Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts.

Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h2SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h2SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.

Comorbidities and outcomes in South Asian individuals with chronic kidney disease: an observational primary care cohort.

BACKGROUND: South Asian (SA) individuals are more likely to develop end-stage renal disease (ESRD), but how chronic kidney disease (CKD) differs in relation to demographics, comorbidities and outcomes has not been studied. We aimed to study differences in SA individuals with CKD compared with White individuals. METHODS: This was an observational CKD cohort comparing SA with White individuals. Inclusion criteria were ≥18 years of age and two or more Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRs <60 mL/min/1.73 m2 >3 months apart. Individuals with ESRD at baseline were excluded. Baseline characteristics, including eGFR formulae [CKD-EPI and CKD-EPI-Pakistan (CKD-EPI-PK)], were compared. Analysis using competing risk regression for cardiovascular (CV) and ESRD events and Cox proportional hazard model for mortality was performed. RESULTS: From an adult population of 277 248 individuals, 17 248 individuals had CKD, of whom 1990 (11.5%) were of SA ethnicity. Age-adjusted prevalence of CKD was similar between ethnicities. SA individuals were more likely to be male, younger and socioeconomically deprived, and to have diabetes mellitus, CV disease and advanced CKD. Mean CKD-EPI-PK eGFR was 6.5 mL/min/1.73 m2 lower (41.1 versus 47.6, 95% confidence interval for difference 6.47-6.56) than for CKD-EPI. During 5 years of follow-up, 5109 (29.6%) individuals died, 2072 (12.0%) had a CV and 156 (0.90%) an ESRD event. Risk for SA individuals was higher for ESRD, similar to CV events and lower for mortality. Each 1 mL/min/1.73 m2 decrease in CKD-EPI-PK was associated with a 13.1% increased ESRD risk (adjusted subdistribution hazard ratio 0.869, 95% confidence interval 0.841-0.898). CONCLUSIONS: SA individuals with CKD were younger and had more advanced disease than White individuals. Risk of ESRD was higher and CKD-EPI-PK was associated with ESRD risk in SA individuals. Specific CKD interventions, including the use of CKD-EPI-PK, should be considered in SA populations.

Correction: The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1002955.].

Controllable duration and repetition-rate picosecond pulses from a high-average-power OP-GaAs OPO.

We report an orientation-patterned gallium arsenide (OP-GaAs) optical parametric oscillator (OPO) offering a high degree of temporal flexibility with controllable pulse repetition rates from 100 MHz to 1 GHz and pulse durations from ∼95 ps to ∼1.1 ns. The maximum average power of 9.2-W signal (3.3 µm) and 4.5-W idler (4.9 µm) was obtained at a repetition rate of 100 MHz and a pulse duration of ∼95 ps, with a pump power of 34.3 W and at a slope efficiency of 45.4%. The corresponding total average output power of 13.7 W is the highest power achieved to date from an OP-GaAs OPO, to the best of our knowledge.

High-average-power picosecond mid-infrared OP-GaAs OPO.

We report a high-average-power mid-infrared picosecond (ps) optical parametric oscillator (OPO) based on orientation-patterned gallium arsenide (OP-GaAs), with wide wavelength tunability. The OP-GaAs OPO is synchronously pumped by a thulium-doped-fiber (TDF) master oscillator power amplifier (MOPA), seeded by a gain-switched laser diode. At a pump power of 35.3 W and a repetition rate of 100 MHz, a maximum OPO total average output power of 9.7 W (signal 5.7 W (0.60 kW peak power), idler 4.0 W (0.42 kW peak power)) is obtained at signal and idler wavelengths of 3093 nm and 5598 nm, and a thermally induced power roll-off is observed. To mitigate the thermal effects, an optical chopper is placed before the OPO to provide burst mode operation and a reduced thermal load. We achieved a linear growth in OPO output power over the full range of available pump powers in this instance confirming thermal effects as the origin of the roll-off observed under continuous pumping. We estimate the maximum peak powers of the signal and idler are estimated to be over 0.79 kW and 0.58 kW, respectively in this instance. A wide mid-infrared wavelength tuning range of 2895-3342 nm (signal) and 4935-6389 nm (idler) is demonstrated.

The Primary-Secondary Care Partnership to Improve Outcomes in Chronic Kidney Disease (PSP-CKD) Study: A Cluster Randomized Trial in Primary Care.

BACKGROUND: Most patients with CKD are managed in the community. Whether nurse-led CKD management programs improve outcomes in patients with CKD in primary care is unclear. METHODS: To assess the effect of such a program on the rate of renal function decline in patients with CKD (stages 3-5) in primary care in the United Kingdom, we conducted a cluster randomized trial, the Primary-Secondary Care Partnership to Improve Outcomes in Chronic Kidney Disease study. A software program designed for the study created a data file of patients with CKD in participating practices. In 23 intervention practices (11,651 patients), a CKD nurse practitioner worked with nominated practice leads to interpret the data file and implement guideline-based patient-level CKD management interventions. The 23 control practices (11,706 patients) received a data file but otherwise, continued usual CKD care. The primary outcome was defined at the cluster (practice) level as the change from baseline of the mean eGFR of the patients with CKD at 6-month intervals up to 42 months. Secondary outcomes included numbers of patients coded for CKD, mean BP, numbers of patients achieving National Institute for Health and Care Excellence BP targets for CKD, and proteinuria measurement. RESULTS: After 42 months, eGFR did not differ significantly between control and intervention groups. CKD- and proteinuria-related coding improved significantly along with the number of patients achieving BP targets in the intervention group versus usual care. CONCLUSIONS: CKD management programs in primary care may not slow progression of CKD, but they may significantly improve processes of care and potentially decrease the cardiovascular disease burden in CKD and related costs.

The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study.

BACKGROUND: The Kidney Failure Risk Equation (KFRE) uses the 4 variables of age, sex, urine albumin-to-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR) in individuals with chronic kidney disease (CKD) to predict the risk of end stage renal disease (ESRD), i.e., the need for dialysis or a kidney transplant, within 2 and 5 years. Currently, national guideline writers in the UK and other countries are evaluating the role of the KFRE in renal referrals from primary care to secondary care, but the KFRE has had limited external validation in primary care. The study's objectives were therefore to externally validate the KFRE's prediction of ESRD events in primary care, perform model recalibration if necessary, and assess its projected impact on referral rates to secondary care renal services. METHODS AND FINDINGS: Individuals with 2 or more Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR values < 60 ml/min/1.73 m2 more than 90 days apart and a urine ACR or protein-to-creatinine ratio measurement between 1 December 2004 and 1 November 2016 were included in the cohort. The cohort included 35,539 (5.6%) individuals (57.5% female, mean age 75.9 years, median CKD-EPI eGFR 51 ml/min/1.73 m2, median ACR 3.2 mg/mmol) from a total adult practice population of 630,504. Overall, 176 (0.50%) and 429 (1.21%) ESRD events occurred within 2 and 5 years, respectively. Median length of follow-up was 4.7 years (IQR 2.8 to 6.6). Model discrimination was excellent for both 2-year (C-statistic 0.932, 95% CI 0.909 to 0.954) and 5-year (C-statistic 0.924, 95% 0.909 to 0.938) ESRD prediction. The KFRE overpredicted risk in lower (<20%) risk groups. Reducing the model's baseline risk improved calibration for both 2- and 5-year risk for lower risk groups, but led to some underprediction of risk in higher risk groups. Compared to current criteria, using referral criteria based on a KFRE-calculated 5-year ESRD risk of ≥5% and/or an ACR of ≥70 mg/mmol reduced the number of individuals eligible for referral who did not develop ESRD, increased the likelihood of referral eligibility in those who did develop ESRD, and referred the latter at a younger age and with a higher eGFR. The main limitation of the current study is that the cohort is from one region of the UK and therefore may not be representative of primary care CKD care in other countries. CONCLUSIONS: In this cohort, the recalibrated KFRE accurately predicted the risk of ESRD at 2 and 5 years in primary care. Its introduction into primary care for referrals to secondary care renal services may lead to a reduction in unnecessary referrals, and earlier referrals in those who go on to develop ESRD. However, further validation studies in more diverse cohorts of the clinical impact projections and suggested referral criteria are required before the latter can be clinically implemented.

Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin.

In nearly every species examined, administration of the persistent environmental pollutant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD) causes profound immune suppression and thymic atrophy in an aryl hydrocarbon receptor (AhR) dependent manner. Moreover, TCDD alters the development and differentiation of thymocytes, resulting in decreases in the relative proportion and absolute number of double positive (DP, CD4+CD8+) thymocytes, as well as a relative enrichment in the relative proportion and absolute number of double negative (DN, CD4-CD8-) and single-positive (SP) CD4+CD8- and CD4-CD8+ thymocytes. Previous studies suggested that the target for TCDD-induced thymic atrophy resides within the hemopoietic compartment and implicated apoptosis, proliferation arrest of thymic progenitors, and emigration of DN thymocytes to the periphery as potential contributors to TCDD-induced thymic atrophy. However, the precise cellular and molecular mechanisms involved remain largely unknown. Our results show that administration of 10 µg/kg TCDD and 8 mg/kg 2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE) induced AhR-dependent thymic atrophy in mice on day 7, whereas 100 mg/kg indole 3-carbinol (I3C) did not. Though our studies demonstrate that TCDD triggers a twofold increase in the frequency of apoptotic thymocytes, TCDD-induced thymic atrophy is not dependent on Fas-FasL interactions, and thus, enhanced apoptosis is unlikely to be a major mechanistic contributor. Finally, our results show that activation of the AhR in CD11c+ dendritic cells is directly responsible for TCDD-induced alterations in the development and differentiation of thymocytes, which results in thymic atrophy. Collectively, these results suggest that CD11c+ dendritic cells play a critical role in mediating TCDD-induced thymic atrophy and disruption of T lymphocyte development and differentiation in the thymus.

295-kW peak power picosecond pulses from a thulium-doped-fiber MOPA and the generation of watt-level >2.5-octave supercontinuum extending up to 5 µm.

We report a gain-switched diode-seeded thulium doped fiber master oscillator power amplifier (MOPA) producing up to 295-kW picosecond pulses (35 ps) at a repetition rate of 1 MHz with a good beam quality (M2 ~1.3). A narrow-band, grating-based filter was incorporated within the amplifier chain to restrict the accumulation of nonlinear spectral broadening and counter-pumping of a short length of large-mode-area (LMA) fiber was used in the final stage amplifier to further reduce nonlinear effects. Finally, we generated watt-level >2.5-octave supercontinuum spanning from 750 nm to 5000 nm by using the MOPA output to pump an indium fluoride fiber.

Environmental Immunology: Lessons Learned from Exposure to a Select Panel of Immunotoxicants.

Exposure to environmental contaminants can produce profound effects on the immune system. Many classes of xenobiotics can significantly suppress or enhance immune responsiveness depending on the levels (i.e., dose) and context (i.e., timing, route) of exposure. Although defining the effects that toxicants can have on the immune system is a valuable component to improving public health, environmental immunology has greatly enhanced our understanding of how the immune system functions and has provided innovative avenues to explore new immunotherapies. This Brief Review focuses on three examples of how immunotoxicology has benefitted the field of immunology, presenting information on the aryl hydrocarbon receptor signaling pathway, the immunomodulatory effects of nanomaterials, and the impact of xenobiotic exposure on the developing immune system. Collectively, contributions from immunotoxicology have significantly enhanced public health and spurred seminal advances in both basic and applied immunology.

Highly efficient frequency doubling and quadrupling of a short-pulsed thulium fiber laser.

We report the second harmonic generation and fourth harmonic generation of the output from a short-pulsed (~ 80 ps) thulium-doped fiber laser, generating 976 and 488 nm wavelengths with high efficiency. With a narrow-linewidth (0.5 nm) pump at a power of 3.2 W, a second harmonic power of 2.4 W was generated at 976 nm with a conversion efficiency reaching 75%. For FHG, 690 mW of power at 488 nm was obtained from frequency doubling of 976 nm with a conversion efficiency of 30%.

3D imaging of cells in scaffolds: direct labelling for micro CT.

The development of in-vitro techniques to characterise the behaviour of cells in biomedical scaffolds is a rapidly developing field. However, until now it has not been possible to visualise, directly in 3D, the extent of cell migration using a desktop X-ray microCT. This paper describes a new technique based on cell labelling with a radio opacifier (barium sulphate), which permits cell tracking without the need for destructive sample preparation. The ability to track cells is highlighted via a comparison of cell migration through demonstrator lyophilised collagen scaffolds with contrasting pore size and interconnectivity. The results demonstrate the ease with which the technique can be used to characterise the effects of scaffold architecture on cell infiltration.

Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells.

Currently, it is not well understood how ligands of the aryl hydrocarbon receptor (AhR) modify inflammatory responses triggered by Toll-like receptor (TLR) agonists in human dendritic cells (DCs). Here, we show that AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the tryptophan derivatives 6-formylindolo[3,2-b] carbazole (FICZ), kynurenine (kyn), and the natural dietary compound indole-3-carbinol (I3C) differentially modify cytokine expression in human monocyte-derived DCs (MoDCs). The results show that TLR-activated MoDCs express higher levels of AhR and are more sensitive toward the effects of AhR ligands. Depending on the cytokine, treatment with AhR ligands led to a synergistic or antagonistic effect of the TLR-triggered response in MoDCs. Thus, activation of AhR increased the expression of interleukin (IL)-1ß, but decreased the expression of IL-12A in TLR-activated MoDCs. Furthermore, TCDD and FICZ may have opposite effects on the expression of cytochrome P4501A1 (CYP1A1) in TLR8-activated MoDCs indicating that the effect of the specific AhR ligand may depend on the presence of the specific TLR agonist. Gene silencing showed that synergistic effects of AhR ligands on TLR-induced expression of IL-1ß require a functional AhR and the expression of NF-κB RelB. On the other hand, repression of IL-12A by TCDD and FICZ involved the induction of the caudal type homeobox 2 (CDX2) transcription factor. Additionally, the levels of DC surface markers were decreased in MoDCs by TCDD, FICZ and I3C, but not by kyn. Overall, these data demonstrate that AhR modulates TLR-induced expression of cytokines and DC-specific surface markers in MoDCs involving NFκB RelB and the immune regulatory factor CDX2.

Oversizing the tibial component in TKAs: incidence, consequences and risk factors.

PURPOSE: The incidence of anteroposterior overhang of the tibial component after TKA and its effect on clinical outcome were investigated, and the morphometric characteristics of the knees in which tibial baseplates were oversized were identified. METHOD: One hundred and fourteen consecutive TKAs were retrospectively assessed. The dimensions of the tibia were measured on a pre-operative CT scan and were compared with those of the implanted tibial component. We analysed the effect of anteroposterior and mediolateral size variations on clinical outcomes 1 year after surgery. RESULTS: An anteroposterior overhang was observed in 87 % of cases on the lateral plateau, in 88 % on the central plateau and in 25 % on the medial tibial plateau. The mean post-pre-operative size differences were 3.2 ± 2.7, 2.8 ± 2.7 and -1.6 ± 2.3 mm, respectively. (Positive value means oversizing). A mediolateral overhang of the tibial component was found in 61 % of the patients. Oversizing was significantly greater and more frequent in females. Patients oversized in the anteroposterior dimension had lower post-operative pain scores. Patients with mediolateral oversizing had decreased flexion 1 year after surgery. Anteroposterior oversizing was observed more frequently in patients with asymmetric tibial plateaus, while mediolateral oversizing was observed more frequently in patients with small tibias. CONCLUSIONS: This study demonstrates that the incidence of oversized tibial plateau components is surprisingly high and that functional outcomes are lower in the case of mediolateral or anteroposterior oversizing. The risk of oversizing could be predicted as it occurs predominantly in patients with asymmetric proximal tibia and/or small tibia. LEVEL OF EVIDENCE: IV.

High-energy, near- and mid-IR picosecond pulses generated by a fiber-MOPA-pumped optical parametric generator and amplifier.

We report a high-energy picosecond optical parametric generator/amplifier (OPG/A) based on a MgO:PPLN crystal pumped by a fiber master-oscillator-power-amplifier (MOPA) employing direct amplification. An OPG tuning range of 1450-3615 nm is demonstrated with pulse energies as high as 2.6 µJ (signal) and 1.2 µJ (idler). When seeded with a ~100 MHz linewidth diode laser, damage-limited pulse energies of 3.1 µJ (signal) and 1.3 µJ (idler) have been achieved and the signal pulse time-bandwidth product is improved to ~2 times transform-limited. When seeded with a 0.3 nm-bandwidth filtered amplified spontaneous emission source, crystal damage is avoided and maximum pulse energies of 3.8 µJ (signal) and 1.7 µJ (idler) are obtained at an overall conversion efficiency of 45%.

Pulsed laser deposited diode-pumped 7.4 W Yb:Lu2O3 planar waveguide laser.

Fabrication, characterization, and laser performance of an Yb:Lu2O3 planar waveguide laser are reported. Pulsed laser deposition was employed to grow an 8 µm-thick Yb-doped lutetia waveguide on a YAG substrate. X-ray diffraction was used to determine the crystallinity, and spectroscopic characterization showed the absorption and emission cross-sections were indistinguishable from those reported for bulk material. When end-pumped by a diode-laser bar an output power of 7.4 W was achieved, limited by the available pump power, at a wavelength of 1033 nm and a slope efficiency of 38% with respect to the absorbed pump power.

456-mW graphene Q-switched Yb:yttria waveguide laser by evanescent-field interaction.

In this Letter, we present a passively Q-switched Yb:Y2O3 waveguide laser using evanescent-field interaction with an atmospheric-pressure-chemical-vapor-deposited graphene saturable absorber. The waveguide, pumped by a broad area diode laser, produced an average output power of 456 mW at an absorbed power of 4.1 W. The corresponding pulse energy and peak power were 330 nJ and 2 W, respectively. No graphene damage was observed, demonstrating the suitability of top-deposited graphene for high-power operation.

Broadband telecom to mid-infrared supercontinuum generation in a dispersion-engineered silicon germanium waveguide.

We demonstrate broadband supercontinuum generation (SCG) in a dispersion-engineered silicon-germanium waveguide. The 3 cm long waveguide is pumped by femtosecond pulses at 2.4 µm, and the generated supercontinuum extends from 1.45 to 2.79 µm (at the -30 dB point). The broadening is mainly driven by the generation of a dispersive wave in the 1.5-1.8 µm region and soliton fission. The SCG was modeled numerically, and excellent agreement with the experimental results was obtained.

Generation of mode-locked optical pulses at 1035 nm from a fiber Bragg grating stabilized semiconductor laser diode.

We report the generation of transform-limited, ~18 ps optical pulses from a fiber Bragg grating (FBG) stabilized semiconductor laser diode. Up to 7.2 pJ of pulse energy and a peak power of 400mW were achieved when operating at a repetition frequency of 832.6 MHz, a multiple of the cavity (diode + FBG) free spectral range (FSR). A small detuning in the repetition frequency resulted in broader optical pulses. We have shown experimentally the transition from a gain-switched regime of operation to mode-locked operation once the injection current modulation frequency is set to match a harmonic of the cavity FSR. The transition also results in a reduction in the timing jitter of the optical pulses.

Compact, high-pulse-energy, high-power, picosecond master oscillator power amplifier.

We report a compact, stable, gain-switched-diode-seeded master oscillator power amplifier (MOPA), employing direct amplification via conventional Yb(3+)-doped fibers, to generate picosecond pulses with energy of 17.7 µJ and 97-W average output power (excluding amplified spontaneous emission) at 5.47-MHz repetition frequency in a diffraction-limited and single-polarization beam. A maximum peak power of 197 kW is demonstrated. Such a high-energy, high-power, MHz, picosecond MOPA is of great interest for high-throughput material processing. With 13.8-µJ pulse energy confined in the 0.87-nm 3-dB spectral bandwidth, this MOPA is also a promising source for nonlinear frequency conversion to generate high-energy pulses in other spectral regions. We have explored the pulse energy scaling until the stimulated Raman Scattering (SRS) becomes significant (i.e. spectral peak intensity exceeds 1% of that of the signal).