Pediatric tympanostomy tube assessment via deep learning.

PURPOSE: Tympanostomy tube (TT) placement is the most frequently performed ambulatory surgery in children under 15. After the procedure it is recommended that patients follow up regularly for "tube checks" until TT extrusion. Such visits incur direct and indirect costs to families in the form of days off from work, copays, and travel expenses. This pilot study aims to compare the efficacy of tympanic membrane (TM) evaluation by an artificial intelligence algorithm with that of clinical staff for determining presence or absence of a tympanostomy tube within the TM. METHODS: Using a digital otoscope, we performed a prospective study in children (ages 10 months-10 years) with a history of TTs who were being seen for follow up in a pediatric otolaryngology clinic. A smartphone otoscope was used by study personnel who were not physicians to take ear exam images, then through conventional otoscopic exam, ears were assessed by a clinician for tubes being in place or tubes having extruded from the TM. We trained and tested a deep learning (artificial intelligence) algorithm to assess the images and compared that with the clinician's assessment. RESULTS: A total of 123 images were obtained from 28 subjects. The algorithm classified images as TM with or without tube in place. Overall classification accuracy was 97.7 %. Recall and precision were 100 % and 96 %, respectively, for TM without a tube present, and 95 % and 100 %, respectively, for TM with a tube in place. DISCUSSION: This is a promising deep learning algorithm for classifying ear tube presence in the TM utilizing images obtained in awake children using an over-the-counter otoscope available to the lay population. We are continuing enrollment, with the goal of building an algorithm to assess tube patency and extrusion.

Management of hyperosmolar hyperglycaemic state in adults with diabetes.

Hyperglycaemic hyperosmolar state (HHS) is a medical emergency, which differs from diabetic ketoacidosis (DKA) and requires a different approach. The present article summarizes the recent guidance on HHS that has been produced by the Joint British Diabetes Societies for Inpatient Care, available in full at http://www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_HHS_Adults.pdf. HHS has a higher mortality rate than DKA and may be complicated by myocardial infarction, stroke, seizures, cerebral oedema and central pontine myelinolysis and there is some evidence that rapid changes in osmolality during treatment may be the precipitant of central pontine myelinolysis. Whilst DKA presents within hours of onset, HHS comes on over many days, and the dehydration and metabolic disturbances are more extreme. The key points in these HHS guidelines include: (1) monitoring of the response to treatment: (i) measure or calculate the serum osmolality regularly to monitor the response to treatment and (ii) aim to reduce osmolality by 3-8 mOsm/kg/h; (2) fluid and insulin administration: (i) use i.v. 0.9% sodium chloride solution as the principal fluid to restore circulating volume and reverse dehydration, (ii) fluid replacement alone will cause a fall in blood glucose (BG) level, (iii) withhold insulin until the BG level is no longer falling with i.v. fluids alone (unless ketonaemic), (iv) an initial rise in sodium level is expected and is not itself an indication for hypotonic fluids and (v) early use of insulin (before fluids) may be detrimental; and (3) delivery of care: (i) The diabetes specialist team should be involved as soon as possible and (ii) patients should be nursed in areas where staff are experienced in the management of HHS.

Selective ablation of differentiated cells permits isolation of embryonic stem cell lines from murine embryos with a non-permissive genetic background.

Embryonic stem (ES) cells enable the engineering of precise modifications to the mouse genome by gene targeting. Although there are reports of cultured cell contributions to chimaeras in golden hamster, rat and pig, definitive ES cell lines which contribute to the germline have not been demonstrated in any species but mouse. Among mouse strains, genetic background strongly affects the efficiency of ES isolation, and almost all ES lines in use are derived from strain 129 (refs 1,4,5) or, less commonly, C57BL/6 (refs 6-8). The CBA strain is refractory to ES isolation and there are no published reports of CBA-derived ES lines. Hence, CBA mice may provide a convenient model of ES isolation in other species. In ES derivation it is critical that the primary explant be cultured for a sufficient time to allow multiplication of ES cell progenitors, yet without allowing extensive differentiation. Thus, differences in ES derivation between mouse strains may reflect differences in the control of ES progenitor cells by other lineages within the embryo. Here we describe a strategy to continuously remove differentiated cells by drug selection, which generates germline competent ES lines from genotypes that are non-permissive in the absence of selection.

Abnormal liver function tests in patients with Type 1 diabetes mellitus: prevalence, clinical correlations and underlying pathologies.

AIMS: To determine the prevalence of elevated alanine transaminase (ALT) in a large cohort of patients with Type 1 diabetes and to examine the clinical correlations and causes. Methods Patients with Type 1 diabetes mellitus were prospectively recruited and ALT, glycated haemoglobin and lipid profile were measured. Patients with Type 2 diabetes mellitus were recruited as a comparison group. PATIENTS: with abnormal ALT were investigated for underlying causes. Prevalence of abnormal ALT was analysed at three separate cut-offs and multivariable analysis used to identify independent risk factors. RESULTS: Nine hundred and eleven with Type 1 diabetes and 963 with Type 2 diabetes were included. The prevalence of elevated ALT was dependent on the cut-off value: > 30 IU/l in males and > 19 IU/l in females, > 50 and > 63 IU/l was 34.5, 4.3 and 1.9%, respectively, in Type 1 diabetes and 51.4, 8.2 and 3.7%, respectively, in Type 2 diabetes. In Type 1 diabetes an elevated ALT was associated with worse glycaemic control, age > 55 years and elevated triglycerides. Investigation of these patients revealed a cause in 43.6% of patients, predominantly non-alcoholic fatty liver disease (NAFLD). CONCLUSIONS: Elevated ALT is not uncommon in Type 1 diabetes and is associated with NAFLD-related risk factors. Patients with Type 1 diabetes and elevated ALT should be investigated as significant abnormalities may be found which are amenable to interventions.

Human factor IX transgenic sheep produced by transfer of nuclei from transfected fetal fibroblasts.

Ovine primary fetal fibroblasts were cotransfected with a neomycin resistance marker gene (neo) and a human coagulation factor IX genomic construct designed for expression of the encoded protein in sheep milk. Two cloned transfectants and a population of neomycin (G418)-resistant cells were used as donors for nuclear transfer to enucleated oocytes. Six transgenic lambs were liveborn: Three produced from cloned cells contained factor IX and neo transgenes, whereas three produced from the uncloned population contained the marker gene only. Somatic cells can therefore be subjected to genetic manipulation in vitro and produce viable animals by nuclear transfer. Production of transgenic sheep by nuclear transfer requires fewer than half the animals needed for pronuclear microinjection.

Outcomes in patients ≥ 80 years with a diagnosis of a hepatopancreaticobiliary (HPB) malignancy.

Older patients are underrepresented in oncological clinical trials. The incidence of hepatopancreaticobiliary (HPB) malignancies is higher in older patients, but data on outcomes are lacking. This study assessed patient outcomes in those < 80 and ≥ 80 years with a HPB malignancy seen at a tertiary referral centre, The Christie NHS Foundation Trust. Data on patients with a HPB malignancy were collected retrospectively between 2012 and 2017 via on-line case-note review. Survival was calculated using the Kaplan-Meier method and prognostic factors using log-rank analysis. Of 1421 patients, 10% were ≥ 80 years. Of patients < 80 and ≥ 80 years, 56% and 57% had pancreas cancer, 39% and 36% biliary tract cancer, and 5% and 7% had hepatocellular carcinoma, respectively. Amongst patients ≥ 80 years, 75% had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients ≥ 80 years had higher rates of comorbidity; 28% received systemic anti-cancer therapy (SACT), compared with 62% of patients < 80 years. Best supportive care (BSC) was instituted in 44% of older patients, compared with 13% in those < 80 years. Of patients ≥ 80 years who received SACT, 82% received monotherapy. Median overall survival (OS) for patients receiving palliative SACT was 10.07 months (95% CI 8.89-11.08) and 10.10 months (95% CI 6.30-12.30) in patients < 80 and ≥ 80 years, respectively, p 0.41; ECOG PS (p < 0.001) was prognostic for OS in older patients but Adult Comorbidity Evaluation-27 comorbidity score (p = 0.07, when comparing groups of ACE score ≤ 1 and > 1) was not. Baseline factors were similar in both age cohorts, but more comorbidities were present in older patients. Older patients were less likely to receive SACT, but when they did, they had an equivalent benefit in OS to younger patients.

Expression of an engineered form of recombinant procollagen in mouse milk.

We have examined the suitability of the mouse mammary gland for expression of novel recombinant procollagens that can be used for biomedical applications. We generated transgenic mouse lines containing cDNA constructs encoding recombinant procollagen, along with the alpha and beta subunits of prolyl 4-hydroxylase, an enzyme that modifies the collagen into a form that is stable at body temperature. The lines expressed relatively high levels (50-200 micrograms/ml) of recombinant procollagen in milk. As engineered, the recombinant procollagen was shortened and consisted of a pro alpha 2(I) chain capable of forming a triple-helical homotrimer not normally found in nature. Analysis of the product demonstrated that (1) the pro alpha chains formed disulphide-linked trimers, (2) the trimers contained a thermostable triple-helical domain, (3) the N-propeptides were aligned correctly, and (4) the expressed procollagen was not proteolytically processed to collagen in milk.

Audiometric outcomes of tympanoplasty with hydroxylapatite prosthesis: consultant versus trainees.

OBJECTIVE: To assess and compare the audiometric outcomes and surgical complication rates of tympanoplasty with hydroxylapatite (HA) prostheses performed by a single consultant and advanced trainees. STUDY DESIGN: A retrospective case review was undertaken. SETTING: Tertiary referral center. PATIENTS: One hundred eighteen cases of primary and revision tympanoplasty were included in the study performed during a 6-year period. INTERVENTION: Tympanoplasty with HA prosthesis. MAIN OUTCOME MEASURES: Preoperative and postoperative audiometric data were compared for both the consultant and trainee groups. Details of the surgical procedure and operative complications were also recorded. RESULTS: Fifty-eight procedures were performed by the consultant and 60 operations were performed by trainees. The average improvement in air-bone gap (ABG) for consultants was 14.8 dB, with a 95% confidence interval (10.4, 19.2) (paired t test; test statistic: t=6.80, 57 df, p<0.01), whereas for trainees, the average improvement in ABG was 7.8 dB, with a 95% confidence interval (4.1, 11.6) (paired t test; test statistic: t=4.19, 59 df, p<0.01). The difference of 7.0 dB in mean ABG between the 2 groups was significant (two-sample t test; test statistic: t=2.44, 116 df, p=0.02). There was no significant difference in the surgical procedure or in the number of revision operations performed by the consultant or trainees. Surgical complication rates were comparable for the two groups. CONCLUSION: In this series, the consultant achieved a significantly better closure in ABG than trainees for tympanoplasty with HA prostheses.

Current and Emerging Treatments for Postsurgical Cleft Lip Scarring: Effectiveness and Mechanisms.

Cleft lip with or without cleft palate is the most common congenital malformation of the head and the third-most common birth defect. Surgical repair of the lip is the only treatment and is usually performed during the first year of life. Hypertrophic scar (HTS) formation is a frequent postoperative complication that impairs soft tissue form, function, or movement. Multiple lip revision operations are often required throughout childhood, attempting to optimize aesthetics and function. The mechanisms guiding HTS formation are multifactorial and complex. HTS is the result of dysregulated wound healing, where excessive collagen and extracellular matrix proteins are deposited within the wound area, resulting in persistent inflammation and resultant fibrosis. Many studies support the contribution of dysregulated, exaggerated inflammation in scar formation. Fibrosis and scarring result from chronic inflammation that interrupts tissue remodeling in normal wound healing. Failure of active resolution of inflammation pathways has been implicated. The management of HTS has been challenging for clinicians, since current therapies are minimally effective. Emerging evidence that specialized proresolving mediators of inflammation accelerate wound healing by preventing chronic inflammation and allowing natural uninterrupted tissue remodeling suggests new therapeutic opportunities in the prevention and management of HTS.

Abnormal thermoregulation in diabetic autonomic neuropathy.

Hypothermia has been reported to be more common in diabetic people than in nondiabetic people, and we have investigated the possibility that autonomic neuropathy may be associated with disordered thermoregulation. After an overnight fast and maintenance of normoglycemia, 12 insulin-treated diabetic patients with and 11 without neuropathy and 12 nondiabetic control subjects, all less than 55 yr, were subjected to external cooling by perfusing water at 16 degrees C through a liquid-conditioned coverall for less than or equal to 45 min. Patients with autonomic neuropathy had impaired vasoconstriction to cooling, particularly in the foot, calf, and forearm. Core temperature rose by 0.2 degrees C in control subjects and by 0.15 degrees C in patients with diabetes but no neuropathy. In contrast, group mean core temperature was unchanged in those with autonomic neuropathy and fell in 3 subjects (P less than .001). Cooling caused shivering in 6 patients with diabetic autonomic neuropathy, but not in those with neuropathy or control subjects (P less than .05). Baseline metabolic rates were similar in all three groups, but the increase after cooling was significantly greater among those who shivered (P less than .05-.02). Thus, young diabetic patients with autonomic neuropathy have impaired thermoregulation to a relatively short period of external cooling, even during metabolic stability, which may predispose to hypothermia.

Hepatic cirrhosis: a clinico-pathological review of 520 cases.

A clinico-pathological review of 520 patients with hepatic cirrhosis coming to necropsy at the Western Infirmary, Glasgow over the period 1900-69 is reported. There has been an overall increase in incidence of cirrhosis since the 1940s, and this has been largely due to a rise in female incidence. A similar trend in the period 1940-71 has been confirmed at a national level in data abstracted from the Annual Reports of the Registrar General for Scotland. The mean age at death has risen for both sexes. Aetiologically, the cirrhosis was alcoholic in 18.5%, posticteric in 10.4%, cryptogenic in 61.9%, and haemochromatosis was diagnosed in 7.5%. Primary malignant tumours of liver supervened in 12.3%. The causes of death and the morphological patterns of the cirrhosis are reviewed.

Post-cricoid web associated with Rubinstein-Taybi syndrome.

A case of dysphagia due to a post-cricoid web in a seven-year-old boy with Rubinstein-Taybi syndrome is presented. The main features of this syndrome are summarized with particular reference to dysphagia and with previous cases of post-cricoid webs in children reviewed.

Comparison of high fibre diets, basal insulin supplements, and flexible insulin treatment for non-insulin dependent (type II) diabetics poorly controlled with sulphonylureas.

OBJECTIVE: To compare high fibre diet, basal insulin supplements and a regimen of insulin four times daily in non-insulin dependent (type II) diabetic patients who were poorly controlled with sulphonylureas. DESIGN: Run in period lasting 2-3 months during which self monitoring of glucose concentration was taught, followed by six months on a high fibre diet, followed by six months' treatment with insulin in those patients who did not respond to the high fibre diet. SETTING: Teaching hospital diabetic clinics. PATIENTS: 33 patients who had had diabetes for at least two years and had haemoglobin A1 concentrations over 10% despite receiving nearly maximum doses of oral hypoglycaemic agents. No absolute indications for treatment with insulin. INTERVENTIONS: During the high fibre diet daily fibre intake was increased by a mean of 16 g (95% confidence interval 12 to 20 g.) Twenty five patients were then started on once daily insulin. After three months 14 patients were started on four injections of insulin daily. ENDPOINT: Control of diabetes (haemoglobin A1 concentration less than or equal to 10% and fasting plasma glucose concentration less than or equal to 6 mmol/l) or completion of six months on insulin treatment. MEASUREMENTS AND MAIN RESULTS: No change in weight, diet, or concentrations of fasting glucose or haemoglobin A1 occurred during run in period. During high fibre diet there were no changes in haemoglobin A1 concentrations, but mean fasting glucose concentrations rose by 1.7 mmol/l (95% confidence interval 0.9 to 2.5, p less than 0.01). With once daily insulin mean concentrations of fasting plasma glucose fell from 12.6 to 7.6 mmol/l (p less than 0.001) and haemoglobin A1 from 14.6% to 11.2% (p less than 0.001). With insulin four times daily concentrations of haemoglobin A1 fell from 11.5% to 9.6% (p less than 0.02). Lipid concentrations were unchanged by high fibre diet. In patients receiving insulin the mean cholesterol concentrations fell from 7.1 to 6.4 mmol/l (p less than 0.0001), high density lipoprotein concentrations rose from 1.1 to 1.29 mmol/l (p less than 0.01), and triglyceride concentrations fell from 2.67 to 1.86 mmol/l (p less than 0.05). Patients taking insulin gained weight and those taking it four times daily gained an average of 4.2 kg. CONCLUSIONS: High fibre diets worsen control of diabetes in patients who are poorly controlled with oral hypoglycaemic agents. Maximum improvements in control of diabetes were achieved by taking insulin four times daily.

Transgenic livestock as bioreactors: stable expression of human alpha-1-antitrypsin by a flock of sheep.

We have previously described the generation of transgenic sheep expressing human alpha 1-antitrypsin (h alpha 1AT) in their milk. Here, we report the fidelity of transgene transmission and expression by these animals and their progeny. Transgene transmission has been demonstrated in four of six ovine lines studied. Three of these four lines have exhibited stable transmission of the transgene, whereas the fourth has produced some offspring with reduced copy numbers. Sequential lactations of founder animals has yielded very similar levels of h alpha 1AT protein in milk. Moreover, in one line, derived from a founder male, a flock of seven G1 ewes have yielded comparable levels of h alpha 1AT protein in first and second lactation milk. Two G2 ewes of this line have also produced levels of human protein equivalent to their mother. Although the inheritance of the same transgene in mice was reminiscent of the situation in sheep, stable expression was observed in only one or four lines studied. The importance of these observations to the use of transgenic livestock as bioreactors for the production of human proteins is discussed.