Prevalence of histological abnormalities in hysterectomy specimens performed for prolapse. A systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: The practice of histopathological assessment of the uterus following hysterectomy for benign indications including pelvic organ prolapse (POP) surgery is common and often routine. While pathology is not anticipated, the finding of pathology requiring further action is always a concern, in particular CIN (cervical intraepithelial neoplasia) or cervical/uterine malignancy. We aimed to perform a systematic review to understand the prevalence of actionable uterine and cervical pathology in hysterectomy specimens performed for POP. METHODS: A literature search was performed in January 2020 of MEDLINE, Embase and CINAHL using the Healthcare Databases Advanced Search platform. Included studies reported CIN and/or uterine/cervical malignancy in histological assessment of hysterectomy specimens performed purely for POP. Meta-analysis of prevalence was performed using the MetaXL ( www.epigear.com ) add-in for Microsoft Excel. RESULTS: Six hundred seventy-seven records were identified, out of which 34 studies were eligible. Overall prevalence (95% confidence interval [CI]) of endometrial cancer in 33 studies was 0.004 (0.003-0.006), I2 = 41%, number needed to treat (NNT) 1:250. Total actionable uterine pathology was 0.005 (0.003-0.006) in 33 studies, I2 = 35%, NNT = 1:200. Overall prevalence of cervical cancer in 19 papers was 0.001 (0.000-0.002), I2 = 18%, NNT = 1:1000. In 16 studies the overall prevalence of CIN was 0.013 (0.001-0.033), I2 = 95%, NNT = 1:77. Prevalence of total actionable pathology was 0.013 (0.006-0.0023), I2 = 86%, NNT = 1:77. CONCLUSION: The risk of actionable pathology is low, but not negligible. The variation between populations is wide. The prevalence of finding such pathology supports the routine practice of sending all hysterectomy specimens performed for POP for histological assessment.

Outcome of surgical management for midurethral sling complications: a multicentre retrospective cohort study.

INTRODUCTION AND HYPOTHESIS: Suspension of midurethral sling (MUS) surgery in the UK has led to a call for further evidence regarding long-term morbidity and the efficacy of treatments when mesh complications are encountered. We reviewed how many patients who underwent MUS surgery in Teesside, UK, returned to theatre due to a complication and what the outcomes were following this surgical intervention. METHODS: All patients coded to have undergone an MUS procedure between 1 January 2010 and 31 December 2014 in Teesside were reviewed retrospectively (n = 924). Case notes were analysed for patients who returned to theatre up until December 2017 due to complications related to their original MUS. RESULTS: Seventy-one of 924 (7.7%) women returned to theatre for some form of surgical intervention. There was a statistically significant difference in return-to-theatre rate between the transobturator and retropubic approach groups (63/661; 9.5%; confidence interval (CI) 7.3-11.8% v 8/263; 3.0%; CI 0.96%, 5.1%, odds ratio (OR) 3.35, p = 0.001); 2.8% (26/924) underwent shortening, reburying, incision or MUS excision; 1.0% (9/924) underwent steroid injection along the MUS tract; 1.7% (16/924) underwent surgical treatment of detrusor overactivity; 3.0% (28/924) required further stress incontinence surgery. The risk of unresolved chronic pain post-MUS surgery following treatment of complications was 0.2% (2/924). CONCLUSIONS: Our results show a reassuringly low rate of mesh removal following MUS surgery. Furthermore, outcomes were good following surgical management of MUS complications. We advocate compulsory registration of all MUS procedures, follow-up data and complications to provide robust long-term evidence for the future.

Preliminary validation of the coma recovery scale for pediatrics in typically developing young children.

Objective: To examine the basic psychometric features of a modified version of the Coma Recovery Scale-Revised (CRS-R) for use in young children with disorders of consciousness (DoC).Method: The CRS-R was modified to create the Coma Recovery Scale for Pediatrics (CRS-P) and administered to 33 typically developing children (8-59 months). Total scores, subtest scores, and inter-rater reliability were evaluated. Performance on the two items representing emergence to conscious state (CS) - functional object use (FOU) and functional communication (FC) was examined across the age range.Results: Inter-rater reliability of CRS-P subscale scores was adequate (Kw = .87-1.00). All 4-year-olds, 75% of 3-year-olds, 10% of 2-year-olds, and 0% <2 years scored at the CRS-P ceiling. Total and subtest scores were strongly correlated with age as were the two behaviors representing emergence to CS (FOU, FC) - all children >12 months and none <12 months of age met criteria for FOU; all children ≥3 years, 20% between 2 and <3 years, and none <2 years met criteria for FC.Conclusions: The CRS-P is appropriate for use in children as young as 12 months of age, with a strong association between performance and age at administration. The CRS-P also captures emergence to CS, a key clinical milestone.

Management of Early Cervical Stromal Invasion FIGO Stage 1A1 When Margins Are Involved With Cervical Intraepithelial Neoplasia.

OBJECTIVE: Women with International Federation of Gynecology and Obstetrics stage 1A1 cervical carcinoma were evaluated to determine whether repeat excision for large loop excision transformation zone margins positive with cervical intraepithelial neoplasia (CIN) had been undertaken according to the National Health Service Cervical Screening Programme guidelines and if deviations from guidelines adversely affected patient outcome. MATERIALS AND METHODS: We retrospectively studied patients with 1A1 cervical carcinoma treated in our service between May 2010 and July 2015 to determine whether NHSCSP guidelines (May 2010) were followed. This states that if the invasive disease is excised but CIN extends to the excision margin, then a repeat large loop excision transformation zone should be undertaken to exclude further invasive disease and to confirm excision of CIN. RESULTS: Seventeen patients were identified. In one, neither the invasive lesion nor CIN was fully excised. In 5, the lesion and CIN were fully excised. In eleven, the invasive lesion was excised, but CIN was present at a margin. Of these 11 patients, none opted for a repeat excision. All 11 patients had negative cytology at first follow-up (negative up to 4 years [median = 2 years]). CONCLUSIONS: Our outcomes suggest that it may not be necessary to perform a repeat excision for CIN present at the excision margin in women with 1A1 cervical carcinoma when CIN is present either at the endocervical, deep stromal, or ectocervical margin, as long as the invasive focus is fully excised, and patients have been fully counseled and have regular cytology follow-up. This may be an alternative for patients wanting to minimize the risks to fertility posed by repeat excision.

Development and Pilot Testing of the Dual Task Screen in Healthy Adolescents.

Athletes with mild traumatic brain injury (mTBI) should refrain from high-risk activities until recovered (symptom free and cognitive and physical exam findings normalize). Studies have suggested that this examination may not be sufficiently sensitive because dual-task paradigms, which typically assess motor performance while a person simultaneously completes a distractor task, can detect residual deficits in athletes who otherwise appear recovered from mTBI. Paradigms used to date are time-intensive procedures conducted in laboratory settings. Here, we report findings from a pilot study of the Dual Task Screen (DTS), which is a brief evaluation with two dual-task paradigms. In 32 healthy female adolescents, the DTS was administered in a mean of 5.63 min in the community, and every participant had poorer dual-condition performance on at least one of the motor tasks. The DTS is a clinically feasible measure and merits additional study regarding utility in adolescents with mTBIs.

International validation of a dithiothreitol (DTT)-based method to resolve the daratumumab interference with blood compatibility testing.

BACKGROUND: Daratumumab (DARA) consistently interferes with routine blood bank serologic testing by directly binding to CD38 expressed on reagent red blood cells (RBCs). Treating RBCs with dithiothreitol (DTT) eliminates the DARA interference. We conducted an international, multicenter, blinded study aimed at validating the DTT method for use by blood bank laboratories worldwide. STUDY DESIGN AND METHODS: Paired plasma sample unknowns were sent to 25 participating blood bank laboratories. Sample 1 was spiked with DARA only (10 µg/mL), and Sample 2 with DARA plus a clinically significant RBC antibody (anti-D [n = 6], anti-Fya [n = 9], or anti-s [n = 10]). Sites were instructed to perform an antibody screen with and without DTT-treated RBCs and to use a DTT-treated RBC panel for antibody identification. Qualitative data about the DTT method were collected by online survey. The primary outcome was the proportion of study sites able to identify the antibody unknown in the presence of DARA. RESULTS: All sites observed the DARA interference with the antibody screen. The DARA interference was seen with all testing methods (gel, tube, or solid phase). Using the DTT method, 25 of 25 sites (100%) successfully identified the antibody unknown in the presence of DARA. Feedback on the DTT method was positive, with 17 of 19 (90%) sites responding to the survey indicating that they planned to use the DTT method to test clinical samples from DARA-treated patients. CONCLUSION: The DTT method is robust and reproducible and can be implemented by transfusion services worldwide to help provide safe blood products to patients treated with DARA.

Resolving the daratumumab interference with blood compatibility testing.

BACKGROUND: Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS: DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS: Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION: DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.

Cognitive impairment in people with multiple sclerosis: Perception vs. performance - factors that drive perception of impairment differ for patients and clinicians.

BACKGROUND: Neurologists' perceptions of the presence of cognitive impairment (CI) in people with multiple sclerosis (PwMS) may not always align with findings of objective cognitive assessment. The accuracy of self-reported CI in PwMS can also be highly variable across individuals, and may not align with objective measurement of cognitive disturbances. Research suggests that additional factors impact perceived cognitive ability, such as depression and fatigue. Objective cognitive screening regardless of patient or neurologist perception has been recommended but still is often limited in routine care. Moreover, comprehensive neuropsychological assessment is even less routinely done. OBJECTIVE: To explore how neurologists' perceptions of PwMS' CI compare to the perception of the patient by determining whether PwMS and their clinicians are accurate in detecting the presence and degree of CI as defined by a multi-domain validated computerized test battery in PwMS, as well as investigate what factors influence perception of CI in each group. METHODS: PwMS completed a computerized multi-domain cognitive testing battery, and self-reported measures of disease impact (MSIS-29), fatigue (MFIS), and depression (BDI-II). Disability was assessed by the clinician using the Expanded Disability Status Scale (EDSS). Clinicians and patients also provided an estimation of cognitive deficits along a Likert scale. RESULTS: In this cohort of PwMS (N=202, age range: 20 to 88, gender: 71% female), their level of accuracy in detecting attention deficits (k = -.028, p = .010) was low but statistically significant. In contrast, clinicians' accuracy in detecting global CI (k = -.037, p < .001) and a number of specific domain deficits was moderate. Fatigue (p < .001) and cognitive performance (p = .012) significantly predicted patient perceived cognitive deficits. Clinician perceived cognitive performance was significantly predicted by multiple factors: cognitive scores (p < .001), physical disability (p = .011), age (p = .021), and depression (p = .038). CONCLUSION: The need to objectively screen for CI in PwMS, regardless of perception, can be aided by a better understanding of the agreement and discrepancies between the patient and clinician regarding perceived cognitive disturbances and the presence of CI defined by a multi-dimensional objective screening battery.

Risk factors and sonographic endometrial thickness as predictors of tumour stage and histological subtype of endometrial cancer.

We evaluated the association between risk factors for endometrial cancer (EC) and sonographic endometrial thickness (ET) with FIGO stages at diagnosis. We also reported our experience in reliability of sonographic ET as screening tool for either histologic subtype I and II of EC. It was a case series study including 339 patients diagnosed with EC from 2010 to 2017 at the Ipswich Hospital, UK. Women with higher body mass index (BMI) presented at earlier stages when compared to women with lower BMIs (p-value = .046). By contrast, none of the variables: parity (p-value = .1630), use of HRT (p-value 0.7448), tamoxifen (p-value 0.0733) and diabetes (p-value = .1665) were statistically associated to FIGO stages. The mean of ET measurement was not statistically significant associated (p-value 0.0625) to stages. There was no statistic difference on mean ET at diagnosis between histologic subtypes I or II (p-value 0.804). According to our experience, BMI is associated to FIGO stage and endometrial sampling (ES) should be included in the working diagnosis of EC to obtain an early diagnosis in women with high BMIs even in premenopausal. Ultrasonographic measurement of the endometrium is equally reliable at determining cancer, but not at differentiating histologic subtypes I and II uterine cancers. However, ET does not correlate to FIGO stages at diagnosis.

Regional cerebral glucose uptake in the 3xTG model of Alzheimer's disease highlights common regional vulnerability across AD mouse models.

We have previously used fluorodeoxyglucose (FDG) autoradiography to detect the pattern of metabolic declines in two different transgenic mouse models of fibrillar beta-amyloid pathology in Alzheimer's disease (AD), including the PDAPP mouse, which overexpresses a mutant form of human APP, and the PSAPP mouse, which overexpresses mutant forms of the human APP and PS1 genes. In this study, we used the same approach to study a triple-transgenic (3xTG) model of AD, which overexpresses human APP, PS1 and tau mutations, and progressively develops amyloid plaques, neurofibrillary tangles, and synaptic dysfunction. Densitometric measurements from 55 brain regions were characterized and compared in 2, 12, and 18 month-old 3xTG and wildtype control mice (n = 12/group). By 18 months of age, the 3xTG mice had significant reductions in FDG uptake in every measured brain region, including cortical and subcortical gray matter, cerebellar and brainstem regions. However, regional differences in normalized FDG uptake were apparent in the 2- and 12-month-old 3xTG mice, in a brain network pattern reminiscent of our previous analyses in the other mouse models. This prominently included the posterior cingulate/retrosplenial cortex, as in each previously-analyzed model. Overall, our analyses highlight consistencies in brain glucose uptake abnormalities across multiple mouse models of amyloid-associated pathophysiology. These mouse brain regional changes are homologous to alterations seen in PET scans from human AD patients and could thus be useful biomarkers for early testing of novel interventions.

Dysregulation of intestinal crypt cell proliferation and villus cell migration in mice lacking Kruppel-like factor 9.

Krüppel-like factor 9 (Klf9), a zinc-finger transcription factor, is implicated in the control of cell proliferation, cell differentiation, and cell fate. Using Klf9-null mutant mice, we have investigated the involvement of Klf9 in intestine crypt-villus cell renewal and lineage determination. We report the predominant expression of Klf9 gene in small and large intestine smooth muscle (muscularis externa). Jejunums null for Klf9 have shorter villi, reduced crypt stem/transit cell proliferation, and altered lineage determination as indicated by decreased and increased numbers of goblet and Paneth cells, respectively. A stimulatory role for Klf9 in villus cell migration was demonstrated by bromodeoxyuridine labeling. Results suggest that Klf9 controls the elaboration, from intestine smooth muscle, of molecular mediator(s) of crypt cell proliferation and lineage determination and of villus cell migration.