Does the Mutation Type Affect the Response to Cranial Vault Expansion in Children With Apert Syndrome?

LEVEL OF EVIDENCE: III.

Late Deformity Following Fronto-Orbital Reconstructive Surgery for Metopic Synostosis: The Role of Temporalis Muscle.

ABSTRACT: Theories for late-developing deformity (LDD) following fronto-orbital reconstructive surgery (FOR) for metopic synostosis (MS) must explain both its delayed onset and its physical characteristics. This study examined whether FOR-related interference with the normal childhood expansion of temporalis is responsible for its soft tissue component.Three-dimensional reformats of preoperative and postoperative computed tomography scans of MS patients were reviewed. Measurements of vertical and horizontal reach of temporalis against those of the underlying skull (to allow for normal skull growth) were compared with normal subjects. The thickness of temporalis and the development of the temporal crests were also assessed.Mean age at FOR was 17.1 months; interval between surgery and first report of LDD 4.7 years; mean age at computed tomography scan for post-FOR LDD patients 8.8 years. There was a significant difference between vertical and horizontal reach of temporalis in pre-FOR MS patients compared to normal subjects ( P < 0.0017 and P < 0.05, respectively). The vertical age-related reach of temporalis in post-FOR patients after allowing for underlying skull growth was significantly reduced ( P = 0.0045) compared to normal subjects but not its horizontal reach ( P = 0.25). Temporal crests in LDD patients were absent or aberrantly formed while muscle thickness was similar to normal subjects at the 2 levels measured.This study supports the theory that failure of the normal childhood expansion of temporalis is responsible for the soft tissue element of LDD, accounting for both its delayed onset and physical characteristics. Aberrant temporal crest development suggests FOR-related damage as the probable cause.

Structure of a VirD4 coupling protein bound to a VirB type IV secretion machinery.

Type IV secretion (T4S) systems are versatile bacterial secretion systems mediating transport of protein and/or DNA T4S systems are generally composed of 11 VirB proteins and 1 VirD protein (VirD4). The VirB1-11 proteins assemble to form a secretion machinery and a pilus while the VirD4 protein is responsible for substrate recruitment. The structure of VirD4 in isolation is known; however, its structure bound to the VirB1-11 apparatus has not been determined. Here, we purify a T4S system with VirD4 bound, define the biochemical requirements for complex formation and describe the protein-protein interaction network in which VirD4 is involved. We also solve the structure of this complex by negative stain electron microscopy, demonstrating that two copies of VirD4 dimers locate on both sides of the apparatus, in between the VirB4 ATPases. Given the central role of VirD4 in type IV secretion, our study provides mechanistic insights on a process that mediates the dangerous spread of antibiotic resistance genes among bacterial populations.

Observations on the growth of temporalis muscle: A 3D CT imaging study.

This study investigates the hypothesis that there is, during childhood, a disproportionate age-related expansion of the origin of temporalis muscle compared to the growth of the underlying skull. Lateral projections of 50 randomly selected 3D reformatted computerized tomographic (CT) scans (yielding 100 temporalis muscles) of children aged >0.6 to 15 years scanned for conditions that did not affect the shape of their head or face were windowed to provide the optimum delineation of temporalis muscle against the underlying bone. Vertical and anterior-posterior measurements of the muscle made independently by two observers were compared with those of the skull along the same planes. The development of the anterior temporal crest was also assessed. The intraclass correlation coefficient for differences in the measurements made by each observer ranged from good to excellent. The muscle and skull measurements were used to produce a ratio of muscle-to-skull lengths in both vertical and horizontal planes. Analysis of these ratios showed a statistically significant increase in the vertical reach of temporalis with age (Pearson correlation coefficient (R) =0.7826; p < 0.05) compared to the growth of the skull along the planes chosen for the study-but less so for its horizontal reach (R = 0.5073. p < .001). There were no significant differences between right/left or male/female measurements. There was also a substantial level of agreement between both observers in their assessment of the development of the temporal crest. The mean age of children in whom a fully formed temporal crest could be identified (10.6 years) was significantly greater (p < 0.001) than that of the 38 remaining subjects (6.0 years). These results confirm that there is, in response to increased masticatory/dietary demands during childhood, a disproportionate increase in the vertical and (to a lesser extent) horizontal reach of temporalis muscle over its origin from the temporal, frontal, sphenoid, and parietal bones compared the growth of the skull. It is proposed that surgical interference with this normal process is responsible for the soft tissue component of late-developing deformity that can occur following early (at 6-18 months of age) operations for the correction of trigonocephalic head shape associated with metopic synostosis.

Indicators of dementia disease progression in primary care: An electronic health record cohort study.

BACKGROUND AND PURPOSE: The objectives were to assess the feasibility and validity of using markers of dementia-related health as indicators of dementia progression in primary care, by assessing the frequency with which they are recorded and by testing the hypothesis that they are associated with recognised outcomes of dementia. The markers, in 13 domains, were derived previously through literature review, expert consensus, and analysis of regional primary care records. METHODS: The study population consisted of patients with a recorded dementia diagnosis in the Clinical Practice Research Datalink, a UK primary care database linked to secondary care records. Incidence of recorded domains in the 36 months after diagnosis was determined. Associations of recording of domains with future hospital admission, palliative care, and mortality were derived. RESULTS: There were 30,463 people with diagnosed dementia. Incidence of domains ranged from 469/1000 person-years (Increased Multimorbidity) to 11/1000 (Home Pressures). An increasing number of domains in which a new marker was recorded in the first year after diagnosis was associated with hospital admission (hazard ratio for ≥4 domains vs. no domains = 1.24; 95% confidence interval = 1.15-1.33), palliative care (1.87; 1.62-2.15), and mortality (1.57; 1.47-1.67). Individual domains were associated with outcomes with varying strengths of association. CONCLUSIONS: Feasibility and validity of potential indicators of progression of dementia derived from primary care records are supported by their frequency of recording and associations with recognised outcomes. Further research should assess whether these markers can help identify patients with poorer prognosis to improve outcomes through stratified care and targeted support.

Spring-assisted posterior vault expansion-a single-centre experience of 200 cases.

PURPOSE: Children affected by premature fusion of the cranial sutures due to craniosynostosis can present with raised intracranial pressure and (turri)brachycephalic head shapes that require surgical treatment. Spring-assisted posterior vault expansion (SA-PVE) is the surgical technique of choice at Great Ormond Street Hospital for Children (GOSH), London, UK. This study aims to report the SA-PVE clinical experience of GOSH to date. METHODS: A retrospective review was carried out including all SA-PVE cases performed at GOSH between 2008 and 2020. Demographic and clinical data were recorded including genetic diagnosis, craniofacial surgical history, surgical indication and assessment, age at time of surgery (spring insertion and removal), operative time, in-patient stay, blood transfusion requirements, additional/secondary (cranio)facial procedures, and complications. RESULTS: Between 2008 and 2020, 200 SA-PVEs were undertaken in 184 patients (61% male). The study population consisted of patients affected by syndromic (65%) and non-syndromic disorders. Concerns regarding raised intracranial pressure were the surgical driver in 75% of the cases, with the remainder operated for shape correction. Median age for SA-PVE was 19 months (range, 2-131). Average operative time for first SA-PVE was 150 min and 87 for spring removal. Median in-patient stay was 3 nights, and 88 patients received a mean of 204.4 ml of blood transfusion at time of spring insertion. A single SA-PVE sufficed in 156 patients (85%) to date (26 springs still in situ at time of this analysis); 16 patients underwent repeat SA-PVE, whilst 12 underwent rigid redo. A second SA-PVE was needed in significantly more cases when the first SA-PVE was performed before age 1 year. Complications occurred in 26 patients with a total of 32 events, including one death. Forty-one patients underwent fronto-orbital remodelling at spring removal and 22 required additional cranio(maxillo)facial procedures. CONCLUSIONS: Spring-assisted posterior vault expansion is a safe, efficient, and effective procedure based on our 12-year experience. Those that are treated early in life might require a repeat SA-PVE. Long-term follow-up is recommended as some would require additional craniomaxillofacial correction later in life.

Markers of dementia-related health in primary care electronic health records.

OBJECTIVES: Identifying routinely recorded markers of poor health in patients with dementia may help treatment decisions and evaluation of earlier outcomes in research. Our objective was to determine whether a set of credible markers of dementia-related health could be identified from primary care electronic health records (EHR). METHODS: The study consisted of (i) rapid review of potential measures of dementia-related health used in EHR studies; (ii) consensus exercise to assess feasibility of identifying these markers in UK primary care EHR; (iii) development of UK EHR code lists for markers; (iv) analysis of a regional primary care EHR database to determine further potential markers; (v) consensus exercise to finalise markers and pool into higher domains; (vi) determination of 12-month prevalence of domains in EHR of 2328 patients with dementia compared to matched patients without dementia. RESULTS: Sixty-three markers were identified and mapped to 13 domains: Care; Home Pressures; Severe Neuropsychiatric; Neuropsychiatric; Cognitive Function; Daily Functioning; Safety; Comorbidity; Symptoms; Diet/Nutrition; Imaging; Increased Multimorbidity; Change in Dementia Drug. Comorbidity was the most prevalent recorded domain in dementia (69%). Home Pressures were the least prevalent domain (1%). Ten domains had a statistically significant higher prevalence in dementia patients, one (Comorbidity) was higher in non-dementia patients, and two (Home Pressures, Diet/Nutrition) showed no association with dementia. CONCLUSIONS: EHR captures important markers of dementia-related health. Further research should assess if they indicate dementia progression. These markers could provide the basis for identifying individuals at risk of faster progression and outcome measures for use in research.

Chlamydia exploits filopodial capture and a macropinocytosis-like pathway for host cell entry.

Pathogens hijack host endocytic pathways to force their own entry into eukaryotic target cells. Many bacteria either exploit receptor-mediated zippering or inject virulence proteins directly to trigger membrane reorganisation and cytoskeletal rearrangements. By contrast, extracellular C. trachomatis elementary bodies (EBs) apparently employ facets of both the zipper and trigger mechanisms and are only ~400 nm in diameter. Our cryo-electron tomography of C. trachomatis entry revealed an unexpectedly diverse array of host structures in association with invading EBs, suggesting internalisation may progress by multiple, potentially redundant routes or several sequential events within a single pathway. Here we performed quantitative analysis of actin organisation at chlamydial entry foci, highlighting filopodial capture and phagocytic cups as dominant and conserved morphological structures early during internalisation. We applied inhibitor-based screening and employed reporters to systematically assay and visualise the spatio-temporal contribution of diverse endocytic signalling mediators to C. trachomatis entry. In addition to the recognised roles of the Rac1 GTPase and its associated nucleation-promoting factor (NPF) WAVE, our data revealed an additional unrecognised pathway sharing key hallmarks of macropinocytosis: i) amiloride sensitivity, ii) fluid-phase uptake, iii) recruitment and activity of the NPF N-WASP, and iv) the localised generation of phosphoinositide-3-phosphate (PI3P) species. Given their central role in macropinocytosis and affinity for PI3P, we assessed the role of SNX-PX-BAR family proteins. Strikingly, SNX9 was specifically and transiently enriched at C. trachomatis entry foci. SNX9-/- cells exhibited a 20% defect in EB entry, which was enhanced to 60% when the cells were infected without sedimentation-induced EB adhesion, consistent with a defect in initial EB-host interaction. Correspondingly, filopodial capture of C. trachomatis EBs was specifically attenuated in SNX9-/- cells, implicating SNX9 as a central host mediator of filopodial capture early during chlamydial entry. Our findings identify an unanticipated complexity of signalling underpinning cell entry by this major human pathogen, and suggest intriguing parallels with viral entry mechanisms.

Patterns of symptoms before a diagnosis of first episode psychosis: a latent class analysis of UK primary care electronic health records.

BACKGROUND: The nature of symptoms in the prodromal period of first episode psychosis (FEP) remains unclear. The objective was to determine the patterns of symptoms recorded in primary care in the 5 years before FEP diagnosis. METHODS: The study was set within 568 practices contributing to a UK primary care health record database (Clinical Practice Research Datalink). Patients aged 16-45 years with a first coded record of FEP, and no antipsychotic prescription more than 1 year prior to FEP diagnosis (n = 3045) was age, gender, and practice matched to controls without FEP (n = 12,180). Fifty-five symptoms recorded in primary care in the previous 5 years, categorised into 8 groups (mood-related, 'neurotic', behavioural change, volition change, cognitive change, perceptual problem, substance misuse, physical symptoms), were compared between cases and controls. Common patterns of symptoms prior to FEP diagnosis were identified using latent class analysis. RESULTS: Median age at diagnosis was 30 years, 63% were male. Non-affective psychosis (67%) was the most common diagnosis. Mood-related, 'neurotic', and physical symptoms were frequently recorded (> 30% of patients) before diagnosis, and behavioural change, volition change, and substance misuse were also common (> 10%). Prevalence of all symptom groups was higher in FEP patients than in controls (adjusted odds ratios 1.33-112). Median time from the first recorded symptom to FEP diagnosis was 2-2.5 years except for perceptual problem (70 days). The optimal latent class model applied to FEP patients determined three distinct patient clusters: 'no or minimal symptom cluster' (49%) had no or few symptoms recorded; 'affective symptom cluster' (40%) mainly had mood-related and 'neurotic' symptoms; and 'multiple symptom cluster' (11%) consulted for three or more symptom groups before diagnosis. The multiple symptom cluster was more likely to have drug-induced psychosis, female, obese, and have a higher morbidity burden. Affective and multiple symptom clusters showed a good discriminative ability (C-statistic 0.766; sensitivity 51.2% and specificity 86.7%) for FEP, and many patients in these clusters had consulted for their symptoms several years before FEP diagnosis. CONCLUSIONS: Distinctive patterns of prodromal symptoms may help alert general practitioners to those developing psychosis, facilitating earlier identification and referral to specialist care, thereby avoiding potentially detrimental treatment delay.

One Face of Chlamydia trachomatis: The Infectious Elementary Body.

The lifestyle of Chlamydiae is unique: the bacteria alternate between two morphologically distinct forms, an infectious non-replicative elementary body (EB), and a replicative, non-infectious reticulate body (RB). This review focuses on recent advances in understanding the structure and function of the infectious form of the best-studied member of the phylum, the human pathogen Chlamydia trachomatis. Once considered as an inert particle of little functional capacity, the EB is now perceived as a sophisticated entity that encounters at least three different environments during each infectious cycle. We review current knowledge on its composition and morphology, and emerging metabolic activities. These features confer resistance to the extracellular environment, the ability to penetrate a host cell and ultimately enable the EB to establish a niche enabling bacterial survival and growth. The bacterial and host molecules involved in these processes are beginning to emerge.

The impact of socioeconomic status on the link between osteoarthritis and the onset of common comorbidities.

OBJECTIVES: The temporal relationship between osteoarthritis and comorbidity is unclear and may vary with socioeconomic status. The aims of this study were to identify if osteoarthritis was associated with onset of common comorbidities, and if the association was moderated by deprivation. METHODS: Prospective cohort study combining questionnaire and medical record data (n=3910). Associations between osteoarthritis and onset of comorbidity at the three-year follow-up were examined using regression models. Interaction terms and stratified analysis were used to examine moderation. RESULTS: Osteoarthritis was associated with onset of all comorbidities (p<0.05). After adjusting for confounders, osteoarthritis was associated with onset of widespread pain (adjusted odds ratio 2.49; 95% confidence interval 1.96-3.17) and insomnia (1.58;1.14-1.19). Interactions between osteoarthritis and change in income and onset cognitive impairment (p=0.047; onset was higher when income became inadequate), and between osteoarthritis and education and onset widespread pain (p=0.012; onset was higher in those with high levels of education) were significant. CONCLUSIONS: Consulters for osteoarthritis were more likely to develop physical and psychological comorbidities than those without osteoarthritis. The moderation analyses indicated that mechanisms to comorbidity differ by socio-economic strata and a need for different approaches to prevent comorbidity for consulters with OA from different levels of deprivation.

Childhood medulloblastoma-a single institution's historical perspective on survival and functional morbidity.

PURPOSE: To compare results from a third (1995-2010) cohort of children with medulloblastoma with two previous series (J Neurosurg 86:13-21, 1997; Arch Dis Child 54:200-203, 1979) to analyse the effects of management changes aimed at improving both overall and event-free survivals (OS and EFS) and functional outcomes. METHODS: Review of neuro-oncology and imaging databases and previously published results. RESULTS: There was no statistically significant improvement in the 5-year OS for 104 children diagnosed 1995-2010, 61.5% (95% CI, 52.9, 71.6), compared with 50% of the 80 children presenting 1980-1990 (J Neurosurg 86:13-21, 1997) (difference 11.5%; 95% CI, 2.8, 25.4). Five-year OS for 96 children suitable for risk-stratification was overall 66% (95% CI, 57.9, 75.8); standard risk 77.8% (95% CI, 67.4, 89.7); high risk < 3 years 50.0% (95% CI, 32.3, 77.5); high risk ≥ 3 years 54.5% (95% CI, 37.2, 79.9); 5-year EFS were standard risk 68.5% (95% CI, 57.2, 82.1); high risk < 3 years 40.0% (95% CI, 23.4, 68.4); and high risk ≥ 3 years 36.4% (95% CI, 20.9, 63.2); overall 55.2% (95% CI, 46.1, 66.1). Of 62/63 ≥ 5-year survivor, 9 died later from tumour relapse and 4 from second malignancy. Functional outcomes of 62 of the 63 ≥ 5-year survivors: 67.7% had educational issues requiring remedial input; 18% restricted mobility indoors and outdoors; 59.7% hearing impairment (42% prescribed aids). CONCLUSIONS: 1. Comparison of this single-institution series with its predecessor found that revised chemotherapy and RT protocols and greater accuracy of risk stratification did not result in statistically significant improvements in either survival or treatment-related functional disability. 2. Extended (> 5-year) follow-up is essential if 20% of late deaths from relapse and second malignancies are not to be overlooked.

Trends in prescribing of non-steroidal anti-inflammatory drugs in patients with cardiovascular disease: influence of national guidelines in UK primary care.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, but have potential side effects in patients with cardiovascular disease (CVD). Objectives: To determine trends in NSAIDs prescribing between 2002 and 2010 in patients with CVD, and ascertain whether prescribing patterns changed following publication of major national (the Medicines and Healthcare products Regulatory Agency (MHRA) and the National Institute for Health and Clinical Excellence (NICE)) guidance to GPs. Methods: This was an observational database study of adult patients in 11 practices (Staffordshire, England). NSAIDs were categorised into basic, COX-2 and topical. Study duration was divided on a quarterly basis from 2002-quarter-1 to 2010q4. CVD patients were identified using pre-defined Read Codes recorded in the two years prior to each quarter. Quarterly prevalence was determined. Times of significant changes in prescribing trends were determined using Joinpoint Regression, and compared to dates of the five major guidelines (in 2004q4, 2005q1, 2005q3, 2006q4, 2008q1). Results: In CVD patients, the prescription of basic NSAIDs showed a decreasing trend throughout the study period, from 774 (95% CI, 691-863) per 10000 patients in 2002q1 to 245 (204-291) in 2010q4. COX-2 prescribing increased from 232/10000 (187-286) in 2002q1 to 403/10000 (348-464) in 2004q3. Prescribing then fell sharply to 102/10000 (76-134) in 2005q2 before stabilising around 55/10000. Topical NSAIDs prescribing showed a steady increase, starting at 115/10000 (108-123) in 2002q1 and ending at 270/10000 (258-281) in 2010q4. Similar trends were observed in patients without CVD, particularly a sharp drop in COX-2 prescribing also occurred from 2004q4 when initial MHRA guidance was issued. Conclusion: Despite guidelines and a trend toward decreased prescribing, the use of potentially harmful NSAIDs continued in CVD patients. The MHRA directives potentially might have affected patients without CVD who may have inappropriately restricted their use of COX-2.

Outcomes in children with central nervous system tumors disseminated at presentation: a large single-center experience.

PURPOSE: Children with disseminated central nervous system (CNS) tumors have worse outcomes than those with solitary disease, but outcomes of disease dissemination at initial presentation have not been systematically studied and compared across tumor groups to date. We evaluated the impact of tumor dissemination at presentation on management and clinical outcomes in a cohort of consecutively treated children in a single neurosurgical unit over a 14-year period. METHODS: Method used was a retrospective review of data on children presenting to Great Ormond Street Hospital, London, UK, with medulloblastoma, primitive neuroectodermal tumor, atypical teratoid rhabdoid tumor, pilocytic astrocytoma, and ependymoma between 2003 and 2016 inclusive. Uni- and multi-variate analyses were performed to evaluate a range of outcome measures. RESULTS: Three-hundred sixty-one children were identified in total, 53 with disease dissemination at presentation (M:F = 34:19, median age = 3.8 years, range = 7 days-15.6 years) and 308 with solitary tumors (M:F = 161:147, median age = 5.8 years, range = 1 day-16.9 years). Median follow-up was similar irrespective of dissemination status (disseminated tumor 64.0 months, range = 5.2-152.0 months; solitary tumor 74.5 months, range = 4.7-170.1 months; P > 0.05). In multivariate analyses, tumor type and dissemination status at presentation were significantly associated with overall survival (P < 0.0001), risk of recurrence/disease progression (P < 0.01), and event-free survival (P < 0.0001). Subtotal resection was associated with shorter time to recurrence/disease progression (P < 0.01) and worse event-free (P < 0.0001) but not overall survival, whereas treatment with chemotherapy and radiotherapy were associated with improved overall (Ps < 0.0001) and event-free survival (Ps < 0.05). Differences between tumor groups were evident. CONCLUSIONS: Dissemination status at initial presentation significantly affects outcomes in children with CNS tumors.

Post-operative paediatric cerebellar mutism syndrome: time to move beyond structural MRI.

PURPOSE: To determine the value of structural magnetic resonance imaging (MRI) in predicting post-operative paediatric cerebellar mutism syndrome (pCMS) in children undergoing surgical treatment for medulloblastoma. METHODS: Retrospective cohort study design. Electronic/paper case note review of all children with medulloblastoma presenting to Great Ormond Street Hospital between 2003 and 2013. The diagnosis of pCMS was established through a scoring system incorporating mutism, ataxia, behavioural disturbance and cranial nerve deficits. MRI scans performed at three time points were assessed by neuroradiologists blinded to the diagnosis of pCMS. RESULTS: Of 56 children included, 12 (21.4%) developed pCMS as judged by a core symptom of mutism. pCMS was more common in those aged 5 or younger. There was no statistically significant difference in pre-operative distortion or signal change of the dentate or red nuclei or superior cerebellar peduncles (SCPs) between those who did and did not develop pCMS. In both early (median 5 days) and late (median 31 months) post-operative scans, T2-weighted signal change in SCPs was more common in the pCMS group (p = 0.040 and 0.046 respectively). Late scans also showed statistically significant signal change in the dentate nuclei (p = 0.024). CONCLUSIONS: The development of pCMS could not be linked to any observable changes on pre-operative structural MRI scans. Post-operative T2-weighted signal change in the SCPs and dentate nuclei underlines the role of cerebellar efferent injury in pCMS. Further research using advanced quantitative MRI sequences is warranted given the inability of conventional pre-surgical MRI to predict pCMS.

Membrane contact sites between pathogen-containing compartments and host organelles.

Intracellular pathogens survive and replicate within specialised membrane-bound compartments that can be considered as pseudo-organelles. Using the obligate intracellular bacterium Chlamydia as an illustrative example, we consider the modes of lipid transport between pathogen-containing compartments and host organelles, including the formation of static membrane contact sites. We discuss how lipid scavenging can be mediated via the reprogramming of cellular transporters at these interfaces and describe recent data suggesting that pathogen effectors modulate the formation of specific membrane contacts. Further study of these emerging mechanisms is likely to yield new insights into the cell biology of lipid transport and organelle communication, which highlights potential new targets and strategies for future therapeutics. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.

A Chlamydia effector recruits CEP170 to reprogram host microtubule organization.

The obligate intracellular bacterial pathogen Chlamydia trachomatis deploys virulence effectors to subvert host cell functions enabling its replication within a specialized membrane-bound compartment termed an inclusion. The control of the host cytoskeleton is crucial for Chlamydia uptake, inclusion biogenesis and cell exit. Here, we demonstrate how a Chlamydia effector rearranges the microtubule (MT) network by initiating organization of the MTs at the inclusion surface. We identified an inclusion-localized effector that is sufficient to interfere with MT assembly, which we named inclusion protein acting on MTs (IPAM). We established that IPAM recruits and stimulates the centrosomal protein 170 kDa (CEP170) to hijack the MT organizing functions of the host cell. We show that CEP170 is essential for chlamydial control of host MT assembly, and is required for inclusion morphogenesis and bacterial infectivity. Together, we demonstrate how a pathogen effector reprograms the host MT network to support its intracellular development.

Central pathology review with two-stage quality assurance for pathological response after neoadjuvant chemotherapy in the ARTemis Trial.

The ARTemis Trial tested standard neoadjuvant chemotherapy±bevacizumab in the treatment of HER2-negative early breast cancer. We compare data from central pathology review with report review and also the reporting behavior of the two central pathologists. Eight hundred women with HER2-negative early invasive breast cancer were recruited. Response to chemotherapy was assessed from local pathology reports for pathological complete response in breast and axillary lymph nodes. Sections from the original core biopsy and surgical excision were centrally reviewed by one of two trial pathologists blinded to the local pathology reports. Pathologists recorded response to chemotherapy descriptively and also calculated residual cancer burden. 10% of cases were double-reported to compare the central pathologists' reporting behavior. Full sample retrieval was obtained for 681 of the 781 patients (87%) who underwent surgery within the trial and were evaluable for pathological complete response. Four hundred and eighty-three (71%) were assessed by JSJT, and 198 (29%) were assessed by EP. Residual cancer burden calculations were possible in 587/681 (86%) of the centrally reviewed patients, as 94/681 (14%) had positive sentinel nodes removed before neoadjuvant chemotherapy invalidating residual cancer burden scoring. Good concordance was found between the two pathologists for residual cancer burden classes within the 65-patient quality assurance exercise (kappa 0.63 (95% CI: 0.57-0.69)). Similar results were obtained for the between-treatment arm comparison both from the report review and the central pathology review. For pathological complete response, report review was as good as central pathology review but for minimal residual disease, report review overestimated the extent of residual disease. In the ARTemis Trial central pathology review added little in the determination of pathological complete response but had a role in evaluating low levels of residual disease. Calculation of residual cancer burden was a simple and reproducible method of quantifying response to neoadjuvant chemotherapy as demonstrated by performance comparison of the two pathologists.

Band 5 nurses' perceptions and experiences of professional development.

Aim The aim of this qualitative study was to explore band 5 nurses' perceptions and experiences of professional development in an acute care provider to identify what, if any, effect these have on their job satisfaction and intention to stay in post. Method An adapted grounded theory approach was used. Theoretical sampling identified band 5 nurses in their first 24 months of employment in the trust. Data were collected through focus groups and analysed using the constant comparative method. Results Findings suggest that the provision of, and support for, development opportunities affect nurses' job satisfaction, and investment in these opportunities is likely to improve staff retention. Conclusion It is important that resources and funding can be used flexibly so nurse leaders can ensure nursing staff are provided with the training and career progression they require. This will support them to achieve and retain essential competencies, and improve job satisfaction and staff retention.