Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Functional electronic inversion layers at ferroelectric domain walls.

Ferroelectric domain walls hold great promise as functional two-dimensional materials because of their unusual electronic properties. Particularly intriguing are the so-called charged walls where a polarity mismatch causes local, diverging electrostatic potentials requiring charge compensation and hence a change in the electronic structure. These walls can exhibit significantly enhanced conductivity and serve as a circuit path. The development of all-domain-wall devices, however, also requires walls with controllable output to emulate electronic nano-components such as diodes and transistors. Here we demonstrate electric-field control of the electronic transport at ferroelectric domain walls. We reversibly switch from resistive to conductive behaviour at charged walls in semiconducting ErMnO3. We relate the transition to the formation-and eventual activation-of an inversion layer that acts as the channel for the charge transport. The findings provide new insight into the domain-wall physics in ferroelectrics and foreshadow the possibility to design elementary digital devices for all-domain-wall circuitry.

Electron Accumulation and Emergent Magnetism in LaMnO_{3}/SrTiO_{3} Heterostructures.

Emergent phenomena at polar-nonpolar oxide interfaces have been studied intensely in pursuit of next-generation oxide electronics and spintronics. Here we report the disentanglement of critical thicknesses for electron reconstruction and the emergence of ferromagnetism in polar-mismatched LaMnO_{3}/SrTiO_{3} (001) heterostructures. Using a combination of element-specific x-ray absorption spectroscopy and dichroism, and first-principles calculations, interfacial electron accumulation, and ferromagnetism have been observed within the polar, antiferromagnetic insulator LaMnO_{3}. Our results show that the critical thickness for the onset of electron accumulation is as thin as 2 unit cells (UC), significantly thinner than the observed critical thickness for ferromagnetism of 5 UC. The absence of ferromagnetism below 5 UC is likely induced by electron overaccumulation. In turn, by controlling the doping of the LaMnO_{3}, we are able to neutralize the excessive electrons from the polar mismatch in ultrathin LaMnO_{3} films and thus enable ferromagnetism in films as thin as 3 UC, extending the limits of our ability to synthesize and tailor emergent phenomena at interfaces and demonstrating manipulation of the electronic and magnetic structures of materials at the shortest length scales.

Nature of the metal insulator transition in ultrathin epitaxial vanadium dioxide.

We have combined hard X-ray photoelectron spectroscopy with angular dependent O K-edge and V L-edge X-ray absorption spectroscopy to study the electronic structure of metallic and insulating end point phases in 4.1 nm thick (14 units cells along the c-axis of VO2) films on TiO2(001) substrates, each displaying an abrupt MIT centered at ~300 K with width <20 K and a resistance change of ΔR/R > 10(3). The dimensions, quality of the films, and stoichiometry were confirmed by a combination of scanning transmission electron microscopy with electron energy loss spectroscopy, X-ray spectroscopy, and resistivity measurements. The measured end point phases agree with their bulk counterparts. This clearly shows that, apart from the strain induced change in transition temperature, the underlying mechanism of the MIT for technologically relevant dimensions must be the same as the bulk for this orientation.

Utility of peripheral blood B cell subsets analysis in common variable immunodeficiency.

Abnormalities in peripheral blood B cell subsets have been identified in common variable immunodeficiency (CVID) patients and classification systems based upon their numbers have been proposed to predict the clinical features. We analysed B lymphocyte subsets by multi-colour flow cytometry (MFC) in a cohort of well-characterized CVID patients to look at their clinical relevance and validate the published association of different classification criteria (Freiburg, Paris and Euroclass) with clinical manifestations. CVID patients had a reduced proportion of total and switched memory B cells (MBC, swMBC) compared to normal controls (P < 0·0006). Patients classified in Freiburg Ia had a higher prevalence of granulomatous diseases (P = 0·0034). The previously published associations with autoimmune diseases could not be confirmed. The Euroclass classification was not predictive of clinical phenotypes. The absolute numbers of all B cell subsets were reduced in CVID patients compared to controls. There was a significant linear correlation between low absolute total B cells and MBC with granulomatous disease (P < 0·05) and a trend towards lower B cells in patients with autoimmune diseases (P = 0·07). Absolute number of different B cell subsets may be more meaningful than their relative percentages in assessing the risk of granulomatous diseases and possibly autoimmunity.

Short term outcomes after cardiac surgery in a Jehovah's Witness population: an institutional experience.

BACKGROUND: Minimising blood transfusion has a number of medical and logistical benefits, and is of particular importance for followers of the Jehovah's Witness faith. We examined the short term outcomes in this group of patients based on our institutional practice over the past decade. PATIENTS/METHODS: Data on 59 patients (73% male, mean age 66 years [range 40-83]) who identified as Jehovah's Witness was prospectively collected and retrospectively analysed from a systematised database over the period from January 1999 to June 2010. Mean logistic Euroscore was 4.5, with coronary artery bypass procedures most common (44/59, 75%) followed by aortic valve replacement (6/59, 10%). RESULTS: Average haemoglobin (Hb) fell from 142 g/L preoperatively to 109 g/L at discharge. Output from cardiac drains was reduced in patients who received aprotinin (34/59, 58%, p=0.05) compared to tranexaemic acid (11/59, 18%) or no antifibrinolytic (15/59, 25%). Operative mortality was 1/59 (1.7%) with an average length of postoperative stay of 6.2 days. Morbidity rates for neurologic deficit 2/59 (3.4%), deep sternal infection 1/59 (1.7%) and postoperative myocardial infarction 1/59 (1.7%) were within accepted ranges. CONCLUSION: Cardiac surgery can be performed safely in Jehovah's Witness patients with acceptable outcomes.

Fabrication and design of metal nano-accordion structures using atomic layer deposition and interference lithography.

Metal nanostructures have attractive electrical and thermal properties as well as structural stability, and are important for applications in flexible conductors. In this study, we have developed a method to fabricate and control novel complex platinum nanostructures with accordion-like profile using atomic layer deposition on lithographically patterned polymer templates. The template removal process results in unique structural transformation of the nanostructure profile, which has been studied and modeled. Using different template duty cycles and aspect ratios, we have demonstrated a wide variety of cross-sectional profiles from wavy geometry to pipe array patterns. These complex thin metal nanostructures can find applications in flexible/stretchable electronics, photonics and nanofluidics.

Biochemical and genetic characterization of three molybdenum cofactor hydroxylases in Arabidopsis thaliana.

Aldehyde oxidases and xanthine dehydrogenases/oxidases belong to the molybdenum cofactor dependent hydroxylase class of enzymes. Zymograms show that Arabidopsis thaliana has at least three different aldehyde oxidases and one xanthine oxidase. Three different cDNA clones encoding putative aldehyde oxidases (AtAO1, 2, 3) were isolated. An aldehyde oxidase is the last step in abscisic acid (ABA) biosynthesis. AtAO1 is mainly expressed in seeds and roots which might reflect that it is involved in ABA biosynthesis.

Fragmentations and reactions of the organophosphate insecticide Diazinon and its oxygen analog Diazoxon studied by electrospray ionization ion trap mass spectrometry.

The fragmentations and reactions of Diazinon and related compounds have been studied by electrospray ionization ion trap mass spectrometry. Several novel fragmentation and rearrangements have been observed, including an intramolecular thiono-thiolo rearrangement. The stability, in the gas-phase, of the protomers of 2-isopropyl-4-methyl-6-pyrimidinol has been demonstrated. The complexity of the gas phase ion processes observed suggest that, at present, caution should be exercised in using this approach for the analysis of environmental and other samples until our understanding of these processes increases considerably.

An improved colorimetric assay for T cell cytotoxicity in vitro.

An improved colorimetric assay for estimation of cytotoxic T (Tc) cells is described. The method involves staining thioglycollate-induced macrophage targets with the dye neutral red prior to addition of cytotoxic T cells and estimating macrophage survival at the end of the assay by measuring dye remaining in viable targets. The method using macrophage targets is more sensitive than the 51Cr release assay employing macrophages or a variety of other targets. It may be used to detect alloreactive and H-2 restricted Tc cells in both short-term (4 h) and long-term (24 h) assays and overcomes some variability encountered with a previously described colorimetric procedure. Furthermore, the method is cheap, fast, reliable and avoids the use of radioactivity.

A prospective randomized study of prophylactic OKT3 versus equine antithymocyte globulin after heart transplantation--increased morbidity with OKT3.

The aim of this study was to compare the efficacy and toxicity of prophylactic OKT3 and equine antithymocyte globulin when each drug was administered for a similar duration after heart transplantation. Forty-one patients (35 males, 6 females; mean age 46 +/- 2 years) were randomized to receive either OKT3 for 10 days (20 patients) commencing within 24-48 hr of transplantation or ATGAM for 8 days (21 patients) commencing on the day of transplantation. All patients were maintained on triple-agent immunosuppression with prednisolone, azathioprine, and cyclosporine. The two groups were well matched with respect to age, sex distribution, pretransplant cardiac diagnosis, and donor heart ischemic time. Mean duration of follow-up was 14 months (range 9-19 months): Actuarial survival at 12 months was 83 +/- 9 in the OKT3 group and 81 +/- 9 in the ATG group (P = NS). Mean time to first cardiac rejection was 33 +/- 8 days in the OKT3 group compared with 27 +/- 5 days in the ATG group (P = NS). Linearized rejection rate did not differ between the two groups at any time point up to 12 months posttransplant. Viral infections were significantly more common in the OKT3 group: 1.6 +/- 0.3 vs. 0.8 +/- 0.2 infections per patient (P < 0.05). Adverse reactions were more common in patients who received OKT3 prophylaxis and included three patients who developed acute respiratory distress, two of whom required assisted ventilation. In conclusion, prophylactic OKT3 and ATGAM result in comparable rejection rates and survival when administered for a similar duration after cardiac transplantation. OKT3, however, is associated with increased morbidity due to a higher incidence of adverse reactions and of viral infections. These findings suggest that ATGAM is the more suitable cytolytic agent for rejection prophylaxis after heart transplantation.

Cardioprotective effects of pinacidil pretreatment and lazaroid (U74500A) preservation in isolated rat hearts after 12-hour hypothermic storage.

BACKGROUND: Two important processes in the preservation of the function of donor hearts are the maintenance of ATP-sensitive potassium channel activity during myocardial ischemia and the scavenging of reactive oxygen species formed during reperfusion. The aim of this study was to compare the effect of three protocols on the preservation of hemodynamic function in isolated rat hearts after hypothermic storage. These protocols were: (1) pretreatment of the heart with a potassium channel opener (200 microM pinacidil); (2) storage of the heart in an aspartate-enriched extracellular cardioplegic solution containing the lazaroid antioxidant, U74500A (30 microM); and (3) a combination of protocols 1 and 2. METHODS: Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, coronary and aortic flow, and cardiac output were performed. Hearts (n=6 in each group) were then randomized to protocols 1-3, untreated controls, or vehicle-treated controls. Hearts were stored in extracellular-based preservation solution for 12 hr at 2-3 degrees C, remounted on the perfusion apparatus, and stabilized as before; hemodynamic measurements were then repeated. RESULTS: Recovery of hemodynamic function was enhanced by pinacidil pretreatment or incorporation of lazaroid in the storage solution, but the combination of these two treatments produced the best results. CONCLUSIONS: Combined pharmacological activation of ATP-sensitive potassium channels before cardioplegia and the addition of U74500A to the preservation solution is associated with significantly enhanced hemodynamic function in the isolated rat heart after 12 hr of hypothermic storage. These data suggest a novel use for these agents in the transplantation context.

Urinary nitrate excretion is a noninvasive indicator of acute cardiac allograft rejection and nitric oxide production in the rat.

Cytokine induction of calcium-independent nitric oxide synthase is associated with production of large amounts of nitric oxide (NO). NO is a free radical that is rapidly degraded to nitrite and nitrate. Measurement of plasma and urinary nitrate is an indirect marker of NO production and previous studies have demonstrated that plasma nitrate rises with allograft rejection. The purpose of this study was to examine the temporal relationship between the rise in urinary nitrate excretion and the onset of graft rejection, and to determine the effect of conventional immunosuppression on nitrate excretion. The heterotropic model of cardiac transplantation in the rat was used, with Brown-Norway to Lewis allografts and Lewis to Lewis isograft controls. Twenty-four-hour urine specimens were collected before and after transplantation. Urinary nitrate excretion was measured by gas chromatography/mass spectrometry. Each group was treated with (1) no immunosuppression, (2) dexamethasone (3 mg/kg), or (3) CsA (10 mg/kg) on days 0, 1, and 2. Time to rejection for untreated allografts was 5.1 +/- 0.1 days, extending to 8.4 +/- 0.5 and 9.6 +/- 0.4 days with dexamethasone and CsA treatment, respectively. There was a significant rise in nitrate excretion on days 4, 7, and 9 for control, dexamethasone-treated, and CsA-treated allografts, respectively, preceding evidence of rejection. Untreated allograft rejection was associated with a peak in nitrate excretion 8 times that of basal excretion by isografts. Treatment of the allografts with dexamethasone and CsA significantly attenuated peak nitrate excretion compared with untreated allografts with a only a 2- to 3-fold rise preceding rejection. Results indicate that allograft rejection is associated with a dramatic increase in peak urinary nitrate excretion that is attenuated by standard immunosuppressive therapy. An increase in nitrate excretion precedes evidence of graft rejection, and may serve as a noninvasive marker of graft rejection.

Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation.

Prior studies of cardiac transplant recipients have shown that pravastatin reduces 12-month rejection and mortality after cardiac transplantation and simvastatin reduces 4-year mortality, low-density lipoprotein (LDL) cholesterol levels, and intimal thickening. In a 12-month observational study, cardiac transplant recipients received open-label pravastatin 40 mg (n = 42) or simvastatin 20 mg daily (n = 45) on an alternating basis from the time of transplantation. Lipid levels, safety, and post-transplant outcomes were compared. We found no significant differences in total LDL or high-density lipoprotein cholesterol, triglycerides, linearized infection or rejection rates, liver function tests, or immunosuppressant dosages between groups at 1, 3, 6, or 12 months. Rhabdomyolysis or myositis occurred only in patients on simvastatin (n = 6, 13.3%) with no episodes for patients on pravastatin (p = 0. 032). Survival at 12 months on an actual treatment basis was 97.6% for patients on pravastatin and 83.7% for those on simvastatin (p = 0.078). Immunosuppression-related deaths occurred in only 2.4% (1 patient) on pravastatin vs 15.6% (n = 7) on simvastatin (p = 0.06). Pravastatin and simvastatin resulted in comparable lipid profiles. Pravastatin use was however free from the high rates of rhabdomyolysis and myositis seen with simvastatin use. Pravastatin was additionally associated with a trend toward superior survival, attributable to fewer immunosuppression-related deaths. For safety and pharmacokinetic reasons, pravastatin should be considered the statin of choice after heart transplantation.

Initial steroid-free versus steroid-based maintenance therapy and steroid withdrawal after heart transplantation: two views of the steroid question.

To determine any benefit of maintenance steroids in a cyclosporine and azathioprine immunosuppressive regimen, 112 heart transplant recipients were prospectively randomized to receive cyclosporine, azathioprine, and prednisolone (n = 59) or cyclosporine and azathioprine (n = 53). Of the 53 double-therapy patients, 47% were converted to maintenance steroids for resistant rejection or renal dysfunction. In a comparison of true double-therapy (n = 28) versus true triple-therapy (n = 59) groups, actuarial survival and systolic function did not differ. Linearized rejection during the first 3 months was lower with triple therapy than with double therapy (1.5 +/- 0.18 vs 2.3 +/- 0.23 episodes/100 patient-days; p less than 0.01) as were requirements for cytolytic therapy for rejection with hemodynamic compromise. Patients receiving triple therapy had significantly higher serum cholesterol levels and antihypertensive agent requirements at all annual time points up to 5 years. The rate of steroid-related morbidity (diabetes, bone complications, cataracts, and obesity) was low in both groups and did not differ significantly. Of the 204 patients receiving triple therapy at this unit, 45 underwent steroid withdrawal. The initial success rate was 69%, and an additional 14% of those who initially failed succeeded on the second attempt. Any rejection after steroid cessation tended to occur within 6 weeks. There were, however, no substantial short-term benefits in body weight or lipid or blood pressure control. In patients in whom infection or growth retardation was an indication for steroid withdrawal, these generally improved after cessation. Until predictive markers for the likely success of steroid withdrawal are identified, the case for steroid withdrawal, as opposed to steroid minimization, does not seem compelling.

Five-year follow-up of a randomized double-drug versus triple-drug therapy immunosuppressive trial after heart transplantation.

To determine the role of maintenance steroids in a cyclosporine and azathioprine immunosuppressive regimen, 112 heart transplant recipients were prospectively randomized to group I (n = 59; cyclosporine, azathioprine, and prednisolone) or group II (n = 53; cyclosporine and azathioprine). All patients received 7 days of induction with antithymocyte globulin. Patients receiving double-drug therapy who required four treatments for rejection were converted to maintenance steroids. This was necessary in 47% of the patients. Actuarial survival at 5 years was 82% in group I and 85% in group II. Linearized rejection in the first 3 months was lower with triple-drug therapy than with double-drug therapy (1.5 +/- 0.18 versus 2.3 +/- 0.23 episodes/100 patient days, p less than 0.01) but did not differ beyond 3 months. No significant differences were noted in 3-year left ventricular ejection fraction (0.56 +/- 0.09 versus 0.58 +/- 0.12 units), serum creatinine level (0.14 +/- 0.04 versus 0.14 +/- 0.03 mmol/L), or number with coronary artery disease (10 versus 13), diabetes, or bone complications. Patients receiving triple-drug therapy, however, had higher serum cholesterol level at 3 years (6.2 +/- 0.9 versus 5.4 +/- 1.2 mmol/L; p = 0.022) and required more antihypertensive agents (1.3 +/- 0.8 versus 0.8 +/- 0.6; p = 0.016). Similar trends emerged when patients receiving true double-drug therapy were compared with those patients who were "converted." Therapy with double versus triple immunosuppressive therapy results in similar 5-year survival and systolic function, using this protocol of converting recurrent rejectors on double-drug therapy to maintenance steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical heart transplantation. Total lymphoid irradiation for resistant rejection after heart transplantation: only moderate success medium-term.

Total lymphoid irradiation (640 cGy) was given to 19 heart and 1 heart-lung recipients on maintenance triple therapy at a mean of 4.9 +/- 4 months after transplantation (range 46 to 519 days). Mean number of treated rejection episodes before, during, and after total lymphoid irradiation was 6.4 +/- 1.7, 0.8 +/- 1.2, and 1.2 +/- 1.3 episodes per patient, respectively. During total lymphoid irradiation, 37% had at least one episode of rejection requiring treatment; after total lymphoid irradiation, 42% had no further rejection episodes, 21% had one further episode, and 37% had 2 or more episodes. Metastatic squamous cell carcinoma in one patient and coronary artery disease in three of five patients studied to date is of concern and requires longer follow-up.

Adjunctive use of inhaled nitric oxide during implantation of a left ventricular assist device.

BACKGROUND: The aim of this study was to evaluate the efficacy of inhaled nitric oxide in the prevention and reversal of pulmonary hypertension during and after left ventricular assist device implantation. METHODS: Inhaled nitric oxide (20 ppm) was administered to seven consecutive patients undergoing implantation of a left ventricular assist device at the time of implantation and for the first 24 hours after operation. RESULTS: Withdrawal of inhaled nitric oxide at 24 hours after operation was associated with a significant rise in both the transpulmonary gradient (from 8+/-1 to 14+/-2 mm Hg, p < 0.01) and in pulmonary vascular resistance (from 110+/-19 to 196+/-32 dynes x sec x cm[-5], p < 0.01). In two patients, the rise in pulmonary vascular resistance resulted in a critical fall in left ventricular assist device flow and hemodynamic deterioration, necessitating urgent reinstitution of inhaled nitric oxide. CONCLUSION: The administration of inhaled nitric oxide at the time of left ventricular assist device implantation prevents rises in pulmonary vascular resistance that in some patients result in critical reductions in left ventricular assist device flow. We suggest that inhaled nitric oxide is a useful adjunctive treatment that should be routinely available at the time of left ventricular assist device implantation.

Immune reconstitution following peripheral blood stem cell transplantation, autologous bone marrow transplantation and allogeneic bone marrow transplantation.

The rate and pattern of recovery of total lymphocytes, T cell subsets, B cells and NK cells were compared for 12 months following recovery phase peripheral blood stem cell (PBSC) autotransplantation (n = 49), autologous (n = 7) and allogeneic BMT (n = 11). The PBSC group had a significantly faster recovery of total lymphocyte count, total T cells (CD3+ cells), CD8 cells and CD4 cells than the allogeneic BMT group. The pattern of earlier recovery of CD8 cells than CD4 cells was the same for each type of transplant. Reconstitution following autologous BMT was intermediate between PBSC and allogeneic BMT. Multivariate analysis identified type of transplant, number of mononuclear cells transplanted and conditioning regimen as significantly influencing immune recovery.

Gut protection by cyclophosphamide "priming" in patients receiving high-dose melphalan--effect of drug scheduling.

A "priming" injection of cyclophosphamide (400 mg/m2 given i.v. on day -7) has been shown to reduce intestinal permeability and thus gut toxicity in patients receiving high-dose melphalan. To determine the optimal timing for this injection, patients receiving 200 mg/m2 melphalan with an autologous bone marrow transplant were randomly assigned to receive cyclophosphamide at 5, 7 or 9 days before the melphalan. The median percentage of [51Cr]-ethylenediaminetetraacetic acid excretion was similar (9.1% vs 7.1% vs 7.7%, respectively), with equivalent duration of WHO grade 2-4 mucositis and diarrhoea being recorded for each group. Thus, the timing of the cyclophosphamide prime is not critical, and the priming injection may be given between 5 and 9 days prior to high-dose melphalan.