Scalable stable comb-to-tone integrated RF photonic drive for superconducting qubits.

The recent advent of quantum computing has the potential to overhaul security, communications, and scientific modeling. Superconducting qubits are a leading platform that is advancing noise-tolerant intermediate-scale quantum processors. The implementation requires scaling to large numbers of superconducting qubits, circuit depths, and gate speeds, wherein high-purity RF signal generation and effective cabling transport are desirable. Fiber photonic-enhanced RF signal generation has demonstrated the principle of addressing both signal generation and transport requirements, supporting intermediate qubit numbers and robust packaging efforts; however, fiber-based approaches to RF signal distribution are often bounded by their phase instability. Here, we present a silicon photonic integrated circuit-based version of a photonic-enhanced RF signal generator that demonstrates the requisite stability, as well as a path towards the necessary signal fidelity.

Distinct risks, clinical characteristics and outcomes by age at time of HIV diagnosis.

OBJECTIVES: New HIV diagnoses in persons aged > 50 years (hereafter 'older persons') are becoming more common; the clinical features and outcomes of these older individuals are poorly described. METHODS: We conducted a retrospective cohort study of all new adult HIV diagnoses between October 1989 and December 2019 in southern Alberta, Canada. Differences in risk for HIV acquisition and screening, sociodemographic/clinical characteristics, and causes of death were compared between individuals younger and older than 50 years at the time of diagnosis. RESULTS: New HIV diagnoses in persons > 50 years old increased from 7% in 1990 to 18% in 2019. Risk for HIV acquisition and screening reasons differed by age. Heterosexual sex (29%) was the greatest risk factor among older persons, contrasting with male same sex activity in younger persons (51%) (P < 0.001). Illness was the most common indication for testing in older persons (47%), whereas younger persons were more likely to have requested testing (34%) (P < 0.001). Relationship status differed, with 33% of older persons being married to an opposite sex partner versus 12% in younger persons (P < 0.001). Although older persons had a lower mean nadir CD4 count (132 cells/µL) than younger persons (181 cells/µL) (P < 0.001), 80% of deaths between 2010 and 2019 in the older group were attributable to non-AIDS-related causes versus 47% in younger patients. Since 2000, AIDS-related deaths and potential years of life lost have declined for both age groups. CONCLUSION: The increase in new HIV diagnoses in persons aged > 50 years in southern Alberta suggests that older individuals require customized approaches for optimizing HIV diagnosis and treatment.

Infrared thermography and ulcer prevention in the high-risk diabetic foot: data from a single-blind multicentre controlled clinical trial.

AIM: To assess the usefulness of monthly thermography and standard foot care to reduce diabetic foot ulcer recurrence. METHODS: People with diabetes (n = 110), neuropathy and history of ≥ 1 foot ulcer participated in a single-blind multicentre clinical trial. Feet were imaged with a novel thermal imaging device (Diabetic Foot Ulcer Prevention System). Participants were randomized to intervention (active thermography + standard foot care) or control (blinded thermography + standard foot care) and were followed up monthly until ulcer recurrence or for 12 months. Foot thermograms of participants from the intervention group were assessed for hot spots (areas with temperature ≥ 2.2°C higher than the corresponding contralateral site) and acted upon as per local standards. RESULTS: After 12 months, 62% of participants were ulcer-free in the intervention group and 56% in the control group. The odds ratios of ulcer recurrence (intervention vs control) were 0.82 (95% CI 0.38, 1.8; P = 0.62) and 0.55 (95% CI 0.21, 1.4; P = 0.22) in univariate and multivariate logistic regression analyses, respectively. The hazard ratios for the time to ulcer recurrence (intervention vs control) were 0.84 (95% CI 0.45, 1.6; P = 0.58) and 0.67 (95% CI 0.34, 1.3; P = 0.24) in univariate and multivariate Cox regression analyses, respectively. CONCLUSIONS: Monthly intervention with thermal imaging did not result in a significant reduction in ulcer recurrence rate or increased ulcer-free survival in this cohort at high risk of foot ulcers. This trial has, however, informed the design of a refined study with longer follow-up and group stratification, further aiming to assess the efficacy of thermography to reduce ulcer recurrence.

Citalopram and sertraline exposure compromises embryonic bone development.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.

Overcoming structural inequalities in oral health: the role of dental curricula.

To date the role of health professional schools in addressing oral health inequalities have been minimal, as attempts have focused principally upon systemic reform and broader societal obligations. Professionalism is a broad competency that is taught throughout dental schools and encompasses a range of attributes. Professionalism as a competency draws some debate and appears to be a shifting phenomenon. We may ask if professionalism in the dental curricula may be better addressed by social accountability? Social accountability directs oral health professional curricula (education, research, and service activities) towards addressing the priority health concerns of the community, in our case oral health inequalities. Although working toward dental schools becoming more socially accountable seems like a sensible way to address oral health inequalities, it might have limitations. We will consider some of the challenges in the dental curricula by considering some of the political, structural, social and ethical factors that influence our institutions and our graduates.

Mode-locked ultrashort pulse generation from on-chip normal dispersion microresonators.

We describe generation of stable mode-locked pulse trains from on-chip normal dispersion microresonators. The excitation of hyperparametric oscillation is facilitated by the local dispersion disruptions induced by mode interactions. The system is then driven from hyperparametric oscillation to the mode-locked state with over 200 nm spectral width by controlled pump power and detuning. With the continuous-wave-driven nonlinearity, the pulses sit on a pedestal, akin to a cavity soliton. We identify the importance of pump detuning and wavelength-dependent quality factors in stabilizing and shaping the pulse structure, to achieve a single pulse inside the cavity. We examine the mode-locking dynamics by numerically solving the master equation and provide analytic solutions under appropriate approximations.

Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family.

Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder for which subtyping through molecular analysis can help determine the eventual phenotype and prognosis. We used whole-exome sequencing to identify a new homozygous splice-site mutation in ST14 (IVS5+1G>A), encoding matriptase, in a 4-year-old girl with ARCI from a consanguineous Kuwaiti family. Clinically, she also had hypotrichosis, which supported a diagnosis of ARCI type 11. Only four previous examples of pathogenic mutations in ST14 have been reported, and our findings expand the genotype-phenotype correlation for this subtype of ARCI. Our patient was the second child born to these parents; the first (deceased) and third children had congenital brain and eye abnormalities, of uncertain aetiology and with no precise diagnosis. Further analysis of our patient's exome dataset revealed heterozygosity for a splice-site mutation in POMT1 (IVS4+1G>T), encoding the protein O-mannosyltransferase, a gene implicated in Walker-Warburg syndrome. DNA sequencing in the third child showed homozygosity for this mutation in POMT1. The first-cousin parents were both heterozygous for the splice-site mutations in ST14 and POMT1. In this family, whole-exome sequencing provided accurate subtyping of a form of ARCI in one child and provide an explanation for an undiagnosed developmental disorder in two other children, findings that improve the prospects for diagnostic accuracy and genetic counselling, and demonstrate the impact of next-generation sequencing technologies on clinical genetics.

Founder mutation in dystonin-e underlying autosomal recessive epidermolysis bullosa simplex in Kuwait.

Only two homozygous nonsense mutations in the epidermal isoform of the dystonin gene, DST-e, have been reported previously in autosomal recessive epidermolysis bullosa simplex (EBS); the affected pedigrees were Kuwaiti and Iranian. This subtype of EBS is therefore considered to be a rare clinicopathological entity. In this study, we identified four seemingly unrelated Kuwaiti families in which a total of seven individuals had predominantly acral trauma-induced blistering since infancy. All affected individuals were homozygous for the mutation p.Gln1124* in DST-e, the same mutation that was identified in the originally reported family from Kuwait. Haplotype analysis in the five pedigrees (including the previous case) revealed a shared block of ~60 kb of genomic DNA across the site of the mutation, consistent with a founder effect. Most heterozygotes had no clinical abnormalities although one subject had mild transient skin fragility during childhood, an observation noted in the previously reported Iranian pedigree, suggesting that the condition may also be semidominant in some pedigrees rather than purely autosomal recessive. Our study reveals propagation of a mutant ancestral allele in DST-e throughout Kuwait, indicating that this subtype of EBS may be more common in Kuwait, and perhaps other Middle Eastern countries, than is currently appreciated.

Whole-exome sequencing improves mutation detection in a diagnostic epidermolysis bullosa laboratory.

BACKGROUND: Subtypes of inherited epidermolysis bullosa (EB) vary significantly in their clinical presentation and prognosis. Establishing an accurate diagnosis is important for genetic counselling and patient management. Current approaches in EB diagnostics involve skin biopsy for immunohistochemistry and transmission electron microscopy, and Sanger sequencing of candidate genes. Although informative in most cases, this approach can be expensive and laborious and may fail to identify pathogenic mutations in ~15% of cases. OBJECTIVES: Next-generation DNA sequencing (NGS) technologies offer a fast and efficient complementary diagnostic strategy, but the value of NGS in EB diagnostics has yet to be explored. The aim of this study was to undertake whole-exome sequencing (WES) in nine cases of EB in which established diagnostic methods failed to make a genetic diagnosis. METHODS: Whole-exome capture was performed using genomic DNA from each case of EB, followed by massively parallel sequencing. Resulting reads were mapped to the human genome reference hg19. Potentially pathogenic mutations were subsequently confirmed by Sanger sequencing. RESULTS: Analysis of WES data disclosed biallelic pathogenic mutations in each case, with all mutations occurring in known EB genes (LAMB3, PLEC, FERMT1 and COL7A1). This study demonstrates that NGS can improve diagnostic sensitivity in EB compared with current laboratory practice. CONCLUSIONS: With appropriate diagnostic platforms and bioinformatics support, WES is likely to increase mutation detection in cases of EB and improve EB diagnostic services, although skin biopsy remains an important diagnostic investigation in current clinical practice.

Mutations in EXPH5 result in autosomal recessive inherited skin fragility.

Several different genes have been implicated in the pathophysiology of inherited blistering skin diseases. Recently, autosomal recessive loss-of-function mutations in EXPH5 (encoding exophilin-5, also known as Slac2-b, a protein involved in intracellular vesicle transport) were identified in a new mechanobullous disease resembling a form of epidermolysis bullosa simplex (EBS). Here, we searched for mutations in EXPH5 in a 4-year-old white boy with EBS in whom initial Sanger sequencing of known genes implicated in intraepidermal skin fragility failed to identify pathogenic mutations. Transmission electron microscopy of rubbed nonlesional patient skin revealed disruption of keratinocytes in the lower epidermis with cytolysis and acantholysis, keratin filament clumping and prominent perinuclear cytoplasmic vesicles, and provided the clue to the candidate gene pathology. Sanger sequencing of genomic DNA showed compound heterozygosity for two new mutations in EXPH5, c.1947dupC (p.Pro649fsPro*11) and c.2249C>A (p.Ser750*). Immunofluorescence microscopy of patient skin showed a complete absence of exophilin-5 labelling. This case represents the third pedigree with EXPH5 mutations resulting in inherited skin fragility. The clinical and molecular data expand genotype-phenotype correlation in this new form of EBS and demonstrate the important role of exophilin-5 in keratinocyte cell biology.

Mutations in the 180-kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa.

Junctional epidermolysis bullosa (JEB) is a heterogeneous autosomal recessively inherited blistering skin disorder associated with fragility at the dermal-epidermal junction. Characteristic ultrastructural findings in JEB are abnormalities in the hemidesmosome-anchoring filament complexes. These focal attachment structures, which extend from the intracellular compartment of the basal keratinocytes to the underlying basement membrane, have been shown to be hypoplastic or rudimentary in different forms of JEB. Previously, in different JEB phenotypes, mutations have been found in the three genes for the anchoring filament component laminin 5 (LAMA3, LAMB3, and LAMC2) and in the gene for the hemidesmosome-associated integrin beta 4 subunit. Here, we describe the first mutations in the gene encoding the 180-kD bullous pemphigoid antigen (BPAG2), a transmembranous hemidesmosomal collagen, also known as type XVII collagen (COL17A1). The patient is affected with generalized atrophic benign epidermolysis bullosa (GABEB), a rare variant of JEB, and is a compound heterozygote for premature termination codons on both alleles. These novel findings emphasize the molecular heterogeneity of this group of genodermatoses, and attest to the importance of BPAG2 in maintaining adhesion between the epidermis and the dermis.

Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome.

Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin, have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8-10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis.

Plectin deficiency results in muscular dystrophy with epidermolysis bullosa.

We report that mutation in the gene for plectin, a cytoskeleton-membrane anchorage protein, is a cause of autosomal recessive muscular dystrophy associated with skin blistering (epidermolysis bullosa simplex). The evidence comes from absence of plectin by antibody staining in affected individuals from four families, supportive genetic analysis (localization of the human plectin gene to chromosome 8q24.13-qter and evidence for disease segregation with markers in this region) and finally the identification of a homozygous frameshift mutation detected in plectin cDNA. Absence of the large multifunctional cytoskeleton protein plectin can simultaneously account for structural failure in both muscle and skin.

Enhanced Raman scattering in slow-light photonic crystals for chip-scale frequency conversion and optical amplification.

We present measurements of enhanced Raman scattering in silicon slow-light photonic crystal waveguides. By utilizing both the Bragg gap edge dispersion of TM-like modes for pump enhancement and the TE-like fundamental mode onset for Stokes enhancement, a six-fold increase in the spontaneous Raman scattering was observed in the double slow-light regime. Both forward and backward Stokes signals are examined, with continuous-wave measurements, in our low-loss photonic crystal membranes. The measured nonlinear enhancement matches well with our numerical model and simulations, and are described in detail in this paper. These observations support the development of chip-scale frequency conversion and optical amplification in silicon nanophotonics.

Payment for participation in research: a pursuit for the poor?

Poor people predominate as a subgroup of those who take part in healthy volunteer research. They are subjected to minimised but unknown risks and unpleasant burdens so that the safety of new medicines can be evaluated. This is prima facie unfair especially given that the poor are often unable to access expensive medicines. Although participants in this kind of research often do receive compensation for their time, these payments are usually capped at a very low level. This paper defends a version of a reimbursement model for the payment of research subjects. This model is practical, would benefit those without an income who take part in research, and would make it possible for those in regular work to take part in phase 1 research.

Interpreting the declaration of Helsinki (2008): "must", "should" and different kinds of obligation.

The Declaration of Helsinki is widely regarded as the preeminent code of research ethics. Revised six times since 1964, the versions differ in their substantive requirements, and also in the way that obligations are expressed, especially regarding the use of the prescriptors "should" and "must". The 2000 version contained roughly two-thirds "should" versus one-third " must". But this ratio was inversed in the final 2008 version--although in its penultimate draft practically all occurrences of "must" had been replaced with "should". We consider and analyze the significance of these variations for policy and practice. We argue that the Declaration can plausibly be viewed as 'soft law'. In interpreting it in legislative and jurisdictional contexts the terms "should" and "must" cannot be seen as synonymous. Even if the soft-law claim is rejected, and the Declaration is viewed as providing ethical guidance only, the question of how to interpret "should" and "must" remains. We explore three possible interpretations: categorical versus hypothetical requirements; perfect versus imperfect obligations; and aspiration versus obligation. We conclude that the most plausible way of understanding the distinction is in relation to the strength of the categorical obligations which the Declaration seeks to set out.

Identification of secreted proteins associated with obesity and type 2 diabetes in Psammomys obesus.

OBJECTIVE: Skeletal muscle produces a variety of secreted proteins that have important roles in intercellular communication and affects processes such as glucose homoeostasis. The objective of this study was to develop a novel Signal Sequence Trap (SST) in conjunction with cDNA microarray technology to identify proteins secreted from skeletal muscle of Psammomys obesus that were associated with obesity and type 2 diabetes (T2D). DESIGN: Secreted proteins that were differentially expressed between lean, normal glucose tolerant (NGT), overweight and impaired glucose tolerant (IGT) and obese, T2D P. obesus were isolated using SST in conjunction with cDNA microarray technology. Subsequent gene expression was measured in tissues from P. obesus by real-time PCR (RT-PCR). RESULTS: The SST yielded 1600 positive clones, which were screened for differential expression. A total of 91 (approximately 6%) clones were identified by microarray to be differentially expressed between NGT, IGT and T2D P. obesus. These clones were sequenced to identify 51 genes, of which only 27 were previously known to encode secreted proteins. Three candidate genes not previously associated with obesity or type 2 diabetes, sushi domain containing 2, collagen and calcium-binding EGF domains 1 and periostin (Postn), as well as one gene known to be associated, complement component 1, were shown by RT-PCR to be differentially expressed in skeletal muscle of P. obesus. Further characterization of the secreted protein Postn revealed it to be predominantly expressed in adipose tissue, with higher expression in visceral compared with subcutaneous adipose depots. CONCLUSION: SST in conjunction with cDNA microarray technology is a powerful tool to identify differentially expressed secreted proteins involved in complex diseases such as obesity and type 2 diabetes. Furthermore, a number of candidate genes were identified, in particular, Postn, which may have a role in the development of obesity and type 2 diabetes.

The JNM1 gene in the yeast Saccharomyces cerevisiae is required for nuclear migration and spindle orientation during the mitotic cell cycle.

JNM1, a novel gene on chromosome XIII in the yeast Saccharomyces cerevisiae, is required for proper nuclear migration. jnm1 null mutants have a temperature-dependent defect in nuclear migration and an accompanying alteration in astral microtubules. At 30 degrees C, a significant proportion of the mitotic spindles is not properly located at the neck between the mother cell and the bud. This defect is more severe at low temperature. At 11 degrees C, 60% of the cells accumulate with large buds, most of which have two DAPI staining regions in the mother cell. Although mitosis is delayed and nuclear migration is defective in jnm1 mutant, we rarely observe more than two nuclei in a cell, nor do we frequently observe anuclear cells. No loss of viability is observed at 11 degrees C and cells continue to grow exponentially with increased doubling time. At low temperature the large budded cells of jnm1 mutants exhibit extremely long astral microtubules that often wind around the periphery of the cell. jnm1 mutants are not defective in chromosome segregation during mitosis, as assayed by the rate of chromosome loss, or nuclear migration during conjugation, as assayed by the rate of mating and cytoduction. The phenotype of a jnm1 mutant is strikingly similar to that for mutants in the dynein heavy chain gene (Eshel, D., L. A. Urrestarazu, S. Vissers, J.-C. Jauniaux, J. C. van Vliet-Reedijk, R. J. Plants, and I. R. Gibbons. 1993. Proc. Natl. Acad. Sci. USA. 90:11172-11176; Li, Y. Y., E. Yeh, T. Hays, and K. Bloom. 1993. Proc. Natl. Acad. Sci. USA. 90:10096-10100). The JNM1 gene product is predicted to encode a 44-kD protein containing three coiled coil domains. A JNM1:lacZ gene fusion is able to complement the cold sensitivity and microtubule phenotype of a jnm1 deletion strain. This hybrid protein localizes to a single spot in the cell, most often near the spindle pole body in unbudded cells and in the bud in large budded cells. Together these results point to a specific role for Jnm1p in spindle migration, possibly as a subunit or accessory protein for yeast dynein.