steps) into routine breastfeeding support in birth hospitals. Maternal perspective to breastfeeding support is important to consider as mothers and their infants are in the center of that support. Objectives: To review and synthesize the existing literature on maternal perceptions and experiences of breastfeeding support in Baby-Friendly hospitals. A sub-aim was to describe differences in breastfeeding support between Baby-Friendly hospitals and non-Baby-Friendly hospitals from maternal perspective. Data sources and review methods: An integrative literature review. A systematic literature search was conducted in October 2021 in five databases: PubMed, CINAHL, Cochrane, Scopus, Web of Science. Original peer-reviewed studies published in English exploring maternal viewpoints on breastfeeding support in Baby-Friendly hospitals were included. Two reviewers independently screened the titles (n=914), abstracts (n=226), and full texts (n=47). The review comprised of seventeen studies and includes both quantitative studies (n=14) and qualitative studies (n=3). Inductive content analysis and descriptive synthesis were conducted. Results: Most studies (n=14) measured hospitals’ compliance with the Ten Steps practices from maternal perspective. Mothers were provided with breastfeeding information and encouragement, however, a qualitative finding indicated that information focused on positive aspects of breastfeeding. Early skin-to-skin contact between the mother and infant was well facilitated although often not lasting more than 30 min. Breastfeeding was facilitated by practical support but according to findings of two qualitative studies, support was not always adequate to address mothers’ problems with breastfeeding. Most mothers were exclusively breastfeeding during the hospital stay and no supplemental milk was offered to infant. Mothers were roomed-in together with their infant and were mostly encouraged to breastfeed on demand. Differences between Baby-Friendly hospitals and non-Baby-Friendly hospitals were observed particularly for steps 6 and 9: supplementary feeding and pacifier use were less common in Baby-Friendly hospitals. Conclusions: From the maternal perspective, breastfeeding support in the Baby-Friendly hospitals was mainly but not completely in adherence with the Ten Steps practices. Low compliance with some of the Ten Steps indicates a need for a more frequent assessment of the breastfeeding support practices and consideration of strategies facilitating a more sustainable implementation of the initiative. Regardless of some shortcomings with the breastfeeding support, mothers were mainly satisfied with the support in the hospital. Mothers in the Baby-Friendly hospitals perceived that breastfeeding support was more adherent to the Ten Steps compared to mothers in non-Baby-Friendly hospitals.

Background: According to the biodiversity hypothesis of immune-mediated diseases, lack of microbiological diversity in the everyday living environment is a core reason for dysregulation of immune tolerance and – eventually – the epidemic of immune-mediated diseases in western urban populations. Despite years of intense research, the hypothesis was never tested in a double-blinded and placebo-controlled intervention trial. Objective: We aimed to perform the first placebo-controlled double-blinded test that investigates the effect of biodiversity on immune tolerance. Methods: In the intervention group, children aged 3–5 years were exposed to playground sand enriched with microbially diverse soil, or in the placebo group, visually similar, but microbially poor sand colored with peat (13 participants per treatment group). Children played twice a day for 20 min in the sandbox for 14 days. Sand, skin and gut bacterial, and blood samples were taken at baseline and after 14 days. Bacterial changes were followed for 28 days. Sand, skin and gut metagenome was determined by high throughput sequencing of bacterial 16 S rRNA gene. Cytokines were measured from plasma and the frequency of blood regulatory T cells was defined as a percentage of total CD3 +CD4 + T cells. Results: Bacterial richness (P

Background: Up to half of all men who undergo primary radiotherapy for localized prostate cancer (PCa) experience local recurrence. Objective: To evaluate the safety and early functional and oncological outcomes of salvage magnetic resonance imaging–guided transurethral ultrasound ablation (sTULSA) for men with localized radiorecurrent PCa. Design, setting, and participants: This prospective, single-center phase 1 study (NCT03350529) enrolled men with biopsy-proven localized PCa recurrence after radiotherapy. Multiparametric magnetic resonance imaging (mpMRI) and 18F prostate-specific membrane antigen-1007 (18F PSMA-1007) positron emission tomography (PET)-computed tomography (CT) were used to confirm organ-confined disease localization. Patients underwent either whole-gland or partial sTULSA, depending on their individual tumor characteristics. Outcome measurements and statistical analysis: Patients were followed at 3-mo intervals. Adverse events (AEs, Clavien-Dindo scale), functional status questionnaires (Expanded Prostate Cancer Index [EPIC]-26, International Prostate Symptom Score, International Index of Erectile Function-5), uroflowmetry, and prostate-specific antigen (PSA) were assessed at every visit. Disease control was assessed at 1 yr using mpMRI and 18F-PSMA-1007 PET-CT, followed by prostate biopsies. Results and limitations: Eleven patients (median age 69 yr, interquartile range [IQR] 68–74) underwent sTULSA (3 whole-gland, 8 partial sTULSA) and have completed 12-mo follow-up. Median PSA was 7.6 ng/ml (IQR 4.9–10) and the median time from initial PCa diagnosis to sTULSA was 11 yr (IQR 9.5–13). One grade 3 and three grade 2 AEs were reported, related to urinary retention and infection. Patients reported a modest degradation in functional status, most significantly a 20% decline in the EPIC-26 irritative/obstructive domain at 12 mo. A decline in maximum flow rate (24%) was also observed. At 1 yr, 10/11 patients were free of any PCa in the targeted ablation zone, with two out-of-field recurrences. Limitations include the nonrandomized design, limited sample size, and short-term oncological outcomes. Conclusions: sTULSA appears to be safe and feasible for ablation of radiorecurrent PCa, offering encouraging preliminary oncological control. Patient summary: We present safety and 1-yr functional and oncological outcomes of magnetic resonance imaging–guided transurethral ultrasound ablation (TULSA) as a salvage treatment for local prostate cancer recurrence after primary radiation. Salvage TULSA is safe and shows the ability to effectively ablate prostate cancer recurrence, with acceptable toxicity.

Background: In modern urban environments children have a high incidence of inflammatory disorders, including allergies, asthma, and type 1 diabetes. The underlying cause of these disorders, according to the biodiversity hypothesis, is an imbalance in immune regulation caused by a weak interaction with environmental microbes. In this 2-year study, we analyzed bacterial community shifts in the soil surface in day-care centers and commensal bacteria inhabiting the mouth, skin, and gut of children. We compared two different day-care environments: standard urban day-care centers and intervention day-care centers. Yards in the latter were amended with biodiverse forest floor vegetation and sod at the beginning of the study. Results: Intervention caused a long-standing increase in the relative abundance of nonpathogenic environmental mycobacteria in the surface soils. Treatment-specific shifts became evident in the community composition of Gammaproteobacteria, Negativicutes, and Bacilli, which jointly accounted for almost 40 and 50% of the taxa on the intervention day-care children’s skin and in saliva, respectively. In the year-one skin swabs, richness of Alpha-, Beta-, and Gammaproteobacteria was higher, and the relative abundance of potentially pathogenic bacteria, including Haemophilus parainfluenzae, Streptococcus sp., and Veillonella sp., was lower among children in intervention day-care centers compared with children in standard day-care centers. In the gut, the relative abundance of Clostridium sensu stricto decreased, particularly among the intervention children. Conclusions: This study shows that a 2-year biodiversity intervention shapes human commensal microbiota, including taxa that have been associated with immune regulation. Results indicate that intervention enriched commensal microbiota and suppressed the potentially pathogenic bacteria on the skin. We recommend future studies that expand intervention strategies to immune response and eventually the incidence of immune-mediated diseases.

d-xylose reductase is a member of the aldo-keto reductase family, and is involved in d-xylose and l-arabinose conversion through the Pentose Catabolic Pathway (PCP) in fungi. In this study, we biochemically characterized a newly identified second d-xylose reductase (XyrB) from Aspergillus niger. This NADPH-dependent reductase is able to efficiently convert d-xylose and l-arabinose, and it has the highest affinity for these sugars of all currently known fungal pentose reductases. A combination of biochemical data, transcriptomics and phylogenetic analysis further illustrated the role of XyrB in the PCP.Enzymes: D-xylose reductase (EC 1.1.1.307), L-arabinose reductase (EC 1.1.1.21).

Plasma lipid concentrations cannot properly account for the complex interactions prevailing in lipoprotein (patho)physiology. Sequential ultracentrifugation (UCF) is the gold standard for physical lipoprotein isolations allowing for subsequent analyses of the molecular composition of the particles. Due to labor and cost issues, however, the UCF-based isolations are usually done only for VLDL, LDL, and HDL fractions; sometimes with the addition of intermediate density lipoprotein (IDL) particles and the fractionation of HDL into HDL2 and HDL3 (as done here; n = 302). We demonstrate via these data, with the lipoprotein lipid concentration and composition information combined, that the self-organizing map (SOM) analysis reveals a novel data-driven in silico phenotyping of lipoprotein metabolism beyond the experimentally available classifications. The SOM-based findings are biologically consistent with several well-known metabolic characteristics and also explain some apparent contradictions. The novelty is the inherent emergence of complex lipoprotein associations; e.g., the metabolic subgrouping of the associations between plasma LDL cholesterol concentrations and the structural subtypes of LDL particles. Importantly, lipoprotein concentrations cannot pinpoint lipoprotein phenotypes. It would generally be beneficial to computationally enhance the UCF-based lipoprotein data as illustrated here. Particularly, the compositional variations within the lipoprotein particles appear to be a fundamental issue with metabolic and clinical corollaries.

Background: Physician's intention to prescribe drugs could potentially be used to improve targeting of alcohol interventions and enhanced disease management to patients with a high risk of severe alcohol-related harm within outpatient settings., Methods: Comparison of ten-year incidence trajectories of 13.8 million reimbursed purchases of prescription drugs among 303,057 Finnish men and women of whom 7490 ultimately died due to alcohol-related causes (Alc+), 14,954 died without alcohol involvement (Alc-), and 280,613 survived until the end of 2007., Results: 5-10 years before death, 88% of the persons with an Alc+ death had received prescription medication, and over two-thirds (69%) had at least one reimbursed purchase of drugs for the alimentary tract and metabolism, the cardiovascular system, or the nervous system. Among persons with an Alc+ death, the incidence rate (IR) for purchases of hypnotics, and sedatives was 1.38 times higher (95% confidence interval (CI):1.32,1.44) compared to those with an Alc- death, and 4.07 times higher (95%CI:3.92,4.22) compared to survivors; and the IR for purchases of anxiolytics was 1.40 times higher (95%CI:1.34,1.47) compared to those with an Alc- death, and 3.61 times higher (95%CI:3.48,3.78) compared to survivors., Conclusions: Using physician's intention to prescribe drugs affecting the alimentary tract and metabolism, cardiovascular system and nervous system could potentially be used to flag patients who might benefit from screening, targeted interventions or enhanced disease management. In particular, patients who are to be prescribed anxiolytics, hypnotics, and sedatives, and antidepressants may benefit from enhanced interventions targeted to problem drinking., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: We investigated the association between social determinants and a broad selection of drug-related deaths in a general population., Methods: We conducted a follow-up of an 11% random sample of working-age Finnish residents for 1996-2007 linked with an oversampling of deaths and population registration data on social characteristics. We defined total drug-related deaths as those from psychoactive substance use disorders and drug-induced poisonings (drug-induced deaths) as well as drug-related accidents, homicides, illnesses, and suicides., Results: The number of drug-related deaths was three times that of drug-induced deaths. We found the highest hazard ratios (HRs) for total drug-related mortality for long-term unemployment (4.9; 95% confidence interval [CI], 4.3-5.6), short-term unemployment (3.9; 95% CI, 3.5-4.4), and retirement (5.8; 95% CI, 5.1-6.8). The HRs were highest for mortality related to psychoactive substance use disorders and lowest for mortality related to drug-related suicides. The differences were large for both sexes., Conclusions: Drug-related mortality was associated with social disadvantage; however, the strength of the association varied by drug-related cause of death. Primary and secondary prevention of drug use should particularly target disadvantaged groups., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Reasons for socioeconomic inequalities in alcohol harm are not sufficiently understood. One explanation relates to differential exposure to alcohol by socioeconomic status (SES). The present study investigated socioeconomic inequalities in alcohol use in two countries with high alcohol consumption and alcohol harm., Methods: Data from nationally representative surveys in 2009-2010 in Chile and in 2008-2011 in Finland were used. Surveys comprised 3477 participants in Chile and 9994 in Finland aged 30-64 years. Outcome measures included abstinence, weekly consumption of pure alcohol, heavy volume drinking and heavy episodic drinking (HED). We employed a novel method in alcohol research, the concentration index, to measure socioeconomic inequalities., Results: Alcohol abstinence showed a strong association with lower SES in Chile and Finland. These were largely driven by inequalities among women in Chile and older subgroups in Finland. In both countries, women aged 45-64 of higher SES showed higher weekly consumption of pure alcohol and heavy volume drinking. Heavy volume drinking among Chilean women aged 45-64 showed the highest inequality, favouring higher SES. HED was equally distributed among SES groups in Chile; in Finland HED disproportionally affected lower SES groups., Conclusions: Lower SES was associated with higher abstinence rates in both countries and heavy episodic drinking in Finland. Heavy volume drinking was more prevalent in middle-aged women of high SES. The results identified groups for targeted interventions, including middle-aged higher SES women, who traditionally have not been specifically targeted. The concentration index could be a useful measure of inequalities in alcohol use., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The association between DUI (driving under the influence) and disadvantaged social background has been shown in cross-sectional studies, but less is known about the processes behind this phenomenon. We aimed to examine the effect of DUI arrest on subsequent social disadvantage in Finland during 1993-2006 to provide more understanding about the dynamics of DUI and marginalization and to study DUI arrest as a potential point of intervention., Methods: In this longitudinal, register-based study the Register of DUI suspects (n=68894) was linked with the Employment Register. An age- and gender-matched reference population (n=67740) was drawn from the general Finnish population. A multi-state model was used to estimate the transition intensities between three different states (advantaged social status/disadvantaged social status/death) among three different DUI groups (alcohol only, prescription drugs, illicit drugs)., Results: Compared to references, the movement of DUI suspects between different social states was more dynamic in that they were more likely to either move to a disadvantaged social state or to an improved status (except DUI suspects using prescription drugs). A DUI's relative risk of death compared to references was high, especially if currently in advantaged social status. The effect of DUI did not diminish over time., Conclusions: Driving under the influence is associated with an increased long-term risk for social disadvantage. DUI arrest could serve as an opportunity for intervention in the marginalization process., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)