The use of enhanced intrinsic feedback for motor learning in stroke survivors: Clinical trial protocol.

BACKGROUND: Stroke can lead to lasting sensorimotor deficits of the upper limb (UL) persisting into the chronic phase despite intensive rehabilitation. A major impairment of reaching after stroke is a decreased range of active elbow extension, which in turn leads to the use of compensatory movements. Retraining movement patterns relies on cognition and motor learning principles. Implicit learning may lead to better outcomes than explicit learning. Error augmentation (EA) is a feedback modality based on implicit learning resulting in improved precision and speed of UL reaching movements in people with stroke. However, accompanying changes in UL joint movement patterns have not been investigated. The objective of this study is to determine the capacity for implicit motor learning in people with chronic stroke and how this capacity is affected by post-stroke cognitive impairments. METHODS: Fifty-two subjects who have chronic stroke will practice reaching movements 3×/wk. for 9 wk. in a virtual reality environment. Participants will be randomly allocated to 1 of 2 groups to train with or without EA feedback. Outcome measures (pre-, post- and follow-up) will be: endpoint precision, speed, smoothness, and straightness and joint (UL and trunk) kinematics during a functional reaching task. The degree of cognitive impairment, lesion profile, and integrity of descending white matter tracts will be related to training outcomes. CONCLUSIONS: The results will inform us which patients can best benefit from training programs that rely on motor learning and utilize enhanced feedback. TRIAL STATUS: Ethical approval for this study was finalized in May 2022. Recruitment and data collection is actively in progress and is planned to finish in 2026. Data analysis and evaluation will occur subsequently, and the final results will be published.

Participation of ipsilateral cortical descending influences in bimanual wrist movements in humans.

There are contralateral and less studied ipsilateral (i), indirect cortical descending projections to motoneurons (MNs). We compared ipsilateral cortical descending influences on MNs of wrist flexors by applying transcranial magnetic stimulation (TMS) over the right primary motor cortex at actively maintained flexion and extension wrist positions in uni- and bimanual tasks in right-handed participants (n = 23). The iTMS response includes a short latency (~ 25 ms) motor evoked potential (iMEP), a silent period (iSP) and a long latency (~ 60 ms) facilitation called rebound (iRB). We also investigated whether the interaction between the two hands while holding an object in a bimanual task involves ipsilateral cortical descending influences. In the unimanual task, iTMS responses in the right wrist flexors were unaffected by changes in wrist position. In the bimanual task with an object, iMEPs in the right wrist flexors were larger when the ipsilateral wrist was in flexion compared to extension. Without the object, only iRB were larger when the ipsilateral wrist was extended. Thus, ipsilateral cortical descending influences on MNs were modulated only in bimanual tasks and depended on how the two hands interacted. It is concluded that the left and right cortices cooperate in bimanual tasks involving holding an object with both hands, with possible involvement of oligo- and poly-synaptic, as well as transcallosal projections to MNs. The possible involvement of spinal and transcortical stretch and cutaneous reflexes in bimanual tasks when holding an object is discussed in the context of the well-established notion that indirect, referent control underlies motor actions.

Low rate of new-onset primary biliary cholangitis in a cohort of anti-mitochondrial antibody-positive subjects over six years of follow-up.

BACKGROUND AND AIMS: Anti-mitochondrial antibodies (AMA) are closely linked to primary biliary cholangitis (PBC). The prevalence of AMA in the general population is low, and AMA positivity may precede PBC. We aimed to determine the natural history of subjects with positive AMA. METHODS: In total, 302 patients were tested AMA-positive over a ten-year period. Of these, immunoblotting confirmed specific AMA in 184 (29 male, 155 female, age 59.6 ± 14.1 years). These subjects were invited to our liver outpatient clinic for clinical and biochemical re-evaluation. Detailed clinical history data were additionally collected from the hospital computer system and by telephone. The subsequent course with regard to mortality, liver-related morbidity, extrahepatic co-morbidities and effectiveness of PBC treatment was determined in 150 subjects (81.5%). RESULTS: After 5.8 ± 5.6 years of follow-up (FU), of 184 AMA-positive subjects, 28 subjects (15.2%; liver-related mortality n = 5) were deceased, and 122 subjects (66.3%) completed FU while 34 subjects (18.5%) were not available for FU. The 122 patients who completed FU were 63 patients with established PBC, six de novo cases of PBC (10.2% of 59 initially at risk), 42 (34.4%) subjects were still AMA-positive without PBC, and 11 (9.0%) subjects were AMA-negative at FU. CONCLUSIONS: Anti-mitochondrial antibodies-positive patients without PBC at baseline infrequently developed PBC over six years of FU. AMA positivity represented a transient serological autoimmune phenomenon in a significant proportion of subjects.

Clinical and metabolic characterization of obese subjects without non-alcoholic fatty liver: A targeted metabolomics approach.

INTRODUCTION: As a small proportion of obese individuals do not develop metabolic complications and non-alcoholic fatty liver disease (NAFLD), this study aimed to provide a comprehensive clinical, metabolic and genetic description of obese subjects with healthy livers. METHODS: A total of 183 subjects were stratified, according to BMI, presence of metabolic syndrome, biochemical liver tests and hepatic steatosis on ultrasound, into: (i) lean controls (n = 69); (ii) obese healthy (n = 50); and (iii)obese NAFLD (n = 62) groups. Detailed clinical, genetic and metabolic evaluations were then performed. RESULTS: Obese healthy subjects did not differ in glucose parameters from lean controls, and had a lower rate of minor TM6SF2 gene variants compared with obese NAFLD (2/49 vs. 11/60, respectively; P = 0.035) and lean controls (13/64; P = 0.035), but significantly higher leptin concentrations than lean controls (P < 0.001); they also higher adiponectin concentrations (P < 0.001), and lower TNF-α and IL-6 concentrations (P = 0.01 and P < 0.001, respectively), than obese NAFLD subjects. Also, metabolomic studies identified ether- and ester-containing phospholipids [PC ae C44:6, PC ae C42:5, PC aa C40:4; P < 0.001, corrected by the false discovery rate (FDR) method] and found that the amino-acids lysine, glycine and isoleucine (FDR < 0.001) differed between the two obese groups, but not between lean controls and obese healthy subjects. CONCLUSION: Obese people with healthy livers are characterized by intact glucose homoeostasis, lower pro-inflammatory cytokine levels, and higher adiponectin and leptin concentrations compared with obese people with NAFLD. In addition, the major allele of TM6SF2, a set of phosphatidylcholines and several amino acids are associated with healthy livers in obesity.

High power generation of THz from 1550-nm photoconductive emitters.

Two photoconductive emitters - one with a self-complementary square spiral antenna, and the other with a resonant slot antenna - were fabricated on a GaAs epilayer embedded with ErAs quantum dots. Driven with 1550 nm mode-locked lasers, ~117 µW broadband THz power was generated from the device with the spiral antenna, and ~1.2 µW from the device with resonant slot antenna. The optical-to-THz conversion is through extrinsic photoconductivity.

Understanding CD30 biology and therapeutic targeting: a historical perspective providing insight into future directions.

CD30 is a member of the tumor necrosis factor receptor superfamily. It is characteristically expressed in certain hematopoietic malignancies, including anaplastic large cell lymphoma and Hodgkin lymphoma, among others. The variable expression of CD30 on both normal and malignant lymphoid cells has focused research efforts on understanding the pathogenesis of CD30 upregulation, its contribution to lymphomagenesis through anti-apoptotic mechanisms, and its effect on cell survival. Given the restriction of CD30 to certain tumor types, the logical extension of this has been to attempt to exploit it as a therapeutic target. The efficacy of naked anti-CD30 antibodies in practice was, however, modest. Moreover, combinations with bacterial toxins and radioimmunoconjugates have also had limited success. The development of the antibody-drug compound brentuximab vedotin (BV), however, has rejuvenated interest in CD30 as a tumor target. Phase I and II clinical trials in Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T cell lymphoma, and even CD30-expressing B-cell lymphomas, have shown the compound is well tolerated, but more importantly, able to deliver meaningful disease control even in patients with multiply relapsed or refractory disease. FDA approval has been granted for its use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. A recent phase III trial of BV in cutaneous T-cell lymphoma has confirmed its superiority to standard of care therapies. In this manuscript, we explore the history of CD30 as a tumor marker and as a therapeutic target, both in the laboratory and in the clinic, with a view to understanding future avenues for further study.

Morbidity and mortality associated with rewarming hypothermic very low birth weight infants.

OBJECTIVES: In very low birthweight (VLBW) infants, hypothermia is associated with poor outcomes. The goal of this study is to assess the relationship between the rate of rewarming these babies and their outcomes. METHODS: This is a retrospective cohort study of 98 inborn VLBW infants who were hypothermic (<36°C rectally) upon admission to the NICU. A logistic regression model was used to examine the relationship between the rates of rewarming and time to achieve euthermia and the following outcomes: death, intraventricular hemorrhage, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis and retinopathy of prematurity. RESULTS: Prolonged rewarming time was associate with increased odds of mortality (OR 1.273 95% CI 1.032-1.571). No associations between rewarming rates and any of the outcomes were seen. Once birthweight was included in a multiple logistic regression model, the association between mortality and rewarming time was no longer significant. Outcomes that were not associated with either rate or time of rewarming (even in a univariate model) were: bronchopulmonary dysplasia, intraventricular hemorrhage, severe intraventricular hemorrhage, necrotizing enterocolitis and retinopathy of prematurity. CONCLUSION: In moderately hypothermic VLBW infants, after accounting for birthweight, no association between rewarming and outcome is seen.

Electronic Enhancement of the Exciton Coherence Time in Charged Quantum Dots.

Minimizing decoherence due to coupling of a quantum system to its fluctuating environment is at the forefront of quantum information and photonics research. Nature sets the ultimate limit, however, given by the strength of the system's coupling to the electromagnetic field. Here, we establish the ability to electronically control this coupling and enhance the optical coherence time of the charged exciton transition in quantum dots embedded in a photonic waveguide. By manipulating the electronic wave functions through an applied lateral electric field, we increase the coherence time from ∼1.4 to ∼2.7 ns. Numerical calculations reveal that longer coherence arises from the separation of charge carriers by up to ∼6 nm, which leads to a 30% weaker transition dipole moment. The ability to electronically control the coherence time opens new avenues for quantum communication and novel coupling schemes between distant qubits.

Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma.

Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P<0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P=7.4 × 10(-12)) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.

Squamate hatchling size and the evolutionary causes of negative offspring size allometry.

Although fecundity selection is ubiquitous, in an overwhelming majority of animal lineages, small species produce smaller number of offspring per clutch. In this context, egg, hatchling and neonate sizes are absolutely larger, but smaller relative to adult body size in larger species. The evolutionary causes of this widespread phenomenon are not fully explored. The negative offspring size allometry can result from processes limiting maximal egg/offspring size forcing larger species to produce relatively smaller offspring ('upper limit'), or from a limit on minimal egg/offspring size forcing smaller species to produce relatively larger offspring ('lower limit'). Several reptile lineages have invariant clutch sizes, where females always lay either one or two eggs per clutch. These lineages offer an interesting perspective on the general evolutionary forces driving negative offspring size allometry, because an important selective factor, fecundity selection in a single clutch, is eliminated here. Under the upper limit hypotheses, large offspring should be selected against in lineages with invariant clutch sizes as well, and these lineages should therefore exhibit the same, or shallower, offspring size allometry as lineages with variable clutch size. On the other hand, the lower limit hypotheses would allow lineages with invariant clutch sizes to have steeper offspring size allometries. Using an extensive data set on the hatchling and female sizes of > 1800 species of squamates, we document that negative offspring size allometry is widespread in lizards and snakes with variable clutch sizes and that some lineages with invariant clutch sizes have unusually steep offspring size allometries. These findings suggest that the negative offspring size allometry is driven by a constraint on minimal offspring size, which scales with a negative allometry.

Monolithic device for modelocking and stabilization of frequency combs.

We demonstrate a device that integrates a III-V semiconductor saturable absorber mirror with a graphene electro-optic modulator, which provides a monolithic solution to modelocking and noise suppression in a frequency comb. The device offers a pure loss modulation bandwidth exceeding 5 MHz and only requires a low voltage driver. This hybrid device provides not only compactness and simplicity in laser cavity design, but also small insertion loss, compared to the previous metallic-mirror-based modulators. We believe this work paves the way to portable and fieldable phase-coherent frequency combs.