Multi-qubit entanglement and algorithms on a neutral-atom quantum computer.

Gate-model quantum computers promise to solve currently intractable computational problems if they can be operated at scale with long coherence times and high-fidelity logic. Neutral-atom hyperfine qubits provide inherent scalability owing to their identical characteristics, long coherence times and ability to be trapped in dense, multidimensional arrays1. Combined with the strong entangling interactions provided by Rydberg states2-4, all the necessary characteristics for quantum computation are available. Here we demonstrate several quantum algorithms on a programmable gate-model neutral-atom quantum computer in an architecture based on individual addressing of single atoms with tightly focused optical beams scanned across a two-dimensional array of qubits. Preparation of entangled Greenberger-Horne-Zeilinger (GHZ) states5 with up to six qubits, quantum phase estimation for a chemistry problem6 and the quantum approximate optimization algorithm (QAOA)7 for the maximum cut (MaxCut) graph problem are demonstrated. These results highlight the emergent capability of neutral-atom qubit arrays for universal, programmable quantum computation, as well as preparation of non-classical states of use for quantum-enhanced sensing.

Taking therapeutic apheresis services to patients in South Africa: An eight year review of SANBS mobile therapeutic apheresis service, 2013-2020.

INTRODUCTION: A 20 year review of health and health care presents the multiple challenges faced by South Africans. Health and poverty is highlighted with 45% of population living on approximately US$ 2 per day and 10 million living on less than US$ 1 per day. Widening disparities in health care provision between public and private sector hospital services exist. The South African population includes the largest number of people living with HIV infection/AIDS of any country in the world, with a 70% estimate of 7.5 million people living with HIV on antiretroviral therapy. The South African National Blood Service provides a mixed model therapeutic apheresis service including mobile service and fixed-site therapeutic apheresis and an apheresis collection of hematopoietic stem cell (HPC-A) service. Therapeutic apheresis modalities offered by SANBS include plasmapheresis, red cell exchange, leukocyte and platelet reduction. In addition, collection of plasma, thrombocytes, mononuclear cells including CD34+ cells (HPCs) and granulocytes by apheresis for plasma and cellular therapies, and customised apheresis products for research purposes is offered. An operational database for the period 2013 to 2020 was reviewed to characterise the SANBS's mixed therapeutic apheresis service and HPC-A service from 2013 to 2020 in terms of patient numbers, patient demographics, patient procedures, therapeutic apheresis indication or diagnosis, therapeutic apheresis modality, hospital service type, and the American Society for Apheresis (ASFA) category of diagnosis. METHODS: A retrospective review of therapeutic apheresis patients referred to SANBS characterising patient numbers, patient demographics, patient procedures, therapeutic apheresis indication or diagnosis, therapeutic apheresis modality (Linz, 2017), hospital service type, and the ASFA category of diagnosis (Padmanabhan et al., 2019) for the period 01 January 2013 to 31 December 2020 was completed. Data is obtained from a SANBS operational routinely utilised to record patient procedure data. Patient procedure data is manually recorded by apheresis nurses and indexed on to the operational database, with both processes audited. The review period is a convenience sample. Storage of the database and access of the operational database is in compliance with the Protection of Personal Information Act (Government Gazette, 2013). Therapeutic apheresis modalities analysed include Plasmapheresis, Red Cell Exchange, Leukopheresis, Thrombocytapheresis, Lymphocyte collection, Granulocyte collection, Haematopoietic stem cell collection by apheresis and customised apheresis products for research purposes. Customised apheresis products for research purposes is excluded from this review. Descriptive statistics is used. RESULTS: For the review period, 2,485 unique patients with 120 unique indications as recorded by referring clinicians received 13,518 procedures involving 7 therapeutic apheresis modalities at 78 hospitals (21 public sector and 57 private sector) and at 3 SANBS blood donor centres in 7 provinces of South Africa. The age range of patients serviced is 4 months to 90 years (median = 39.5 years) (figure 1), 91% by procedure count was for patients 21 years of age or older, 62% were female, with 10,783 (79.6%) procedures performed in public sector hospitals. In all patients, the most common indications was plasmapheresis for thrombotic thromobocytopaenic purpura (52.5% of cumulative procedures), HPC-A for multiple myeloma (7.86%) and Antibody-mediated kidney transplant rejection (4.90%). Plasmapheresis was the most common therapeutic apheresis modality used (82.5% of cumulative procedures) followed by HPC-A (13.7%) and leukoreduction (3.39%). A range of indications for plasmapheresis (n = 65) and HPC-A (n = 41) were observed. Red cell exchange procedures was performed for patients with severe malaria and sickle cell disease indications. For leukoreduction indications, all patients were adults managed in public sector facilities and all were symptomatic. The most common indications were Chronic Myelogenous Leukemia, Chronic Lymphocytic Leukaemia and Multiple Myeloma. A pooled, total white cell count average of 457 × 109/L (range 141-689 × 109/L) prior to first procedure. Despite complex challenges for a national mixed model service, successful patient outcomes in emergent indications such as TTP (Louw et al., 2018; Swart et al., 2019) and engraftment post HPC-A in HSCT in multiple centres (Glatt, personal communication) are reported. CONCLUSION: The review confirms that apheresis medicine is increasingly used in South Africa in patients in both public and private sector, with the most common modalities being plasmapheresis, HPC-A and leukoreduction. Patients with HIV-associated TTP is the most commonly referred patient in both paediatric and adult patients and this is anticipated to continue. A growing HSCT transplant network capacity in South Africa is augmented through the mixed model mobile and fixed-site therapeutic apheresis services, including a mobile HPC-A service. The increasing number of HPC-A is a trend towards increasing numbers of patients support to HSCT for both adults and paediatric patients in private and public sector hospitals.

Sensory perception testing by monofilaments in the digits of controls and workers with HAVS.

OBJECTIVE: To determine if heavy manual work affects sensory perception in the digits and whether Semmes-Weinstein monofilaments (SWM) can be used as a screening tool to detect sensory neuropathy in the digits of workers exposed to hand-transmitted vibration (HTV). METHODS: A cross-sectional study of office workers, heavy manual workers not exposed to HTV and workers with hand-arm vibration syndrome (HAVS). Sensory perception was measured in the digits by SWM using a forced-choice method to determine variability by sex, age, hand and digit. Frequency distributions were used to determine limit values and linear weighted kappa for intra-digit variability. Poisson regression was used to explore the relationship between sensory perception by SWM and abnormalities of thermal and vibration perception in the hands of workers with HAVS. RESULTS: The sensory perception threshold of office workers did not vary by hand or digit. It was significantly lower in women < 30 than women aged ≥ 30 years. The 95th percentile for heavy manual workers was 1.00 (95% CI 0.60-1.00) and significantly higher than for office workers at 0.16 (95% CI 0.16-0.16). Heavy manual workers > 50 years had the highest threshold at 1.40 (95% CI 1.00-2.00). Weighted kappa for reliability was 0.63 (95% CI 0.53-0.70). A mean SWM threshold of ≥ 1.0 gram-force had a 79% sensitivity and 64% specificity for detecting abnormalities of thermal and vibration perception in the ipsilateral index and little fingers of workers with HAVS. CONCLUSIONS: SWM are a useful screening tool for detecting sensory loss in the digits of workers exposed to HTV.

Weyl Consistency Conditions and γ_{5}.

The treatment of γ_{5} in dimensional regularization leads to ambiguities in field-theoretic calculations, of which one example is the coefficient of a particular term in the four-loop gauge beta functions of the standard model. Using Weyl consistency conditions, we present a scheme-independent relation between the coefficient of this term and a corresponding term in the three-loop Yukawa beta functions, where a semi-naïve treatment of γ_{5} is sufficient, thereby fixing this ambiguity. We briefly outline an argument by which the same method fixes similar ambiguities at higher orders.

International consensus criteria for diagnosing and staging hand-arm vibration syndrome.

PURPOSE: In the 30 years since the Stockholm Workshop Scale (SWS) was published, the scientific literature on hand-arm vibration syndrome (HAVS) has grown and experience has been gained in its practical application. This research was undertaken to develop an up-to-date evidence-based classification for HAVS by seeking consensus between experts in the field. METHODS: Seven occupational physicians who are clinically active and have had work published on HAVS in the last 10 years were asked to independently take part in a three-round iterative Delphi process. Consensus was taken when 5/7 (72%) agreed with a particular statement. Experts were asked to provide evidence from the literature or data from their own research to support their views. RESULTS: Consensus was achieved for most of the questions that were used to develop an updated staging system for HAVS. The vascular and neurological components from the SWS are retained, but ambiguous descriptors and tests without adequately developed methodology such as tactile discrimination, or discriminating power such as grip strength, are not included in the new staging system. A blanching score taken from photographs of the hands during vasospastic episodes is recommended in place of self-recall and frequency of attacks to stage vascular HAVS. Methods with the best evidence base are described for assessing sensory perception and dexterity. CONCLUSIONS: A new classification has been developed with three stages for the clinical classification of vascular and neurological HAVS based on international consensus. We recommend it replaces the SWS for clinical and research purposes.

Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling.

Lithium chloride (LiCl) exhibits significant therapeutic potential as a treatment for osteoarthritis. Hedgehog signaling is activated in osteoarthritis, where it promotes chondrocyte hypertrophy and cartilage matrix catabolism. Hedgehog signaling requires the primary cilium such that maintenance of this compartment is essential for pathway activity. Here we report that LiCl (50 mM) inhibits Hedgehog signaling in bovine articular chondrocytes such that the induction of GLI1 and PTCH1 expression is reduced ​ by 71 and 55%, respectively. Pathway inhibition is associated with a 97% increase in primary cilia length from 2.09 ± 0.7 µm in untreated cells to 4.06 ± 0.9 µm in LiCl-treated cells. We show that cilia elongation disrupts trafficking within the axoneme with a 38% reduction in Arl13b ciliary localization at the distal region of the cilium, consistent with the role of Arl13b in modulating Hedgehog signaling. In addition, we demonstrate similar increases in cilia length in human chondrocytes in vitro and after administration of dietary lithium to Wistar rats in vivo. Our data provide new insights into the effects of LiCl on chondrocyte primary cilia and Hedgehog signaling and shows for the first time that pharmaceutical targeting of the primary cilium may have therapeutic benefits in the treatment of osteoarthritis.

Systematic Review: Occupational illness in the waste and recycling sector.

BACKGROUND: The waste and recycling sector is a growing part of industry. Whether health surveillance is indicated and how it should be undertaken is unclear. AIMS: To undertake a review of the literature to identify hazards to health, biological effects and occupational illnesses for workers in the sector. METHODS: A systematic review of the published literature and two UK databases. RESULTS: Rates of fatal, non-fatal injuries and self-reported work-related illness were found to be higher in the waste and recycling sector than in UK industry as a whole. There was an increased prevalence of respiratory, gastro-intestinal and skin complaints in workers exposed to compost relative to controls. They may also be at increased risk of extrinsic allergic alveolitis, allergic bronchopulmonary aspergillosis, occupational asthma and abnormalities of lung function. Workers involved with the recycling of batteries and cables may be at risk of lead poisoning and exposure to other heavy metals. There were case reports of mercury poisoning from the recycling of fluorescent lights. Cases of occupational asthma have been reported in association with wood and paper recycling. The recycling of e-waste may cause exposure to heavy metals and organic pollutants, such as polybrominated diphenyl ethers, dioxins and polyaromatic hydrocarbons, which have been associated with damage to DNA and adverse neonatal outcomes. CONCLUSIONS: Ill-health and adverse biological effects have been described in waste and recycling workers, but their true prevalence has probably not been captured. Targeted health surveillance may be required to assess exposure and to identify occupational illness.

Can skin disease cause neuropathic pain? A study in pachyonychia congenita.

INTRODUCTION: Pachyonychia congenita (PC) is a rare skin disorder caused by an autosomal dominant mutation in one of five genes encoding keratin (K6a, K6b, K6c, K16 or K17; each defining one PC subtype). Pain is a prominent symptom, but its severity and type are poorly characterized. METHODS: In total, 35 genotyped US patients with PC consented to clinical assessment including the quality of life (QoL) questionnaire EQ-5D-3L, the Brief Pain Inventory (BPI) and painDETECT. Abbreviated quantitative sensory testing (QST) was also performed, and included mechanical detection threshold (MDT), mechanical pain threshold (MPT), wind-up pain ratio (WUR) and vibration detection threshold (VDT). RESULTS: Significant pain in patients with PC was confirmed, as indicated by mean BPI severity and interference of 4.2 ± 1.7 and 4.4 ± 2.2, respectively, as well as QoL impairment, as indicated by mean EQ-5D index of 0.69 ± 0.18. PD identified neuropathic pain in 62% of patients, the remainder being nociceptive. The painDETECT score was most significantly related to EQ-5D index (R(2)  = 0.26, P = 0.02). The K17 and K6a subtypes exhibited significantly worse QoL (0.584 and 0.613 respectively) than the K16 and K6b subtypes (P = 0.02). In QST analysis, abnormal pressure pain (assessed as MPT) was frequently observed, with more than half of patients with PC affected (54%), and 57% of patients with K17 also exhibiting abnormality in minimum touch threshold (assessed as MDT, P < 0.05). Very few patients were receiving analgesic therapy appropriate for neuropathic pain. CONCLUSION: Significant neuropathic pain was observed in PC, which warrants appropriate treatment. The health states observed in this sample are at a level that the average US citizen would forfeit one-third of their remaining lifespan to avoid.

Primary cilia distribution and orientation during involution of the bovine mammary gland.

The regulation of mammary gland involution occurs through multiple levels including environmental factors, hormones, and local intramammary signals. Primary cilia (PC) are signaling organelles that sense biochemical and biophysical extracellular stimuli and are vital for cellular and tissue function. The aim of this study was to examine the distribution, incidence, and orientation of PC. Furthermore, we determined changes in expression levels of the signal transducer and activator of transcription (STAT)6 at the onset of bovine mammary gland involution. Mammary tissue was collected from pasture-fed, primiparous, nonpregnant Friesian dairy cows at mid lactation (n=5 per group) killed 6-h after milking (lactating controls) and during involution after 7 and 28 d of nonmilking (NM). Fluorescent immunohistochemistry and confocal microscopy of tissue sections showed that PC were present on luminal secretory epithelial cells (SEC), myoepithelial cells (MEC), and stromal fibroblast cells (SFC). Furthermore, in all 3 experimental groups, different PC positions or orientations relative to the cell surface were identified on SEC and MEC, which projected toward the lumen and were either straight, bent, or deflected against the apical cell surface, whereas PC in SFC were confined to the interalveolar space. However, by 28-d NM, fewer PC projected into the luminal space and most appeared deflected or projected toward the interalveolar space. Furthermore, by 28-d NM, with the increase in stromal connective tissue, more PC were detected within the interalveolar and interlobular stroma. At 28-d NM, we observed a decrease in luminal cilia relative to the total number of cilia. The number of ciliated cells in the total fraction (SEC, MEC, and SFC) was the same for all 3 groups, although in the luminal fraction (SEC and MEC), PC per nuclei increased by 28-d NM relative to lactation. At all 3 stages, we detected variations in shape and orientation of PC within the same alveolus, with some PC projecting directly into lumen, whereas others appeared to be bent or deflected flat against the cell surface. Within each treatment, the average number of bent cilia was low, whereas the average number of deflected cilia was higher than the average number of cilia projecting directly into the lumen. Quantitative real-time reverse transcription PCR analysis showed that expression levels of milk protein genes (αS1-casein, α-lactalbumin, and κ-casein) declined and that of lactoferrin increased in the involuted mammary tissue following NM, compared with lactating controls. Although STAT6 mRNA levels did not change following NM, STAT6 protein levels did increase following 28-d NM compared with the control lactation group. In conclusion, PC were detected in all cell types in the mammary gland, and changes in orientation during involution suggest the potential for PC to play a role in signal transduction through both mechanosensation and chemosensation. Furthermore, the STAT6-mediated signaling pathway may have a role during involution of the mammary gland.

The relationship between clinical and standardized tests for hand-arm vibration syndrome.

BACKGROUND: Standardized laboratory tests are undertaken to assist the diagnosis and staging of hand-arm vibration syndrome (HAVS), but the strength of the relationship between the tests and clinical stages of HAVS is unknown. AIMS: To assess the relationship between the results of thermal aesthesiometry (TA), vibrotactile (VT) thresholds and cold provocation (CP) tests with the modified Stockholm scales for HAVS and to determine whether the relationship is affected by finger skin temperature. METHODS: Consecutive records of workers referred to a Tier 5 HAVS assessment centre from 2006 to 2015 were identified. The diagnosis and staging of cases was undertaken from the clinical information contained in the records. Cases with alternative or mixed diagnoses were excluded and staging performed according to the modified Stockholm scale without knowledge of the results of the standardized laboratory tests. RESULTS: A total of 279 cases of HAVS were analysed. Although there was a significant trend for sensorineural (SN) and vascular scores to increase with clinical stage (P < 0.01), there was no significant difference in scores between 2SN early and 2SN late or between 2SN late and 3SN. There was moderate correlation between the TA and VT scores and the clinical SN stages (r = 0.6). This correlation did not change when subjects were divided into those with a finger skin temperature <30 and >30°C. CP scores distributed bimodally and correlated poorly with clinical staging (r = 0.2). CONCLUSIONS: Standardized SN tests distinguish between the lower Stockholm stages, but not above 2SN early. This has implications for health surveillance and UK policy.

Vascular hand-arm vibration syndrome--magnetic resonance angiography.

The diagnosis of vascular hand-arm vibration syndrome (HAVS) requires consistent symptoms, photographic evidence of digital blanching and sufficient exposure to hand-transmitted vibration (HTV; A(8) > 2.5 m/s2). There is no reliable quantitative investigation for distinguishing HAVS from other causes of Raynaud's phenomenon and from normal individuals. Hypothenar and thenar hammer syndromes produce similar symptoms to HAVS but are difficult to diagnose clinically and may be confused with HAVS. Magnetic resonance angiography (MRA) is a safe and minimally invasive method of visualizing blood vessels. Three cases of vascular HAVS are described in which MRA revealed occlusions of the ulnar, radial and superficial palmar arteries. It is proposed that HTV was the cause of these occlusions, rather than blows to the hand unrelated to vibration, the assumed mechanism for the hammer syndromes. All three cases were advised not to expose their hands to HTV despite one of them being at Stockholm vascular stage 2 (early). MRA should be the investigation of choice for stage 2 vascular HAVS or vascular HAVS with unusual features or for a suspected hammer syndrome. The technique is however technically challenging and best done in specialist centres in collaboration with an occupational physician familiar with the examination of HAVS cases. Staging for HAVS should be developed to include anatomical arterial abnormalities as well as symptoms and signs of blanching. Workers with only one artery supplying a hand, or with only one palmar arch, may be at increased risk of progression and therefore should not be exposed to HTV irrespective of their Stockholm stage.

PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes.

BACKGROUND: Expression of programmed death ligand 1 (PD-L1) in solid tumours has been shown to predict whether patients are likely to respond to anti-PD-L1 therapies. To estimate the therapeutic potential of PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression in a large collection of breast tumours. PATIENTS AND METHODS: Correlations between CD274 (PD-L1) copy number, transcript and protein levels were evaluated in tumours from 418 patients recruited to the METABRIC genomic study. Immunohistochemistry was used to detect PD-L1 protein in breast tumours in tissue microarrays from 5763 patients recruited to the SEARCH population-based study (N = 4079) and the NEAT randomised, controlled trial (N = 1684). RESULTS: PD-L1 protein data was available for 3916 of the possible 5763 tumours from the SEARCH and NEAT studies. PD-L1 expression by immune cells was observed in 6% (235/3916) of tumours and expression by tumour cells was observed in just 1.7% (66/3916). PD-L1 was most frequently expressed in basal-like tumours. This was observed both where tumours were subtyped by combined copy number and expression profiling [39% (17/44) of IntClust 10 i.e. basal-like tumours were PD-L1 immune cell positive; P < 0.001] and where a surrogate IHC-based classifier was used [19% (56/302) of basal-like tumours were PD-L1 immune cell positive; P < 0.001]. Moreover, CD274 (PD-L1) amplification was observed in five tumours of which four were IntClust 10. Expression of PD-L1 by either tumour cells or infiltrating immune cells was positively correlated with infiltration by both cytotoxic and regulatory T cells (P < 0.001). There was a nominally significant association between PD-L1 and improved disease-specific survival (hazard ratio 0.53, 95% confidence interval 0.26-1.07; P = 0.08) in ER-negative disease. CONCLUSIONS: Expression of PD-L1 is rare in breast cancer, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. PD-L1 inhibition may benefit the 19% of patients with basal-like tumours in which the protein is expressed. NEAT CLINICALTRIALSGOV: NCT00003577.

Attribution of mental illness to work: a Delphi study.

BACKGROUND: Clinicians may be asked whether mental ill-health has been caused by work but there is no guidance on how this judgement should be made. AIMS: To seek a consensus on the factors that should be considered and how they should be sought when attributing mental ill-health to work. METHODS: A three-round Delphi study involving expert academics, occupational physicians, psychiatrists and psychologists. We deemed consensus had been reached when 66% or more of the experts were in agreement. RESULTS: Of 54 invited experts, 35 (65%) took part in the first round, 30 of these 35 (86%) in the second and 29 of these 30 (97%) in the final round. Consensus was reached for 11 workplace stressors: high job strain; effort-reward imbalance; major trauma; interpersonal conflict; inadequate support; role ambiguity; person-job mismatch; organizational injustice; organizational culture; work scheduling and threats to job security. Seven personal factors were identified as being important: previous mental illness; personality traits of neuroticism; adverse life events or social circumstances; resilience; a family history of mental illness and secondary gain. The worker, manager and co-workers were thought to be the most useful sources of workplace information. Consensus was reached for a definition of occupational mental illness but not for a threshold of work-relatedness. CONCLUSIONS: The attribution of mental ill-health to work is complex and involves the consideration of both workplace stressors and personal factors of vulnerability. Clinical consultation with an occupational physician who is familiar with the workplace is central to the process.

Prevalence of human papillomavirus among oesophageal squamous cell carcinoma cases: systematic review and meta-analysis.

BACKGROUND: Oncogenic human papillomavirus (HPV) has been hypothesised as a risk factor for oesophageal squamous cell carcinoma (OSCC), but aetiological research has been limited by the varying methodology used for establishing HPV prevalence. The aims of this systematic review and meta-analysis were to estimate the prevalence of HPV DNA detected in OSCC tumours and the influence of study characteristics. METHODS: Study-level estimates of overall and type-specific HPV prevalence were meta-analysed to obtain random-effects summary estimates. RESULTS: This analysis included 124 studies with a total of 13 832 OSCC cases. The average HPV prevalence (95% confidence interval) among OSCC cases was 0.277 (0.234, 0.320) by polymerase chain reaction; 0.243 (0.159, 0.326) by in situ hybridisation; 0.304 (0.185, 0.423) by immunohistochemistry; 0.322 (0.154, 0.490) by L1 serology; and 0.176 (0.061, 0.292) by Southern/slot/dot blot. The highest HPV prevalence was found in Africa and Asia, notably among Chinese studies from provinces with high OSCC incidence rates. CONCLUSIONS: Future research should focus on quantifying HPV in OSCC cases using strict quality control measures, as well as determining the association between HPV and OSCC incidence by conducting large, population-based case-control studies. Such studies will provide a richer understanding of the role of HPV in OSCC aetiology.

Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients.

BACKGROUND: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. PATIENTS AND METHODS: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. RESULTS: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1). CONCLUSIONS: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.

Investigating the Needs and Concerns of Lesbian, Gay, Bisexual, Transgender, Queer, or Questioning Cancer Patients.

The needs and concerns of lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ+) patients with cancer remain poorly understood. This is important as LGBTQ+ patients have an elevated risk of developing certain cancers and have poorer oncologic outcomes compared to non-LGBTQ+ patients. The lack of research may be linked to the complexity of studying the needs and concerns of this patient population. This review aimed to describe the evidence that sought to identify the needs and concerns of LGBTQ+ cancer patients. Studies were extracted using keywords such as "LGBTQ" and "Oncology." Patient participants were excluded if they did not identify as LGBTQ+ and if they did not have cancer or were not cancer survivors. Healthcare professionals were excluded if they were not oncology specific. A total of 22 studies met our inclusion criteria. LGBTQ+ cancer patients expressed concerns surrounding heteronormative assumptions made by healthcare professionals, a lack of LGBTQ±specific cancer support groups, and psychosexual concerns such as erectile dysfunction following cancer treatment. Oncology healthcare professionals lacked the knowledge and education that are required to manage this patient cohort. Further research is required to investigate the needs and concerns of LGBTQ+ cancer patients specifically in the radiation oncology setting.

In praise of postgraduate career clinics: Translating health professionals' willingness to engagement.

AIM: To capture and retain healthcare staff in postgraduate courses relevant to individual career aspirations, service requirements and continuous practice development (CPD) within an English UK university. DESIGN: Two virtual career clinics for postgraduate practitioners to engage in CPD offers within the university. An online post-enrolment online survey to explore their experiences of engagement with the university. METHODS: Mixed: qualitative and quantitative methods. Engaging 10 participants attended the career clinics, and 42 participants with an online survey. RESULTS: The career clinics were well received by participants who mapped CPD requirements and individual career aspirations. The surveys exposed challenges with marketing and enrolment; however, these were mitigated with support. Four recommendations are presented within this paper applicable to the international postgraduate education of all health practitioners.

A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed, platinum-sensitive ovarian cancer.

BACKGROUND: Pertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer. PATIENTS AND METHODS: Patients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms. RESULTS: A total of 149 patients received either chemotherapy with pertuzumab (arm A, n=74) or chemotherapy alone (arm B, n=75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone. CONCLUSIONS: The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.

Primary cilia mediate mechanotransduction through control of ATP-induced Ca2+ signaling in compressed chondrocytes.

We investigated the role of the chondrocyte primary cilium in mechanotransduction events related to cartilage extracellular matrix synthesis. We generated conditionally immortalized wild-type (WT) and IFT88(orpk) (ORPK) mutant chondrocytes that lack primary cilia and assessed intracellular Ca(2+) signaling, extracellular matrix synthesis, and ATP release in response to physiologically relevant compressive strains in a 3-dimensional chondrocyte culture system. All conditions were compared to unloaded controls. We found that cilia were required for compression-induced Ca(2+) signaling mediated by ATP release, and an associated up-regulation of aggrecan mRNA and sulfated glycosaminosglycan secretion. However, chondrocyte cilia were not the initial mechanoreceptors, since both WT and ORPK cells showed mechanically induced ATP release. Rather, we found that primary cilia were required for downstream ATP reception, since ORPK cells did not elicit a Ca(2+) response to exogenous ATP even though WT and ORPK cells express similar levels of purine receptors. We suggest that purinergic Ca(2+) signaling may be regulated by polycystin-1, since ORPK cells only expressed the C-terminal tail. This is the first study to demonstrate that primary cilia are essential organelles for cartilage mechanotransduction, as well as identifying a novel role for primary cilia not previously reported in any other cell type, namely cilia-mediated control of ATP reception.

The incidence of type 2 diabetes in the United Kingdom from 1991 to 2010.

AIMS: To characterize the incidence of type 2 diabetes in the UK over the previous 20 years; and determine if there has been an increase in people aged 40 years or less at diagnosis. METHODS: For this retrospective cohort study, patients newly diagnosed with type 2 diabetes between 1991 and 2010 were identified from the UK Clinical Practice Research Datalink (CPRD). Patient data were grouped into 5-year intervals by year of diagnosis and age at diagnosis. A standardized incidence ratio (SIR) was determined (1991-1995 = 100). The percentage of newly diagnosed patients for each age group and aged ≤40 years was calculated for each 5-year calendar period. The incidence rate by age and 5-year calendar period was also determined. RESULTS: In 2010, the crude incidence rate of type 2 diabetes was 515 per 100,000 population. The overall SIR increased to 158 (95% CI 157-160, p < 0.001), 237 (235-238, p < 0.001) and 275 (273-276, p < 0.001) for 1996-2000, 2001-2005 and 2006-2010, respectively. For those ≤40, the respective values were 217 (209-226, p < 0.001), 327 (320-335, p < 0.001) and 598 (589-608, p < 0.001). An increase in incidence occurred with increasing 5-year calendar period. The incidence of type 2 diabetes was higher for males after the age of 40 and higher for females aged ≤40. The percentage of patients aged ≤40 years at diagnosis increased with each increasing 5-year calendar period (5.9, 8.4, 8.5 and 12.4%, respectively). CONCLUSIONS: There was a significant increase in the incidence of diagnosed type 2 diabetes between 1991 and 2010 and the proportion of people diagnosed at a relatively early age has increased markedly.