Healthcare visits for new neurodevelopmental problems before and during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic disrupted healthcare delivery. We hypothesized that children with neurodevelopmental problems would have reduced healthcare utilization during the pandemic compared to before the pandemic. METHODS: We conducted a population-based study of healthcare visits for new neurodevelopmental problems among children ages 0-6 years in Ontario, Canada. Our outcome measure was rate per 1000 children-months for healthcare visits for new neurodevelopmental problems. We compared changes in monthly rates before and during the pandemic using interrupted time series analysis (ITSA). RESULTS: The rate of new neurodevelopmental problems before the pandemic was 6.31 per 1000 children-months and during the pandemic was 6.58 per 1000 children-months. However, using ITSA, there were no differences in monthly rates of healthcare visits for new neurodevelopmental problems before and during the pandemic. The observed rate during the first 30 days of the pandemic dropped to 3.40 per 1000 children-months. CONCLUSION: We found no significant difference in rates of healthcare visits for new neurodevelopmental problems before and during the pandemic. There was a decrease in the number of visits during the first 30 days of the pandemic compared to all months prior. IMPACT: This study found no significant difference in rates of healthcare visits for new neurodevelopmental problems before and during the pandemic. There was a decrease in the number of visits during the first 30 days of the pandemic compared to all months prior. This study adds information on healthcare access for children during the COVID-19 pandemic. The rapid deployment of virtual healthcare delivery in Ontario, Canada may explain the fast recovery of healthcare utilization for children with neurodevelopmental problems.

Impact of performance and information feedback on medical interns' confidence-accuracy calibration.

Diagnostic errors are a major, largely preventable, patient safety concern. Error interventions cannot feasibly be implemented for every patient that is seen. To identify cases at high risk of error, clinicians should have a good calibration between their perceived and actual accuracy. This experiment studied the impact of feedback on medical interns' calibration and diagnostic process. In a two-phase experiment, 125 medical interns from Dutch University Medical Centers were randomized to receive no feedback (control), feedback on their accuracy (performance feedback), or feedback with additional information on why a certain diagnosis was correct (information feedback) on 20 chest X-rays they diagnosed in a feedback phase. A test phase immediately followed this phase and had all interns diagnose an additional 10 X-rays without feedback. Outcome measures were confidence-accuracy calibration, diagnostic accuracy, confidence, and time to diagnose. Both feedback types improved overall confidence-accuracy calibration (R2No Feedback = 0.05, R2Performance Feedback = 0.12, R2Information Feedback = 0.19), in line with the individual improvements in diagnostic accuracy and confidence. We also report secondary analyses to examine how case difficulty affected calibration. Time to diagnose did not differ between conditions. Feedback improved interns' calibration. However, it is unclear whether this improvement reflects better confidence estimates or an improvement in accuracy. Future research should examine more experienced participants and non-visual specialties. Our results suggest that feedback is an effective intervention that could be beneficial as a tool to improve calibration, especially in cases that are not too difficult for learners.

School-based health care: improving academic outcomes for inner-city children-a prospective cohort quasi-experimental study.

BACKGROUND: We examined whether a school-based health center model improved academic achievement compared to usual care. METHODS: This was a quasi-experimental prospective cohort study. The primary outcome was an academic achievement. In addition, we analyzed sociodemographic characteristics and their relationship to academic achievement, and the wait time for a developmental assessment. RESULTS: The differences in change of grades over time (from 2016/2017 to 2018/2019) were small for reading (-0.83, 95% CI -3.48, 1.82, p = 0.51), writing (-1.11, 95% CI -3.25, 1.03, p = 0.28), and math (0.06, 95% CI -3.08, 2.94, p = 0.98). The experimental arm's average wait time for developmental assessment was 3.4 months. CONCLUSION: In this small, quasi-experimental prospective cohort study, we did not find evidence that our SBHC model improved academic achievement; however, the wait time at the SBHCs was considerably less than the provincial wait time for a developmental assessment. TRIAL REGISTRATION: NCT04540003. IMPACT: This study describes a unique and innovative school-based health center model. Our findings support the benefits of school-based health centers in diagnosing and treating children with developmental and mental health disorders for disadvantaged communities. This study did not find an improvement in academic achievement for school-based health center users. This study found that the wait time to developmental assessment was shorter for school-based health center users compared to the wait time reported in the community. Pandemic-associated school disruptions have highlighted the importance of accessible school-based health services for children requiring mental health and developmental assessments and care.

Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2.

Failure of remyelination is largely responsible for sustained neurologic symptoms in multiple sclerosis (MS). MS lesions contain hyaluronan deposits that inhibit oligodendrocyte precursor cell (OPC) maturation. However, the mechanism behind this inhibition is unclear. We report here that Toll-like receptor 2 (TLR2) is expressed by oligodendrocytes and is up-regulated in MS lesions. Pathogen-derived TLR2 agonists, but not agonists for other TLRs, inhibit OPC maturation in vitro. Hyaluronan-mediated inhibition of OPC maturation requires TLR2 and MyD88, a TLR2 adaptor molecule. Ablated expression of TLR2 also enhances remyelination in a lysolecithin animal model. Hyaluronidases expressed by OPCs degrade hyaluronan to hyaluronan oligomers, a requirement for hyaluronan/TLR2 signaling. MS lesions contain both TLR2(+) oligodendrocytes and low-molecular-weight hyaluronan, consistent with their importance to remyelination in MS. We thus have defined a mechanism controlling remyelination failure in MS where hyaluronan is degraded by hyaluronidases into hyaluronan oligomers that block OPC maturation and remyelination through TLR2-MyD88 signaling.

Operative time, length of stay and reoperation rates for orthognathic surgery.

Orthognathic surgery improves quality of life in terms of oral function and facial aesthetics. Our aim was to establish and compare operative time and length of inpatient stay for orthognathic procedures, and to assess the reoperation rate. Departmental electronic data base was used to identify all patients undergoing orthognathic surgery in a single unit between the 01/01/2016 and the 01/08/2018. 251 patients were identified who underwent 409 orthognathic surgery procedures. The mean operating time for a bimaxillary osteotomy (n=107) was 139.3 min. For single jaw procedures, the mean operating time for a Le Fort I osteotomy (n= 42) was 82.2 min and for a bilateral sagittal split osteotomy (BSSO) (n= 102) was 80.3min. Bimaxillary osteotomy combined with genioplasty (n=17) this increased the operating time on average by 31 min. and of a BSSO combined with a genioplasty (n=14) by 27 mins. The mean postoperative hospital stay was 1.2 ± 0.2 days. 96.4% patients spent only one postoperative night in hospital. 6/251 (2.4%) patients required re-operation. In regression analysis, age was the only significant factor in increasing length of stay (p<0.008), 95% CI 0.03-0.2). Our review shows short operating times and postoperative inpatient stays in a large cohort of patients undergoing orthognathic surgery. This is combined with a low reoperation rate. This may point to a patient benefit from high volume orthognathic centres.

Process mapping and Lean principles applied to orthognathic surgery.

Process mapping in industry is a well-established tool to improve efficiency. It is defined as a quality improvement technique that breaks down a process, or task, into its individual components, or steps, then analyses it. Lean principles are used to reduce waste and produce consistently good outcomes. Improving the operative efficiency of orthognathic surgery has many benefits. There is increasing demand for this complex surgery, and patients have appropriately high expectations with relation to their outcome. There are also increasing pressures for hospitals to reduce costs. In a recent paper by our group (Bowe et al, in press), we have published operating times for orthognathic procedures that are significantly shorter than in previously available series, with an average time for a bimaxillary osteotomy of 2 hours and 19 mins. Through observation of the senior authors' uniform technique, refined from experience of over 2,000 cases, a bimaxillary osteotomy was broken down into individual steps, all arranged in a process-mapped template with which to increase efficiency and results. We show here the multiple small operative efficiencies we have developed, and the Lean surgical principles which we use. This has enabled us to reduce the operative time of these common procedures, without compromising outcomes. This study presents an approach to process map bimaxillary orthognathic operations and shows how the application of Lean principles improves operative efficiency, and produces consistent results.

Sentinel lymph node biopsy for melanoma of the head and neck: a multicentre study to examine safety, efficacy, and prognostic value.

Sentinel lymph node biopsy (SLNB) is an accurate staging procedure for malignant melanoma but its use in patients with melanoma of the head and neck has been questioned in the past because of a perceived record of poor safety and accuracy. Technical improvements have sought to redress this. Vital structures and variable lymphatic pathways can make its use in the head and neck challenging. In our study we have examined the data and the experiences of clinicians from University Hospital Southampton and the Royal Surrey County Hospital. We retrospectively analysed the data and case notes of 143 patients who had SLNB to establish its safety, efficacy, and prognostic value. The detection rate of at least one sentinel lymph node was 100%. Nodes positive for metastatic melanoma were found in 20% of patients. Of them, 76% went on to have completion lymphadenectomy. Multivariate Cox regression analysis suggested that positive SLNB was a strong predictor of reduced overall survival for all Breslow-thickness melanomas (HR=3.9, p=0.019) and intermediate melanomas (HR=6.3, p=0.007). It predicted reduced recurrence-free survival for all melanomas (HR=7.4, p<0.001) and was a strong predictor for those of intermediate thickness (HR=8.3, p<0.001). The false negative rate was 9.4% and false omission rate 2.6%. Temporary and permanent morbidity rates were 2.1% and 0%, respectively. SLNB for melanoma in the head and neck is a safe, accurate staging procedure that offers prognostically useful information. The upstaging of disease allows access to trial-based targeted treatments.

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

Potential pathological application of immunocytochemical methods to the detection of micrometastases.

Immunocytochemical methods can be used to demonstrate tumor products and antigens at the cellular level. This approach facilitates the classification of tumors and the detection of small metastatic tumor foci in biopsy material from various sites including the bone marrow.

The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma.

Human cathepsin K is a novel cysteine protease previously reported to be restricted in its expression to osteoclasts. Immunolocalization of cathepsin K in breast tumor bone metastases revealed that the invading breast cancer cells expressed this protease, albeit at a lower intensity than in osteoclasts. In situ hybridization and immunolocalization studies were subsequently conducted to demonstrate cathepsin K mRNA and protein expression in samples of primary breast carcinoma. Expression of cathepsin K mRNA was confirmed by reverse transcription PCR and Southern analysis in a number of human breast cancer cell lines and in primary human breast tumors and their metastases. As this protease is known to degrade extracellular matrix, including bone matrix proteins, it is possible that cathepsin K may contribute to the invasive potential of breast cancer cells, including those that metastasize to bone. Thus, cathepsin K may be a potential target leading to the design of novel drugs for cancer therapy.

Loss of orofacial tissue secondary to septic shock caused by Streptococcus pneumoniae.

Purpura fulminans is a rare complication of septic shock with a high mortality. It can result in a severe loss of skin, and often amputation of limbs. Managing the loss of tissue is a challenge that requires a multidisciplinary approach.

The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2.

Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non-BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non-BRCA1/2 families. Breast cancers in non-BRCA1/2 families were of lower grade (P = 0.0018), showed fewer mitoses (P < 0.0001), less nuclear pleomorphism (P = 0.0014), less lymphocytic infiltrate (P < 0.0001), a lesser extent of the tumor with a continuous pushing margin (P = 0.004), a lesser extent of the tumor composed of solid sheets of cells (P = 0.0047), less necrosis (P = 0.002), and wereparison with BRCA2 tumors, non-BRCA1/2 tumors were lower grade (P = 0.017) and exhibited less pleomorphism (P = 0.01) and more tubule formation (P = 0.05). In comparison with control breast cancers unselected for a family history of the disease, non-BRCA1/2 tumors were of significantly lower grade (P = 0.001), showed less pleomorphism (P = 0.0002), and had a lower mitotic count (P = 0.003). The results indicate that non-BRCA1/2 breast cancers differ histologically from both BRCA1 and BRCA2 breast cancers and are overall of lower grade. They also suggest that non-BRCA1/2 breast cancers differ from nonfamilial breast cancers, but these differences may be attributable to various types of bias.

Increased microglial activation and protein nitration in white matter of the aging monkey.

Activated microglia are important pathological features of a variety of neurological diseases, including the normal aging process of the brain. Here, we quantified the level of microglial activation in the aging rhesus monkey using antibodies to HLA-DR and inducible nitric oxide synthase (iNOS). We observed that 3 out of 5 white matter areas but only 1 of 4 cortical gray matter regions examined showed significant increases in two measures of activated microglia with age, indicating that diffuse white matter microglial activation without significant gray matter involvement occurs with age. Substantial levels of iNOS and 3-nitrotyrosine, a marker for peroxynitrite, increased diffusely throughout subcortical white matter with age, suggesting a potential role of nitric oxide in age-related white matter injury. In addition, we found that the density of activated microglia in the subcortical white matter of the cingulate gyrus and the corpus callosum was significantly elevated with cognitive impairment in elderly monkeys. This study suggests that microglial activation increases in white matter with age and that these increases may reflect the role of activated microglia in the general pathogenesis of normal brain aging.

Micrometastases in breast cancer: long-term follow-up of the first patient cohort.

"Micrometastases" can be identified in the bone marrow of patients with apparently localised breast cancer using an immunocytochemical stain for epithelial membrane antigen (EMA). Of 39 women who had marrow samples examined at the time of initial presentation (37), or with locally recurrent disease (2), 13 (33%) had samples which contained small numbers of EMA positive cells. 10 out of 23 (44%) lymph-node positive patients were marrow positive, compared to 1 out of 14 (7%) lymph node negative cases (P = 0.03). Long-term follow-up (median 9.5 years) has shown that 11 out of 13 (85%) patients with micrometastases have developed metastatic disease compared to 8 out of 26 (31%) with negative bone marrow aspirates (P less than 0.05). The small number of EMA positive cells detected in bone marrow samples probably reflects the high metastatic potential of primary or recurrent cancers rather than established microscopic deposits; it is not yet clear whether the finding of such micrometastases will act as an independent variable compared to established prognostic factors.

Angiogenesis and invasive recurrence in ductal carcinoma in situ of the breast.

The development of an invasive recurrence following treatment for ductal carcinoma in situ (DCIS) converts a non-fatal disease to one associated with mortality. To date, no pathological or molecular features have been found to predict for the type of recurrence. Previous studies have suggested that in DCIS angiogenesis may be an important factor in determining the transformation from in situ to invasive carcinoma. We looked at 355 cases of DCIS and found that 32 had subsequently developed recurrent disease. In these 32 cases and in matched controls, periductal vascular density was determined using morphometry and anti-endothelial antibodies, von Willebrand factor (vWF) and CD34. Vascular density was related to the risk of both invasive and in situ recurrence. Normal lobules at least 2 mm away were used as controls. Differences in the phenotype of individual blood vessels was detected by performing dual staining immunofluorescence on selected cases. The microvessel density (MVD), as detected with the CD34 antibody, was higher around foci of DCIS than around normal breast lobules (P=0.001). Furthermore, it was significantly higher in cases of DCIS that recurred (P<0.0001). The findings with the vWF antibody were less clear cut and suggested a trend in decreasing MVD with increasingly aggressive disease. Dual immunofluorescence staining shows that the increase in MVD seen around DCIS is due to an increase in CD34+/vWF-blood vessels. An increase in CD34+/vWF-of blood vessels may be able to predict cases of DCIS that are at a high risk of developing a recurrence.

Consistency of histopathological reporting of breast lesions detected by screening: findings of the U.K. National External Quality Assessment (EQA) Scheme. U. K. National Coordinating Group for Breast Screening Pathology.

The aim of the scheme was to determine consistency of histopathological reporting in the United Kingdom National Breast Screening Programme. This external quality assessment scheme involved 51 sets of 12 slides which were circulated to 186-251 pathologists at intervals of 6 months for 3 years. Participants recorded their diagnoses on standard reporting forms, which were submitted to the U.K. National Cancer Screening Evaluation Unit for analysis. A high level of consistency was achieved in diagnosing major categories of breast disease including invasive carcinoma and the important borderline lesions, radial scar and ductal carcinoma in situ (DCIS), the latter exceeding a national target set prior to the onset of the scheme. Atypical hyperplasia (AH) was reported with much less consistency although, where it was the majority opinion, over 86% of diagnoses were of benign disorders and only 14% were of DCIS. Inconsistency was encountered in subtyping and measuring DCIS, the former apparently due to current uncertainties about classification and the latter to poor circumscription, variation in size in different sections and merging with zones of AH. Reporting prognostic features of invasive carcinomas was variable. Measurement of size was achieved with adequate consistency except in a small number of very poorly circumscribed tumours. Grading and subtyping were inconsistent although the latter was not specifically tested and will be the subject of future study. Members of the National Coordinating Group achieved greater uniformity than the remainder of the participants in all diagnostic categories, but both groups experienced similar types of problem. Our findings suggest that participation in the scheme improves diagnostic consistency. In conclusion, consistency in diagnosing invasive carcinoma and radial scar is excellent, and good in DCIS, but improvements are desirable in diagnosing atypical hyperplasia, classifying DCIS and reporting certain prognostic features of invasive tumours. Such improvements will require further research, the development of improved diagnostic criteria and the dissemination of clearer guidelines.

Causes of inconsistency in diagnosing and classifying intraductal proliferations of the breast. European Commission Working Group on Breast Screening Pathology.

It is now widely recognised that classifying ductal carcinoma in situ (DCIS) of the breast and diagnosing atypical ductal hyperplasia are associated with significant interobserver variation. Two possible reasons for this inconsistency are differences in the interpretation of specified histological features and field selection where morphology is heterogeneous. In order to investigate the relative contribution of these two factors to inconsistent interpretation of intraductal proliferations, histological sections of 32 lesions were sent to 23 European pathologists followed 3 years later by images of small parts of these sections. Kappa statistics for diagnosing hyperplasia of usual type, atypical ductal hyperplasia and ductal carcinoma in situ were 0.54, 0.35 and 0.78 for sections and 0.47, 0.29 and 0.78 for images, respectively, showing that most of the inconsistency is due to differences in morphological interpretation. Improvements can thus be expected only if diagnostic criteria or methodology are changed. In contrast, kappa for classifying DCIS by growth pattern was very low at 0.23 for sections and better at 0.47 for images, reflecting the widely recognised variation in the growth pattern of DCIS. Higher kappa statistics were obtained when any mention of an individual growth pattern was included in that category, thus allowing multiple categories per case; but kappa was still higher for images than sections. Classifying DCIS by nuclear grade gave kappa values of 0.36 for sections and 0.49 for images, indicating that intralesional heterogeneity has hitherto been underestimated as a cause of inconsistency in classifying DCIS by this method. More rigorous assessment of the proportions of the different nuclear grades present could lead to an improvement in consistency.

Histopathologic types of benign breast lesions and the risk of breast cancer: case-control study.

The hypothetical multistep model of carcinogenesis indicates that breast cancer develops via a series of intermediate hyperplastic lesions through in situ to invasive carcinoma. To identify the risk inherent within the different morphologic lesions, we have analyzed the data from 674 benign biopsy specimens comprising 120 cases who subsequently developed breast cancer and 382 controls (matched for age and date of biopsy) spanning a period up to 20 years of follow-up (mean 66.95 months). In this series we have confirmed an increased risk associated with certain types of benign breast lesions. Atypical lobular hyperplasia was the most significant risk factor for breast cancer with more unfavorable outcome in patients <50 years of age (p = 0.003) and a relative risk (RR) of 4.55 (confidence interval [CI] 1.77-11.69). Hyperplasia of usual type showed an RR of 1.53 (CL 1.10-2.13) with a statistically worse probability of survival (cancer-free time) for patients >50 years. For atypical ductal hyperplasia the RR was 2.03 (CI 0.80-1.39). Blunt duct adenosis was significantly more common in cases progressing to breast cancer compared with controls, showing an RR of 2.08 (CI 1.12-2.85). We describe in detail the criteria of morphologic changes observed in blunt duct adenosis and define, for the first time, the level of risk associated with each of its six subtypes. Improved knowledge of breast carcinogenesis will provide insight for defining high-risk groups thus resulting in improved screening and management regimens.