Southern Hemisphere climate variability forced by Northern Hemisphere ice-sheet topography.

The presence of large Northern Hemisphere ice sheets and reduced greenhouse gas concentrations during the Last Glacial Maximum fundamentally altered global ocean-atmosphere climate dynamics. Model simulations and palaeoclimate records suggest that glacial boundary conditions affected the El Niño-Southern Oscillation, a dominant source of short-term global climate variability. Yet little is known about changes in short-term climate variability at mid- to high latitudes. Here we use a high-resolution water isotope record from West Antarctica to demonstrate that interannual to decadal climate variability at high southern latitudes was almost twice as large at the Last Glacial Maximum as during the ensuing Holocene epoch (the past 11,700 years). Climate model simulations indicate that this increased variability reflects an increase in the teleconnection strength between the tropical Pacific and West Antarctica, owing to a shift in the mean location of tropical convection. This shift, in turn, can be attributed to the influence of topography and albedo of the North American ice sheets on atmospheric circulation. As the planet deglaciated, the largest and most abrupt decline in teleconnection strength occurred between approximately 16,000 years and 15,000 years ago, followed by a slower decline into the early Holocene.

Modelling a Consultant Workforce for the United Kingdom: needs-based planning for Dental Public Health.

OBJECTIVE: To develop a needs-based workforce planning model to explore specialist workforce capacity and capability for the effective, efficient, and safe provision of services in the United Kingdom (UK); and test the model using Dental Public Health (DPH). BASIC RESEARCH DESIGN: Data from a national workforce survey, national audit, and specialty workshops in 2020 and 2021 set the parameters for a safe effective DPH workforce. A working group drawing on external expertise, developed a conceptual workforce model which informed the mathematical modelling, taking a Markovian approach. The latter enabled the consideration of possible scenarios relating to workforce development. It involved exploration of capacity within each career stage in DPH across a time horizon of 15 years. Workforce capacity requirements were calculated, informed by past principles. RESULTS: Currently an estimated 100 whole time equivalent (WTE) specialists are required to provide a realistic basic capacity nationally for DPH across the UK given the range of organisations, population growth, complexity and diversity of specialty roles. In February 2022 the specialty had 53.55 WTE academic/service consultants, thus a significant gap. The modelling evidence suggests a reduction in DPH specialist capacity towards a steady state in line with the current rate of training, recruitment and retention. The scenario involving increasing training numbers and drawing on other sources of public health trained dentists whilst retaining expertise within DPH has the potential to build workforce capacity. CONCLUSIONS: Current capacity is below basic requirements and approaching 'steady state'. Retention and innovative capacity building are required to secure and safeguard the provision of specialist DPH services to meet the needs of the UK health and care systems.

Noncarious cervical lesions: Morphology and progression, prevalence, etiology, pathophysiology, and clinical guidelines for restoration.

PURPOSE: To synthesize the literature regarding noncarious cervical lesions (NCCLs) and propose clinical guidelines when lesion restoration is indicated. MATERIAL AND METHODS: A PubMed search was performed related to NCCL morphology, progression, prevalence, etiology, pathophysiology, and restoration. RESULTS: NCCLs form as either rounded (saucerlike) depressions with smooth, featureless surfaces that progress mainly in height or as V-shaped indentations that increase in both height and depth. Prevalence ranges from less than 10% to over 90% and increases with age. Common locations are the facial surfaces of maxillary premolars. They have a multifactorial etiology due to personal habits such as excessive horizontal toothbrushing and consumption of acidic foods and drinks. Occlusal factors have been identified as contributing to the prevalence of NCCLs in some studies, whereas other studies indicate there is no relationship. The concept of abfraction has been proposed whereby mechanical stress from occlusal loading plays a role in the development and progression of NCCLs with publications supporting the concept and others indicating it lacks the required clinical documentation. Regardless of the development mechanism, demineralization occurs and they are one of the most common demineralization diseases in the body. Treatment should be managed conservatively through preventive intervention with restorative treatment delayed until it becomes necessary due to factors such as lesion progression, impact on patient's quality of life, sensitivity, poor esthetics, and food collection may necessitate restoration. Composite resins are commonly used to restore NCCLs although other materials such as glass ionomer and resin-modified glass ionomer are also used. Sclerotic dentin does not etch like normal dentin and therefore it has been recommended to texture the dentin surface with a fine rotary diamond instrument to improve restoration retention. Some clinicians use mechanical retention to increase retention. Beveling of enamel is used to increase the bonding area and retention as well as enhance the esthetic result by gradually creating a color change between the restoration and tooth. Both multistep and single-step adhesives have been used. Dentin etching should be increased to 30 seconds due to the sclerotic dentin with the adhesive agent applied using a light scrubbing motion for 20 seconds but without excessive force that induces substantial bending of a disposable applicator. Both flowable and sculptable composite resins have been successfully used with some clinicians applying and polymerizing a layer of flowable composite resin and then adding an external layer of sculptable composite resin to provide enhanced resistance to wear. When caries is present, silver diamine fluoride has been used to arrest the caries rather than restore the lesion. CONCLUSIONS: Noncarious cervical lesions (NCCLs) form as smooth saucerlike depressions or as V-shaped notches. Prevalence values as high as 90% and as low as 10% have been reported due to habits such as excessive toothbrushing and an acidic diet. Occlusal factors have been proposed as contributing to their presence but it remains controversial. Publications have both supported and challenged the concept of abfraction. They are one of the most common demineralization diseases in the body. Conservative treatment through prevention is recommended with restorative treatment delayed as long as possible. When treatment is needed, composite resins are commonly used with proposed restorative guidelines including texturing the sclerotic dentin, beveling the enamel, potential use of mechanical retention, 30 seconds of acid etching, and use of either multistep or single-step adhesives in conjunction with a light scrubbing motion for 20 seconds without excessive force placed on disposable applicators.

Pathophysiology of Demineralization, Part II: Enamel White Spots, Cavitated Caries, and Bone Infection.

PURPOSE OF REVIEW: Compare noninfectious (part I) to infectious (part II) demineralization of bones and teeth. Evaluate similarities and differences in the expression of hard tissue degradation for the two most common chronic demineralization diseases: osteoporosis and dental caries. RECENT FINDINGS: The physiology of demineralization is similar for the sterile skeleton compared to the septic dentition. Superimposing the pathologic variable of infection reveals a unique pathophysiology for dental caries. Mineralized tissues are compromised by microdamage, demineralization, and infection. Osseous tissues remodel (turnover) to maintain structural integrity, but the heavily loaded dentition does not turnover so it is ultimately at risk of collapse. A carious tooth is a potential vector for periapical infection that may be life-threatening. Insipient caries is initiated as a subsurface decalcification in enamel that is not detectable until a depth of ~400µm when it becomes visible as a white spot. Reliable detection and remineralization of invisible caries would advance cost-effective wellness worldwide.

Pathophysiology of Demineralization, Part I: Attrition, Erosion, Abfraction, and Noncarious Cervical Lesions.

PURPOSE OF THE REVIEW: Compare pathophysiology for infectious and noninfectious demineralization disease relative to mineral maintenance, physiologic fluoride levels, and mechanical degradation. RECENT FINDINGS: Environmental acidity, biomechanics, and intercrystalline percolation of endemic fluoride regulate resistance to demineralization relative to osteopenia, noncarious cervical lesions, and dental caries. Demineralization is the most prevalent chronic disease in the world: osteoporosis (OP) >10%, dental caries ~100%. OP is severely debilitating while caries is potentially fatal. Mineralized tissues have a common physiology: cell-mediated apposition, protein matrix, fluid logistics (blood, saliva), intercrystalline ion percolation, cyclic demineralization/remineralization, and acid-based degradation (microbes, clastic cells). Etiology of demineralization involves fluid percolation, metabolism, homeostasis, biomechanics, mechanical wear (attrition or abrasion), and biofilm-related infections. Bone mineral density measurement assesses skeletal mass. Attrition, abrasion, erosion, and abfraction are diagnosed visually, but invisible subsurface caries <400µm cannot be detected. Controlling demineralization at all levels is an important horizon for cost-effective wellness worldwide.

Success of infrazygomatic crest bone screws: patient age, insertion angle, sinus penetration, and terminal insertion torque.

INTRODUCTION: The aim of this study was to assess the 6-month survival (success) rate for infrazygomatic crest (IZC) bone screws relative to patient age, insertion angle, sinus penetration, and terminal insertion torque. METHODS: One hundred consecutive patients (27 males, 73 females; mean age 25.8 years; age range, 11.0-53.8 years) received IZC temporary anchorage devices (TADs) bilaterally (n = 200). Each TAD was routinely loaded with up to 14 oz (397 g or 389 cN), reactivated monthly, and followed for 6 months. Terminal insertion torque was measured, and radiographs were assessed to determine the length of the TAD engaged in bone and depth of penetration into the maxillary sinus. RESULTS: Compared with nonpenetrating IZC TADs, the mean results for the 96 (48%) TADs that did penetrate the sinus were: 3.23 mm of sinus penetration, 21.3% decrease in terminal insertion torque, and 31.5% less bone contact at the TAD osseous interface. Perforation prevalence increased with age from 35.7% (11-19 years) to 62.5% (>30 years) (P <0.01). Terminal insertion torque increased from 11-19 years to 20-29 years because of increasing bone density with age but then decreased at >30 years because of increased incidence of sinus penetration (P <0.05). Sinus penetration had no significant effect on IZC TAD survival. About 5% of the devices did fail when the final insertion torque was significantly (P <0.05) decreased to 7.37 N-cm compared with the mean torque of 11.63 N-cm for successful TADs. CONCLUSIONS: Both sinus perforation and IZC bone quality increased with age. Sinus penetration did not significantly affect the 6 month survival rate of IZC TADs because the loss of bone quantity at the interface was offset by the age-related increase in bone quality at the IZC site.

Non-specific rheumatic manifestations in patients with Hashimoto's thyroiditis: a pilot cross-sectional study.

PURPOSE: Hashimoto's thyroiditis (HT) is often associated with rheumatic disorders (arthritis, etc.), but many HT patients report non-specific rheumatic signs and symptoms in the absence of clinically evident rheumatic diseases. Aim of this study was to evaluate the prevalence of non-specific rheumatic manifestations (RMs) in HT subjects without classified autoimmune comorbidities. METHODS: 500 HT patients (467 F, 33 M; median age 41 years, range 14-69) and 310 age- and sex-matched controls, consecutively referred to the Endocrine Unit of Messina University Hospital, were evaluated for non-specific RMs. None took L-thyroxine. EXCLUSION CRITERIA: autoimmune comorbidities, infectious, and/or inflammatory diseases, history of neoplasia, BMI > 30 kg/m2. RESULTS: In our HT cohort, 100 patients (20%) complained of one or more RMs, vs 21 controls (6.8%; P < 0.001). There were minimal differences between the manifestations recorded in the two groups, the most common being polyarthralgias and myalgias/fibromyalgia, but non-specific RMs occurred threefold more in HT patients. Comparing HT patients with RMs (96 F and 4 M) with those affected by HT alone, female sex was prevalent (F:M ratio 24:1 vs 5:1) with higher age at diagnosis (median 43 vs 37 years; P < 0.001). HT patients with RMs (62%) were mostly euthyroid (median TSH 2.0 µIU/L) and only 7% overtly hypothyroid, discouraging a possible causal relationship between thyroid dysfunction per se and RMs. CONCLUSIONS: A significant percentage of HT patients complains of non-specific rheumatic signs and symptoms, in the absence of other diagnosed systemic comorbidities and regardless of thyroid functional status, deserving careful evaluation and prolonged follow-up.

The Temporomandibular Joint: A Critical Review of Life-Support Functions, Development, Articular Surfaces, Biomechanics and Degeneration.

The temporomandibular joint is a highly conserved articulation because it promotes survival and propagation via the essential functions of mastication, communication, and routine mating success (dentofacial esthetics). The temporomandibular joint is a unique secondary joint formed between the endochondral temporal bone and the mandibular secondary condylar cartilage via Indian hedgehog and bone morphogenetic protein signaling that is closely related to ear development. A dynamic epigenetic environment is provided by Spry1 and Spry2 genetic induction of the lateral pterygoid and temporalis muscles. Mechanical loading of the condylar periosteum during fetal development produces a superficial layer of fibrocartilage that separates from the condyle to form the interposed temporomandibular joint disc. The articular surfaces of the condyle and fossa are dynamically modified periosteum that has healing and regenerative capability. This unique tissue is composed of a superficial fibrous layer (synovial surface) with an underlying proliferative (cambium) layer that produces a cushioning layer of fibrocartilage which subsequently forms bone. Prior to occlusion of the first primary (deciduous) molars at about 16 months, facial development is dominated by primary genetic mechanisms. After achieving posterior functional occlusion, biomechanics enhances temporomandibular joint maturation, and assumes control of facial growth, development and adaptation. Concurrently, hypothalamus control of musculoskeletal physiology shifts from insulin-like growth factor IGF2 to IGF1, which affects bone via muscular loading (biomechanics). Three layers of temporomandibular joint fibrocartilage are resistant to heavy functional loading, but parafunctional clenching may result in degeneration that is first manifest as trabecular sclerosis of the mandibular condyle.

Does the Stomatognathic System Adapt to Changes in Occlusion? Best Evidence Consensus Statement.

PURPOSE: The purpose of this Best Evidence Consensus Statement was to evaluate the existing literature on the stomatognathic system's ability to adapt to occlusal changes. MATERIALS AND METHODS: The search term stomatognathic system was not useful as it resulted in over 400,000 results nor was the search term temporomandibular joint adaptation with 738 results due to the large number of references not related to the topic. The terms stomatognathic system adaptation to occlusal changes (186 results), teeth flexion (139 results), muscle adaptation to dental occlusion (278 results), and occlusal changes and neuroplasticity (11 results) provided the best selection of articles related to the topic. Limiting the above searches to systematic reviews and randomized controlled clinical trials resulted in multiple publications that were related to the question.9-13 Other literature reviews, data-based publications, and expert opinion resources have been included due to their relationship to the question. RESULTS: From the extensive list of search results, 242 articles were determined to be potentially related to the focus question and were evaluated with 56 being included in this paper. It was determined that the stomatognathic system adapts to occlusal changes through the temporomandibular joint, muscles, teeth and bone. The dynamically modified periosteum on the articulator surfaces of the condyle and fossa has a unique load-bearing morphology with 3 subarticular layers of fibrocartilage that absorb and dissipate both peak (impact) and sustained loads. Adaptability of the TMJs and muscles can be documented through studies where artificially produced occlusal interferences were placed in patients and those study participants with normal temporomandibular joints (TMJs) adapted fairly well whereas those with a previous history of temporomandibular disorders (TMD) did not adapt as well. CONCLUSIONS: Available evidence indicates patients generally adapt to the occlusal change inherent in orthodontic treatment, mandibular advancement surgery, and the use of mandibular advancement devices. The head and neck muscles also adapt to occlusal changes in patients without a history of TMD. The dentition adapts to changes through the bone and periodontal ligaments as well as the ability of teeth to undergo slight flexion under masticatory loading. This article is protected by copyright. All rights reserved.

Split phosphorus fertiliser applications as a strategy to reduce incidental phosphorus losses in surface runoff.

Organic soils have low sorption capacities for phosphorus (P), and may pose a risk of P loss to water if P applications to these soils coincide with runoff events. Little is known about the magnitude of exports of P in overland flow following application of P fertiliser onto these soils, or on the influence of the frequency on P losses and persistence. The number of P fertiliser applications was surveyed across 39 commercial farms to assess current practice and inform the design of a rainfall runoff experiment to evaluate the effect of frequency of P applications on losses and persistence across time. Superphosphate (16% P) was applied in single (equivalent to 30 and 55 kg P ha-1 applied at day 0) and split (equivalent to 15 and 27.5 kg P ha-1 applied in two doses at days 0 and 55) applications to an organic soil inclined at a slope of 6% in a rainfall simulator experiment. The surface runoff of dissolved reactive phosphorus (DRP) was measured in controlled 30-min rainfall simulations conducted intermittently over an 85-day period. The DRP losses in surface runoff after the first rainfall event were 44.6 and 97.8 mg L-1 for single applications of 30 and 55 kg ha-1, respectively, and 13.3 and 21.8 mg L-1 for the same rates split in two doses, indicating that single P applications had disproportionately bigger impacts on losses than split applications. This supports the idea that frequent, but smaller, P applications can minimise the impact of fertilisation on waters. Dissolved reactive P concentrations remained significantly higher than those from the control samples until the end the experiment for almost all the P treatments, highlighting the long-lasting effects of added P and the elevated risk of P losses on organic soils. For climates with frequent rainfall events, which are likely to coincide with fertiliser applications, smaller but more frequent P applications can reduce the risk of P transfer as opposed to one single application.

Determining risk factors that increase hospitalizations in patients with systemic lupus erythematosus.

Introduction Systemic lupus erythematosus (SLE) is a complex disease that is associated with significant mortality and an increased risk of hospitalization. Several validated instruments are available to measure disease activity in SLE patients. However, these instruments were not designed to screen for SLE patients at an increased risk of hospitalization. These instruments also fail to incorporate some data that are easily obtainable from electronic health records, such as the frequency of missed outpatient appointments. Methods All patients at a single academic medical center with an International Classification of Disease (ICD-10) code for SLE (M32) that were seen at least once between 2010 and 2017 were identified. Of these 3552 patients, 813 were randomly selected for chart review using a random number generator, and 226 were verified to have seen an outpatient rheumatologist and met the American College of Rheumatology Classification Criteria for SLE. Physician notes, laboratory values, and appointment information were reviewed, and relevant data were extracted. Weighted Cox regression models were used to estimate the risk of hospitalization and develop a screening algorithm, and receiver operating characteristic (ROC) curve analysis was performed to evaluate the algorithm. Results There were 160 patients with no lupus-related hospitalizations and 66 patients with such a hospitalization. In a multivariate analysis accounting for age, gender, and race, serum creatinine >1.20 mg/dL, white blood cell count > 10 (thousand)/µL, hemoglobin <11 g/dL, platelets < 180 (thousand)/µL, high risk immunosuppression use, missing between 0 and 20% of appointments, and missing ≥ 20% of appointments were associated with an increased risk of hospitalizations. Our proposed screening algorithm does well identifying SLE patients at risk of hospitalization (area under the curve (AUC): 0.90, 95% CI: 0.86-0.94). We recommend flagging patients with a score of ≥ 3 (sensitivity: 0.95; specificity: 0.54). Conclusions A new screening algorithm accounting for serum creatinine, white blood cell count, hemoglobin, platelets, high-risk immunosuppression, and the proportion of missed appointments may be useful in identifying SLE patients at an increased risk of hospitalization. Missing appointments may be a proxy for an underlying variable (such as access to health care) that is directly related to an increased risk of hospitalization.

Part I: Development and Physiology of the Temporomandibular Joint.

PURPOSE OF REVIEW: Investigate the developmental physiology of the temporomandibular joint (TMJ), a unique articulation between the cranium and the mandible. RECENT FINDINGS: Principal regulatory factors for TMJ and disc development are Indian hedgehog (IHH) and bone morphogenetic protein (BMP-2). The mechanism is closely associated with ear morphogenesis. Secondary condylar cartilage emerges as a subperiosteal blastema on the medial surface of the posterior mandible. The condylar articular surface is immunoreactive for tenascin-C, so it is a modified fibrous periosteum with an underlying proliferative zone (cambrium layer) that differentiates into fibrocartilage. The latter cushions high loads and subsequently produces endochondral bone. The TMJ is a heavily loaded joint with three cushioning layers of fibrocartilage in the disc, as well as in subarticular zones in the fossa and mandibular condyle. The periosteal articular surface produces fibrocartilage to resist heavy loads, and has unique healing and adaptive properties for maintaining life support functions under adverse environmental conditions.

Part II: Temporomandibular Joint (TMJ)-Regeneration, Degeneration, and Adaptation.

PURPOSE OF REVIEW: Elucidate temporomandibular joint (TMJ) development and pathophysiology relative to regeneration, degeneration, and adaption. RECENT FINDINGS: The pharyngeal arch produces a highly conserved stomatognathic system that supports airway and masticatory function. An induced subperiosteal layer of fibrocartilage cushions TMJ functional and parafunctional loads. If the fibrocartilage disc is present, a fractured mandibular condyle (MC) regenerates near the eminence of the fossa via a blastema emanating from the medial periosteal surface of the ramus. TMJ degenerative joint disease (DJD) is a relatively painless osteoarthrosis, resulting in extensive sclerosis, disc destruction, and lytic lesions. Facial form and symmetry may be affected, but the residual bone is vital because distraction continues to lengthen the MC with anabolic bone modeling. Extensive TMJ adaptive, healing, and regenerative potential maintains optimal, life support functions over a lifetime. Unique aspects of TMJ development, function, and pathophysiology may be useful for innovative management of other joints.

Interdisciplinary treatment for a compensated Class II partially edentulous malocclusion: Orthodontic creation of a posterior implant site.

A 36-year-old woman with good periodontal health sought treatment for a compensated Class II partially edentulous malocclusion associated with a steep mandibular plane (SN-MP, 45°), 9 missing teeth, a 3-mm midline discrepancy, and compromised posterior occlusal function. She had multiple carious lesions, a failing fixed prostheses in the mandibular right quadrant replacing the right first molar, and a severely atrophic edentulous ridge in the area around the mandibular left first and second molars. After restoration of the caries, the mandibular left third molar served as anchorage to correct the mandibular arch crowding. The mandibular left second premolar was retracted with a light force of 2 oz (about 28.3 cN) on the buccal and lingual surfaces to create an implant site between the premolars. Modest lateral root resorption was noted on the distal surface of the mandibular left second premolar after about 7 mm of distal translation in 7 months. Six months later, implants were placed in the mandibular left and right quadrants; the spaces were retained with the fixed appliance for 5 months and a removable retainer for 1 month. Poor cooperation resulted in relapse of the mandibular left second premolar back into the implant site, and it was necessary to reopen the space. When the mandibular left fixture was uncovered, a 3-mm deep osseous defect on the distobuccal surface was found; it was an area of relatively immature bundle bone, because the distal aspect of the space was reopened after the relapse. Subsequent bone grafting resulted in good osseous support of the implant-supported prosthesis. The relatively thin band of attached gingiva on the implant at the mandibular right first molar healed with a recessed contour that was susceptible to food impaction. A free gingival graft restored soft tissue form and function. This severe malocclusion with a discrepancy index value of 28 was treated to an excellent outcome in 38 months of interdisciplinary treatment. The Cast-Radiograph Evaluation score was 13. However, the treatment was complicated by routine relapse and implant osseous support problems. Retreatment of space opening and 2 additional surgeries were required to correct an osseous defect and an inadequate soft tissue contour. Orthodontic treatment is a viable option for creating implant sites, but fixed retention is required until the prosthesis is delivered. Bone augmentation is indicated at the time of implant placement to offset expected bone loss. Complex restorative treatment may result in routine complications that are effectively managed with interdisciplinary care.

Severe unilateral scissors-bite with a constricted mandibular arch: Bite turbos and extra-alveolar bone screws in the infrazygomatic crests and mandibular buccal shelf.

A 33-year-old woman had a chief complaint of difficulty chewing, caused by a constricted mandibular arch and a unilateral full buccal crossbite (scissors-bite or Brodie bite). She requested minimally invasive treatment but agreed to anchorage with extra-alveolar temporary anchorage devices as needed. Her facial form was convex with protrusive but competent lips. Skeletally, the maxilla was protrusive (SNA, 86°) with an ANB angle of 5°. Amounts of crowding were 5 mm in the mandibular arch and 3 mm in the maxillary arch. The mandibular midline was deviated to the left about 2 mm, which was consistent with a medially and inferiorly displaced mandibular right condyle. Ectopic eruption of the maxillary right permanent first molar to the buccal side of the mandibular first molar cusps resulted in a 2-mm functional shift of the mandible to the left, which subsequently developed into a full buccal crossbite on the right side. Treatment was a conservative nonextraction approach with passive self-ligating brackets. Glass ionomer bite turbos were bonded on the occlusal surfaces of the maxillary left molars at 1 month into treatment. An extra-alveolar temporary anchorage device, a 2 × 12-mm OrthoBoneScrew (Newton A, HsinChu City, Taiwan), was inserted in the right mandibular buccal shelf. Elastomeric chains, anchored by the OrthoBoneScrew, extended to lingual buttons bonded on the lingually inclined mandibular right molars. Cross elastics were added as secondary uprighting mechanics. The maxillary right bite turbos were reduced at 4 months and removed 1 month later. At 11 months, bite turbos were bonded on the lingual surfaces of the maxillary central incisors, and an OrthoBoneScrew was inserted in each infrazygomatic crest. The Class II relationship was resolved with bimaxillary retraction of the maxillary arch with infrazygomatic crest anchorage and intermaxillary elastics. Interproximal reduction was performed to correct the black interdental spaces and the anterior flaring of the incisors. The scissors-bite and lingually inclined mandibular right posterior segment were sufficiently corrected after 3 months of treatment to establish adequate intermaxillary occlusion in the right posterior segments to intrude the maxillary right molars. The anterior bite turbos opened space for extrusion of the posterior teeth to level the mandibular arch, and the infrazygomatic crest bone screws anchored the retraction of the maxillary arch. In 27 months, this difficult malocclusion, with a Discrepancy Index score of 25, was treated to a Cast-Radiograph Evaluation score of 22 and a pink and white esthetic score of 3.

Diagnosis and conservative treatment of skeletal Class III malocclusion with anterior crossbite and asymmetric maxillary crowding.

A man, aged 28 years 9 months, came for an orthodontic consultation for a skeletal Class III malocclusion (ANB angle, -3°) with a modest asymmetric Class II and Class III molar relationship, complicated by an anterior crossbite, a deepbite, and 12 mm of asymmetric maxillary crowding. Despite the severity of the malocclusion (Discrepancy Index, 37), the patient desired noninvasive camouflage treatment. The 3-Ring diagnosis showed that treatment without extractions or orthognathic surgery was a viable approach. Arch length analysis indicated that differential interproximal enamel reduction could resolve the crowding and midline discrepancy, but a miniscrew in the infrazygomatic crest was needed to retract the right buccal segment. The patient accepted the complex, staged treatment plan with the understanding that it would require about 3.5 years. Fixed appliance treatment with passive self-ligating brackets, early light short elastics, bite turbos, interproximal enamel reduction, and infrazygomatic crest retraction opened the vertical dimension of the occlusion, improved the ANB angle by 2°, and achieved excellent alignment, as evidenced by a Cast Radiograph Evaluation score of 28 and a Pink and White dental esthetic score of 3.

Canine-lateral incisor transposition: Controlling root resorption with a bone-anchored T-loop retraction.

A 12-year-old girl presented with a Class II Division 1 malocclusion, complicated by a complete transposition of the maxillary left canine into the position normally occupied by the left lateral incisor. Dental and medical histories were noncontributory. Brackets were bonded on all maxillary teeth, from first molar to first molar, except for the left lateral incisor. Because the lateral incisor was not engaged on the archwire, the tooth was free to physiologically move out of the path of canine root movement. To prepare the site for canine retraction, a coil spring was used to open space between the left central incisor and the first premolar. A 2 × 12-mm stainless steel miniscrew was placed in the infrazygomatic crest, labial to the mesiodistal cusp of the maxillary left first molar. A 0.019 × 0.025-in titanium-molybdenum alloy T-loop, anchored by the miniscrew, was used to retract the canine root over the labial surface of the root of the distally positioned lateral incisor. In 24 months, this difficult malocclusion, with a Discrepancy Index score of 18, was treated to a Cast-Radiograph Evaluation score of 26.

The Role of Maternal Gestational Diabetes in Inducing Fetal Endothelial Dysfunction.

Gestational diabetes mellitus (GDM) is known to be associated with fetal endothelial dysfunction, however, the mechanisms are not fully understood. This study examines the effect of maternal diabetes on fetal endothelial function and gene expression under physiological glucose conditions (5 mM). Human umbilical vein endothelial cell (HUVEC) isolated from diabetic mothers (d.HUVEC) grew more slowly than HUVEC isolated from healthy mothers (c.HUVEC) and had delayed doubling time despite increased levels of total vascular endothelial growth factor (VEGF) expression and protein production as determined by real-time PCR and ELISA respectively. Using western blot, the levels of antiproliferative VEGF165b isoform were increased in d.HUVEC relative to c.HUVEC. Successful VEGF165b knockdown by small interfering RNA (siRNA) resulted in increased proliferation of d.HUVEC measured by MTT, compared with negative siRNA control, to similar levels measured in c.HUVEC. In addition, d.HUVEC generated excess levels of ROS as revealed by 2',7' Dichlorodihydrofluorescein Diacetate (DCFH-DA) and Nitrotetrazolium blue (NBT). Using microarray, 102 genes were differentially overexpressed between d.HUVEC versus c.HUVEC (>1.5-fold change; P < 0.05). Functional clustering analysis of these differentially expressed genes revealed participation in inflammatory responses (including adhesion) which may be related to pathological outcomes. Of these genes, ICAM-1 was validated as upregulated, confirming microarray results. Additional confirmatory immunofluorescence staining revealed increased protein expression of ICAM-1 compared with c.HUVEC which was reduced by vitamin C treatment (100 µM). Thus, maternal diabetes induces persistent alterations in fetal endothelial function and gene expression following glucose normalization and antioxidant treatment could help reverse endothelium dysfunction.

Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors.

OBJECTIVE: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. METHODS: Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. RESULTS: Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. CONCLUSIONS: VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.