Giant Terahertz Birefringence in an Ultrathin Anisotropic Semimetal.

Manipulating the polarization of light at the nanoscale is key to the development of next-generation optoelectronic devices. This is typically done via waveplates using optically anisotropic crystals, with thicknesses on the order of the wavelength. Here, using a novel ultrafast electron-beam-based technique sensitive to transient near fields at THz frequencies, we observe a giant anisotropy in the linear optical response in the semimetal WTe2 and demonstrate that one can tune the THz polarization using a 50 nm thick film, acting as a broadband wave plate with thickness 3 orders of magnitude smaller than the wavelength. The observed circular deflections of the electron beam are consistent with simulations tracking the trajectory of the electron beam in the near field of the THz pulse. This finding offers a promising approach to enable atomically thin THz polarization control using anisotropic semimetals and defines new approaches for characterizing THz near-field optical response at far-subwavelength length scales.

Improved temporal resolution in ultrafast electron diffraction measurements through THz compression and time-stamping.

We present an experimental demonstration of ultrafast electron diffraction (UED) with THz-driven electron bunch compression and time-stamping that enables UED probes with improved temporal resolution. Through THz-driven longitudinal bunch compression, a compression factor of approximately four is achieved. Moreover, the time-of-arrival jitter between the compressed electron bunch and a pump laser pulse is suppressed by a factor of three. Simultaneously, the THz interaction imparts a transverse spatiotemporal correlation on the electron distribution, which we utilize to further enhance the precision of time-resolved UED measurements. We use this technique to probe single-crystal gold nanofilms and reveal transient oscillations in the THz near fields with a temporal resolution down to 50 fs. These oscillations were previously beyond reach in the absence of THz compression and time-stamping.

Psilocybin enhances insightfulness in meditation: a perspective on the global topology of brain imaging during meditation.

In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin.

Characterization and Determinants of Long-Term Immune Recovery Under Suppressive Antiretroviral Therapy.

OBJECTIVE: We developed a robust characterization of immune recovery trajectories in people living with HIV on antiretroviral treatment (ART) and relate our findings to epidemiological risk factors and bacterial pneumonia. METHODS: Using data from the Swiss HIV Cohort Study and the Zurich Primary HIV Infection Cohort Study (n = 5907), we analyzed the long-term trajectories of CD4 cell and CD8 cell counts and their ratio in people living with HIV on ART for at least 8 years by fitting nonlinear mixed-effects models. The determinants of long-term immune recovery were investigated using generalized additive models. In addition, prediction accuracy of the modeled trajectories and their impact on the fit of a model for bacterial pneumonia was assessed. RESULTS: Overall, our population showed good immune recovery (median plateau [interquartile range]-CD4: 718 [555-900] cells/µL, CD8: 709 [547-893] cells/µL, CD4/CD8: 1.01 [0.76-1.37]). The following factors were predictive of recovery: age, sex, nadir/zenith value, pre-ART HIV-1 viral load, hepatitis C, ethnicity, acquisition risk, and timing of ART initiation. The fitted models proved to be an accurate and efficient way of predicting future CD4 and CD8 cell recovery dynamics: Compared with carrying forward the last observation, mean squared errors of the fitted values were lower by 1.3%-18.3% across outcomes. When modeling future episodes of bacterial pneumonia, using predictors derived from the recovery dynamics improved most model fits. CONCLUSION: We described and validated a method to characterize individual immune recovery trajectories of people living with HIV on suppressive ART. These trajectories accurately predict long-term immune recovery and the occurrence of bacterial pneumonia.

Monitoring the Evolution of Relative Product Populations at Early Times during a Photochemical Reaction.

Identifying multiple rival reaction products and transient species formed during ultrafast photochemical reactions and determining their time-evolving relative populations are key steps toward understanding and predicting photochemical outcomes. Yet, most contemporary ultrafast studies struggle with clearly identifying and quantifying competing molecular structures/species among the emerging reaction products. Here, we show that mega-electronvolt ultrafast electron diffraction in combination with ab initio molecular dynamics calculations offer a powerful route to determining time-resolved populations of the various isomeric products formed after UV (266 nm) excitation of the five-membered heterocyclic molecule 2(5H)-thiophenone. This strategy provides experimental validation of the predicted high (∼50%) yield of an episulfide isomer containing a strained three-membered ring within ∼1 ps of photoexcitation and highlights the rapidity of interconversion between the rival highly vibrationally excited photoproducts in their ground electronic state.

The persistence of memory in ionic conduction probed by nonlinear optics.

Predicting practical rates of transport in condensed phases enables the rational design of materials, devices and processes. This is especially critical to developing low-carbon energy technologies such as rechargeable batteries1-3. For ionic conduction, the collective mechanisms4,5, variation of conductivity with timescales6-8 and confinement9,10, and ambiguity in the phononic origin of translation11,12, call for a direct probe of the fundamental steps of ionic diffusion: ion hops. However, such hops are rare-event large-amplitude translations, and are challenging to excite and detect. Here we use single-cycle terahertz pumps to impulsively trigger ionic hopping in battery solid electrolytes. This is visualized by an induced transient birefringence, enabling direct probing of anisotropy in ionic hopping on the picosecond timescale. The relaxation of the transient signal measures the decay of orientational memory, and the production of entropy in diffusion. We extend experimental results using in silico transient birefringence to identify vibrational attempt frequencies for ion hopping. Using nonlinear optical methods, we probe ion transport at its fastest limit, distinguish correlated conduction mechanisms from a true random walk at the atomic scale, and demonstrate the connection between activated transport and the thermodynamics of information.

Immune Monitoring-Guided Versus Fixed Duration of Antiviral Prophylaxis Against Cytomegalovirus in Solid-Organ Transplant Recipients: A Multicenter, Randomized Clinical Trial.

BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. METHODS: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection. CLINICAL TRIALS REGISTRATION: NCT02538172.

Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity.

Infection with Mycobacterium tuberculosis (MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood. In a cohort of individuals with HIV (PWH) with and without suppressed HIV-1 viral load, the transcriptomic profiles of peripheral blood mononuclear cells (PBMC) clustered in individuals infected with Mycobacterium tuberculosis (MTB) compared to carefully matched controls. Subsequent functional annotation analysis disclosed alterations in the IL-6, TNF, and KRAS pathways. Notably, MTB-associated genes demonstrated an inverse correlation with HIV-1 viremia, evident at both on individual gene level and when employed as a gene score. In sum, our data show that MTB infection in PWH is associated with a shift in the activation state of the immune system, displaying an inverse relationship with HIV-1 viral load. These results could provide an explanation for the observed increased antiretroviral control associated with MTB infection in PWH.

T-Cell Exhaustion in HIV-1/Hepatitis C Virus Coinfection Is Reduced After Successful Treatment of Chronic Hepatitis C.

Background: T-cell responses during chronic viral infections become exhausted, which is reflected by upregulation of inhibitory receptors (iRs) and increased interleukin 10 (IL-10). We assessed 2 iRs-PD-1 (programmed cell death protein 1) and Tim-3 (T-cell immunoglobulin and mucin domain-containing protein 3)-and IL-10 mRNAs in peripheral blood mononuclear cells (PBMCs) and their soluble analogs (sPD-1, sTim-3, and IL-10) in plasma in chronic HIV-1/hepatitis C virus (HCV) coinfection and explored the effect of HCV treatment on these markers. We also aimed to establish whether iR expression may be determined by the HCV CD8+ T-cell immunodominant epitope sequence. Methods: Plasma and PBMCs from 31 persons with chronic HIV-1/HCV coinfection from the Swiss HIV Cohort Study were collected before and after HCV treatment. As controls, 45 persons who were HIV-1 negative with chronic HCV infection were recruited. Exhaustion markers were assessed by enzyme-linked immunosorbent assay in plasma and by quantitative reverse transcription polymerase chain reaction in PBMCs. Analysis of an HCV epitope sequence was conducted by next-generation sequencing: HLA-A*02-restricted NS31073-1081 and NS31406-1415 and HLA-A*01-restricted NS31436-1444. Results: The study revealed higher plasma sPD-1 (P = .0235) and IL-10 (P = .002) levels and higher IL-10 mRNA in PBMCs (P = .0149) in HIV-1/HCV coinfection. A decrease in plasma sPD-1 (P = .0006), sTim-3 (P = .0136), and IL-10 (P = .0003) and Tim-3 mRNA in PBMCs (P = .0210) was observed following successful HCV treatment. Infection with the HLA-A*01-restricted NS31436-1444 ATDALMTGY prototype variant was related to higher sTim-3 levels than infection with the ATDALMTGF escape variant (P = .0326). Conclusions: The results underscore the synergistic effect of coinfection on expression of exhaustion markers, their reduction following successful HCV treatment and imply that iR levels may operate on an epitope-specific manner.

Femtosecond Electronic and Hydrogen Structural Dynamics in Ammonia Imaged with Ultrafast Electron Diffraction.

Directly imaging structural dynamics involving hydrogen atoms by ultrafast diffraction methods is complicated by their low scattering cross sections. Here we demonstrate that megaelectronvolt ultrafast electron diffraction is sufficiently sensitive to follow hydrogen dynamics in isolated molecules. In a study of the photodissociation of gas phase ammonia, we simultaneously observe signatures of the nuclear and corresponding electronic structure changes resulting from the dissociation dynamics in the time-dependent diffraction. Both assignments are confirmed by ab initio simulations of the photochemical dynamics and the resulting diffraction observable. While the temporal resolution of the experiment is insufficient to resolve the dissociation in time, our results represent an important step towards the observation of proton dynamics in real space and time.

Ultrafast X-Ray Scattering Reveals Composite Amplitude Collective Mode in the Weyl Charge Density Wave Material (TaSe_{4})_{2}I.

We report ultrafast x-ray scattering experiments of the quasi-1D charge density wave (CDW) material (TaSe_{4})_{2}I following ultrafast infrared photoexcitation. From the time-dependent diffraction signal at the CDW sidebands we identify a 0.11 THz amplitude mode derived primarily from a transverse acoustic mode of the high-symmetry structure. From our measurements we determine that this mode interacts with the valence charge indirectly through another collective mode, and that the CDW system in (TaSe_{4})_{2}I has a composite nature supporting multiple dynamically active structural degrees of freedom.

Complete Metabolic Response to Combined Immune Checkpoint Inhibition after Progression of Metastatic Colorectal Cancer on Pembrolizumab: A Case Report.

DNA mismatch repair deficient (dMMR) and microsatellite instable (MSI) metastatic colorectal cancer (mCRC) can be successfully treated with FDA- and EMA-approved immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab (as single agents targeting the anti-programmed cell death protein-1 (PD-1)) or combinations of a PD-1 inhibitor with ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-targeting antibody. The best treatment strategy beyond progression on single-agent ICI therapy remains unclear. Here, we present the case of a 63-year-old male with Lynch-syndrome-associated, microsatellite instability-high (MSI-H) mCRC who achieved a rapid normalization of his tumor markers and a complete metabolic remission (CMR), currently lasting for ten months, on sequential ICI treatment with the combination of nivolumab and ipilimumab followed by nivolumab maintenance therapy after progression on single-agent anti-PD-1 ICI therapy. The therapy was well-tolerated, and no immune-related adverse events occurred. To the best of our knowledge, this is the first case of a sustained metabolic complete remission in an MSI-H mCRC patient initially progressing on single-agent anti-PD-1 therapy. Thus, dMMR mCRC patients might benefit from sequential immune checkpoint regimens even with long-term responses. However, further sophistication of clinical algorithms for treatment beyond progression on single-agent ICI therapy in MSI-mCRC is urgently needed.

Understanding the Decline of Incident, Active Tuberculosis in People With Human Immunodeficiency Virus in Switzerland.

BACKGROUND: People with human immunodeficiency virus type 1 (HIV-1) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear. METHODS: We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures. RESULTS: In 21 528 PWH, LTBI prevalence declined from 15.1% in 2001% to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (hazard ratio [HR] 9.8, 5.8-16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease. CONCLUSIONS: TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need.

Successful use of extracorporeal life support and hemadsorption in the context of venlafaxine intoxication requiring cardiopulmonary resuscitation: a case report.

Venlafaxine is a serotonin and noradrenalin reuptake inhibitor prescribed as an antidepressant. Overdose clinically manifests with neurological, cardiovascular and gastrointestinal abnormalities based on, amongst others, serotonin syndrome and can be life-threatening due to cardiovascular collapse. Besides immediate decontamination via gastric lavage and inhibition of enteral absorption through active charcoal, successful hemadsorption with CytoSorb® has been reported. We present the case of a 17-year-old female who required extracorporeal life support (ECLS) for cardiovascular collapse as a result of life-threatening venlafaxine intoxication. Serial serum blood concentrations of venlafaxine/desmethylvenlafaxine on admission at a tertiary hospital (approx. 24 h after ingestion) and subsequently 6 h and 18 h thereafter, as well as on days 2 and 4, were measured. CytoSorb® was initiated 6 h after admission and changed three times over 72 h. The initial blood concentration of venlafaxine/desmethylvenlafaxine was 53.52 µmol/l. After 6 h, it declined to 30.7 µmol/l and CytoSorb® was initiated at this point. After 12 h of hemadsorption, the blood level decreased to 9.6 µmol/l. On day 2, it was down to 7.17 µmol/l and decreased further to 3.74 µmol/l. Additional continuous renal replacement therapy using CVVHD was implemented on day 5. The combination of hemadsorption, besides traditional decontamination strategies along maximal organ supportive therapy with ECLS, resulted in the intact neurological survival of the highest venlafaxine intoxication reported in the literature to date. Hemadsorption with CytoSorb® might help to reduce blood serum levels of venlafaxine. Swift clearance of toxic blood levels may support cardiovascular recovery after life-threatening intoxications.

Terahertz-Driven Local Dipolar Correlation in a Quantum Paraelectric.

Light-induced ferroelectricity in quantum paraelectrics is a new avenue of achieving dynamic stabilization of hidden orders in quantum materials. In this Letter, we explore the possibility of driving a transient ferroelectric phase in the quantum paraelectric KTaO_{3} via intense terahertz excitation of the soft mode. We observe a long-lived relaxation in the terahertz-driven second harmonic generation (SHG) signal that lasts up to 20 ps at 10 K, which may be attributed to light-induced ferroelectricity. Through analyzing the terahertz-induced coherent soft-mode oscillation and finding its hardening with fluence well described by a single-well potential, we demonstrate that intense terahertz pulses up to 500 kV/cm cannot drive a global ferroelectric phase in KTaO_{3}. Instead, we find the unusual long-lived relaxation of the SHG signal comes from a terahertz-driven moderate dipolar correlation between the defect-induced local polar structures. We discuss the impact of our findings on current investigations of the terahertz-induced ferroelectric phase in quantum paraelectrics.

Ultrafast Optomechanical Strain in Layered GeS.

Strong coupling between light and mechanical strain forms the foundation for next-generation optical micro- and nano-electromechanical systems. Such optomechanical responses in two-dimensional materials present novel types of functionalities arising from the weak van der Waals bond between atomic layers. Here, by using structure-sensitive megaelectronvolt ultrafast electron diffraction, we report the experimental observation of optically driven ultrafast in-plane strain in the layered group IV monochalcogenide germanium sulfide (GeS). Surprisingly, the photoinduced structural deformation exhibits strain amplitudes of order 0.1% with a 10 ps fast response time and a significant in-plane anisotropy between zigzag and armchair crystallographic directions. Rather than arising due to heating, experimental and theoretical investigations suggest deformation potentials caused by electronic density redistribution and converse piezoelectric effects generated by photoinduced electric fields are the dominant contributors to the observed dynamic anisotropic strains. Our observations define new avenues for ultrafast optomechanical control and strain engineering within functional devices.

CD4:CD8 Ratio and CD8 Cell Count and Their Prognostic Relevance for Coronary Heart Disease Events and Stroke in Antiretroviral Treated Individuals: The Swiss HIV Cohort Study.

INTRODUCTION: HIV infection leads to a persistent expansion of terminally CD8 T cells and CD8 T suppressor cells, a marker of chronic immune activation leading to a low CD4:CD8 ratio that may persist in the presence of potent antiretroviral therapy and regained CD4 helper cells. It remains unclear whether a low CD4:CD8 ratio is associated with cardiovascular diseases. METHODS: We conducted an observational cohort study to investigate the association of immune depression and activation as characterized by the proxy of the CD4:CD8 ratio on the hazard of coronary heart disease (CHD) and stroke among treated individuals living with HIV, while accounting for viral load and known risk factors for cardiovascular diseases and exposure to abacavir or protease inhibitors. We used Cox proportional hazard models with time-dependent cumulative and lagged exposures to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4, CD8, and CD4:CD8 immunological markers were not associated with an increased hazard for CHD. CD8 cell count lagged at 12 months above 1000 cells per µL increased the hazard of stroke, after adjusting for sociodemographics, cardiovascular risk factors, and exposure to specific types of antiretroviral drugs. CONCLUSIONS: This analysis of treated HIV-positive individuals within a large cohort with long-term follow-up does not provide evidence for a prognostic role of immune dysregulation regarding CHD. However, increased CD8 cell count may be a moderate risk factor for stroke. Early detection and treatment of HIV-positive individuals are crucial for an optimal immune restoration and a limited CD8 cells expansion.