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Biallelic pathogenic variants in theANO10gene cause spinocerebellar ataxia recessive type 10. We report two patients, both compound heterozygous forANO10variants, including two novel variants. Both patients had onset of cerebellar ataxia in adulthood with slow progression and presented corticospinal tract signs, eye movement abnormalities and cognitive executive impairment. One of them had temporal lobe epilepsy and she also carried a heterozygous variant inCACNB4, a potential risk gene for epilepsy. Both patients had pronounced cerebellar atrophy on cerebral magnetic resonance imaging (MRI) and reduced metabolic activity in cerebellum as well as in the frontal lobes on 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography ((18F)FDG PET) scans. We provide comprehensive clinical, radiological and genetic data on two patients carrying likely pathogenicANO10gene variants. Furthermore, we provide evidence for a cerebellar as well as a frontal involvement on brain (18F)FDG PET scans which has not previously been reported.

BackgroundImproving jump-landing technique during rehabilitation is important and may be achieved through different feedback techniques, i.e., internal focus of attention (IF) or external focus of attention using a target (EF). However, there is a lack of evidence on the most effective feedback technique after anterior cruciate ligament reconstruction (ACLR). The purpose of this study was to investigate the potential difference in jump-landing techniques between IF and EF instructions in patients after ACLR.MethodsThirty patients (12 females, mean age 23.26 ± 4.91 years) participated after ACLR. Patients were randomly assigned into two groups that each followed a different testing sequence. Patients performed a drop vertical jump-landing test after receiving instructions with varying types of focus of attention. The Landing Error Scoring System (LESS) assessed the jump-landing technique.ResultsEF was associated with a significantly better LESS score (P < 0.001) compared with IF. Only EF instructions led to improvements in jump-landing technique.ConclusionUsing a target as EF resulted in a significantly better jump-landing technique than IF in patients after ACLR. This indicates that increased use of EF could or might result in a better treatment outcome during ACLR rehabilitation.

Consumption of traditional foods is decreasing amid a lifestyle transition in Greenland as incidence of type 2 diabetes (T2D) increases. In homozygous carriers of a TBC1D4 variant, conferring postprandial insulin resistance, the risk of T2D is markedly higher. We investigated the effects of traditional marine diets on glucose homoeostasis and cardio-metabolic health in Greenlandic Inuit carriers and non-carriers of the variant in a randomised crossover study consisting of two 4-week dietary interventions: Traditional (marine-based, low-carbohydrate) and Western (high in imported meats and carbohydrates). Oral glucose tolerance test (OGTT, 2-h), 14-d continuous glucose and cardio-metabolic markers were assessed to investigate the effect of diet and genotype. Compared with the Western diet, the Traditional diet reduced mean and maximum daily blood glucose by 0·17 mmol/l (95 % CI 0·05, 0·29; P = 0·006) and 0·26 mmol/l (95 % CI 0·06, 0·46; P = 0·010), respectively, with dose-dependency. Furthermore, it gave rise to a weight loss of 0·5 kg (95 % CI; 0·09, 0·90; P = 0·016) relative to the Western diet and 4 % (95 % CI 1, 9; P = 0·018) lower LDL:HDL-cholesterol, which after adjustment for weight loss appeared to be driven by HDL elevation (0·09 mmol/l (0·03, 0·15), P = 0·006). A diet–gene interaction was indicated on insulin sensitivity in the OGTT (p = 0·093), which reflected a non-significant increase of 1·4 (–0·6, 3·5) mmol/l in carrier 2-h glucose. A Traditional diet marginally improved daily glycaemic control and plasma lipid profile compared with a Westernised diet in Greenlandic Inuit. Possible adverse effects on glucose tolerance in carriers of the TBC1D4 variant warrant further studies.

Multiple myeloma (MM) is an incurable bone marrow cancer characterized by the development of osteolytic lesions due to the myeloma-induced increase in osteoclastogenesis and decrease in osteoblastic activity. The standard treatment of MM often involves proteasome inhibitors (PIs), which can also have a beneficial off-target bone anabolic effect. However, long-term treatment with PIs is unadvised due to their high side-effect burden and inconvenient route of administration. Ixazomib is a new-generation, oral PI that is generally well tolerated; however, its bone effect remains unknown. Here, we describe the 3-month results of a single-center phase II clinical trial investigating the effect of ixazomib treatment on bone formation and bone microstructure. Thirty patients with MM in stable disease not receiving antimyeloma treatment for ≥3 months and presenting ≥2 osteolytic lesions received monthly ixazomib treatment cycles. Serum and plasma samples were collected at baseline and monthly thereafter. Sodium 18F-Fluoride positron emission tomography (NaF-PET) whole-body scans and trephine iliac crest bone biopsies were collected before and after three treatment cycles. The serum levels of bone remodeling biomarkers suggested an early ixazomib-induced decrease in bone resorption. NaF-PET scans indicated unchanged bone formation ratios; however, histological analyses of bone biopsies revealed a significant increase in bone volume per total volume after treatment. Further analyses of bone biopsies showed unchanged osteoclast number and COLL1A1High-expressing osteoblasts on bone surfaces. Next, we analyzed the superficial bone structural units (BSUs), which represent each recent microscopic bone remodeling event. Osteopontin staining revealed that following treatment, significantly more BSUs were enlarged (>200,000 μm2), and the distribution frequency of their shape was significantly different from baseline. Overall, our data suggest that ixazomib induces overflow remodeling-based bone formation by decreasing the level of bone resorption and promoting longer bone formation events, making it a potentially valuable candidate for future maintenance treatment.

BackgroundNeoehrlichia mikurensis (N. mikurensis) is a newly discovered tick-borne pathogen that can inflict life-threatening illness in immunocompromised patients. N. mikurensis infection is only detectable by polymerase chain reaction (PCR)-based methodologies. We describe three distinct clinical manifestations of N. mikurensis infection (neoehrlichiosis) in Danish patients receiving B-lymphocyte-depleting therapy, rituximab, for underlying hematological, rheumatological, or neurological disorders. All three patients went through a protracted pre-diagnostic period.MethodsN. mikurensis DNA was detected and confirmed using two methods. Blood was tested by specific real-time PCR targeting the groEL gene and by 16S and 18S profiling followed by sequencing. Bone marrow was analyzed by 16S and 18S profiling.ResultsN. mikurensis was detected in blood samples in all three cases and in bone marrow from one of the three. The severity of the symptoms ranged from prolonged fever lasting more than 6 months to life-threatening hyperinflammation in the form of hemophagocytic lymphohistiocytosis (HLH). Interestingly, all patients presented with splenomegaly and two with hepatomegaly. After starting doxycycline therapy, symptoms were relieved within a few days, and biochemistry and organomegaly quickly normalized.ConclusionWe present three Danish patients recognized by the same clinician over a period of 6 months, strongly suggesting that many cases are going unrecognized. Second, we describe the first case of N. mikurensis-induced HLH and emphasize the potential severity of undetected neoehrlichiosis. Background: Neoehrlichia mikurensis (N. mikurensis) is a newly discovered tick-borne pathogen that can inflict life-threatening illness in immunocompromised patients. N. mikurensis infection is only detectable by polymerase chain reaction (PCR)-based methodologies. We describe three distinct clinical manifestations of N. mikurensis infection (neoehrlichiosis) in Danish patients receiving B-lymphocyte-depleting therapy, rituximab, for underlying hematological, rheumatological, or neurological disorders. All three patients went through a protracted pre-diagnostic period. Methods: N. mikurensis DNA was detected and confirmed using two methods. Blood was tested by specific real-time PCR targeting the groEL gene and by 16S and 18S profiling followed by sequencing. Bone marrow was analyzed by 16S and 18S profiling. Results: N. mikurensis was detected in blood samples in all three cases and in bone marrow from one of the three. The severity of the symptoms ranged from prolonged fever lasting more than 6 months to life-threatening hyperinflammation in the form of hemophagocytic lymphohistiocytosis (HLH). Interestingly, all patients presented with splenomegaly and two with hepatomegaly. After starting doxycycline therapy, symptoms were relieved within a few days, and biochemistry and organomegaly quickly normalized. Conclusion: We present three Danish patients recognized by the same clinician over a period of 6 months, strongly suggesting that many cases are going unrecognized. Second, we describe the first case of N. mikurensis-induced HLH and emphasize the potential severity of undetected neoehrlichiosis.

Variation in fatty acid (FA) composition of blubber collected in 1998 from 170 common minke whales (Balaenoptera acutorostrata) was used to study population structure in the North Atlantic. Samples from seven IWC management units were analysed: West Greenland (‘WG’, n = 69); East Greenland (‘CG’, n = 3); Jan Mayen (‘CM’, n = 24); Svalbard (‘ES’, n = 16); the Barents Sea (‘EB’, n = 30); Vestfjorden/Lofoten (‘EC’, n = 7); and the North Sea (‘EN’, n = 21). FA analyses were conducted on both deep and superficial blubber with a one-step extraction and esterification method followed by gas-chromatography. The 43 FAs identified comprised 93-99% of total FAs. CART and MANOVA analyses on FA signatures in both blubber sections suggested a ‘3-geographic Regions model’ where the regions were Greenland (WG, CG), the Northeast Atlantic (CM, ES, EB, EC) and the North Sea (EN). This is in general agreement with a genetic study on the same samples and suggests that differences in FA signatures can be used for studying population structure in minke whales. Potential variation in FA signatures caused by internal and environmental factors needs to be better understood. It is recommended that future studies of blubber FA signatures in minke whales include samples from their entire North Atlantic range (including Canadian and Icelandic waters). Samples should be collected from a pre-specified body site to rule out possible internal variation and during a narrow time-window in the same year to rule out seasonal exchange between areas.

Objectives: To examine associations between socioeconomic factors and (1) adherence to methicillin-resistant Staphylococcus aureus (MRSA) posttreatment follow-up swab sampling after 1 and 6 months and (2) successful decolonization treatment. Design: Cohort study with 2 years of follow-up. Data on patients diagnosed with MRSA were extracted from a regional MRSA database and national registries. We used a cluster-based logistic regression model to estimate the adjusted odds ratios (aOR) and 95% confidence interval (CI) for associations between socioeconomic factors and decolonization treatment. Setting: Danish primary health care. Results: The rate of adherence to posttreatment follow-up swab sampling among 2,536 cases 1 month after decolonization treatment was 66% (95% CI, 64%–68%), and it decreased to 30% (95% CI, 28%–32%) after 6 months. Living in intermediate municipalities (76–159 inhabitants/km2) or having retired were associated with completed posttreatment follow-up swabs 1 month after decolonization treatment: aOR, 1.40 (95% CI, 1.2–1.74) and aOR, 2.67 (95% CI, 1.16–6.13), respectively. The rate of successful decolonization treatment 2 years after initiating treatment was 36% (95% CI, 34%–38%). Factors associated with successful decolonization treatment included individuals with higher education (aOR, 1.62; 95% CI, 1.22–2.15), early retirees (aOR, 1.63; 95% CI, 1.12–2.38), those living in intermediate municipalities (ie, 160–900+ inhabitants/km2; aOR, 1.35; 95% CI, 1.08–1.68), and those living in predominantly urban municipalities (ie, 160–900+ inhabitants/km2; aOR, 2.04; 95% CI, 1.5–2.76). Conclusions: Disparities in the effect of decolonization treatment and adherence to MRSA follow-up sampling among MRSA-positive individuals appear to be largely explained by the level of education, area of residence, and employment status.

Background: Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC. Methods: The study included 23 132 consecutive symptomatic patients evaluated for coronary artery disease using coronary computed tomography angiography (CTA) from the Western Denmark Heart Registry, a seminational, multicenter-based registry with longitudinal registration of patient and procedure data. We assessed the association of LDL-C level obtained before CTA with ASCVD (myocardial infarction and ischemic stroke) events occurring during follow-up stratified by CAC>0 versus CAC=0 using Cox regression models adjusted for baseline characteristics. Outcomes were identified through linkage among national registries covering all hospitals in Denmark. We replicated our results in the National Heart, Lung, and Blood Institute –funded Multi-Ethnic Study of Atherosclerosis. Results: During a median follow-up of 4.3 years, 552 patients experienced a first ASCVD event. In the overall population, LDL-C (per 38.7 mg/dL increase) was associated with ASCVD events occurring during follow-up (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.04–1.24]). When stratified by the presence or absence of baseline CAC, LDL-C was only associated with ASCVD in the 10 792/23 132 patients (47%) with CAC>0 (aHR, 1.18 [95% CI, 1.06–1.31]); no association was observed among the 12 340/23 132 patients (53%) with CAC=0 (aHR, 1.02 [95% CI, 0.87–1.18]). Similarly, a very high LDL-C level ( > 193 mg/dL) versus LDL-C 0 (aHR, 2.42 [95% CI, 1.59–3.67]) but not in those without CAC (aHR, 0.92 [0.48–1.79]). In patients with CAC=0, diabetes, current smoking, and low high-density lipoprotein cholesterol levels were associated with future ASCVD events. The principal findings were replicated in the Multi-Ethnic Study of Atherosclerosis. Conclusions: LDL-C appears to be almost exclusively associated with ASCVD events over ≈5 years of follow-up in middle-aged individuals with versus without evidence of coronary atherosclerosis. This information is valuable for individualized risk assessment among middle-aged people with or without coronary atherosclerosis.

OBJECTIVE The aim of this study was to evaluate the effects of needle flexor tendon tenotomy treatment of the diabetic hammertoe deformity. RESEARCH DESIGN AND METHODS A multicenter randomized controlled trial of individuals with diabetes and ulcers or impending ulcers associated with hammertoes was performed between 1 November 2019 and 31 March 2021. Participants were stratified by the presence of ulcers or impending ulcers. Participants were randomly assigned to tenotomy and standard nonsurgical treatment or to standard nonsurgical treatment alone. Primary outcomes were time to ulcer healing and progression from impending ulcer to active ulcer. RESULTS Of 224 screened participants with diabetes, 95 (59.0% men) were included. The mean follow-up was 291 ± 70 days, 28 (29.5%) had type 1 diabetes, mean diabetes (presented with 25–75% quartile) duration was 20 (13–26) years, and mean age was 67.7 ± 9.8 years. Of the included participants, 16 had ulcers, of whom 8 were randomly assigned to intervention. Of the remaining 79 with impending ulcers, 39 were randomly assigned to intervention. For participants with ulcers, healing rates favored tenotomy (100% vs. 37.5%, P = 0.026) as did time to ulcer healing (P = 0.04). For those with impending ulcers, incidence of progression to an active ulcer was lower (1 vs. 7, P = 0.028) and the number of ulcer-free days higher (P = 0.043) in the tenotomy group. No serious adverse events were recorded. CONCLUSIONS This randomized study showed that the simple procedure of needle flexor tendon tenotomy was effective and safe when treating and preventing ulcers associated with the diabetic hammertoe deformity.

Functional MRI (fMRI) and EEG may reveal residual consciousness in patients with disorders of consciousness (DoC), as reflected by a rapidly expanding literature on chronic DoC. However, acute DoC is rarely investigated, although identifying residual consciousness is key to clinical decision-making in the intensive care unit (ICU). Therefore, the objective of the prospective, observational, tertiary centre cohort, diagnostic phase IIb study ‘Consciousness in neurocritical care cohort study using EEG and fMRI’ (CONNECT-ME, NCT02644265) was to assess the accuracy of fMRI and EEG to identify residual consciousness in acute DoC in the ICU. Between April 2016 and November 2020, 87 acute DoC patients with traumatic or non-traumatic brain injury were examined with repeated clinical assessments, fMRI and EEG. Resting-state EEG and EEG with external stimulations were evaluated by visual analysis, spectral band analysis and a Support Vector Machine (SVM) consciousness classifier. In addition, within- and between-network resting-state connectivity for canonical resting-state fMRI networks was assessed. Next, we used EEG and fMRI data at study enrolment in two different machine-learning algorithms (Random Forest and SVM with a linear kernel) to distinguish patients in a minimally conscious state or better (≥MCS) from those in coma or unresponsive wakefulness state (≤UWS) at time of study enrolment and at ICU discharge (or before death). Prediction performances were assessed with area under the curve (AUC). Of 87 DoC patients (mean age, 50.0 ± 18 years, 43% female), 51 (59%) were ≤UWS and 36 (41%) were ≥ MCS at study enrolment. Thirty-one (36%) patients died in the ICU, including 28 who had life-sustaining therapy withdrawn. EEG and fMRI predicted consciousness levels at study enrolment and ICU discharge, with maximum AUCs of 0.79 (95% CI 0.77–0.80) and 0.71 (95% CI 0.77–0.80), respectively. Models based on combined EEG and fMRI features predicted consciousness levels at study enrolment and ICU discharge with maximum AUCs of 0.78 (95% CI 0.71–0.86) and 0.83 (95% CI 0.75–0.89), respectively, with improved positive predictive value and sensitivity. Overall, both machine-learning algorithms (SVM and Random Forest) performed equally well. In conclusion, we suggest that acute DoC prediction models in the ICU be based on a combination of fMRI and EEG features, regardless of the machine-learning algorithm used.

Background: Estimates of the severity of the SARS-CoV-2 omicron variant (B.1.1.529) are crucial to assess the public health impact associated with its rapid global dissemination. We estimated the risk of SARS-CoV-2-related hospitalisations after infection with omicron compared with the delta variant (B.1.617.2) in Denmark, a country with high mRNA vaccination coverage and extensive free-of-charge PCR testing capacity. Methods: In this observational cohort study, we included all RT-PCR-confirmed cases of SARS-CoV-2 infection in Denmark, with samples taken between Nov 21 (date of first omicron-positive sample) and Dec 19, 2021. Individuals were identified in the national COVID-19 surveillance system database, which included results of a variant-specific RT-PCR that detected omicron cases, and data on SARS-CoV-2-related hospitalisations (primary outcome of the study). We calculated the risk ratio (RR) of hospitalisation after infection with omicron compared with delta, overall and stratified by vaccination status, in a Poisson regression model with robust SEs, adjusted a priori for reinfection status, sex, age, region, comorbidities, and time period. Findings: Between Nov 21 and Dec 19, 2021, among the 188 980 individuals with SARS-CoV-2 infection, 38 669 (20·5%) had the omicron variant. SARS-CoV-2-related hospitalisations and omicron cases increased during the study period. Overall, 124 313 (65·8%) of 188 980 individuals were vaccinated, and vaccination was associated with a lower risk of hospitalisation (adjusted RR 0·24, 95% CI 0·22–0·26) compared with cases with no doses or only one dose of vaccine. Compared with delta infection, omicron infection was associated with an adjusted RR of hospitalisation of 0·64 (95% CI 0·56–0·75; 222 [0·6%] of 38 669 omicron cases admitted to hospital vs 2213 [1·5%] of 150 311 delta cases). For a similar comparison by vaccination status, the RR of hospitalisation was 0·57 (0·44–0·75) among cases with no or only one dose of vaccine, 0·71 (0·60–0·86) among those who received two doses, and 0·50 (0·32–0·76) among those who received three doses. Interpretation: We found a significantly lower risk of hospitalisation with omicron infection compared with delta infection among both vaccinated and unvaccinated individuals, suggesting an inherent reduced severity of omicron. Our results could guide modelling of the effect of the ongoing global omicron wave and thus health-care system preparedness. Funding: None.

Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in genetic diagnostics are part of this development due to the ability to analyze multiple genes or whole genomes fast and to an affordable prize. This requires knowledge and capability to evaluate genetic variants correctly in a clinical setting. Here we report a Menkes disease case, born after ART, where genetic screening and variant scoring failed to identify an egg donor as carrier of this fatal X-linked disorder. The gene variant is a deletion of a single base pair leading to a frameshift and premature termination of the protein, predicted to result in no or severely diminished function. The variant would be classified as likely pathogenic (class 4) and should be readily detectable by molecular genetic screening techniques. We wish to highlight this case to prevent future similar cases. IVI Igenomix has developed and embarked on an ambitious screening program to detect and prevent a large number of inherited severe childhood disorders in ART pregnancies. The company has recently achieved ISO 15189 certification with competence to evaluate and deliver timely, accurate, and reliable results. Failure to identify a pathogenic variant in the ATP7A gene leading to birth of two boys with Menkes disease invokes the required procedures to screen and detect disease-causing gene variants. This calls for ethical and legal considerations in ART diagnostics to prevent fatal errors like the present.

Nitrophenolates (NPs) are molecular anions that can undergo charge-transfer(CT) transitions determined by the degree of electron delocalization betweenthe phenolate oxygen (donor group) and the nitro group (acceptor). Herewe have studied four different NPs: 4’-nitro-[1,1’-biphenyl]-4-olate (1),7-nitro-9H -carbazol-2-olate (NH linker, 2), 7-nitrodibenzo[b,d]furan-3-olate (oxygen linker, 3), and 7-nitrodibenzo[b,d]thiophen-3-olate (sulphurlinker, 4), and recorded their electronic absorption spectra when isolatedin vacuo to determine the effect of locking the biphenyl spacer group betweenthe donor and acceptor on transition energies. Absorption was identified fromion dissociation (action spectroscopy) using a homebuilt setup (sector massspectrometer combined with pulsed laser). We find that the absorption isbroad in the visible region for all four NPs with significant vibronic features.The lowest energy peak is at 601 ± 4 nm, 606 ± 4 nm, 615 ± 4 nm, and620 ± 4 nm, for 3, 4, 2, and 1, respectively. NP 1 is flexible, and its lowestenergy structure is nonplanar while the other three NPs are planar accordingto density functional theory calculations. Hence in the case of 1 the electronic transition has a higher degree of CT than for the other three, accounting for itsabsorption furthest to the red. Our work demonstrates that oxygen and sulphurare best at conveying the electronic coupling between the donor and acceptorsites as 3 and 4 absorb furthest to the blue (i.e., the degree of CT is lowestfor these two NPs). Based on the average spacing between the peaks in thevibrational progressions, coupling occurs to skeleton vibrational modes withfrequencies of 649 ± 69 cm−1 (3), 655 ± 49 cm−1 (4), and 697 ± 52 cm−1 (2).

AC K N OW L E D G M E N T S This study was funded by projects: IB20089 from the Consejería de Economía, Ciencia y Agenda Digital of the Junta de Extremadura and Fondo Europeo de Desarrollo Regional, P11-RNM-7038 from Junta de Andalucía, and PR(19_ECO_0070) from Ayudas Fundación BBVA a Equipos de Investigación Científica 2019. MF was supported by a Juan de la Cierva 2017 Formación contract (FJCI-2017-34394) from the Ministry of Science, Innovation and Universities, by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie (grant agreement No 844285, ‘EpiEcoMod’) and she is currently funded by a Ramón y Cajal postdoctoral contract (RYC2021- 031613-I) from the Spanish Ministry of Science and Innovation (MICINN). JJP was supported by the Fundación Tatiana Pérez de Guzmán el Bueno. JMP was supported by ProyExcel_00049 financed by Proyectos I+D+i of Junta de Andalucía 2021. LGL was supported by Junta de Extremadura (IB20089, Post-Doc grant). JM was supported by a Juan de la Cierva - Formación contract (FJCI-2017-34109) from the Ministry of Science, Innovation and Universities, and he is currently supported by a postdoctoral researcher contract for scientific excellence under the Plan Propio de I+D+i of the Universidad de Castilla - La Mancha (UCLM), co-funded by the European Social Fund Plus (ESF+). LZG was supported by funds from the Hungary's National Research, Development and Innovation Office (K135841, RRF-2.3.1-21-2022- 00006). We also acknowledge the comments of four anonymous reviewers who improved the final version of this manuscript., DATA AVA I L A B I L I T Y S TAT E M E N T Data supporting the conclusions of this study are available in the supplementary material to this article. Any further details are available from the corresponding author on reasonable request., Aim The increasing spread of vector-borne diseases has resulted in severe health concerns for humans, domestic animals and wildlife, with changes in land use and the introduction of invasive species being among the main possible causes for this increase. We explored several ecological drivers potentially affecting the local prevalence and richness of avian malaria parasite lineages in native and introduced house sparrows (Passer domesticus) populations. Location Global. Time period 2002–2019. Major taxa studied Avian Plasmodium parasites in house sparrows. Methods We analysed data from 2,220 samples from 69 localities across all continents, except Antarctica. The influence of environment (urbanization index and human density), geography (altitude, latitude, hemisphere) and time (bird breeding season and years since introduction) were analysed using generalized additive mixed models (GAMMs) and random forests. Results Overall, 670 sparrows (30.2%) were infected with 22 Plasmodium lineages. In native populations, parasite prevalence was positively related to urbanization index, with the highest prevalence values in areas with intermediate urbanization levels. Likewise, in introduced populations, prevalence was positively associated with urbanization index; however, higher infection occurred in areas with either extreme high or low levels of urbanization. In introduced populations, the number of parasite lineages increased with altitude and with the years elapsed since the establishment of sparrows in a new locality. Here, after a decline in the number of parasite lineages in the first 30 years, an increase from 40 years onwards was detected. Main conclusions Urbanization was related to parasite prevalence in both native and introduced bird populations. In invaded areas, altitude and time since bird introduction were related to the number of Plasmodium lineages found to be infecting sparrows., Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, Grant/Award Number: P11-RNM-7038, Fundación BBVA, Grant/Award Number: PR(19_ECO_0070, Junta de Extremadura, Grant/Award Number: IB20089 and PO17024, Marie Sklodowska- Curie Actions, Grant/Award Number: 844285, Ministerio de Ciencia, Innovación y Universidades, Grant/Award Number: FJCI-2017-34109 and FJCI-2017-34394, Proyectos I+D+i of Junta de Andalucía 2021, Grant/Award Number: ProyExcel_00049, Universidad de Castilla- La Mancha

Guidelines recommend active fever prevention for 72 hours after cardiac arrest. Data from randomized clinical trials of this intervention have been lacking.We randomly assigned comatose patients who had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause to device-based temperature control targeting 36°C for 24 hours followed by targeting of 37°C for either 12 or 48 hours (for total intervention times of 36 and 72 hours, respectively) or until the patient regained consciousness. The primary outcome was a composite of death from any cause or hospital discharge with a Cerebral Performance Category of 3 or 4 (range, 1 to 5, with higher scores indicating more severe disability; a category of 3 or 4 indicates severe cerebral disability or coma) within 90 days after randomization. Secondary outcomes included death from any cause and the Montreal Cognitive Assessment score (range, 0 to 30, with higher scores indicating better cognitive ability) at 3 months.A total of 393 patients were randomly assigned to temperature control for 36 hours, and 396 patients were assigned to temperature control for 72 hours. At 90 days after randomization, a primary end-point event had occurred in 127 of 393 patients (32.3%) in the 36-hour group and in 133 of 396 patients (33.6%) in the 72-hour group (hazard ratio, 0.99; 95% confidence interval, 0.77 to 1.26; P = 0.70) and mortality was 29.5% in the 36-hour group and 30.3% in the 72-hour group. At 3 months, the median Montreal Cognitive Assessment score was 26 (interquartile range, 24 to 29) and 27 (interquartile range, 24 to 28), respectively. There was no significant between-group difference in the incidence of adverse events.Active device-based fever prevention for 36 or 72 hours after cardiac arrest did not result in significantly different percentages of patients dying or having severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).

BackgroundGastrointestinal motility is important for adequate uptake of fluids and nutrition but is often impaired in hospitalised patients. Prokinetic agents enhance gastrointestinal motility and are prescribed for many hospitalised patients. In this scoping review, we aimed to systematically describe the body of evidence on the use of prokinetic agents in hospitalised patients. We hypothesised, that the body of evidence would be limited and derive from heterogeneous populations.MethodsWe conducted this scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews statement. We searched Medline, Embase, Epistemonikos and the Cochrane Library for studies assessing the use of prokinetic agents on any indication and outcome in adult hospitalised patients. We used a modified version of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence.ResultsWe included 102 studies with a total of 8830 patients. Eighty-six studies were clinical trials (84%), and 52 (60%) of these were conducted in the intensive care unit, with feeding intolerance as the main indication. In the non-intensive care setting the indications were wider; most studies assessed use of prokinetic agents before gastroscopy to improve visualisation. The most studied prokinetic agent was metoclopramide (49% of studies) followed by erythromycin (31%). In total 147 outcomes were assessed with only 67% of the included studies assessing patient-centred outcomes, and with gastric emptying as the most frequently reported outcome. Overall, the data provided no firm evidence on the balance between the desirable and undesirable effects of prokinetic agents.ConclusionsIn this scoping review, we found that the studies addressing prokinetic agents in hospitalised adults had considerable variations in indications, drugs and outcomes assessed, and that the certainty of evidence was judged to be low to very low.

Extracts of Eremophila phyllopoda subsp. phyllopoda showed alpha-glucosidase and PTP1B inhibitory activity with IC50 values of 19.6 and 13.6 mu g/mL, respectively. High-resolution alpha-glucosidase/PTP1B/radical scavenging profiling was performed to establish a triple high-resolution inhibition profile that allowed direct pinpointing of the constituents responsible for one or more of the observed bioactivities. Subsequent targeted isolation and purification by analytical-scale HPLC led to the identification of 21 previously undescribed serrulatane diterpenoids, eremophyllanes A-U, as well as two known serrulatane diterpenoids, 1 beta- trihydroxyserrulatane (8) and 1 alpha-trihydroxyserrulatane (10d), and five known furofuran lignans, (+)-piperitol (6), horsfieldin (7e), (-)-sesamin (9), (+)-sesamin (10h), and asarinin (10i). Their structures were elucidated by extensive analysis of HRMS and 1D and 2D NMR spectroscopic data. The relative configurations of the previously undescribed compounds were established by analysis of ROESY spectra as well as by DFT-GIAO NMR calculations followed by DP4+ probability analysis. The absolute configurations were determined by comparison of experimental and calculated ECD spectra. Serrulatane diterpenoids 7b and 14 exhibited alpha- glucosidase inhibitory activity with IC50 values of 28.4 and 64.2 mu M, respectively, while 11, 12, 14, and 15 exhibited PTP1B inhibitory activity with IC50 values ranging from 16.6 to 104.6 mu M. Hypothetical routes for formation of all identified serrulatane diterpenoids are proposed. Refereed/Peer-reviewed

Elisabeth Kjær Jensen,1,&ast; Thomas K Ringsted,1,&ast; Joakim M Bischoff,1 Morten A Petersen,2 Kirsten Møller,3,4 Henrik Kehlet,5 Mads U Werner1,6 1Department of Anaesthesia, Pain and Respiratory Support, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 2Statistical Research Unit, Department of Palliative Care, Bispebjerg Hospital, Copenhagen, Denmark; 3Department of Neuroanaesthesiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 4Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Section for Surgical Pathophysiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 6Department of Clinical Sciences, Lund University, Lund, Sweden&ast;These authors contributed equally to this workCorrespondence: Elisabeth Kjær Jensen, Multidisciplinary Pain Center 7612, Department of Anesthesia, Pain and Respiratory Support, Neuroscience Center, Rigshospitalet, Ole Maaløes Vej 26, Copenhagen N, 2200, Denmark, Tel +45 3545 7612, Email elisabeth.kjaer@live.dkPurpose: After groin hernia repair (globally more than 20 million/year) 2– 4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy.Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory “component” indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8– 11.5) months before and 4.0 (3.5– 4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed.Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of − 2.0, − 2.5, and − 2.0 NRS (0/10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function (“deafferentation”). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001).Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep “pain generator”. The QST-analyses are useful adjuncts in mechanism-based somatosensory research.Keywords: groin, hernia repair, chronic post-surgical pain, reoperation, sensory thresholds

Aims Cardiogenic shock (CS) is known to induce an inflammatory response. The prognostic utility of this remains unclear. To investigate the association between C-reactive protein (CRP) levels and leucocyte count and mortality in patients with acute myocardial infarction complicated by CS (AMICS). Methods and results Consecutive patients (N = 1716) admitted between 2010 and 2017 with an individually validated diagnosis of AMICS were included. The analysis was restricted to patients alive at 48 h after first medical contact and a valid CRP and leucocyte measurement at 48 ± 12 h from the first medical contact. A combined inflammatory score for each patient was computed by summing the CRP and leucocyte count z-scores to normalize the response on a standard deviation scale. Associations with mortality were analysed using a multivariable Cox proportional hazards model stratified by inflammatory response quartiles: Of the 1716 patients in the cohort, 1111 (64.7%) fulfilled inclusion criteria. The median CRP level at 48 h was 145 mg/dL [interquartile range (IQR) 96–211]. The median leucocyte count was 12.6 × 10−9/L (IQR 10.1–16.4). Patients with the highest inflammatory response (Q4) had lower median left ventricular ejection fractions and higher lactate levels at the time of diagnosis. The 30-day all-cause mortality rates were 46% in Q4 and 21% in Q1 (P < 0.001). In multivariable models, the inflammatory response remained associated with mortality [hazard ratio (HR)Q4 2.32, 95% confidence interval (CI) 1.59–3.39, P < 0.001]. The finding was also significant in AMICS patients presenting with out-of-hospital cardiac arrest following multivariable adjustment (HRQ4 3.37, 95% CI 2.02–4.64, P < 0.001). Conclusion Cardiogenic shock induces an acute inflammatory response, the severity of which is associated with mortality.

AIM: We aimed to improve bone health management of children with Cerebral Palsy (CP) by reviewing studies investigating bisphosphonate therapy in children with CP and other types of secondary osteoporosis.METHODS: We included trials on bisphosphonate treatment reporting any direct bone measurement or fracture outcome. All studies of patients with CP were included. We also included all controlled trials of children with secondary bone fragility as well as observational studies with ≥20 participants or at least three years of follow-up. Studies were assessed according to PRISMA guidelines using the RoB2-tool and the Newcastle-Ottawa Scale.RESULTS: We reviewed 1,004 studies and found 38 eligible. Some studies were sufficiently homogeneous to include in a meta-analysis and we found a one-year effect on lumbar spine bone mineral density (BMD) Z-score of +0.65 after oral and +1.21 after intravenous bisphosphonates in children with secondary osteoporosis. Further, data on adverse events and post-treatment follow-up were reviewed. Limitations were heterogeneity and small size of the included studies.CONCLUSION: Meta-analysis consistently showed significant BMD increases with bisphosphonates in children with secondary osteoporosis. Direct evidence of the effect of bisphosphonates on reducing fractures is lacking. We found no reports of long-term adverse events yet longer studies are needed.

Investigate change in physical activity following an 8-week education and exercise therapy program for patients with knee/hip osteoarthritis, focusing on those with low physical activity level. Furthermore, to evaluate associations between changes in pain intensity and physical activity.Data from the Good Life with osteoArthritis in Denmark (GLA:D®) registry, at baseline, immediately after completion, and 12 months after entering the program was used. Measures of interest were UCLA activity scale (1-10) and Visual Analog Scale for pain intensity (0-100 mm). Changes in physical activity levels (low 1-4, moderate 5-6, and high 7-10) over three time points were investigated. Asymmetric fixed effects regression models were used to evaluate the association between clinically relevant change in pain (≥15 mm) and change in physical activity level from baseline to 12 months.37% with low activity level at baseline (n = 4,836) and 69% of all patients (n = 17,454) reached or maintained at least a moderate physical activity level at follow-ups. Surprisingly, both an improvement (β = 1.44, P 0.001) and a worsening (β = 1.18, P 0.001) in pain intensity was associated with increased physical activity in low activity patients. For all patients a similar trend was observed (β = 0.51, P 0.001 and β = 0.11, P = 0.215, respectively).In low active knee or hip OA patients, a third of patients participating in an education and exercise therapy program reached and maintained at least a moderate physical activity level for 1 year. The improvement in physical activity was not dependent on pain reduction.

BACKGROUND & AIMS In patients with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in cACLD patients. METHODS A detailed laboratory workup of cACLD patients recruited from the VIENNA cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG≥10mmHg) and severe PH (i.e. HVPG≥16mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. RESULTS Among 1232 cACLD patients, the CSPH and severe PH prevalence in VIENNA (n = 163, 67.4%/35.0%) and the validation cohort (n = 1069, 70.3%/34.7%) were similar. The MLMs were based on 3 (3P; platelets, bilirubin, INR) or 5 (5P; +cholinesterase, +gamma-glutamyl transferase, +aPTT replacing INR) laboratory parameters. The MLMs performed robustly in VIENNA with best AUROCs for CSPH by 5P-MLM: 0.813 and for severe PH by 5P-MLM: 0.887 and compared favourably to liver stiffness measurement (AUROC: 0.808). Their performance in external validation datasets was heterogeneous (AUROCs 0.589-0.887). Training on the merged cohort optimized the MLM performance for CSPH (AUROCs: 3P: 0.775, 5P: 0.789) and for severe PH (AUROCs 3P: 0.737, 5P: 0.828). CONCLUSIONS Internally-trained MLMs reliably predicted PH severity in the VIENNA cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify patients with CSPH or severe PH, thus, at risk for hepatic decompensation. LAY SUMMARY The gold standard for diagnosing portal hypertension is the invasive measurement of the hepatic venous pressure gradient. In this work, we selected the most suitable, widely available laboratory parameters for machine learning models to predict the likelihood and severity of portal hypertension in patients with compensated cirrhosis. This will aid in the identification of patients who are at the highest risk for subsequent hepatic decompensation.

Background mRNA-based COVID-19 vaccines have short- and long-term efficacy in healthy individuals, but their efficacy in patients with psoriasis receiving immunomodulatory therapy is less studied. Objectives To investigate long-term immunity after COVID-19 vaccination in patients with psoriasis receiving immunomodulatory therapy. Methods A prospective cohort study including patients (n = 123) with psoriasis receiving methotrexate (MTX) or biologics and controls (n = 226). Only mRNA-based COVID-19 vaccines administered with standard intervals between doses were investigated. Markers of immunity included SARS-CoV-2 spike glycoprotein-specific IgG and IgA, neutralizing capacity, and interferon-γ release from T cells stimulated with peptides of the SARS-CoV-2 spike glycoprotein. Results The proportion of IgG responders was lower 6 months after vaccination in patients receiving anti-tumour necrosis factor (TNF) treatment compared with controls. Anti-TNF treatment was associated with lower IgG levels (β = −0.82, 95% confidence interval −1.38 to −0.25; P = 0.001). The median neutralizing index was lower in the anti-TNF group [50% inhibition (interquartile range [IQR] 37–89)] compared with controls [98% inhibition (IQR 96–99)]; P < 0.001. Cellular responses were numerically lowest in the anti-TNF group. Conclusions Treatment with anti-TNF has an impact on the immunity elicited by mRNA-based COVID-19 vaccination in patients with psoriasis, resulting in a faster waning of humoral and cellular markers of immunity; however, the clinical implications are unknown.

Earth science education should provide space for students to engage with real-world problems involving complex earth systems and their societal implications. However, the ill-structured nature of such problems creates uncertainty among both teachers and learners. To explore the effect of this uncertainty, we designed and taught a bachelor-level earth science course that introduced geology students to computational practices allowing them to work with authentic data, methods, and ill-structured problems. In addition, the course was designed entirely for active learning and formative assessment. Students provided reflection notes as part of every learning activity, and a series of focus group interviews were conducted at the end of the course to triangulate student experiences with computational practices and problem solving in groups. Our findings suggest that the introduction of computational practices to novices, combined with the transition from passive to active forms of learning, were major sources of uncertainty. This uncertainty needs to be understood and confronted in order for students to engage with real-world problems in an effective manner. On the other hand, our results indicate that collaborative work in groups can alleviate some of the effects of this uncertainty. Our study also supports the systematic use of student reflections as a means of fostering feedback literacy among students as well as teachers.

The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom). Data on invasive EOC diagnosed in women aged 15-99 years during 1995-2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group, and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995-2014 among women aged 65-99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma 'not otherwise specified' with estimates ranging between 4.4% and 7.4% in women aged 15-64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival. This article is protected by copyright. All rights reserved.

BACKGROUND: There is an urgent need for early detection of lung cancer. Screening with low-dose computed tomography (LDCT) is now implemented in the US. Supplementary use of a lung cancer biomarker with high specificity is desirable.OBJECTIVE: To assess the diagnostic properties of a biomarker panel consisting of cytokeratin 19 fragment (CYFRA 21-1), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125).METHODS: A cohort of 250 high-risk patients was investigated on suspicion of lung cancer. Ahead of diagnostic work-up, blood samples taken. Cross-validated prediction models were computed to assess lung cancer detection properties.RESULTS: In total 32% (79/250) of patients were diagnosed with lung cancer. Area under the curve (AUC) for the three biomarkers was of 0.795, with sensitivity/specificity of 57%/93% and negative predictive value of 83%. When combining the biomarkers with US screening criteria, the AUC was 0.809, while applying only US screening criteria on the cohort, yielded an AUC of 0.62. The ability of the biomarkers to detect stage I-II lung cancer was substantially lower; AUC 0.54.CONCLUSIONS: In a high-risk cohort, the detection properties of the three biomarkers were acceptable compared to current LDCT screening criteria. However, the ability to detect early stage lung cancer was low.

A new species of the zoarcid genus Pyrolycus Machida & Hashimoto, 2002, Pyrolycus jaco sp. nov., is described from a hydrothermal seep environment named Jacó Scar in the eastern Pacific of Costa Rica. Four specimens were collected in 2018 between 1746–1795 m among tubeworm colonies around the seep. The new species is differentiated from its two western Pacific congeners by having a shorter head, snout, jaw, and pectoral fins. It is further diagnosed by having three postorbital pores and two occipital pores. Molecular sequences of the cytochrome c oxidase I gene are provided and are the first for the genus. The character states indicating miniaturization in this species are discussed. This is the first vertebrate species known from this composite reducing ecosystem and is the fourth hydrothermally-associated zoarcid from the eastern Pacific.

Background: This study tested the hypothesis that training reduces resting sympathetic activity and improves baroreflex control in both hypertensive and normotensive men but reduces blood pressure only in hypertensive men.Methods: Middle-aged/older un-medicated stage-1 hypertensive males (mean age 55±3 yrs; n=13) and normotensive controls (mean age 60±5 yrs; n=12) participated in 8 weeks of supervised high-intensity interval spinning training. Before and after training, muscle sympathetic nerve activity (MSNA) and blood pressure were measured at rest and during a sympatho-excitatory cold pressor test (CPT). Based on the measurements, baroreceptor sensitivity and baroreceptor threshold were calculated.Results: Resting MSNA and baroreceptor sensitivity were similar for the hypertensive and the normotensive groups. Training lowered MSNA (ppp>0.05) alter the MSNA or blood pressure response to CPT or increase baroreceptor sensitivity but reduced (pConclusion: The dissociation between the training induced changes in resting MSNA, lack of change in baroreflex sensitivity and the change in blood pressure, suggests that MSNA is not a main cause of the blood pressure reduction with exercise training in un-medicated middle-aged/older men.