Applying Mendelian randomization to appraise causality in relationships between smoking, depression and inflammation.

Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, (an archetypal generalized inflammatory marker) and/or IL-6 activity, as a potential explanation for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated reciprocal relationships of lifetime smoking with depression (ORSmk-Dep = 2.01, 95% CI 1.71-2.37, p < 0.001; ORDep-Smk = 1.09, 95% CI 1.06-1.13, p < 0.001), CRP levels and IL-6 activity (ORSmk-CRP = 1.40, 95% CI 1.21-1.55, p < 0.001; ORCRP-Smk = 1.03, 95% CI 1.02-1.05, p < 0.001, ORIL-6/CRP-Smk = 1.06 (1.03-1.09), p < 0.001). These associations were also supported by the majority of the robust MR methods performed. We did not find evidence for a reciprocal relationship between CRP levels (using > 500 genetic instruments for CRP) and depression (ORCRP-Dep = 1.01, 95% CI 0.99-1.04; ORDep-CRP = 1.03, 95% CI 0.99-1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to measures of generalized inflammation, but we found evidence for an attenuation of the smoking-depression association in multivariable mendelian randomization when adjusting for IL-6 activity, suggesting that the IL-6 pathway may be at least in part responsible for the association of smoking and depression. Our study supports potential bidirectional causal associations between lifetime smoking and depression which may be at least in part explained by the IL-6 signalling pathway. The IL-6 pathway may represent a putative therapeutic target for smoking and to mitigate the effects of smoking on depression.

Wide & Deep neural network model for patch aggregation in CNN-based prostate cancer detection systems.

Prostate cancer (PCa) is one of the most commonly diagnosed cancer and one of the leading causes of death among men, with almost 1.41 million new cases and around 375,000 deaths in 2020. Artificial Intelligence algorithms have had a huge impact on medical image analysis, including digital histopathology, where Convolutional Neural Networks (CNNs) are used to provide a fast and accurate diagnosis, supporting experts in this task. To perform an automatic diagnosis, prostate tissue samples are first digitized into gigapixel-resolution whole-slide images. Due to the size of these images, neural networks cannot use them as input and, therefore, small subimages called patches are extracted and predicted, obtaining a patch-level classification. In this work, a novel patch aggregation method based on a custom Wide & Deep neural network model is presented, which performs a slide-level classification using the patch-level classes obtained from a CNN. The malignant tissue ratio, a 10-bin malignant probability histogram, the least squares regression line of the histogram, and the number of malignant connected components are used by the proposed model to perform the classification. An accuracy of 94.24% and a sensitivity of 98.87% were achieved, proving that the proposed system could aid pathologists by speeding up the screening process and, thus, contribute to the fight against PCa.

Preliminary report: Surgical outcomes following genitoplasty in children with moderate to severe genital atypia.

INTRODUCTION: Prior studies of outcomes following genitoplasty have reported high rates of surgical complications among children with atypical genitalia. Few studies have prospectively assessed outcomes after contemporary surgical approaches. OBJECTIVE: The current study reported the occurrence of early postoperative complications and of cosmetic outcomes (as rated by surgeons and parents) at 12 months following contemporary genitoplasty procedures in children born with atypical genitalia. STUDY DESIGN: This 11-site, prospective study included children aged ≤2 years, with Prader 3-5 or Quigley 3-6 external genitalia, with no prior genitoplasty and non-urogenital malformations at the time of enrollment. Genital appearance was rated on a 4-point Likert scale. Paired t-tests evaluated differences in cosmesis ratings. RESULTS: Out of 27 children, 10 were 46,XY patients with the following diagnoses: gonadal dysgenesis, PAIS or testosterone biosynthetic defect, severe hypospadias and microphallus, who were reared male. Sixteen 46,XX congenital adrenal hyperplasia patients were reared female and one child with sex chromosome mosaicism was reared male. Eleven children had masculinizing genitoplasty for penoscrotal or perineal hypospadias (one-stage, three; two-stage, eight). Among one-stage surgeries, one child had meatal stenosis (minor) and one developed both urinary retention (minor) and urethrocutaneous fistula (major) (Summary Figure). Among two-stage surgeries, three children developed a major complication: penoscrotal fistula, glans dehiscence or urethral dehiscence. Among 16 children who had feminizing genitoplasty, vaginoplasty was performed in all, clitoroplasty in nine, external genitoplasty in 13, urethroplasty in four, perineoplasty in five, and total urogenital sinus mobilization in two. Two children had minor complications: one had a UTI, and one had both a mucosal skin tag and vaginal mucosal polyp. Two additional children developed a major complication: vaginal stenosis. Cosmesis scores revealed sustained improvements from 6 months post-genitoplasty, as previously reported, with all scores reported as good or satisfied. DISCUSSION: In these preliminary data from a multi-site, observational study, parents and surgeons were equally satisfied with the cosmetic outcomes 12 months after genitoplasty. A small number of patients had major complications in both feminizing and masculinizing surgeries; two-stage hypospadias repair had the most major complications. Long-term follow-up of patients at post-puberty will provide a better assessment of outcomes in this population. CONCLUSION: In this cohort of children with moderate to severe atypical genitalia, preliminary data on both surgical and cosmetic outcomes were presented. Findings from this study, and from following these children in long-term studies, will help guide practitioners in their discussions with families about surgical management.

Prospective assessment of cosmesis before and after genital surgery.

INTRODUCTION: Little data exist about the surgical interventions taking place for children with disorders of sex development (DSD). Most studies that have evaluated cosmetic outcomes after genitoplasty have included retrospective ratings by a physician at a single center. OBJECTIVE: The present study aimed to: 1) describe frequency of sex assignment, and types of surgery performed in a cohort of patients with moderate-to-severe genital ambiguity; and 2) prospectively determine cosmesis ratings by parents and surgeons before and after genital surgery. STUDY DESIGN: This prospective, observational study included children aged <2 years of age, with no prior genitoplasty at the time of enrollment, moderate-to-severe genital atypia, and being treated at one of 11 children's hospitals in the United States of America (USA). Clinical information was collected, including type of surgery performed. Parents and the local pediatric urologist rated the cosmetic appearance of the child's genitalia prior to and 6 months after genitoplasty. RESULTS: Of the 37 children meeting eligibility criteria, 20 (54%) had a 46,XX karyotype, 15 (40%) had a 46,XY karyotype, and two (5%) had sex chromosome mosaicism. The most common diagnosis overall was congenital adrenal hyperplasia (54%). Thirty-five children had surgery; 21 received feminizing genitoplasty, and 14 had masculinizing genitoplasty. Two families decided against surgery. At baseline, 22 mothers (63%), 14 fathers (48%), and 35 surgeons (100%) stated that they were dissatisfied or very dissatisfied with the appearance of the child's genitalia. Surgeons rated the appearance of the genitalia significantly worse than mothers (P < 0.001) and fathers (P ≤ 0.001) at baseline. At the 6-month postoperative visit, cosmesis ratings improved significantly for all groups (P < 0.001 for all groups). Thirty-two mothers (94%), 26 fathers (92%), and 31 surgeons (88%) reported either a good outcome, or they were satisfied (see Summary Figure); there were no significant between-group differences in ratings. DISCUSSION: This multicenter, observational study showed surgical interventions being performed at DSD centers in the USA. While parent and surgeon ratings were discordant pre-operatively, they were generally concordant postoperatively. Satisfaction with postoperative cosmesis does not necessarily equate with satisfaction with the functional outcome later in life. CONCLUSION: In this cohort of children with genital atypia, the majority had surgery. Parents and surgeons all rated the appearance of the genitalia unfavorably before surgery, with surgeons giving worse ratings than parents. Cosmesis ratings improved significantly after surgery, with no between-group differences.

The SloR metalloregulator is involved in the Streptococcus mutans oxidative stress response.

SloR, a 25-kDa metalloregulatory protein in Streptococcus mutans modulates the expression of multiple genes, including the sloABC operon that encodes essential Mn2+ transport and genes that promote cariogenesis. In this study, we report on SloC- and SloR-deficient strains of S. mutans (GMS284 and GMS584, respectively) that demonstrate compromised survivorship compared with their UA159 wild-type progenitor and their complemented strains (GMS285 and GMS585, respectively), when challenged with streptonigrin and/or in growth competition experiments. The results of streptonigrin assays revealed significantly larger zones of inhibition for GMS584 than for either UA159 or GMS585, indicating weakened S. mutans survivorship in the absence of SloR. Competition assays revealed a compromised ability for GMS284 and GMS584 to survive peroxide challenge compared with their SloC- and SloR-proficient counterparts. These findings are consistent with a role for SloC and SloR in S. mutans aerotolerance. We also predicted differential expression of oxidative stress tolerance genes in GMS584 versus UA159 and GMS585 when grown aerobically. The results of quantitative RT-PCR experiments revealed S. mutans sod, tpx, and sloC expression that was upregulated in GMS584 compared with UA159 and GMS585, indicating that the impact of oxidative stress on S. mutans is more severe in the absence of SloR than in its presence. The results of electrophoretic mobility shift assays indicate that SloR does not bind to the sod or tpx promoter regions directly, implicating intermediaries that may arbitrate the SloR response to oxidative stress.

Medical status, functional status and drug utilization patterns of a population of older dental patients in Winnipeg, Manitoba.

Despite the wealth of epidemiological studies that have evaluated the oral health status of older Canadian dental patients, comprehensive epidemiologic data on their medical status, functional status and drug utilization patterns are deficient. To address this deficiency, the authors evaluated 170 older dental patients (> or = 65 years, mean = 82 years, sex distribution = 77.1 per cent female, 22.9 per cent male) in Winnipeg, Manitoba. Study participants averaged five medical conditions per person (males = females). The most prevalent conditions were vision deficits, cardiovascular disorders and orthopedic problems. Functional assessment of the Activities of Daily Living revealed that study participants were essentially independent. Within the study population, 90 per cent were taking at least one medication (mean = 2.8 drugs per person), most of which were analgesics, diuretics and gastrointestinal agents. Drug utilization rates were consistent with other studies that have evaluated prescribing patterns in community-dwelling older Canadian adults.

Oral health status of a population of community-dwelling older Canadians.

A sample of 170 responsive residents of seniors housing centres in Winnipeg, Canada, were studied, (>65 years, mean 82 years), with the objectives of relating their dental state to their perception of need and uptake of service. Only 6% rated their oral health as poor, 46% reported a dental visit within the previous year and 68% felt they needed dental treatment. A lack of perceived need (88%) was the primary reason why dental care was not sought more frequently. Hygiene practices revealed that only 7% brushed < 1 time/day, 60% never flossed, 14% cleaned their dentures <1 time/day, and 42% slept with their dentures. Dental histories showed that examination (94%), prosthodontic treatment (76%), and restorative services (65%) were the most commonly sought treatments. Perceived dental needs included prosthodontic treatment (39%), periodontal/prophylactic treatment (10%), restorative treatment (9%) and pain relief (9%). Study subjects had 2.8 decayed teeth, a DMFT of 25.1, and a Root Caries Index of 38%. CPITN scores of 3 or 4 in at least one sextant were found in 80% of subjects. Of the 41% edentulous, all wore complete dentures but 15% of complete upper dentures and 51% of complete lower dentures fitted poorly. Of the partial dentures, 20% fitted poorly. Soft tissue anomalies were seen in 67% of subjects and 47% had TMJ anomalies. Overall, 77% of edentulous subjects and all dentate subjects required some dental treatment even though 46% had seen a dentist within the preceding year. It is concluded that appropriate management of such people needs further attention.

Epidemiology of root caries.

Many epidemiological studies have been conducted on a variety of populations. Unfortunately, comparison of the prevalence data, and to a lesser degree of the incidence data, between the various studies is of little use due to the lack of standardised diagnostic criteria, reporting methods and population diversity. In the few incidence studies which have been conducted around 30-40% of people developed root caries, although many adults in the population appear to have been affected by root caries. Many risk factors associated with the occurrence of root caries have been identified and these include oral, medical, mental, behavioural and psychosocial conditions.

Elder abuse and the dentists' awareness and knowledge of the problem--a national survey.

A national sample of 1,775 Canadian dentists, representing 13.2 per cent of all Canadian dentists, were evaluated via a mailed questionnaire about their knowledge, awareness of, and experiences with victims of elder abuse and/or neglect. In all, 83.3 per cent of respondents were aware, to varying extents, of elder abuse or neglect. Of the dentists observing a patient suspected to have been a victim of neglect or abuse, 40.6 per cent reported incidents of neglect, while physical abuse was seen 59.4 per cent of the time. The types of neglect most frequently observed included: neglect of personal hygiene (31.8 per cent), failure to provide adequate medical/dental care (30.2 per cent), and failure to provide adequate supervision (20.1 per cent). The most frequently reported signs of physical abuse were bruises and welts (21.8 per cent), broken denture prostheses (12.1 per cent), fractured and avulsed teeth (11.5 per cent), and abrasions and lacerations (10.3 per cent). Where abuse was observed, dentists provided dental treatment in 53.2 per cent of the cases and made emergency medical referrals in 20.3 per cent of the cases. This study demonstrates that dentists have identified cases of abuse and/or neglect, and therefore should be consulted in the abuse/neglect identification and assessment process.

Medical and dental status of a culture in transition, the case of the Inuit elderly of Canada.

The medical and dental status, and drug utilisation patterns of Canadian Inuit elders (60+ years) were evaluated. Inuit elders averaged 6.3 medical conditions per person, primarily nervous systems-sense organ deficits, respiratory problems and systemic infections. The mean number of drugs being used was 2.5 per person, primarily analgesics, bronchodilators and antibiotics. Poorly fitting dentures, and high levels of tooth decay, periodontal disease, soft tissue and TMJ anomalies were documented. Compared to older southern Canadians, the medical and dental findings for these Inuit elders were different. Drug utilisation rates were consistent with older southern Canadians, but different drugs were taken.

Familial varices of the colon and small bowel.

We describe two patients, brother and sister, with identical pathology, whose only clinical presentation was recurrent massive lower digestive tract bleeding. Haemorrhage was due to a complex form of familial venous vascular malformation in the digestive tract, represented by the existence of varices of colon, small intestine and, to a lesser extent, oesophagus and gastric funcus. We have been able to study, examine and treat both patients for 9 and 3 years respectively.

Oral health status of a group of elderly Canadian Inuit (Eskimo).

Fifty-four Inuit elders, representing 90% of the individuals 60 yr of age and older in three communities in the Keewatin region of the Canadian Northwest Territories, were examined for dental caries, periodontal disease, levels of edentulism, and the fit and quality of denture prostheses. These elders had a mean of 2.8 +/- 3.5 decayed teeth and a DMFT of 26 +/- 13 which reflected significant tooth loss. The Root Caries Index for subjects with gingival recession was 19%. Periodontal pocket assessments revealed that 86% of the individuals examined had CPITN readings of either 3 or 4. Over one third of the elders were totally edentulous, most of them female. Only 47% of these individuals wore complete dentures. Denture fit assessment revealed that 36% of the complete maxillary dentures and 42% of the complete mandibular dentures fit poorly. The overall oral health findings for these Inuit elders differed from those found in other older populations; however, the present findings may be the norm for a population undergoing a cultural transition.

Principles of enamel etching.

Amongst the innovations that have changed the practice of dentistry over the past three decades, the acid-etch technique and the use of composite resins may be regarded as two of the most influential. In 1955, Michael Buonocore, a researcher at the Eastmen Dental Centre in Rochester, New York, made the astute observation that the application of weak inorganic acid could alter the surface enamel so that bonding of a resin to the surface could take place. Buonocore experimented with acrylic resins but found these were much too weak to withstand the stresses exerted upon them in the mouth. It was not until Rafael Bowen developed a unique system containing 25 percent by weight of polymerisable monomer and 75 percent by weight of a vitreous filler--the composite resin--that the acid-etch technique became an effect procedure. This article reviews historical and current research, in the search to optimise the resin to enamel bond.

Bond strength of fiber-reinforced composite resin restorations.

Severe tooth wear is common in older dentate individuals, with one treatment option being composite resin restorations reinforced with a suitable matrix. This study evaluated the use of high modulus polyethylene (Celanese) fibers as a reinforcing matrix for composite resin. Human mandibular incisor teeth were sectioned to simulate severe tooth wear. Sectioned surfaces were measured, the teeth paired and assigned to control or test sample groups, and further assigned to be tested with a labial or lingual shearing force. A phosphorylated dentin bonding adhesive was applied to the abraded dentin surface. Labial and lingual intra-enamel bevel preparations were cut on each specimen. A piece of Celanese fabric was bonded onto the acid-etched labial and lingual bevels of the test specimens using an enamel bonding agent. Class IV composite resin restorations were then placed onto the test and control specimens. Following water storage, the specimens were subjected to shearing forces. Bond strengths for test specimens were significantly greater (p < 0.03) than the controls. Specimens with a labially applied force also had significantly higher bond strengths (p < 0.001). SEM analysis revealed adhesive bond failures over dentin surfaces, with cohesive bond failures within the composite resin. Celanese fibers maintained the restorations on the teeth, although adhesive failures were seen between the fibers and enamel bonding agent.

Effects of warm air-drying and spreading on resin bonding.

The purpose of this study was to compare the effect on resin-to-enamel bonding produced by warm air from a hair dryer, and to correlate changes in resin bond strength with resin tag structure. Herculite-XR resin composite and Bondlite bonding resin were used. The three technique variables were the type of air used for drying, air dryer distance, and drying and spreading time. Control samples were dried and the bonding resin spread with a dental air syringe, whereas warm air from a hair dryer was used on the experimental samples. The bond strength (MPa) was determined in shear at a crosshead speed of 1 mm/min. Following bond strength evaluation, the teeth were immersed in 10% HCl for enamel dissolution and the resin tag structure was examined with the SEM. ANOVA analyses of shear bond strengths were performed. Warm air-drying and spreading for 15 seconds at 6 cm and 5 seconds at 6 cm respectively, produced statistically greater shear bond strengths (x = 20.4 +/- 4.4 MPa, P less than 0.05). The other drying time/distance combinations, including the control (x = 14.4 +/- 3.3 MPa), were not statistically different. Differences in resin tag structure were qualitatively evident under the SEM, with sharp tags produced by the warm air-drying and spreading techniques, compared to the blunt tags created by syringe air-drying and spreading. Warm air-drying and spreading significantly improved the bond strength. No apparent correlation exists between bond strength and tag length.

Clinical application of Geristore glass-ionomer restorative in older dentitions.

Geristore is a new multi-use dual-cure glass-ionomer restorative that has been introduced recently. There are many clinical applications for this material, some of which are presented in this article.

Effects of warm air-drying on intra-pulpal temperature.

This study was designed to determine what effects different warm air-drying conditions have on the intra-pulpal temperature (IPT), with or without chamber preparation and with or without an acid-etching treatment of the enamel. Four human maxillary centrals and four cuspids had lingual access openings prepared to accommodate a thermal sensor probe. Half of the specimens received a labial chamber preparation and half were acid-etched. All specimens were stored in water at 37 degrees C prior to testing. Labial aspects were positioned at 2 cm and 6 cm from the nozzle of a 500W hair dryer and IPTs were recorded after 15, 30, 45, and 60-second exposures. Exposure times for the acid-etched samples were modified to 10 seconds at 2 cm and 15 seconds at 6 cm. Results showed that for unetched teeth, increases in the IPT were greater at the 2 cm/15-second exposure (a 10.4-12.0 degrees C increase) than at the 6 cm/15-second exposure (a 3.9-6.6 degrees C increase). Even greater temperature changes were seen as the exposure times were increased to 30, 45, and 60 seconds. When the teeth were acid-etched, IPT rises of 5.6-10.1 degrees C and 5.8-8.7 degrees C were measured at 2 cm/10 seconds and at 6 cm/15 seconds, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)