Timing of Primary Surgery for Cleft Palate.

BACKGROUND: Among infants with isolated cleft palate, whether primary surgery at 6 months of age is more beneficial than surgery at 12 months of age with respect to speech outcomes, hearing outcomes, dentofacial development, and safety is unknown. METHODS: We randomly assigned infants with nonsyndromic isolated cleft palate, in a 1:1 ratio, to undergo standardized primary surgery at 6 months of age (6-month group) or at 12 months of age (12-month group) for closure of the cleft. Standardized assessments of quality-checked video and audio recordings at 1, 3, and 5 years of age were performed independently by speech and language therapists who were unaware of the trial-group assignments. The primary outcome was velopharyngeal insufficiency at 5 years of age, defined as a velopharyngeal composite summary score of at least 4 (scores range from 0 to 6, with higher scores indicating greater severity). Secondary outcomes included speech development, postoperative complications, hearing sensitivity, dentofacial development, and growth. RESULTS: We randomly assigned 558 infants at 23 centers across Europe and South America to undergo surgery at 6 months of age (281 infants) or at 12 months of age (277 infants). Speech recordings from 235 infants (83.6%) in the 6-month group and 226 (81.6%) in the 12-month group were analyzable. Insufficient velopharyngeal function at 5 years of age was observed in 21 of 235 infants (8.9%) in the 6-month group as compared with 34 of 226 (15.0%) in the 12-month group (risk ratio, 0.59; 95% confidence interval, 0.36 to 0.99; P = 0.04). Postoperative complications were infrequent and similar in the 6-month and 12-month groups. Four serious adverse events were reported (three in the 6-month group and one in the 12-month group) and had resolved at follow-up. CONCLUSIONS: Medically fit infants who underwent primary surgery for isolated cleft palate in adequately resourced settings at 6 months of age were less likely to have velopharyngeal insufficiency at the age of 5 years than those who had surgery at 12 months of age. (Funded by the National Institute of Dental and Craniofacial Research; TOPS ClinicalTrials.gov number, NCT00993551.).

Multiple oppositions intervention: effective phonological treatment of two children with cleft lip and palate and severe speech sound disorder.

The purpose of this study was to investigate if multiple oppositions intervention (MOI) generated widespread change in the phonological systems of two children with cleft lip and palate (CLP) and severe speech sound disorders (SSD). We treated two children (ages 5;4 and 5;6) with CLP and severe SSD using MOI for 24 and 29 sessions. We measured the percentage consonants correct (PCC) for target consonants and untreated consonants in non-treatment single words, as well as PCC for connected speech. Data points were collected in the baseline, intervention, and maintenance phase with post-tests conducted immediately after intervention and at 1, 3, 6 and 12 months. Two speech and language therapists (SLTs) unfamiliar with the children performed phonetic transcriptions, and we calculated intra- and inter-rater agreement. We graphed the data, and used permutation tests to analyse the probability that the observed increases in PCC were due to random chance. Both children experienced considerable improvements in PCC across all measures at the first post-test, supporting the impact of MOI on their entire phonological system. The PCC continued to increase during the maintenance phase. By the final post-test, the PCC in connected speech exceeded 90% for both children, reducing their SSD classification to mild. Our findings support that a phonological, contrastive intervention approach targeting multiple consonants simultaneously can create system-wide phonological change for children with CLP and severe SSD. Further research with more participants is needed to strengthen these findings.

Inter-rater reliability in classification of canonical babbling status based on canonical babbling ratio in infants with isolated cleft palate randomised to Timing of Primary Surgery for Cleft Palate (TOPS).

Canonical babbling (CB) is commonly defined as present when at least 15% of all syllables produced are canonical, in other words a canonical babbling ratio (CBR) ≥0.15. However, there is limited knowledge about inter-rater reliability in classification of CB status based on CBR and inter-rater differences in assessment of CBR. We investigated inter-rater reliability of experienced Speech Language Therapists (SLTs) on: classification of CB status based on CBR ≥ 0.15, CBRs and the total number of syllables per infant used to calculate CBR.Each infant (n = 484) was video-recorded at a clinical site in play interaction with their parent as part of the randomised controlled trial Timing of Primary Surgery for Cleft Palate. Each recording was subsequently assessed by three independent SLTs, from a pool of 29 SLTs. They assessed the recordings in real time.The three assessing SLTs agreed in classification of CB status in 423 (87.4%) infants, with higher complete agreement for canonical (91%; 326/358) than non-canonical (77%; 97/126). The average difference in CBR and total number of syllables identified between the SLT assessments of each infant was 0.12 and 95, respectively.This study provided new evidence that one trained SLT can reliably classify CB status (CBR ≥ 0.15) in real time when there is clear distinction between the observed CBR and the boundary (0.15); however, when the observed CBR approaches the boundary multiple SLT assessments are beneficial. Thus, we recommend to include assessment of inter-rater reliability, if the purpose is to compare CBR and total syllable count across infants or studies.Trial registration number here: www.clinicaltrials.gov, identifier NCT00993551.

Longitudinal study of the development of obstruent correctness from ages 3 to 5 years in 108 Danish children with unilateral cleft lip and palate: a sub-study within a multicentre randomized controlled trial.

BACKGROUND: Speech-sound development in preschoolers with unilateral cleft lip and palate (UCLP) as a group is delayed/disordered, and obstruents comprise the most vulnerable sound class. AIMS: To evaluate the development of obstruent correctness (PCC-obs) and error types (cleft speech characteristics (CSCs) and developmental speech characteristics (DSCs)) from ages 3-5 and to investigate possible predictors (error types, velopharyngeal dysfunction (VPD) and gender) of PCC-obs at age 5 in two groups of children with UCLP. METHODS & PROCEDURES: Subgroup analysis was conducted within a multicentre randomized controlled trial (RCT) of primary surgery (Scandcleft Project). A total of 125 Danish children with UCLP received lip and soft palate repair around 4 months of age and early hard palate closure at 12 months (EHPC group) or late hard palate closure at 36 months (LHPC group). Audio and video recordings of a naming test were available for 108 children at ages 3 and 5, and recordings were transcribed phonetically by blinded raters. OUTCOMES & RESULTS: PCC-obs scores increased significantly from ages 3-5 in both groups, but with small effect sizes in the EHPC group that had higher scores at age 3 than the LHPC group. DSCs decreased in both groups whereas CSCs only decreased in the LHPC group that had more CSCs at age 3 than the EHPC group. The frequency of CSCs at age 3 was a significant predictor of PCC-obs scores at age 5 in both groups. DSCs significantly improved the logistic regression model in the EHPC group, whereas VPD and gender did not significantly improve the model in either group. CONCLUSIONS & IMPLICATIONS: Although PCC-obs developed significantly from ages 3 to 5, children with UCLP as a group did not catch up to typically developing Danish children at age 5. Furthermore, the LHPC group at age 5 did not reach the 3-year level of the EHPC group, which means that delaying hard palate closure until age 3 is detrimental to obstruent development. Both CSCs and DSCs at age 3 were important predictors of PCC-obs at age 5 and should be considered when determining need for intervention.

Interlinked DNA nano-circles for measuring topoisomerase II activity at the level of single decatenation events.

DNA nano-structures present appealing new means for monitoring different molecules. Here, we demonstrate the assembly and utilization of a surface-attached double-stranded DNA catenane composed of two intact interlinked DNA nano-circles for specific and sensitive measurements of the life essential topoisomerase II (Topo II) enzyme activity. Topo II activity was detected via the numeric release of DNA nano-circles, which were visualized at the single-molecule level in a fluorescence microscope upon isothermal amplification and fluorescence labeling. The transition of each enzymatic reaction to a micrometer sized labeled product enabled quantitative detection of Topo II activity at the single decatenation event level rendering activity measurements in extracts from as few as five cells possible. Topo II activity is a suggested predictive marker in cancer therapy and, consequently, the described highly sensitive monitoring of Topo II activity may add considerably to the toolbox of individualized medicine where decisions are based on very sparse samples.

Validation of three-dimensional wound measurements using a novel 3D-WAM camera.

To monitor wound healing, it is essential to obtain accurate and reliable wound measurements. Various methods have been used to measure wound size including three-dimensional (3D) measurement devices enabling wound assessment from a volume perspective. However, the currently available methods are inaccurate, costly, or complicated to use. As a consequence, we have developed a 3D-wound assessment monitor (WAM) camera, which is able to measure wound size in three-dimension and to assess wound characteristics. The aim of the study was to assess the intrarater and interrater reliability of the 3D wound measurements using the 3D camera and to compare these with traditional measurement methods. Four raters measured 48 wounds using the 3D camera, digital imaging method (2D area), and gel injection into the wound cavity (volume). The data were analyzed using linear mixed effect model. Intraclass and interclass correlation coefficient (ICC) and Bland-Altman plots were used to assess intrarater and interrater reliability for the 3D camera and agreement between the methods. The Bland-Altman plots for intrarater reliability showed minor differences between the measurements, especially the 3D area and perimeter measurements. Moreover, ICCs were very high for both the intrarater and interrater reliability for the 2D area, 3D area, and perimeter measurements (ICCs > 0.99), although slightly lower for the volume measurements (ICC = 0.946-0.950). Finally, a high agreement was found between the 3D camera and the traditional methods (2D area and volume) assessed by narrow 95% prediction intervals and high ICCs above 0.97. In conclusion, the 3D-WAM camera is an accurate and reliable method, which is useful for several types of wounds. However, the volume measurements were primarily useful in large, deep wounds. Moreover, the 3D images are based on digital technology and therefore carry the possibility for use in remote settings.

Influence of timing of delayed hard palate closure on articulation skills in 3-year-old Danish children with unilateral cleft lip and palate.

BACKGROUND: Differing results regarding articulation skills in young children with cleft palate (CP) have been reported and often interpreted as a consequence of different surgical protocols. AIMS: To assess the influence of different timing of hard palate closure in a two-stage procedure on articulation skills in 3-year-olds born with unilateral cleft lip and palate (UCLP). Secondary aims were to compare results with peers without CP, and to investigate if there are gender differences in articulation skills. Furthermore, burden of treatment was to be estimated in terms of secondary surgery, hearing and speech therapy. METHODS & PROCEDURES: A randomized controlled trial (RCT). Early hard palate closure (EHPC) at 12 months versus late hard palate closure (LHPC) at 36 months in a two-stage procedure was tested in a cohort of 126 Danish-speaking children born with non-syndromic UCLP. All participants had the lip and soft palate closed around 4 months of age. Audio and video recordings of a naming test were available from 113 children (32 girls and 81 boys) and were transcribed phonetically. Recordings were obtained prior to hard palate closure in the LHPC group. The main outcome measures were percentage consonants correct adjusted (PCC-A) and consonant errors from blinded assessments. Results from 36 Danish-speaking children without CP obtained previously by Willadsen in 2012 were used for comparison. OUTCOMES & RESULTS: Children with EHPC produced significantly more target consonants correctly (83%) than children with LHPC (48%; p < .001). In addition, children with LHPC produced significantly more active cleft speech characteristics than children with EHPC (p < .001). Boys achieved significantly lower PCC-A scores than girls (p = .04) and produced significantly more consonant errors than girls (p = .02). No significant differences were found between groups regarding burden of treatment. The control group performed significantly better than the EHPC and LHPC groups on all compared variables.

Development and validation of a screening procedure to identify speech-language delay in toddlers with cleft palate.

The purpose of this study was to develop and validate a clinically useful speech-language screening procedure for young children with cleft palate ± cleft lip (CP) to identify those in need of speech-language intervention. Twenty-two children with CP were assigned to a +/- need for intervention conditions based on assessment of consonant inventory using a real-time listening procedure in combination with parent-reported expressive vocabulary. These measures allowed evaluation of early speech-language skills found to correlate significantly with later speech-language performance in longitudinal studies of children with CP. The external validity of this screening procedure was evaluated by comparing the +/- need for intervention assignment determined by the screening procedure to experienced speech-language pathologist (SLP)s' clinical judgement of whether or not a child needed early intervention. The results of real-time listening assessment showed good-excellent inter-rater agreement on different consonant inventory measures. Furthermore, there was almost perfect agreement between the children selected for intervention with the screening procedure and the clinical judgement of experienced SLPs indicate that the screening procedure is a valid way of identifying children with CP who need early intervention.

Methods to assess area and volume of wounds - a systematic review.

Wound measurement is important in monitoring the healing process of chronic wounds and in evaluating the effect of treatment. The objective of this systematic review was to evaluate evidence from the literature on accuracy, agreement, reliability and feasibility of wound measurement techniques described since 1994. Studies were identified by searching the electronic databases PubMed, Embase and Cochrane Library. Of the 12 013 studies identified, 43 were included in the review. A total of 30 papers evaluated techniques for measuring wound area and 13 evaluated techniques for measuring wound volume. The six approaches for measuring wound area were simple ruler method (10 papers), mathematical models (5 papers), manual planimetry (10 papers), digital planimetry (16 papers), stereophotogrammetry (2 papers) and digital imaging method (20 papers). Of these studies, 10 evaluated accuracy, 15 agreement, 17 reliability and 25 mentioned feasibility. The number of wounds examined in the studies was highly variable (n = 3-260). Studies evaluating techniques for measuring wound volume included between 1 and 50 wounds and evaluated accuracy (4 studies), agreement (6 studies), reliability (8 studies) and feasibility (12 studies). Digital planimetry and digital imaging were considered the most accurate and reliable methods for area measurement, particularly in larger and irregularly shaped wounds. None of the three-dimensional technologies have so far had a major impact, because of their low accuracy, high cost and complexity in handling the system set-up.

[Treatment of acute and chronic ulcers].

Chronic ulcers are most often seen as a complication to venous leg ulcers, diabetic foot ulcers and pressure ulcers. Ulcers often display an underlying medical condition, which makes it mandatory to treat these individuals in a multidisciplinary setting. Modern ulcer therapy has changed over the latest decade, and as described in this review a number of new modalities have been included. The major group of ulcers often presents with well-defined features, but attention should be directed towards ulcers with atypic appearance such as ulcers related to calciphylaxis, hypertension (Martorell) and pyoderma.

[Acutely induced diabetes mellitus in a 63-year-old female after treatment with ipilimumab for metastatic melanoma].

Immune checkpoint inhibitors have improved survival rate in patients with advanced melanoma, but also have the potential to induce several adverse events. We report on a 63-year-old woman who had advanced melanoma and was admitted with diabetic ketoacidosis, which had occurred upon treatment with ipilimumab. On admission, the C-peptide level was low, and the HbA1c concentration was 50 mmol/l indicating a rapid onset of the disease. The patient had also been diagnosed with thyroiditis. Diabetes mellitus is a rare and serious side effect of treatment with ipilimumab, and we recommend being aware of this due to the rapid course.

[Immune checkpoint inhibitors and endocrinological side effects].

Immune checkpoint inhibitors including anti-cytotoxic T-lymphocyte-associated antigen-4 and anti-programmed cell death-1 have revolutionized cancer therapy but have also induced serious immune-related adverse events including hormonal dysfunction. The objective of this review is to characterize the incidence, clinical presentation, management and prognosis of the endocrine-related adverse events including hypophysitis, thyroid dysfunction and diabetes mellitus. Combination therapy is associated with an increased risk of adverse events. We recommend close monitoring of the hormone levels and glycaemic status during and a year after treatment.

The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis.

Thymic dendritic cells (DC) play a role in central tolerance. Three thymic DC subtypes have been described: plasmacytoid DC (pDC) and two conventional DC (cDC), CD8α+ Sirpα- DC and Sirpα+ CD8α- cDC. Both pDC and Sirpα+ cDC can take up antigen in periphery and migrate into the thymus in response to chemokine signaling via CCR9 and CCR2 respectively. CCL2 is a major ligand for CCR2 and we previously showed that it was constitutively expressed in thymus, and that mice overexpressing CCL2 in thymus had reduced numbers of autoreactive T cells but elevated numbers of pDC. We have here investigated the role of CCL2-CCR2 axis in thymic pDC migration. We found that pDC expressed CCR2 at a high level and that their frequency was decreased in thymus, spleen and inguinal lymph nodes in mice lacking CCR2, but not in mice lacking CCL2. pDC migration towards the cortex or medulla within the thymus was not affected by CCL2 or CCR2 deficiency. Although some thymic progenitors expressed CCR2, this did not include those that give rise to pDC. Based on these results, we propose that CCR2 is involved in pDC homeostasis but its ligand CCL2 does not play a major role.

Real-time investigation of human topoisomerase I reaction kinetics using an optical sensor: a fast method for drug screening and determination of active enzyme concentrations.

Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using camptothecin derivatives. These drugs convert the hTopI activity into a cellular poison, and hence the cytotoxic effects of camptothecin derivatives correlate with the hTopI activity. Therefore, fast and reliable techniques for high throughput measurements of hTopI activity are of high clinical interest. Here we demonstrate potential applications of a fluorophore-quencher based DNA sensor designed for measurement of hTopI cleavage-ligation activities, which are the catalytic steps affected by camptothecin. The kinetic analysis of the hTopI reaction with the DNA sensor exhibits a characteristic burst profile. This is the result of a two-step ping-pong reaction mechanism, where a fast first reaction, the one creating the signal, is followed by a slower second reaction necessary for completion of the catalytic cycle. Hence, the burst profile holds information about two reactions in the enzymatic mechanism. Moreover, it allows the amount of active enzyme in the reaction to be determined. The presented results pave the way for future high throughput drug screening and the potential of measuring active hTopI concentrations in clinical samples for individualized treatment.

Newly diagnosed type 1 diabetes complicated by ketoacidosis and peripheral thrombosis leading to transfemoral amputation.

Peripheral vascular thromboembolism is a rarely described complication of diabetic ketoacidosis. We report a 41-year-old otherwise healthy man admitted with ketoacidosis and ischaemia of the left foot. The patient was unsuccessfully treated with thromboendarterectomy, and the extremity was ultimately amputated. The patient had no family history of cardiovascular disease, and all blood sample analyses for hypercoagulability were negative. We recommend an increased focus on peripheral thromboembolism, when treating patients with severe ketoacidosis.