External validation of prognostic models to predict stillbirth using International Prediction of Pregnancy Complications (IPPIC) Network database: individual participant data meta-analysis.

OBJECTIVE: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. METHODS: MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. RESULTS: Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. CONCLUSIONS: The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Risk of fragility fracture among patients with late-onset psoriasis: a UK population-based study.

This study aimed to examine fracture risk in patients with late-onset psoriasis. A cohort study was conducted using primary care records from the Clinical Practice Research Datalink. Psoriasis patients had a 10% increased risk of fracture compared to matched controls (hazard ratio (HR) = 1.10; 95% confidence interval (CI) 1.04, 1.16). INTRODUCTION: This study aimed to examine fracture risk in patients with late-onset psoriasis and investigate the effect of methotrexate on fracture risk. METHODS: A cohort study was conducted using primary care records from the UK-based Clinical Practice Research Datalink. Individuals aged 40 years and over, with incident (new onset) diagnoses of psoriasis, were identified from 1990 to 2004 and followed up until 2015. For each exposed individual, up to four age-, gender-, and practice-matched controls were randomly selected. Incidence rates of fragility fracture (hip, vertebral, spine, radius or unspecified site) per 10,000 person-years were calculated and hazard rates were compared to the unexposed using Cox regression models. The risk of fracture was also estimated, within the exposed group for patients receiving/not receiving methotrexate. RESULTS: Twenty-four thousand two hundred nineteen patients with psoriasis and 94,820 controls were identified. The absolute rate of fracture in psoriasis patients was 58 per 10,000 person-years (95% CI 55, 61) and 53 per 10,000 person-years in the matched controls (CI 52, 54). Psoriasis patients had a 10% increased risk of fracture compared to their matched controls (HR = 1.10; 95% CI 1.04, 1.16). Methotrexate use was not associated with increased risk (HR = 0.91; 95% CI 0.72, 1.15). CONCLUSIONS: Identifying additional clinical factors associated with increased fracture risk is important in improving fracture risk stratification. Further work is needed to determine the relationship between age of onset of psoriasis and fracture risk, explore causative explanations, and identify if existing fracture risk stratification tools underestimate fracture risk in patients with psoriasis.

A mixed methods exploration of physiotherapist's approaches to analgesic use among patients with hip osteoarthritis.

OBJECTIVE: To explore how physiotherapists currently address analgesic use among patients with hip osteoarthritis, and their beliefs about the acceptability of prescribing for these patients. METHODS: A cross-sectional questionnaire was mailed to 3126 UK-based physiotherapists. Approaches to analgesic use among patients with hip osteoarthritis were explored using a case vignette. Semi-structured telephone interviews were undertaken with 21 questionnaire responders and analysed thematically. SETTING: UK. PARTICIPANTS: Physiotherapists who had treated a patient with hip osteoarthritis in the previous 6 months. RESULTS: Questionnaire response: 53% (n=1646). One thousand one hundred forty eight physiotherapists reported treating a patient with hip osteoarthritis in the last 6 months (applicable responses), of whom nine (1%) were non-medical prescribers. Nearly all physiotherapists (98%) reported that they would address analgesic use for the patient with hip osteoarthritis, most commonly by signposting them to their GP (83%). Fifty six percent would discuss optimal use of current medication, and 33%, would discuss use of over-the-counter medications. Interviews revealed that variations in physiotherapists' approaches to analgesic use were influenced by personal confidence, patient safety concerns, and their perceived professional remit. Whilst many recognised the benefits of analgesia prescribing for both patients and GP workload, additional responsibility for patient safety was a perceived barrier. CONCLUSIONS: How physiotherapists currently address analgesic use with patients with hip osteoarthritis is variable. Although the potential benefits of independent prescribing were recognised, not all physiotherapist want the additional responsibility. Further guidance supporting optimisation of analgesic use among patients with hip OA may help better align care with best practice guidelines and reduce GP referrals.

Applying causal mediation methods to clinical trial data: What can we learn about why our interventions (don't) work?

BACKGROUND: Many randomized controlled trials (RCTs) of psychosocial interventions for low back pain (LBP) have been found to have only small effects on disability outcomes. Investigations of the specific mechanisms that may lead to an improvement in outcome have therefore been called for. METHODS: We present an application of the causal inference approach to mediation analysis using the example of a cluster RCT in a primary care population with (sub)acute LBP randomized to either usual GP care (n = 171) or a minimal psychosocial intervention (n = 143). Mediation analysis explored the causal pathway between treatment allocation and disability at 3 months by considering pain catastrophizing, fear-avoidance beliefs, distress and receiving and following advice as potential mediators, all measured at 6 weeks. We have attempted to explain this approach to mediation analysis in a step-by-step manner to help clinical researchers apply this method more easily. RESULTS: In unadjusted mediation analyses, fear-avoidance beliefs were identified as a mediator of treatment on disability, with an indirect effect of -0.30 (95% CI: -0.86, -0.03), although this relationship was found to be non-significant after adjusting for age, gender and baseline scores. This finding supports the trial authors' hypothesis that while fear-avoidance beliefs are important, this intervention may not have targeted them strongly enough to lead to change. CONCLUSION: The use of mediation analysis to identify what factors may be part of the causal pathway between intervention and outcome, regardless of whether the intervention was successful, can provide useful information and insight into how to improve future interventions. SIGNIFICANCE: This study presents a step-by-step approach to mediation analysis using the causal inference framework to investigate why a psychosocial intervention for LBP was unsuccessful. Fear-avoidance beliefs were found to mediate the relationship between treatment and disability, although not when controlling for baseline scores.

Brachial plexopathy in breast carcinoma--an unsolved problem.

Brachial plexus involvement from carcinoma of the breast produces a severe disability which presents difficulties in diagnosis and treatment. Five patients who suffered this complication are described and the problems they present are discussed.

Radiation retinopathy following treatment of posterior nasal space carcinoma.

Posterior nasal space carcinoma has a high mortality and most patients are treated with radiotherapy. Radiation retinopathy was encountered in 7 out of 10 survivors included in this study. Five of the affected patients lost vision as a result of the retinopathy. One patient required laser photocoagulation and responded well to this treatment. There was a variation in the severity of the retinopathy among the patients studied despite the fact that all patients received a similar dose of radiotherapy. We suspect that previously unrecognised factors in the planning of radiotherapy fields may explain this difference.

Human antiretinal antibodies in toxoplasma retinochoroiditis.

BACKGROUND/AIMS: Toxoplasma retinochoroiditis (TR) is an important cause of blindness and visual morbidity, affecting young adults. It has been postulated that some of the retinal damage observed in TR is due to antiretinal autoimmune mechanisms. METHODS: Humoral antiretinal autoimmunity in TR was investigated by indirect immunofluorescence (IIF) on normal human cadaveric retina and by a human retinal S-antigen ELISA. 36 patients with TR were separated on clinical grounds into those with first recurrence of disease (n = 18) or those with multiple recurrences (n = 18). Patients were also segregated into those with active (n = 28) or quiescent disease (n = 8). Serum from 16 normal controls (six with positive toxoplasma serology and 10 without) with no evidence of eye disease and 12 patients with idiopathic retinal vasculitis (IRV) were also tested. RESULTS: Sera from 34 of the 36 patients (94%) with TR demonstrated photoreceptor layer reactivity by IIF contrasting with six of 16 normal controls (p = < 0.001) and three of 12 IRV patients (p = < 0.001). Titres of antiphotoreceptor antibody were also higher among TR patients than controls. Sera from 27 of the 36 TR patients, 10 of 16 normals, and nine of 12 retinal vasculitis patients possessed anti-human retinal S-antigen antibodies at a titre of 1:400 or more as assessed by ELISA (p = > 0.05). Antiretinal autoantibody as detected by IIF did not run in parallel with S-antigen reactivity. CONCLUSIONS: The data indicate that the extent of antiretinal reactivity within TR is not accounted for by anti-S-antigen antibodies alone. This remarkably high prevalence of antiphotoreceptor antibody in TR as opposed to that found in either healthy or disease controls suggest that these antibodies may be co-pathogenic in toxoplasma retinochoroiditis.

Glottic cancer: results of treatment with radiotherapy in air and hyperbaric oxygen.

This paper is a retrospective analysis of 397 patients with glottic cancer, in which 240 patients were treated in air, and 157 patients in a hyperbaric oxygen chamber (HBO). The three principal dose/time schedules in air and HBO are contrasted, and shown to be iso-effective. The local tumour control rates show a significant improvement in favor of HBO: Stage I, 10%; Stage II, 37%; Stage III, 73%. Morbidity rates are explored, and suggest that the increased local control rate is not attained at the cost of an increased morbidity rate. The planning of the treatment, the preparation of the patient, and any subsequent complications are described. Treatment in the HBO chamber in a busy department has been shown to be a safe and routine procedure.

Physiologic comparison and validation of Stairobic stepping with bench stepping.

To compare the oxygen cost of submaximal exercise on the Stairobic stepping (SS) machine with bench stepping (BS), 12 healthy men and women (mean age 23 years) underwent six different five minute exercise bouts that were randomly assigned. Tests were conducted using standard open circuit calorimetry. SS at 40 and 60 st/min was equal to BS at 20 st/min and SS at 80 st/min was equal to BS at 30 st/min for VE and RER. VO2 was equal at 20 st/min (BS) and 60 st/min (SS), and 30 st/min (BS) and 80 st/min (SS). Stairobic MET (SM) displayed values over-estimated actual MET (AM) values at the two lowest SS rates and under-estimated the AM value at the highest SS rate. Forty-eight observations of the MET response of SS were conducted and analyzed (BMDP2R) in a forward stepping solution. The multiple regression equation calculated for AM was: AM = -0.567 + -0.012 (WT) + 0.063 (rate) + 0.612 (SM) with an adjusted R2 of 0.82 and a SEE of 0.90. The physiologic cost of BS was approximately equal to SS at two to three times the BS rate of stepping.

Effect of controlled burning on survival of floodwater Aedes eggs in Kenya.

The effect of controlled burning on the survival of Aedes mosquito eggs was evaluated in 2 distinct dambo habitats. In a dambo dominated by grasses, egg survival was 3.3% after burning compared with 43.8% in a similar dambo that was not burned. In a dambo dominated by sedges, egg survival was 0.7% after burning compared with 28.5% in a similar dambo that was not burned. Mortality of mosquito eggs appeared to be caused by high temperatures associated with the fire and not elapsed time since egg survival did not decrease with time after burning. The potential for burning to control the mosquito vectors of Rift Valley fever virus is discussed.

Generalised glycogenosis in Brahman cattle.

Generalised glycogenosis was diagnosed in Brahman cattle on 4 Queensland properties on the basis of clinical observations and pathological and biochemical findings. The disease presented as a problem of ill-thrift and poor growth rate in calves which eventually showed nervous signs. Histologically there was vacuolation in the cells of the central nervous system, heart and muscular tissues. Biochemical assay of liver and blood mononuclear cells demonstrated a deficiency of alpha-glucosidase. Parents of affected calves had approximately half the alpha-glucosidase activity of that found in normal cattle.

[The dual function of the proliferating cell nuclear antigen (PCNA) in the response of human cells to UV damages]. / Dvoistvennaia funktsiia iadernogo antigena proliferiruiushchikh kletok (PCNA) v otvete kletok cheloveka na UF-povrezhdeniia.

An auxiliary protein of DNA polymerases delta and epsilon, the proliferating cell nuclear antigen (PCNA), is necessary for efficient DNA replication in vivo and in vitro, and also for the repair synthesis in vitro, but its role in the excision repair of genome in vivo is not exactly established. In S-phase of unirradiated cells, PCNA is tightly bound to focal centers of DNA replication and is not removed by treatment with detergent Triton X-100, but is completely extracted from non-S-phase cells by the indicated detergent. It was shown earlier that after UV-irradiation PCNA could not be removed by the detergent even from non-S-phase cells. It was interpreted as the evidence of PCNA integration into the repair complex and of the participation of this protein in repair synthesis in vivo. In the present work the data were obtained indicating that the role of PCNA in cell response to UV-damage was not confined only to its possible involvement in repair synthesis. With the help of confocal microscopy it was established that in Triton X-100-extracted normal cells PCNA did not colocalize with the well known excision repair protein XPB/ERCC3, defective in cells from Xeroderma pigmentosum (complementation group B) patients. XPB-protein is induced by UV-irradiation in normal cells, and this induction is not observed in repair deficient cells. However, in such cells UV-light induces a detergent-resistant form of PCNA, and this form is obviously not connected with repair. It cannot be excluded that a rapid PCNA immobilization immediately after UV-irradiation of cells is needed for the facilitation of photochemical damage bypass during the subsequent replication of genome.

Investigations into the lack of consensus in the reporting of HLA antibody specificities in the UK.

AIMS: Lack of consensus in HLA antibody reporting in proficiency schemes has previously been attributed to a number of differing factors. This study was set up to eliminate the majority of these factors by reducing analysis to a pure data handling exercise. METHODS: Anonymised raw data files for LABScreen Single Antigen class I and II and related patient information were provided to seven participating centres. The centres reported back the HLA antibody specificities according to their single antigen bead reporting policy. Details of the reporting policy of each centre were retrospectively requested by questionnaire. RESULTS: The number of HLA antibody specificities reported by the different centres varied widely. Software analysis called more HLA antibody specificities than any of the centres. None of the centres matched consensus for reported HLA class I specificities on any of the datasets, and no two centres reported the exact same HLA class I antibody profile; consensus was reached by one centre for HLA class II antibody specificities reported from two of the datasets. Retrospective review found data handling practice between centres to vary widely. CONCLUSIONS: Lack of agreement exists between UK centres in regard to HLA antibody specificity analysis. The fact that the required analysis was limited to interrogation of supplied data files makes the observation more concerning. The root cause of this variation is differences in data handling practice between the participating centres.

Rectal fist insertion. An unusual form of sexual behavior.

Rectal fist insertion (fist fucking) is an uncommon and potentially dangerous sexual practice. This is usually a homosexual activity, but can also be a heterosexual or an autoerotic practice. One known death has been reported associated with rectal fist insertion, in which the complications of anal and colonic tears and bleeding had occurred (see Editor's note). The possibility of drug overdose is also probable, as drugs and alcohol are commonly introduced into the rectum to promote sphincter relaxation and to ease the discomfort of anal dilatation.

Electronic Band Structure of Monolayer Bi on GaP(110).

The two-dimensional electronic band structure of monolayer Bi on GaP(110) has been mapped using angle-resolved UV photoelectron spectroscopy (ARUPS) with synchrotron radiation. Surface photovoltage effects are corrected for by simultaneous second-order core spectroscopy. From valence-band spectra along the four symmetry directions of the surface Brillouin zone at three photon energies it is possible to distinguish three states as surface related. The topmost band is found to be inside the fundamental band gap, at ca 0.75 eV above the bulk valence-band maximum. Comparison with other V/III-V(110) systems shows that this system is not significantly different, despite the relatively large size of the Bi atoms with respect to the GaP lattice; in a selective comparison with InP and GaAs it would appear that Bi-substrate anion bonding is a more important factor than strain.