High Efficiency Planar Geometry Germanium-on-silicon Single-photon Avalanche Diode Detectors

This paper presents the performance of 26 μm and 50 μm diameter planar Ge-on-Si single-photon avalanche diode (SPAD) detectors. The addition of germanium in these detectors extends the spectral range into the short-wave infrared (SWIR) region, beyond the capability of already well-established Si SPAD devices. There are several advantages for extending the spectral range into the SWIR region including: reduced eye-safety laser threshold, greater attainable ranges, and increased depth resolution in range finding applications, in addition to the enhanced capability to image through obscurants such as fog and smoke. The time correlated single-photon counting (TCSPC) technique has been utilized to observe record low dark count rates, below 100 kHz at a temperature of 125 K for up to a 6.6 % excess bias, for the 26 μm diameter devices. Under identical experimental conditions, in terms of excess bias and temperature, the 50 μm diameter device consistently demonstrates dark count rates a factor of 4 times greater than 26 μm diameter devices, indicating that the dark count rate is proportional to the device volume. Single-photon detection efficiencies of up to ~ 29 % were measured at a wavelength of 1310 nm at 125 K. Noise equivalent powers (NEP) down to 9.8 × 10-17 WHz-1/2 and jitters < 160 ps are obtainable, both significantly lower than previous 100 μm diameter planar geometry devices, demonstrating the potential of these devices for highly sensitive and high-speed imaging in the SWIR

Treatment for ascites in adults with decompensated liver cirrhosis:a network meta-analysis

BACKGROUND:Approximately 20% of people with cirrhosis develop ascites. Several different treatments are available; including, among others, paracentesis plus fluid replacement, transjugular intrahepatic portosystemic shunts, aldosterone antagonists, and loop diuretics. However, there is uncertainty surrounding their relative efficacy. OBJECTIVES:To compare the benefits and harms of different treatments for ascites in people with decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for ascites according to their safety and efficacy. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until May 2019 to identify randomised clinical trials in people with cirrhosis and ascites. SELECTION CRITERIA:We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and ascites. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS:We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS:We included a total of 49 randomised clinical trials (3521 participants) in the review. Forty-two trials (2870 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, without other features of decompensation, having mainly grade 3 (severe), recurrent, or refractory ascites. The follow-up in the trials ranged from 0.1 to 84 months. All the trials were at high risk of bias, and the overall certainty of evidence was low or very low. Approximately 36.8% of participants who received paracentesis plus fluid replacement (reference group, the current standard treatment) died within 11 months. There was no evidence of differences in mortality, adverse events, or liver transplantation in people receiving different interventions compared to paracentesis plus fluid replacement (very low-certainty evidence). Resolution of ascites at maximal follow-up was higher with transjugular intrahepatic portosystemic shunt (HR 9.44; 95% CrI 1.93 to 62.68) and adding aldosterone antagonists to paracentesis plus fluid replacement (HR 30.63; 95% CrI 5.06 to 692.98) compared to paracentesis plus fluid replacement (very low-certainty evidence). Aldosterone antagonists plus loop diuretics had a higher rate of other decompensation events such as hepatic encephalopathy, hepatorenal syndrome, and variceal bleeding compared to paracentesis plus fluid replacement (rate ratio 2.04; 95% CrI 1.37 to 3.10) (very low-certainty evidence). None of the trials using paracentesis plus fluid replacement reported health-related quality of life or symptomatic recovery from ascites. FUNDING:the source of funding for four trials were industries which would benefit from the results of the study; 24 trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 21 trials was unclear. AUTHORS' CONCLUSIONS:Based on very low-certainty evidence, there is considerable uncertainty about whether interventions for ascites in people with decompensated liver cirrhosis decrease mortality, adverse events, or liver transplantation compared to paracentesis plus fluid replacement in people with decompensated liver cirrhosis and ascites. Based on very low-certainty evidence, transjugular intrahepatic portosystemic shunt and adding aldosterone antagonists to paracentesis plus fluid replacement may increase the resolution of ascites compared to paracentesis plus fluid replacement. Based on very low-certainty evidence, aldosterone antagonists plus loop diuretics may increase the decompensation rate compared to paracentesis plus fluid replacement

Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients

Pseudo-planar Ge-on-Si Single-photon Avalanche Diode Detector with Record Low Noise-equivalent Power

Single-photon avalanche diode (SPAD) detectors are of significant interest for numerous applications, including light detection and ranging (LIDAR), and quantum technologies such as quantum-key distribution and quantum information processing. Here we present a record low noise-equivalent-power (NEP) for Ge-on-Si SPADs using a pseudo-planar design, showing high detection efficiency in the short-wave infrared; a spectral region which is key for quantum technologies and hugely beneficial for LIDAR. These devices can leverage the benefits of Si avalanche layers, with lower afterpulsing compared to InGaAs/InP, and reduced cost due to Si foundry compatibility. By scaling the SPAD pixels down to 26μm diameter, a step change in performance has been demonstrated, with significantly reduced dark count rates (DCRs), and low jitter (134ps). Ge-on-Si SPADs were fabricated using photolithography techniques and characterised using time-correlated single-photon counting. The DCR reaches as low as kilocount/s at 100K for excess bias up to ~5%. This reduction in DCR enables higher temperature operation; e.g. the DCR of a 26μm diameter pixel at 150 K is approximately equivalent to a 100 μm diameter pixel at 77 K (100s of kilocounts/s). These low values of DCR, coupled with the relatively temperature independent single photon detection efficiencies (SPDE) of ~29% (at 1310nm wavelength) leads to a record low NEP of 7.7×10−17WHz−1/2. This is approximately 2 orders of magnitude lower than previous similarly sized mesa-geometry Ge-on-Si SPADs. This technology can potentially offer a lowcost, Si foundry compatible SPAD operating at short-wave infrared wavelengths, with potential applications in quantum technologies and autonomous vehicle LIDAR

The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis.

Funder: UK‐PBC MRC Stratified MedicineFunder: Pfizer; Id: http://dx.doi.org/10.13039/100004319BACKGROUND AND AIMS: Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second-line therapy in nonresponders to first-line therapy with ursodeoxycholic acid (UDCA). The mechanism for nonresponse to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK-PBC study was established to explore the biological basis of UDCA nonresponse in PBC and identify markers to enhance treatment. APPROACH AND RESULTS: Discovery serum proteomics (Olink) with targeted multiplex validation were carried out in 526 subjects from the UK-PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n = 68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n = 416 treated patients). Nineteen proteins remained at a significant expression level (defined using stringent criteria) in UDCA-treated patients, six of them representing a tightly linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BECs) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and nonresponders in both the discovery and validation cohorts. A linear discriminant analysis, using serum levels of C-X-C motif chemokine ligand 11 and C-C motif chemokine ligand 20 as markers of responder status, indicated a high level of discrimination with an AUC of 0.91 (CI, 0.83-0.91). CONCLUSIONS: UDCA under-response in PBC is characterized by elevation of serum chemokines potentially related to cellular senescence and was previously shown to be released by BECs in PBC, suggesting a potential role in the pathogenesis of high-risk disease. These also have potential for development as biomarkers for identification of high-risk disease, and their clinical utility as biomarkers should be evaluated further in prospective studies

Consensus guidelines for the detection of immunogenic cell death

none82siApoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.Kepp, Oliver; Senovilla, Laura; Vitale, Ilio; Vacchelli, Erika; Adjemian, Sandy; Agostinis, Patrizia; Apetoh, Lionel; Aranda, Fernando; Barnaba, Vincenzo; Bloy, Norma; Bracci, Laura; Breckpot, Karine; Brough, David; Buqué, Aitziber; Castro, Maria G; Cirone, Mara; Colombo, Maria I; Cremer, Isabelle; Demaria, Sandra; Dini, Luciana; Eliopoulos, Aristides G; Faggioni, Alberto; Formenti, Silvia C; Fučíková, Jitka; Gabriele, Lucia; Gaipl, Udo S; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giese, Nathalia A; Guo, Zong Sheng; Hemminki, Akseli; Herrmann, Martin; Hodge, James W; Holdenrieder, Stefan; Honeychurch, Jamie; Hu, Hong-Min; Huang, Xing; Illidge, Tim M; Kono, Koji; Korbelik, Mladen; Krysko, Dmitri V; Loi, Sherene; Lowenstein, Pedro R; Lugli, Enrico; Ma, Yuting; Madeo, Frank; Manfredi, Angelo A; Martins, Isabelle; Mavilio, Domenico; Menger, Laurie; Merendino, Nicolò; Michaud, Michael; Mignot, Gregoire; Mossman, Karen L; Multhoff, Gabriele; Oehler, Rudolf; Palombo, Fabio; Panaretakis, Theocharis; Pol, Jonathan; Proietti, Enrico; Ricci, Jean-Ehrland; Riganti, Chiara; Rovere-Querini, Patrizia; Rubartelli, Anna; Sistigu, Antonella; Smyth, Mark J; Sonnemann, Juergen; Spisek, Radek; Stagg, John; Sukkurwala, Abdul Qader; Tartour, Eric; Thorburn, Andrew; Thorne, Stephen H; Vandenabeele, Peter; Velotti, Francesca; Workenhe, Samuel T; Yang, Haining; Zong, Wei-Xing; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, LorenzoKepp, Oliver; Senovilla, Laura; Vitale, Ilio; Vacchelli, Erika; Adjemian, Sandy; Agostinis, Patrizia; Apetoh, Lionel; Aranda, Fernando; Barnaba, Vincenzo; Bloy, Norma; Bracci, Laura; Breckpot, Karine; Brough, David; Buqué, Aitziber; Castro, Maria G; Cirone, Mara; Colombo, Maria I; Cremer, Isabelle; Demaria, Sandra; Dini, Luciana; Eliopoulos, Aristides G; Faggioni, Alberto; Formenti, Silvia C; Fučíková, Jitka; Gabriele, Lucia; Gaipl, Udo S; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giese, Nathalia A; Guo, Zong Sheng; Hemminki, Akseli; Herrmann, Martin; Hodge, James W; Holdenrieder, Stefan; Honeychurch, Jamie; Hu, Hong Min; Huang, Xing; Illidge, Tim M; Kono, Koji; Korbelik, Mladen; Krysko, Dmitri V; Loi, Sherene; Lowenstein, Pedro R; Lugli, Enrico; Ma, Yuting; Madeo, Frank; Manfredi, Angelo A; Martins, Isabelle; Mavilio, Domenico; Menger, Laurie; Merendino, Nicolò; Michaud, Michael; Mignot, Gregoire; Mossman, Karen L; Multhoff, Gabriele; Oehler, Rudolf; Palombo, Fabio; Panaretakis, Theocharis; Pol, Jonathan; Proietti, Enrico; Ricci, Jean Ehrland; Riganti, Chiara; Rovere Querini, Patrizia; Rubartelli, Anna; Sistigu, Antonella; Smyth, Mark J; Sonnemann, Juergen; Spisek, Radek; Stagg, John; Sukkurwala, Abdul Qader; Tartour, Eric; Thorburn, Andrew; Thorne, Stephen H; Vandenabeele, Peter; Velotti, Francesca; Workenhe, Samuel T; Yang, Haining; Zong, Wei Xing; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenz

The Helium abundance and Delta Y / Delta Z in Lower Main Sequence stars

We use nearby K dwarf stars to measure the helium-to-metal enrichment ratio, a diagnostic of the chemical history of the Solar Neighbourhood. Our sample of K dwarfs has homogeneously determined effective temperatures, bolometric luminosities and metallicities, allowing us to fit each star to the appropriate stellar isochrone and determine its helium content indirectly. We use a newly computed set of Padova isochrones which cover a wide range of helium and metal content. Our theoretical isochrones have been checked against a congruous set of main sequence binaries with accurately measured masses, to discuss and validate their range of applicability. We find that the stellar masses deduced from the isochrones are usually in excellent agreement with empirical measurements. Good agreement is also found with empirical mass-luminosity relations. Despite fitting the masses of the stars very well, we find that anomalously low helium content (lower than primordial helium) is required to fit the luminosities and temperatures of the metal poor K dwarfs, while more conventional values of the helium content are derived for the stars around solar metallicity. We have investigated the effect of diffusion in stellar models and LTE assumption in deriving metallicities. Neither of these is able to resolve the low helium problem alone and only marginally if the cumulated effects are included, unless we assume a mixing-length which is strongly decreasing with metallicity. Further work in stellar models is urgently needed. The helium-to-metal enrichment ratio is found to be Delta Y / Delta Z = 2.1 +/- 0.9 around and above solar metallicity, consistent with previous studies, whereas open problems still remain at the lowest metallicities. Finally, we determine the helium content for a set of planetary host stars.Comment: 29 pages, 13 figures, replaced to match published version in MNRA

Are HIV/AIDS Conspiracy Beliefs a Barrier to HIV Prevention Among African Americans?

Objectives: This study examined endorsement of HIV/AIDS conspiracy beliefs and their relations to consistent condom use and condom attitudes among African Americans. Methods: We conducted a telephone survey with a random sample of 500 African Americans aged 15 to 44 years and living in the contiguous United States. Results: A significant proportion of respondents endorsed HIV/AIDS conspiracy beliefs. Among men, stronger conspiracy beliefs were significantly associated with more negative condom attitudes and inconsistent condom use independent of selected sociodemographic characteristics, partner variables, sexually transmitted disease history, perceived risk, and psychosocial factors. In secondary follow-up analyses, men’s attitudes about condom use partially mediated the effects of HIV/AIDS conspiracy beliefs on condom use behavior. Conclusions: HIV/AIDS conspiracy beliefs are a barrier to HIV prevention among African Americans and may represent a facet of negative attitudes about condoms among black men. To counter such beliefs, government and public health entities need to work toward obtaining the trust of black communities by addressing current discrimination within the health care system as well as by acknowledging the origin of conspiracy beliefs in the context of historical discrimination