HTLV in Sweden.

Sweden is a country with a low prevalence of human lymphotropic T-cell virus (HTLV) infection, estimated at < 0.005%, but the infection rate is notably higher in specific risk groups such as HTLV-2 among intravenous drug users (IVDU) and people originating from HTLV-1 highly endemic areas. Thus, in the most recent study from 2012, the prevalence of HTLV-2 among IVDU in Stockholm was 3.2%. However, much of the epidemiological data on HTLV in Sweden stems from studies conducted primarily between the 1990s and 2007, and the impact of migration to Sweden during the past 15 years has not been evaluated. Despite Sweden's status as a country with generally low prevalence of HTLV, it is prudent to anticipate and prepare for several potential challenges associated with HTLV infection in the future. Proactive measures to enhance awareness, alongside strategies to curtail transmission and mitigate complications, are crucial for addressing this relatively rare, but significant health issue. In this work, we review the current epidemiological knowledge about HTLV in Sweden and discuss future Swedish perspectives.

Surgery for carpal tunnel syndrome in patients with and without diabetes-Is there a difference in the frequency of surgical procedures?

Carpal tunnel syndrome (CTS) occurs more often among individuals with diabetes. The aim of this retrospective observational registry study was to examine whether individuals with diabetes and CTS are treated surgically to the same extent as individuals with CTS but without diabetes. Data on CTS diagnosis and surgery were collected from the Skåne Healthcare Register (SHR). A total of 35,105 individuals (age ≥ 18 years) diagnosed with CTS from 2004-2019 were included. Data were matched to the Swedish National Diabetes Register (NDR. Cox regression models were used to calculate the risk of the use of surgical treatment. Of the 35,105 included individuals with a CTS diagnosis, 17,662 (50%) were treated surgically, and 4,966 (14%) had diabetes. A higher number of individuals with diabetes were treated surgically (2,935/4,966, 59%) than individuals without diabetes (14,727/30,139, 49%). In the Cox regression model, diabetes remained a significant risk factor for surgical treatment (PR 1.14 (95% CI 1.11-1.17)). Individuals with type 1 diabetes were more frequently treated surgically (490/757, 65%) than individuals with type 2 diabetes (2,445/4,209, 58%). There was no difference between the sexes and their treatment. The duration of diabetes was also a risk factor for surgical treatment in diabetes type 2, but high HbA1c levels were not. Individuals with diabetes are more likely to be treated surgically for CTS than individuals without diabetes. Individuals with type 1 diabetes are more likely to be treated surgically for CTS than individuals with type 2 diabetes.

A new interactive computer simulation system for violence risk assessment of mentally disordered violent offenders.

BACKGROUND: Assessment of risk of future violence has developed from reliance on static indicators towards a more dynamic approach. In the latter context, however, the offender is seldom confronted with real life situations. AIMS: The aim of this study is to evaluate a computer-based system--Reactions on Display, which presents human interactions based on real-life situations--for its effectiveness in distinguishing between potentially violent offenders with mental disorder and a healthy comparison group. METHODS: Male offenders with autism spectrum disorders or psychosis were recruited from specialist forensic psychiatric units in Sweden and healthy participants from the local communities. Each consenting participant was presented with film clips of a man in neutral and violent situations, which at critical moments stopped the story to ask him to predict the thoughts, feelings and actions of the actor. RESULTS: Offender patients, irrespective of diagnosis, detected fewer emotional reactions in the actor in the non-violent sequence compared with controls. When asked to choose one of four violent actions, the offender patients chose more violent actions than did the controls. They also reported fewer physical reactions in the actors when actors were being violent. There were also some examples of incongruent or deviant responses by some individual patients. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The use of interactive computer simulation techniques is not only generally acceptable to offender patients, but it also helps to differentiate their current response style to particular circumstances from that of healthy controls in a way that does not rely on their verbal abilities and may tap more effectively into their emotional reactions than standard verbal questions and answer approaches. This may pave the way for Reactions on Display providing a useful complement to traditional risk assessment, and a training route with respect to learning more empathic responding, thus having a role in aiding risk management.

Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial.

BACKGROUND: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration. METHODS: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 µg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery. RESULTS: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly. CONCLUSION: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824).

Mapping the folding free energy surface for metal-free human Cu,Zn superoxide dismutase.

Mutations at many different sites in the gene encoding human Cu,Zn superoxide dismutase (SOD) are known to be causative agents in amyotrophic lateral sclerosis (ALS). One explanation for the molecular basis of this pathology is the aggregation of marginally soluble, partially structured states whose populations are enhanced in the protein variants. As a benchmark for testing this hypothesis, the equilibrium and kinetic properties of the reversible folding reaction of a metal-free variant of SOD were investigated. Reversibility was achieved by replacing the two non-essential cysteine residues with non-oxidizable analogs, C6A/C111S, to produce apo-AS-SOD. The metal-free pseudo-wild-type protein is folded and dimeric in the absence of chemical denaturants, and its equilibrium folding behavior is well described by an apparent two-state mechanism involving the unfolded monomer and the native dimer. The apparent free energy of folding in the absence of denaturant and at standard state is -20.37(+/- 1.04) kcal (mol dimer)(-1). A global analysis of circular dichroism kinetic traces for both unfolding and refolding reactions, combined with results from small angle X-ray scattering and time-resolved fluorescence anisotropy measurements, supports a sequential mechanism involving the unfolded monomer, a folded monomeric intermediate, and the native dimer. The rate-limiting monomer folding reaction is followed by a near diffusion-limited self-association reaction to form the native dimer. The relative population of the folded monomeric intermediate is predicted not to exceed 0.5% at micromolar concentrations of protein under equilibrium and both strongly unfolding and refolding conditions for metal-free pseudo-wild-type SOD.

The relationship between chain connectivity and domain stability in the equilibrium and kinetic folding mechanisms of dihydrofolate reductase from E.coli.

The role of domains in defining the equilibrium and kinetic folding properties of dihydrofolate reductase (DHFR) from Escherichia coli was probed by examining the thermodynamic and kinetic properties of a set of variants in which the chain connectivity in the discontinuous loop domain (DLD) and the adenosine-binding domain (ABD) was altered by permutation. To test the concept that chain cleavage can selectively destabilize the domain in which the N- and C-termini are resident, permutations were introduced at one position within the ABD, one within the DLD and one at a boundary between the domains. The results demonstrated that a continuous ABD is required for a stable thermal intermediate and a continuous DLD is required for a stable urea intermediate. The permutation at the domain interface had both a thermal and urea intermediate. Strikingly, the observable kinetic folding responses of all three permuted proteins were very similar to the wild-type protein. These results demonstrate a crucial role for stable domains in defining the energy surface for the equilibrium folding reaction of DHFR. If domain connectivity affects the kinetic mechanism, the effects must occur in the sub-millisecond time range.

The coordination of the isomerization of a conserved non-prolyl cis peptide bond with the rate-limiting steps in the folding of dihydrofolate reductase.

The propensity for peptide bonds to adopt the trans configuration in native and unfolded proteins, and the relatively slow rates of cis-trans isomerization reactions, imply that the formation of cis peptide bonds in native conformations are likely to limit folding reactions. The role of the conserved cis Gly95-Gly96 peptide bond in dihydrofolate reductase (DHFR) from Escherichia coli was examined by replacing Gly95 with alanine. The introduction of a beta carbon at position 95 is expected to increase the propensity for the trans isomer and perturb the isomerization reaction required to reach the native conformation. Although G95A DHFR is 1.30 kcal mol(-1) less stable than the wild-type protein, it adopts a well-folded structure that can be chemically denatured in a cooperative fashion. The mutant protein also retains the complex refolding kinetic pattern attributed to a parallel-channel mechanism in wild-type DHFR. The spectroscopic response upon refolding monitored by Trp fluorescence and the absence of a Trp/Trp exciton coupling apparent in the far-UV CD spectrum of the wild-type protein, however, indicated that the tertiary structure of the folded state for G95A DHFR is altered. The addition of methotrexate (MTX), a tight-binding inhibitor, to folded G95A DHFR restored the exciton coupling and the fluorescence properties through five slow kinetic events whose relaxation times are independent of the ligand and the denaturant concentrations. The results were interpreted to mean that MTX-binding drives the formation of the cis isomer of the peptide bond between Ala95 and Gly96 in five compact and stable but not wild-type-like conformations that contain the trans isomer. Folding studies in the presence of MTX for both wild-type and G95A DHFR support the notion that the cis peptide bond between Gly95 and Gly96 in the wild-type protein forms during four parallel rate-limiting steps, which are primarily controlled by folding reactions, and lead directly to a set of native, or native-like, conformers. The isomerization of the cis peptide bond is not a source of the parallel channels that characterize the complex folding mechanism for DHFR.

Spasticity after stroke: its occurrence and association with motor impairments and activity limitations.

BACKGROUND AND PURPOSE: There is no consensus concerning the number of patients developing spasticity or the relationship between spasticity and disabilities after acute stroke. The aim of the present study was to describe the extent to which spasticity occurs and is associated with disabilities (motor impairments and activity limitations). METHODS: Ninety-five patients with first-ever stroke were examined initially (mean, 5.4 days) and 3 months after stroke with the Modified Ashworth Scale for spasticity; self-reported muscle stiffness; tendon reflexes; Birgitta Lindmark motor performance; Nine Hole Peg Test for manual dexterity; Rivermead Mobility Index; Get-Up and Go test; and Barthel Index. RESULTS: Of the 95 patients studied, 64 were hemiparetic, 18 were spastic, 6 reported muscle stiffness, and 18 had increased tendon reflexes 3 months after stroke. Patients who were nonspastic (n=77) had statistically significantly better motor and activity scores than spastic patients (n=18). However, the correlations between muscle tone and disability scores were low, and severe disabilities were seen in almost the same number of nonspastic as spastic patients. CONCLUSIONS: Although spasticity seems to contribute to disabilities after stroke, spasticity was present in only 19% of the patients investigated 3 months after stroke. Severe disabilities were seen in almost the same number of nonspastic as spastic patients. These findings indicate that the focus on spasticity in stroke rehabilitation is out of step with its clinical importance. Careful and continual evaluation to establish the cause of the patient's disabilities is essential before a decision is made on the most proper rehabilitation approach.

Metal-free ALS variants of dimeric human Cu,Zn-superoxide dismutase have enhanced populations of monomeric species.

Amino acid replacements at dozens of positions in the dimeric protein human, Cu,Zn superoxide dismutase (SOD1) can cause amyotrophic lateral sclerosis (ALS). Although it has long been hypothesized that these mutations might enhance the populations of marginally-stable aggregation-prone species responsible for cellular toxicity, there has been little quantitative evidence to support this notion. Perturbations of the folding free energy landscapes of metal-free versions of five ALS-inducing variants, A4V, L38V, G93A, L106V and S134N SOD1, were determined with a global analysis of kinetic and thermodynamic folding data for dimeric and stable monomeric versions of these variants. Utilizing this global analysis approach, the perturbations on the global stability in response to mutation can be partitioned between the monomer folding and association steps, and the effects of mutation on the populations of the folded and unfolded monomeric states can be determined. The 2- to 10-fold increase in the population of the folded monomeric state for A4V, L38V and L106V and the 80- to 480-fold increase in the population of the unfolded monomeric states for all but S134N would dramatically increase their propensity for aggregation through high-order nucleation reactions. The wild-type-like populations of these states for the metal-binding region S134N variant suggest that even wild-type SOD1 may also be prone to aggregation in the absence of metals.

A pilot for a computer-based simulation system for risk estimation and treatment of mentally disordered offenders.

Risk/need analysis and treatment of mentally disordered offenders (MDOs) take place in constrained clinical settings, but violence has to be considered in a context where both social and cultural factors are of significance. One way to improve treatment and risk/need analysis of MDOs could be to develop simulation systems where users interact with video-based scenarios. The objective of this study was to develop and pilot test a simulation system to be used as a tool to study MDOs and possibly also to play a part in their rehabilitation. Collaboration between simulation and forensic psychiatry experts and a professional film team was set up. A simulation system called 'Reactions on Display' (RoD) was developed and a pilot study with eight patients and 13 staff members was carried out. Results from the study showed that RoD's interface and design were well received by patients and staff. Participants indicated that they found the video sequences realistic and the system enjoyable to use. The pilot study of RoD was positive, but further research should study possible clinical outcomes of the system. However, we believe that RoD could provide an advance in treatment and risk/need analysis of MDOs.