Quantum circuits with many photons on a programmable nanophotonic chip.

Growing interest in quantum computing for practical applications has led to a surge in the availability of programmable machines for executing quantum algorithms1,2. Present-day photonic quantum computers3-7 have been limited either to non-deterministic operation, low photon numbers and rates, or fixed random gate sequences. Here we introduce a full-stack hardware-software system for executing many-photon quantum circuit operations using integrated nanophotonics: a programmable chip, operating at room temperature and interfaced with a fully automated control system. The system enables remote users to execute quantum algorithms that require up to eight modes of strongly squeezed vacuum initialized as two-mode squeezed states in single temporal modes, a fully general and programmable four-mode interferometer, and photon number-resolving readout on all outputs. Detection of multi-photon events with photon numbers and rates exceeding any previous programmable quantum optical demonstration is made possible by strong squeezing and high sampling rates. We verify the non-classicality of the device output, and use the platform to carry out proof-of-principle demonstrations of three quantum algorithms: Gaussian boson sampling, molecular vibronic spectra and graph similarity8. These demonstrations validate the platform as a launchpad for scaling photonic technologies for quantum information processing.

Evaluating Energy Differences on a Quantum Computer with Robust Phase Estimation.

We adapt the robust phase estimation algorithm to the evaluation of energy differences between two eigenstates using a quantum computer. This approach does not require controlled unitaries between auxiliary and system registers or even a single auxiliary qubit. As a proof of concept, we calculate the energies of the ground state and low-lying electronic excitations of a hydrogen molecule in a minimal basis on a cloud quantum computer. The denominative robustness of our approach is then quantified in terms of a high tolerance to coherent errors in the state preparation and measurement. Conceptually, we note that all quantum phase estimation algorithms ultimately evaluate eigenvalue differences.

Stimulated four-wave mixing in linearly uncoupled resonators.

We experimentally demonstrate stimulated four-wave mixing in two linearly uncoupled integrated $ {{\rm Si}_3}{{\rm N}_4} $Si3N4 micro-resonators. In our structure, the resonance combs of each resonator can be tuned independently, with the energy transfer from one resonator to the other occurring in the presence of a nonlinear interaction. This method allows flexible and efficient on-chip control of the nonlinear interaction, and is readily applicable to other third-order nonlinear phenomena.

Detection of multidrug-resistant Gram-negative bacteria from imported reptile and amphibian meats.

AIMS: The food supply is a potential source of antimicrobial resistance. Current surveillance programmes targeting food are limited to beef, pork and poultry and do not capture niche products. In this study, imported reptile and amphibian products were screened for antimicrobial-resistant bacteria. METHODS AND RESULTS: In all, 53 items including soft shell turtles, frog legs, geckos, snakes and a turtle carapace were purchased from specialty markets in Vancouver and Saskatoon, Canada. Samples were selectively cultured for Salmonella sp., Escherichia coli, extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae and meropenem-resistant organisms. Salmonella, all pan-susceptible, were grown from six dried geckos. Escherichia coli were isolated from 19 samples, including ESBL producers from six items. One multidrug-resistant E. coli possessed both the blaCTX-M-55 and mcr-1 genes. An NDM-1-producing Acinetobacter sp. was also isolated from a dried turtle carapace. CONCLUSIONS: Our results suggest that imported reptile and amphibian meats are an underappreciated source of resistant bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: The international trade of food may play a role in the dissemination of resistant bacteria. The presence of these bacteria in niche market foods represents a risk of unknown magnitude to public health and a gap in current national resistance surveillance programmes.

Nonlinear Coupling of Linearly Uncoupled Resonators.

We demonstrate a system composed of two resonators that are coupled solely through a nonlinear interaction, and where the linear properties of each resonator can be controlled locally. We show that this class of dynamical systems has peculiar properties with important consequences for the study of classical and quantum nonlinear optical phenomena. As an example we discuss the case of dual-pump spontaneous four-wave mixing.

Localization of human recombinant adenoviral vectors to the mitochondria following transduction of human cell lines.

Recently, mitochondria have been shown to have a vital role in the innate immune response to viral infection. In response, viruses such as adenovirus, have developed mechanisms to alter mitochondrial function through direct or indirect interaction with the mitochondria. The interaction of human recombinant adenoviral vectors directly with human mitochondria has not previously been shown. We demonstrate that human recombinant adenoviral vectors co-localize to mitochondria. We show that the adenoviral vectors are present within the membranes of the mitochondria and that they cause ultrastructural changes to the cristae. Further, we show that the adenoviral genome is also present in intact mitochondria. We have posited that the interaction between the adenovirus and the mitochondria may act to inhibit mitochondrial function. We have also posited that the transport of the adenoviral genome to the mitochondria may allow the future use of this vector as a tool for gene therapy of mitochondrial diseases. Keywords: mitochondria; human recombinant adenovirus; gene therapy; viral vectors; mitochondrial DNA; electron microscopy.

Late-stage optimization of a tercyclic class of S1P3-sparing, S1P1 receptor agonists.

Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.

Control of Established Gingivitis and Dental Plaque Using a 1450 ppm Fluoride/Zinc-based Dentifrice: A Randomized Clinical Study.

PURPOSE: To investigate the clinical efficacy in controlling established gingivitis and dental plaque of a 1450 ppm fluoride as sodium monofluorophosphate (SMFP)/zinc-based dentifrice, as compared to a zinc-free dentifrice with 1450 ppm fluoride as SMFP after six months product use. METHODS: A six-month clinical study, with eighty-six (86) subjects, was conducted in Chengdu, China, using a double-blind, randomized, parallel-group treatment design. After a baseline evaluation, study subjects were randomly assigned to one of the two study treatments: 1) 1450 ppm fluoride as SMFP/zinc-based dentifrice (Test) or 2) 1450 ppm fluoride as SMFP/zinc-free dentifrice (Negative Control). Subjects were provided with a soft bristle toothbrush and brushed their teeth twice daily (morning and evening) for one minute with their assigned dentifrice. After three months, and again after six months of product use, subjects returned to the testing facility for their followup gingivitis and plaque examinations. Statistical analyses were performed separately for the gingivitis assessments and dental plaque assessments using the appropriate statistical methods. All statistical tests of hypotheses were two-sided, and employed a level of significance of α = 0.05. RESULTS: After three and six months of product use, subjects assigned to the Test treatment exhibited statistically significant (p < 0.001) reductions in gingival index and plaque index scores as compared to subjects assigned to the Negative Control treatment. CONCLUSION: The results of this single-center, double-blind, parallel-group and randomized clinical study support the conclusion that a 1450 ppm fluoride as SMFP/zinc-based dentifrice provides clinically meaningful and statistically significant reductions in gingivitis (23.8%) and dental plaque (22.5%) as compared to a 1450 ppm fluoride as SMFP/zinc-free dentifrice over a six-month period of twice-daily product use.

Piperazinyl-oxadiazoles as selective sphingosine-1-phosphate receptor agonists.

The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg.

Ischaemic Priapism and Glucose-6-Phosphate Dehydrogenase Deficiency: A Mechanism of Increased Oxidative Stress?

Ischaemic priapism is a devastating urological condition that has the potential to cause permanent erectile dysfunction. The disorder has been associated with numerous medical conditions and the use of pharmacotherapeutic agents. The aetiology is idiopathic in a number of cases. There are two prior case reports of the association of ischaemic priapism and glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report on a third case of priapism associated with G6PD deficiency and review recently described molecular mechanisms of increased oxidative stress in the pathophysiology of ischaemic priapism. The case report of a 32-year old Afro-Caribbean male with his first episode of major ischaemic priapism is described. Screening for common causes of ischaemic priapism, including sickle cell disease was negative. Glucose-6-phosphate dehydrogenase deficiency was discovered on evaluation for priapism. Penile aspiration was performed and erectile function was good post treatment.Glucose-6-phosphate dehydrogenase deficiency is a cause for ischaemic priapism and should be a part of the screening process in idiopathic causes of the disorder. Increased oxidative stress occurs in G6PD deficiency and may lead to priapism.

Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors.

The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.

Pyrazolopyrimidines as dual Akt/p70S6K inhibitors.

Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.

Breast cancer-associated antigen, DF3/MUC1, induces apoptosis of activated human T cells.

Given the plethora of well-documented breast carcinoma-associated antigens in humans including MAGE-1, -2 and -3, mutated p53, p21ras, HER-2/neu and DF3/MUC-1, coupled with evidence that humoral and cytotoxic T-cell responses against these antigens exist, the central dilemma facing tumor immunologists is why the host immune response is so inefficient. One possibility is that tumor cells themselves are either inefficient or ineffective antigen-presenting cells (APCs). The failure of tumor cells to function as APCs may be due to their inability to process and present the antigen, the absence or insufficient numbers of adhesion and costimulatory molecules or, potentially, the secretion of inhibitory cytokines. Therefore, we sought to determine whether human breast cancer cell lines could function as APCs and, if not, to identify mechanism(s) responsible for this defect. Here, we show that human breast cancer cell lines fail to present alloantigen. This defect does not reside in their inherent capacity to present antigen but rather is due to apoptosis of activated T cells induced by exposure to the breast carcinoma-associated mucin antigen, DF3/MUC1. These results support the hypothesis that DF3/MUC1 may contribute to the paucity of clinically significant anticarcinoma-specific immune responses.

Penile cancer in Jamaicans managed at the University Hospital of the West Indies.

OBJECTIVES: The aim of this study is to determine the prevalence and clinicopathological correlates of penile cancer as well as the clinical outcomes in a sample of Jamaicans managed at the University Hospital of the West Indies (UHWI). METHODS: All available records of patients diagnosed with penile cancer from 1998-2008 at the UHWI were obtained. Patient demographics, circumcision status, sexually transmitted infection status, lesion duration, location and size, and lymph node status were obtained. Histology, differentiation and stage were recorded. Information was obtained regarding treatment and outcome. The current data were compared with a previous report from UHWI in 1959. RESULTS: The records of 22 of 26 patients with penile cancer were available for review. Mean (SD) age of patients was 68 (13) years. Eighteen (86%) patients were uncircumcised Mean tumour size was 5.7 (2.6) cm; 8 (36%) lesions involved the entire penis. Sixteen (73%) lesions had clinically regional disease and 11 (52%) patients had advanced pathological stage. Surgical treatment was performed in 15 (68%) patients. Case fatality was 38%, with median survival following surgical intervention of 38 person-months. The major predictor of death in this series was increasing age (HR = 1.06, 95% CI 0.99, 1.1, p = 0.079). There was an increase in age and clinical stage of the cancer at presentation in the current series; however there was no difference in survival. CONCLUSION: Penile cancer is an uncommon cancer, seen at an advanced stage in Jamaicans. Overall survival is poor and advanced age is a major predictor of death.

Radical prostatectomy outcomes at the University Hospital of the West Indies: 2000-2007.

OBJECTIVES: Prostate cancer is the commonest cancer in Jamaican men with an age-specific incidence of 65.5 per 100 000 and also the commonest cause of male cancer death. This study reports on the oncological outcome and morbidity after radical retropubic prostatectomy. SUBJECTS AND METHODS: The records of 116 patients with clinically localized prostate cancer (cT1c- T2) who underwent radical retropubic prostatectomy at the University Hospital of the West Indies from January 2000 to December 2007 were examined. Preoperative Prostate specific antigen (PSA), clinical stage and Gleason score were recorded. Operative time, blood loss, hospital stay and complications were assessed. Oncological outcome was assessed using biochemical progression. Disease progression was defined by PSA value of 0.4 ng/ml or greater. RESULTS: Mean patient age was 61 (43-75) years. The mean presenting PSA was 10.1 (2-25.1) ng/ml. Mean Gleason score on preoperative biopsy was 6. The commonest clinical stage was T1c (68%). Nodal involvement was seen in only one patient. The positive surgical margin rate was 15.5%. Mean operating time was 246 minutes and mean estimated blood loss was 1.44 L. The mean hospital stay was 6.9 days and 17% of patients developed minor complications, with no treatment or disease related deaths. Five-year biochemical-free survival was 78.4%. CONCLUSIONS: Oncological outcomes after radical retropubic prostatectomy in Jamaica appear to meet global standards with acceptable morbidity.

Body mass index and prostate specific antigen levels in Jamaican men.

OBJECTIVE: To investigate the relationship between body mass index (BMI) and prostate specific antigen (PSA) levels in Jamaican men. METHODS: Men, 40-79 years old, attending public and private urology clinics in Kingston, Jamaica were recruited to a case-control study on the role of dietary and lifestyle factors on prostate cancer. Trained interviewers administered questionnaires and measured weight and height using standardized techniques. Blood samples for PSA were measured at a central laboratory using a micro-particle enzyme immunoassay method. Prostate biopsy was used to confirm prostate cancer. Multivariable linear regression was used to examine the relationship between BMI and PSA separately in the cases and controls. RESULTS: Data from 501 men (233 cases and 263 controls) were assessed. Thirty-five per cent of subjects were overweight and 13% were obese. Among cases, the median PSA was 35.3 ng/dL in normal weight, 26.1 ng/dL in overweight and 14.5 ng/dL in obese men (p = 0.02). For controls, median PSA was 2.0 ng/dL in normal weight, 1.3 ng/dL in overweight and 1.1ng/dl in obese men (p = 0.01). Among cases, BMI was negatively associated with PSA (B(SE) per 5 kg/m2 (BMI difference = -0.51 (0.13); p < 0.01) and remained significant after adjustment for age, sexual activity, smoking, use of statins and tumour grade. For controls, the BMI was also inversely related to the PSA (B(SE) per 5 kg/m2 difference -0.17 (0.07)) but the effect became of borderline significance after adjusting for age. CONCLUSIONS: Prostate specific antigen was inversely related to body mass index in Jamaican men with prostate cancer. Clinicians should consider this association when interpreting PSA results.

[Terminology for classifying the porcine reproductive and respiratory syndrome virus (PRRSV) status of swine herds]. / Terminologie zur Klassifizierung des PRRSV-Status von Schweineherden.

Standardized terminology for the porcine reproductive and respiratory syndrome virus (PRRSV) status of swine herds is necessary to facilitate communication between veterinarians, swine producers, genetic companies, and other industry participants. It is also required for implementation of regional and national efforts towards PRRSV control and elimination. The purpose of this paper is to provide a herd classification system for describing the PRRSV status of herds, based upon a set of definitions reflecting the biology and ecology of PRRSV. The herd classification system was developed by a definitions committee formed jointly by the American Association of Swine Veterinarians (AASV) and the United States Department of Agriculture PRRS-Coordinated Agricultural Project, and was approved by the AASV Board of Directors on March 9, 2010. The committee included veterinarians from private practice and industry, researchers, and representatives from AASV and the National Pork Board. Breeding herds, with or without growing pigs on the same premises, are categorized as Positive Unstable (Category I), Positive Stable (Category II), Provisional Negative (Category III), or Negative (Category IV) on the basis of herd shedding and exposure status. Growing-pig herds are categorized as Positive or Negative. Recommended testing procedures and decision rules for herd classification are detailed.

What still presents urgently to ENT during a pandemic? Experience of an ENT rapid access clinic during the coronavirus disease 2019 pandemic.

OBJECTIVES: This study sought to determine the conditions that still present to ENT despite government advice to avoid unnecessary travel. It also assessed the impact of social distancing on pathologies presenting to ENT and reviewed the usefulness of telephone consultations in semi-urgent presentations. METHOD: A retrospective review was conducted of 97 instances of patient care carried out in the rapid access ENT clinic at a large district general hospital. RESULTS: Otitis externa and foreign bodies represented 25 per cent and 13 per cent of consultations respectively. Tonsillitis and peritonsillar abscess were uncommon, representing 6 per cent of total consultations. Telephone appointments represented only 28 per cent of total consultations; however, they appeared to reduce the number of physical appointments required. CONCLUSION: Otitis externa and foreign bodies continue to be common during the pandemic. Social distancing measures reduced the number of tonsillitis and quinsy presentations. Telephone consultations are effective for certain urgent presentations to ENT, most noticeably nasal trauma and follow up of non-serious pathologies.