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Introduction/Aims: Fatigue (subjective perception) and fatigability (objective motor performance worsening) are relevant aspects of disability in individuals with spinal muscular atrophy (SMA). The effect of nusinersen on fatigability in SMA patients has been investigated with conflicting results. We aimed to evaluate this in adult with SMA3. Methods: We conducted a multicenter retrospective cohort study, including adult ambulant patients with SMA3, data available on 6‐minute walk test (6MWT) and Hammersmith Functional Motor Scale—Expanded (HFMSE) at baseline and at least at 6 months of treatment with nusinersen. We investigated fatigability, estimated as 10% or higher decrease in walked distance between the first and sixth minute of the 6MWT, at baseline and over the 14‐month follow‐up. Results: Forty‐eight patients (56% females) were included. The 6MWT improved after 6, 10, and 14 months of treatment (p < 0.05). Of the 27 patients who completed the entire follow‐up, 37% improved (6MWT distance increase ≥30 m), 48.2% remained stable, and 14.8% worsened (6MWT distance decline ≥30 m). Fatigability was found at baseline in 26/38 (68%) patients and confirmed at subsequent time points (p < 0.05) without any significant change over the treatment period. There was no correlation between fatigability and SMN2 copy number, sex, age at disease onset, age at baseline, nor with 6MWT total distance and baseline HFMSE score. Discussion: Fatigability was detected at baseline in approximately 2/3 of SMA3 walker patients, without any correlation with clinical features, included motor performance. No effect on fatigability was observed during the 14‐month treatment period with nusinersen. [ABSTRACT FROM AUTHOR]

Seed water imbibition is critical to seedling establishment in tropical forests. The seeds of the neotropical tree Hymenaea courbaril have no oil reserves and have been used as a model to study storage cell wall polysaccharide (xyloglucan – XyG) mobilization. We studied pathways of water imbibition in Hymenaea seeds. To understand seed features, we performed carbohydrate analysis and scanning electron microscopy. We found that the seed coat comprises a palisade of lignified cells, below which are several cell layers with cell walls rich in pectin. The cotyledons are composed mainly of storage XyG. From a single point of scarification on the seed surface, we followed water imbibition pathways in the entire seed using fluorescent dye and NMRi spectroscopy. We constructed composites of cellulose with Hymenaea pectin or XyG. In vitro experiments demonstrated cell wall polymer capacity to imbibe water, with XyG imbibition much slower than the pectin‐rich layer of the seed coat. We found that water rapidly crosses the lignified layer and reaches the pectin‐rich palisade layer so that water rapidly surrounds the whole seed. Water travels very slowly in cotyledons (most of the seed mass) because it is imbibed in the XyG‐rich storage walls. However, there are channels among the cotyledon cells through which water travels rapidly, so the primary cell walls containing pectins will retain water around each storage cell. The different seed tissue dynamic interactions between water and wall polysaccharides (pectins and XyG) are essential to determining water distribution and preparing the seed for germination. [ABSTRACT FROM AUTHOR]

Introduction: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short‐mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first‐line treatment. Methods and Material: The cohort included consecutive patients affected by BCLC‐c and BCLC‐B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first‐line therapy. Population was stratified according to the BMI in under‐, over‐ and normal‐weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product‐limit method of Kaplan–Meier. The role of stratification factors was analysed with log‐rank tests. Results: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal‐weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal‐weight patients, whereas no differences were found between normal‐weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal‐weight patients (HR: 1.7; 95% CI: 1.0–2.8; p =.0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal‐weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal‐weight versus underweight and between normal‐weight versus overweight, which was confirmed at multivariate analysis. Conclusion: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib. [ABSTRACT FROM AUTHOR]

Odontocetes primarily rely on fish, cephalopods, and crustaceans as their main source of nutrition. In the digestive system, their polygastric complex exhibits similarities to that of their closest terrestrial relatives such as cows, sheep, and giraffes, while the entero‐colic tract shares similarities with terrestrial carnivores. The morphology, caliber, and structure of the odontocete intestine are relatively constant, and, since there is no caecum, a distinction between the small and large intestine and their respective subdivisions is difficult. To address this issue, we used the intestinal vascularization pattern, specifically the course and branching of the celiac artery (CA) and the cranial and caudal mesenteric arteries (CrMA and CdMA). A series of pictures and dissections of 10 bottlenose dolphins (Tursiops truncatus) were analyzed. Additionally, we performed a cast by injecting colored polyurethane foam in both arteries and veins to measure the caliber of the arteries and clarify their monopodial or dichotomous branching. Our results showed the presence of multiple duodenal arteries (DAs) detaching from the CA. The CrMA gave origin to multiple jejunal arteries, an ileocolic artery (ICA), and, in six cases, a CdMA. In four specimens, the CdMA directly originated from the abdominal aorta. The ICA gave rise to the mesenteric ileal branches (MIB) and mesenteric anti‐ileal branches and the right colic arteries (RCA) and the middle colic arteries. From the CdMA originated the left colic and cranial rectal arteries (LCA and CrRA). The measurements revealed a mixed monopodial and dichotomous branching scheme. The analysis of the arteries and their branching gave us an instrument, based on comparative anatomy, to distinguish between the different intestinal compartments. We used the midpoint of anastomoses between MIB and RCA to indicate the border between the small and the large intestine, and the midpoint of anastomoses between LCA and CrRA, to tell the colon from the rectum. This pattern suggested an elongation of the duodenum and a shortening of the colic tract that is still present in this species. These findings might be related to the crucial need to possess a long duodenal tract to digest prey ingested whole without chewing. A short aboral part is also functional to avoid gas‐producing colic fermentation. The rare origin of the CdMA on the CrMA might instead be a consequence of the cranial thrust of the abdominopelvic organs related to the loss of the pelvic girdle that occurred during the evolution of cetaceans. [ABSTRACT FROM AUTHOR]

In the Amazon basin, approximately 60% of rainforest thrives on geologically old and highly weathered soils, thus decomposition represents an important mechanism for recycling nutrients from organic matter. Although dead logs and branches constitute up to 14% of the carbon stored in terrestrial ecosystems, woody debris decomposition and mainly the effect of direct nutrient cycling by plant root interaction is poorly studied and often overlooked in ecosystem carbon and nutrient budgets. Here we monitored the decomposition of five different local woody species covering a range of wood density by conducting a long‐term wood decomposition experiment over two years with factorial root presence and phosphorous (P) addition treatments in a central Amazonian rainforest. We hypothesized that woody debris decomposition is accelerated by colonizing fine roots mining for nutrients, possibly strongly affecting wood debris with lower density and higher nutrient concentration (P). We found that root colonization and P addition separately increased wood decay rates, and although fine root colonization increased when P was added, this did not result in a change in wood decay. Nutrient loss from wood was accelerated by P addition, whereas a root presence effect on nutrient mobilization was only detectable at the end of the experiment. Our results highlight the role of fine roots in priming wood decay, although direct nutrient acquisition by plants seems to only occur in more advanced stages of decomposition. On the other hand, the positive effect of P addition may indicate that microbial nutrient mobilization in woody material is driven mainly by wood stoichiometry rather than priming by root activity. [ABSTRACT FROM AUTHOR]

Aim: To determine whether isolated low‐grade germinal matrix‐intraventricular haemorrhages (LG‐GMH‐IVH) and low‐grade punctate cerebellar haemorrhages (LG‐CBH) contribute to the neurodevelopment of infants born preterm with very low birthweight (VLBW). Method: A prospective observational cohort study was conducted on infants born with VLBW hospitalized from January 2012 to July 2017 who had undergone serial cranial ultrasounds since birth and magnetic resonance susceptibility‐weighted imaging of the brain at term‐corrected age. Only those with VLBW carrying isolated LG‐GMH‐IVH (grades 1 or 2) or isolated LG‐CBH (punctate cerebellar haemorrhages ≤4 mm in diameter) or absence of lesions (no‐lesion) were enrolled and followed up to 3 years. The Griffiths Mental Development Scales, Extended and Revised version (GMDS‐ER), were used to assess neurodevelopment, considering unsatisfactory scores less than 85. Behaviour, according to the criteria of the International Classification of Diseases, 10th Revision, and rehabilitation data were noted. Results: Two‐hundred and forty infants with VLBW were enrolled: 34 with LG‐GMH‐IVH, 17 with LG‐CBH, and 189 as no‐lesion. The LG‐GMH‐IVH and LG‐CBH groups scored worse than the no‐lesion group on all GMDS‐ER scores for 1 year, 2 years, and 3 years. The LG‐CBH group scored lower than the LG‐GMH‐IVH group for total GMDS‐ER scores at 1 year and 2 years but not at 3 years. At 3 years, compared with the LG‐CBH group, those with LG‐GMH‐IVH received less and later physical therapy, with more frequent attention problems. The odds ratio for unsatisfactory GMDS‐ER scores corrected for gestational age was 5.75 for LG‐CBH (95% confidence interval 1.92–17.25; p = 0.002) and 2.67 for LG‐GMH‐IVH (95% confidence interval 1.16–6.13; p = 0.02). Interpretation: Low‐grade haemorrhages affect the neurodevelopment of very‐low‐birthweight infants. Early rehabilitation might have contributed to their development. What this paper adds: Low‐grade haemorrhages seem to have an independent role in the adverse neurodevelopment of infants born extremely preterm.Infants born preterm with low‐grade germinal matrix‐intraventricular haemorrhage (LG‐GMH‐IVH) are indicated for physical therapy at a later age than those with low‐grade punctate cerebellar haemorrhage (LG‐CBH).Compared with LG‐CBH, LG‐GMH‐IVH is associated with a greater extent of attention problems at 3 years corrected age. [ABSTRACT FROM AUTHOR]

Background and purpose: Data are reported from the Italian CMT Registry. Methods: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot–Marie–Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted. Results: Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some "rare" genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one‐half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early‐onset CMT. Conclusions: The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials. [ABSTRACT FROM AUTHOR]

This article presents the findings of a study conducted in Italy to evaluate the performance of different ultrasound-based prediction models for distinguishing between benign and malignant adnexal masses. The study included 1431 patients from 21 Italian centers, both oncological and non-oncological. The results showed that the two-step strategy with or without CA125, ADNEX with or without CA125, and SRRisk had similar performance in distinguishing between benign and malignant adnexal tumors, regardless of the expertise of the ultrasound operators. The study provides valuable insights for clinicians and researchers in the field of obstetrics and gynecology. [Extracted from the article]

The need to better balance the promotion of scientific and technological innovation with risk management for consumer protection has inspired several recent reforms attempting to make regulations more flexible and adaptive. The pharmaceutical sector has a long, established regulatory tradition, as well as a long history of controversies around how to balance incentives for needed therapeutic innovations and protecting patient safety. The emergence of disruptive biotechnologies has provided the occasion for regulatory innovation in this sector. This article investigates the regulation of advanced biotherapeutics in the European Union and shows that it presents several defining features of an adaptive regulation regime, notably institutionalized processes of planned adaptation that allow regulators to gather, generate, and mobilize new scientific and risk evidence about innovative products. However, our in‐depth case analysis highlights that more attention needs to be paid to the consequences of the introduction of adaptive regulations, especially for critical stakeholders involved in this new regulatory ecosystem, the capacity and resource requirements placed on them to adapt, and the new tradeoffs they face. In addition, our analysis highlights a deficit in how we currently evaluate the performance and public value proposition of adaptive regulations vis‐à‐vis their stated goals and objectives. [ABSTRACT FROM AUTHOR]

Background and purpose: Fatigue, a disabling symptom in many neuromuscular disorders, has been reported also in Charcot–Marie–Tooth disease (CMT). The presence of fatigue and its correlations in CMT was investigated. Methods: The Modified Fatigue Impact Scale (MFIS) was administered to CMT patients from the Italian Registry and a control group. An MFIS score >38 indicated abnormal fatigue. The correlation with disease severity and clinical characteristics, the Hospital Anxiety and Depression Scale and Epworth Sleepiness Scale scores, and drug use was analysed. Results: Data were collected from 251 CMT patients (136 women) and 57 controls. MFIS total (mean ± standard deviation 32 ± 18.3, median 33), physical (18.9 ± 9.7, 20) and psychosocial (2.9 ± 2.4, 3) scores in CMT patients were significantly higher than controls. Abnormal fatigue occurred in 36% of the patients who, compared to patients with normal scores, had more severe disease (median CMT Examination Score 9 vs. 7), more frequent use of foot orthotics (22% vs. 11%), need of support for walking (21% vs. 8%), hand disability (70% vs. 52%) and positive sensory symptoms (56% vs. 36%). Patients with abnormal fatigue had significantly increased frequency of anxiety/depression/general distress (Hospital Anxiety and Depression Scale), somnolence (Epworth Sleepiness Scale), obesity (body mass index ≥ 30) and use of anxiolytic/antidepressant or anti‐inflammatory/analgesic drugs. Conclusions: Fatigue is a relevant symptom in CMT as 36% of our series had scores indicating abnormal fatigue. It correlated with disease severity but also with anxiety, depression, sleepiness and obesity, indicating different components in the generation of fatigue. CMT patients' management must include treatment of fatigue and of its different generators, including general distress, sleepiness and obesity. [ABSTRACT FROM AUTHOR]

Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5–1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract—primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T‐cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded. [ABSTRACT FROM AUTHOR]

Background and purpose: Hereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult‐onset, progressive, and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene‐silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early‐access program was opened in Italy, and in this article, we present the long‐term outcome of a cohort of Italian ATTRv patients who received inotersen within this program. Methods: This is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early‐access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life–Diabetic Neuropathy, troponin, N‐terminal pro–brain natriuretic peptide, interventricular septum thickness, and body mass index. Results: In total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug‐related hypotension, and amyloid‐negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow‐up available. Conclusions: The long‐term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression. [ABSTRACT FROM AUTHOR]

Background: The morphometric studies of the atrioventricular valves are still limited in the horse. Objectives: To investigate the anatomy of the atrioventricular valves in the horse, focusing on the morphometric features of the valvular leaflets and the tendinous cords. We hypothesised that accessory leaflets occur commonly and exist as independent structures in the atrioventricular valves of the horse. Study design: Descriptive anatomical study. Methods: Twenty normal hearts from slaughtered half‐bred horses were used. The cardiac weight and circumference were recorded. The atrioventricular valves were exposed by excision of the atria, and the tricuspid and mitral annular diameters and circumferences were measured; the number of leaflets and tendinous cords for each atrioventricular ostium were then counted. The atrioventricular valves were isolated and the width, height and thickness of each leaflet were measured. Results: In addition to the principal leaflets, accessory leaflets were identified in 39 of 40 cardiac valves, 2 to 6 accessory leaflets for the mitral valve and 1 to 4 for the tricuspid valve. All the accessory leaflets were separated from the adjacent leaflets at their insertion. They were narrower and thinner than the principal leaflets, and were attached to a single papillary muscle; 95% of the accessory leaflets had two tendinous cords shared with the adjacent leaflets while a minority (34%) had their own specific tendinous cord. Main limitations: Lack of signalment data from the study population. Conclusions: Supernumerary leaflets occurred commonly in the atrioventricular valves of the horse and appeared as independent structures. The clinical relevance of increased numbers of commissures that result from accessory leaflets and their relationship with valvular regurgitation are currently unknown. [ABSTRACT FROM AUTHOR]

Cardiac disease in guinea pigs has been reported in the literature; however, reference intervals for normal radiographic heart size obtained using objective measurement methods have not been provided for this species. The aim of this prospective, reference interval study was to describe cardiac dimensions in presumed healthy guinea pigs using the vertebral heart scale (VHS) from thoracic radiographs, as described for dogs and cats. Furthermore, an anatomical study was carried out to compare the radiographic and anatomical findings. Thoracic radiographs were acquired in right lateral recumbency for 30, client‐owned, conscious, presumed healthy guinea pigs and radiographs were acquired in left lateral recumbency for 10 presumed healthy guinea pigs as comparisons. The influence of sex, age, body weight (BW), and recumbency on the VHS and absolute cardiac measurements was investigated. The median (interquartile range; IQR) VHS was 7.4 (7.1‐7.6). No differences emerged between the VHS measured in right versus left lateral recumbency (P =.41) or between sexes (P =.16). The VHS values were not influenced by age (P =.53) or BW (P =.26). The anatomical study was carried out on 10 guinea pig cadavers, and in situ and ex situ cardiac measurements were taken using a caliper. A median (IQR) 7.5 (7.2‐8.0) VHS was assessed by this anatomical study. The reference intervals provided should be useful tools in the future for the radiographic interpretation of cardiac size in guinea pigs in clinical practice. [ABSTRACT FROM AUTHOR]

It is always a challenge to acquire a clear picture of the pathological processes and changes in any disease. For this purpose, it is advantageous to directly examine the affected organ. Nerve biopsy has been a method of choice for decades to classify peripheral neuropathies and to find clues to uncover their etiology. The histologic examination of the peripheral nerve provides information on axonal or myelin pathology as well as on the surrounding connective tissue and vascularization of the nerve. Minimal requirements of the workup include paraffin histology as well as resin semithin section histology. Cryostat sections, teased fiber preparations and electron microscopy are potentially useful in a subset of cases. Here we describe our standard procedures for the workup of the tissue sample and provide examples of diagnostically relevant findings. [ABSTRACT FROM AUTHOR]

Background: Tumor models resistant to EGFR tyrosine kinase inhibitors or cisplatin express higher levels of the immune checkpoint molecule PD‐L1. We sought to determine whether PD‐L1 expression is elevated in head and neck squamous cell carcinoma (HNSCC) models of acquired cetuximab resistance and whether the expression is regulated by bromodomain and extraterminal domain (BET) proteins. Methods: Expression of PD‐L1 was assessed in HNSCC cell line models of acquired cetuximab resistance. Proteolysis targeting chimera (PROTAC)‐ and RNAi‐mediated targeting were used to assess the role of BET proteins. Results: Cetuximab‐resistant HNSCC cells expressed elevated PD‐L1 compared to cetuximab‐sensitive controls. Treatment with the BET inhibitor JQ1, the BET PROTAC MZ1, or RNAi‐mediated knockdown of BRD2 decreased PD‐L1 expression. Knockdown of BRD2 also reduced the elevated levels of PD‐L1 seen in a model of acquired cisplatin resistance. Conclusions: PD‐L1 is significantly elevated in HNSCC models of acquired cetuximab and cisplatin resistance where BRD2 is the primary regulator. [ABSTRACT FROM AUTHOR]

Recent work within early executive function (EF) seems to suggest that toddlers show distinct patterns of development, involving poorly correlated performance across EF tasks and significant improvements over relatively short periods of time. The present study sought to extend these findings by investigating evidence for these patterns in toddlers and the existence of more traditional patterns of EF (e.g., correlations between tasks, links to language) when using the same tasks in a novel Latin American sample. Eighty toddlers (18–24 months) and sixty young preschoolers (30–36) months completed a battery of EF tasks, early social communication, and receptive and expressive language measures. Results indicated that toddlers showed similar distinct patterns of development (i.e., few relations between tasks and links to responding to joint attention), but by early preschool a more cohesive EF and links to language were present. Further, work demonstrated significant age (older children outperformed younger children), gender (girls outperformed boys), and socioeconomic differences (satisfied basic needs outperformed unsatisfied basic needs, but only on the snack delay). This work provides evidence for patterns of emerging EF development within this novel cultural sample (and evidence for group differences) that may be supported by communicative and representational development. [ABSTRACT FROM AUTHOR]

The oral microbiome is a community of microorganisms, comprised of bacteria, fungi, viruses, archaea, and protozoa, that form a complex ecosystem within the oral cavity. Although minor perturbations in the environment are frequent and compensable, major shifts in the oral microbiome can promote an unbalanced state, known as dysbiosis. Dysbiosis can promote oral diseases, including periodontitis. In addition, oral dysbiosis has been associated with other systemic diseases, including cancer. The objective of this review is to evaluate the epidemiologic evidence linking periodontitis to oral, gastrointestinal, lung, breast, prostate, and uterine cancers, as well as describe new evidence and insights into the role of oral dysbiosis in the etiology and pathogenesis of the cancer types discussed. Finally, we discuss how antimicrobials, antimicrobial peptides, and probiotics may be promising tools to prevent and treat these cancers, targeting both the microbes and associated carcinogenesis processes. These findings represent a novel paradigm in the pathogenesis and treatment of cancer focused on the oral microbiome and antimicrobial-based therapies. [ABSTRACT FROM AUTHOR]

Guinea pigs have proved useful as experimental animal models in studying cerebellar anatomical and structural alterations in human neurological disease; however, they are also currently acquiring increasing veterinary interest as companion animals. The morphometric features of the normal cerebellum in guinea pigs have not been previously investigated using stereology. The objective of the present work was to establish normal volumetric and quantitative stereological parameters for cerebellar tissues in guinea pigs, by means of unbiased design‐based stereology. Cerebellar total volume, gray and white matter volume fractions, molecular and granular layers volume fractions, cerebellar surface area, Purkinje cellular and nuclear volumes, and the Purkinje cell total count were stereologically estimated. For this purpose, cerebellar hemispheres from six adult male guinea pigs were employed. Isotropic, uniform random sections were obtained by applying the orientator method, and subsequently processed for light microscopy. The cerebellar total volume, the white and grey matter volume fractions, and the molecular and granular layer volumes were estimated using the Cavalieri's principle and the point counting system. The cerebellar surface area was estimated through the use of test lines; Purkinje cellular and nuclear volumes were analysed using the nucleator technique, whereas the Purkinje cell total count was obtained by means of the optical disector technique. The mean ± standard deviation total volume of a guinea‐pig cerebellar hemisphere was 0.11 ± 0.01 cm3. The mean volumetric proportions occupied by the gray and white matters were, respectively, 78.0 ± 2.6% and 22.0 ± 2.6%, whereas their mean absolute volumes were found to be 0.21 ± 0.02 cm3 and 0.059 ± 0.006 cm3. The volumes of the molecular and granular layers were estimated at 112.4 ± 20.6 mm3 and 104.4 ± 7.3 mm3, whereas their mean thicknesses were calculated to be 0.184 ± 0.020 mm and 0.17 ± 0.02 mm. The molecular and granular layers accounted for 40.7 ± 3.9% and 37.4 ± 1.8% of total cerebellar volume respectively. The surface area of the cerebellum measured 611.4 ± 96.8 mm2. Purkinje cells with a cellular volume of 3210.1 µm3 and with a nuclear volume of 470.9 µm3 had a higher incidence of occurrence. The mean total number of Purkinje cells for a cerebellar hemisphere was calculated to be 253,090 ± 34,754. The morphometric data emerging from the present study provide a set of reference data which might prove valuable as basic anatomical contribution for practical applications in veterinary neurology. [ABSTRACT FROM AUTHOR]

Vibrissae are tactile hairs found mainly on the rostrum of most mammals. The follicle, which is surrounded by a large venous sinus, is called "follicle‐sinus complex" (FSC). This complex is highly innervated by somatosensitive fibers and reached by visceromotor fibers that innervate the surrounding vessels. The surrounding striated muscles receive somatomotor fibers from the facial nerve. The bottlenose dolphin (Tursiops truncatus), a frequently described member of the delphinid family, possesses this organ only in the postnatal period. However, information on the function of the vibrissal complex in this latter species is scarce. Recently, psychophysical experiments on the river‐living Guiana dolphin (Sotalia guianensis) revealed that the FSC could work as an electroreceptor in murky waters. In the present study, we analyzed the morphology and innervation of the FSC of newborn (n = 8) and adult (n = 3) bottlenose dolphins. We used Masson's trichrome stain and antibodies against neurofilament 200 kDa (NF 200), protein gene product (PGP 9.5), substance P (SP), calcitonin gene‐related peptide, and tyrosine hydroxylase (TH) to characterize the FSC of the two age classes. Masson's trichrome staining revealed a structure almost identical to that of terrestrial mammals except for the fact that the FSC was occupied only by a venous sinus and that the vibrissal shaft lied within the follicle. Immunostaining for PGP 9.5 and NF 200 showed somatosensory fibers finishing high along the follicle with Merkel nerve endings and free nerve endings. We also found SP‐positive fibers mostly in the surrounding blood vessels and TH both in the vessels and in the mesenchymal sheath. The FSC of the bottlenose dolphin, therefore, possesses a rich somatomotor innervation and a set of peptidergic visceromotor fibers. This anatomical disposition suggests a mechanoreceptor function in the newborns, possibly finalized to search for the opening of the mother's nipples. In the adult, however, this structure could change into a proprioceptive function in which the vibrissal shaft could provide information on the degree of rotation of the head. In the absence of psychophysical experiments in this species, the hypothesis of electroreception cannot be rejected. [ABSTRACT FROM AUTHOR]

Herbivory is one of the major biotic stress factors that affect the establishment of plants. However, the main factors that drive herbivory in seedlings of Amazonian tree species are still not well understood. Here we investigated whether contrasting levels of irradiance influence herbivory according to different herbivory indicators and which leaf traits are most related to interspecific variation in herbivory under contrasting irradiance conditions.We measured the leaf area lost as a result of insect herbivory in five tree species planted in a silvicultural system of secondary forest enrichment according to two indicators, herbivore damage (accumulated since plant germination) and herbivory rate (measured over time), and two irradiance conditions, understorey PPFD 2.6 mol·m−2·day−1) and gap PPFD 33.1 mol·m−2·day−1. Furthermore, we related the interspecific variation in herbivory to a set of leaf traits: SLA, RWC, sclerophylly, phenolic compound content, tannins, condensed tannins and non‐structural carbohydrates.Herbivore damage was significantly affected by light availability and species, with the highest percentage variation observed in the Meliaceae (Carapa guianensis and Swietenia macrophylla). For the herbivory rate, only the interspecific variation was significant, with Bertholletia excelsa having the lowest rates. Chemical characteristics (phenolic compounds and tannins) were most related to herbivory rates, as well as highly influenced by light conditions. Non‐structural carbohydrates (starch and sucrose) were also related to the interspecific variation in herbivory.The phenolic compounds and starch, as affected by light quantity, are species dependent. Thus, the selective pressure on herbivores may be driven by species‐dependent responses to light conditions. [ABSTRACT FROM AUTHOR]

Objective: Buccal cells are an ideal surrogate tissue for studying biologic effects of carcinogens or drugs, however inherent fragility and salivary RNAses limit RNA yield. We conducted healthy volunteer trials to optimize collection conditions. Methods: We conducted: (a) a single‐arm crossover study evaluating four test conditions on RNA yield by buccal cytobrush; (b) a single‐arm prospective study evaluating RNA yield by investigator vs self‐collection. Results: Antecedent toothbrushing, time of day, and number of cytobrush strokes did not significantly impact RNA yield. RNA yield was doubled by using 2 vs 1 cytobrush per buccal surface (P =.0054). Self‐collection of buccal cells for RNA was feasible; 36 of 50 (72%) samples passed quality control. Conclusion: RNA yield was doubled by using two cytobrushes per buccal surface. Healthy volunteers can self‐collect sufficient buccal RNA for gene expression studies. Techniques from these pragmatic trials could enhance availability of a limited tissue for serial biomarker measurements. Level of Evidence: 1b—Prognosis Study (Individual prospective cohort study). [ABSTRACT FROM AUTHOR]

The symptomatology of Charcot‐Marie‐Tooth (CMT) disease mainly involves the feet and the hands. To date, there is no consensus on how to evaluate hand function in CMT. The aim of this study is to correlate the data of the engineered glove Hand Test System (HTS) with specific tests and the CMT examination score (CMTES). We analyzed 45 patients with the diagnosis of CMT using HTS, which measures the hand dexterity by specific sequences performed at maximum velocity. We completed the evaluation with the CMTES, tripod pinch and hand grip strength tested by a dynamometer, thumb opposition test (TOT), and Sollerman Hand function test (SHFT), and we conducted a test‐retest with 20 normal subjects. Finger tapping (FT) and index‐medium‐ring‐little (IMRL) sequence showed a significant correlation with CMTES (FT: dominant hand (DH): P =.036; non‐dominant hand (NDH): P =.033; IMRL: DH: P =.009; NDH: P =.046). TOT correlated with CMTES significantly in both hands (P <.0001). tripod pinch showed a statistically significant correlation with CMTES (DH: P =.002; NDH: P =.005). Correlation between the hand grip and CMTES was significant only in DH (DH: P =.002). SHFT had a significant correlation with the CMTES (DH: P =.002). Test‐retest showed a good reliability. HTS parameters correlate with CMTES confirming that this tool is sensitive to the hand deficits. In conclusion, we can state that HTS is a good, simple to use, and objective instrument to evaluate the hand function of CMT patients, but more studies on responsiveness and sensitivity are needed. [ABSTRACT FROM AUTHOR]

Peripheral myelin protein 2 (PMP2) is a small protein located on the cytoplasmic side of compact myelin, involved in the lipids transport and in the myelination process. In the last years few families affected with demyelinating Charcot‐Marie‐Tooth neuropathy (CMT1), caused by PMP2 mutations, have been identified. In this study we describe the first case of a PMP2 in‐frame deletion. PMP2 was analyzed by direct sequencing after exclusion of the most frequent CMT‐associated genes by using a next generation sequencing (NGS) genes panel. Sanger sequencing was used for family's segregation analysis. Molecular modeling analysis was used to evaluate the mutation impact on the protein structure. A novel PMP2: p.I50del has been identified in a child with early onset CMT1 and in three affected family members. All family members show an early onset demyelinating neuropathy without other distinguish features. Molecular modeling analysis and in silico evaluations do not suggest a strong impact on the overall protein structure, but a most likely altered protein function. This study suggests the importance to add PMP2 in CMT NGS genes panels or, at most, to test it after major CMT1 genes exclusion, due to the lack of diagnostic‐addressing additional features. [ABSTRACT FROM AUTHOR]

Small RNAs comprise three families of noncoding regulatory RNAs that control gene expression by blocking mRNA translation or leading to mRNA cleavage. Such post‐transcriptional negative regulation is relevant for both plant development and environmental adaptations. An important biotechnological application of miRNA identification is the discovery of regulators and effectors of cell wall degradation, which can improve/facilitate hydrolysis of cell wall polymers for second‐generation bioethanol production. The recent characterization of plant innate cell wall modifications occurring during root aerenchyma development triggered by ethylene led to the possibility of prospection for mechanisms of cell wall disassembly in sugarcane. By using next‐generation sequencing, 39 miRNAs were identified in root segments along the process of aerenchyma development. Among them, 31 miRNAs were unknown to the sugarcane miRBase repository but previously identified as produced by its relative Sorghum bicolor. Key putative targets related to signal transduction, carbohydrate metabolic process, and cell wall organization or biogenesis were among the most representative gene categories targeted by miRNA. They belong to the subclasses of genes associated with the four modules of cell wall modification in sugarcane roots: cell expansion, cell separation, hemicellulose, and cellulose hydrolysis. Thirteen miRNAs possibly related to ethylene perception and signaling were also identified. Our findings suggest that miRNAs may be involved in the regulation of cell wall degradation during aerenchyma formation. This work also points out to potential molecular tools for sugarcane improvement in the context of second‐generation biofuels. [ABSTRACT FROM AUTHOR]

Background and purpose: Muscle‐strengthening, stretching or proprioceptive treatments may slow symptom progression in Charcot—Marie–Tooth (CMT) neuropathy. The aim of the study was to evaluate safety and efficacy of treadmill training in CMT1A. Methods: We planned a multicenter, prospective, randomized, single‐blind, controlled study. We recruited 53 outpatients affected by CMT1A and randomized them into two treatment groups: one underwent stretching and proprioceptive exercise, whereas the other was additionally treated with treadmill training (TreSPE). Primary outcome measures (OMs) were the walking evaluations and secondary OM was the balance assessment. All participants were assessed at baseline and after 3 and 6 months of treatment. Results: Most patients showed an improvement in at least one OM after 3 months [42/47 (89.4%)] and 6 months [38/40 (95%)] of treatment. No adverse events were reported in either group. Conclusions: The most important finding was that both stretching and proprioceptive exercise and treadmill training had an objective benefit on patients affected by CMT disease, without causing overwork weakness. We had a low rate of drop out and did not find deterioration in motor performance. Our results also confirm that applying evidence‐based medicine methods to rehabilitative research is the correct way to test the efficacy of a treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the effects of earliness (according to FAO class), maturity stage at harvest and environmental conditions on the ensilability of maize hybrids described by their fermentation products and by a fermentation quality index (FQI). Maize hybrids belonging to early (n = 14) and late (n = 15) FAO classes were grown in low, medium and high potential yield areas and harvested at an early (EH), medium (MH) and late maturity stage (LH), that is, at 1/3, 2/3 and 5 d after the 2/3 milk line stage, respectively, according to a split‐plot design. Upon harvest, each sample (n = 522) was analysed for dry matter (DM) and water‐soluble carbohydrates (WSC) before being ensiled in vacuum‐packed bags (n = 1,044). After 60 days of conservation, samples were analysed for DM and fermentation products. In the pre‐ensiling phase, DM was higher in early hybrids (p = .001), low yield areas (p < .001) and at LH maturity (p < .001), whereas WSC contents were higher in early hybrids (p < .001), medium yield areas (p < .001) and at EH maturity (p < .001). With regard to silages, early hybrids had a higher FQI (p < .001), which was highest in areas with a high yield potential (p < .01) and at EH maturity (p < .01). Late hybrids proved to be better suited for low yield areas compared with early hybrids (p < .01) and had a higher FQI at EH and MH than at LH maturity (p < .01). [ABSTRACT FROM AUTHOR]

Background: Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT.Methods: Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR-AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2.Results: When added to cetuximab, EGFR-AS decreased cell viability and xenograft growth compared with EGFR-sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR-AS-related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens.Conclusions: In preclinical models, dual EGFR inhibition with cetuximab and EGFR-AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR-AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy. [ABSTRACT FROM AUTHOR]

Sheldon–Hall syndrome (SHS) is the most common of the distal arthrogryposes (DAs), a group of disorders characterized by congenital non‐progressive contractures. Patients with SHS present with contractures of the limbs and a distinctive triangular facies with prominent nasolabial folds. Calcaneovalgus deformity is frequent, as well as camptodactyly and ulnar deviation. Causative mutations in at least four different genes have been reported (MYH3, TNNI2, TPM2, and TNNT3). MYH3 plays a pivotal role in fetal muscle development and mutations in this gene are associated with Freeman–Sheldon syndrome, distal arthrogryposis 8 (DA8), and autosomal dominant spondylocarpotarsal synostosis. The last two disorders are characterized by skeletal abnormalities, in particular bony fusions. The observation that MYH3 may be mutated in these syndromes has suggested the involvement of this gene in bone development. We report the case of a boy with a novel pathogenic MYH3 mutation, presenting with the classical clinical features of SHS in association with unilateral carpal bone fusion and multiple vertebral fusions. This distinctive phenotype has never been reported in the literature so far and expands the phenotypic spectrum of SHS, endorsing the clinical variability of patients with MYH3‐related disorders. Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3‐related disorders. [ABSTRACT FROM AUTHOR]

We previously reported a novel association between CDKN2A nonpromoter methylation and transcription (ARF/INK4a) in human papillomavirus associated oropharyngeal tumors. In this study we assessed whether nonpromoter CDKN2A methylation in laryngeal squamous cell carcinomas (LXSCC) conferred a similar association with transcription that predicted patient outcome. We compared DNA methylation and ARF/INK4a RNA expression levels for the CDKN2A locus using the Illumina HumanMethylation27 beadchip and RT-PCR in 43 LXSCC tumor samples collected from a prospective study of head and neck cancer patients treated at Montefiore Medical Center (MMC). Validation was performed using RNAseq data on 111 LXSCC tumor samples from the Cancer Genome Atlas (TCGA). The clinical relevance of combined nonpromoter CDKN2A methylation and transcription was assessed by multivariate Cox regression for locoregional recurrence on a subset of 69 LXSCC patients with complete clinicopathologic data from the MMC and TCGA cohorts. We found evidence of CDKN2A nonpromoter hypermethylation in a third of LXSCC from our MMC cohort, which was significantly associated with increased ARF and INK4a RNA expression (Wilcoxon rank-sum, P = 0.007 and 0.003, respectively). A similar association was confirmed in TCGA samples (Wilcoxon rank-sum test P < 0.0001 for ARF and INK4a). Patients with CDKN2A hypermethylation or high ARF/INK4a expression were significantly less likely to develop a locoregional recurrence compared to those with neither of the features, independent of other clinicopatholgic risk factors (adjusted hazard ratio=0.21, 95% confidence interval:0.05-0.81). These results support the conclusion that CDKN2A nonpromoter methylation is associated with increased ARF and INK4a RNA expression, and improved locoregional control in LXSCC. [ABSTRACT FROM AUTHOR]

Background Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC. Methods This single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway. Results Seven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue. Conclusion Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1759-1764, 2016 [ABSTRACT FROM AUTHOR]

Background and purpose Charcot-Marie-Tooth disease (CMT) type 1A is characterized by uniformly reduced nerve conduction velocity (NCV) that is fully penetrant since the first years of life, remains fairly stable through the life and does not correlate with disability whereas compound muscular action potential (CMAP) amplitude does. The aim of the present study was to analyze the large amount of electrophysiological data collected in the ascorbic acid trial in Italy and the UK (CMT-TRIAAL/CMT-TRAUK) and to use these data to gain insights into the pathophysiology of NCV in CMT1A. Methods Baseline electrophysiological data from 271 patients were analysed. Electrophysiological recordings were taken from the motor ulnar, median and peroneal nerves and the sensory ulnar nerve. Distal motor latency ( DML), motor ( MNCV) and sensory ( SNCV) nerve conduction velocity, and amplitudes of CMAPs and sensory action potentials were assessed. Electrophysiological findings were correlated with age of patients at examination and the Charcot-Marie−Tooth Examination Score ( CMTES). Results NCV was markedly and uniformly reduced. CMAP amplitudes were overall reduced but more severely in lower limbs. DML decreased and MNCV and SNCV increased with age of the patients, whereas CMAP amplitudes worsened with age and also correlated with CMTES. Conclusions This is the largest sample of electrophysiological data obtained so far from CMT1A patients. Axonal degeneration as assessed by means of CMAP amplitude reflected clinical impairment and was consistent with a slowly progressive length-dependent neuropathy. All patients typically had markedly slowed NCV that did, however, slightly increase with age of the patients. The improvement of NCV might depend on myelin thickness remodelling that occurs during the adult life of CMT1A patients. [ABSTRACT FROM AUTHOR]

To describe a new test to quantitatively evaluate hand function in patients affected by Charcot-Marie-Tooth neuropathy (CMT). The sensor-engineered glove test (SEGT) was applied to CMT patients (N: 26) and compared with a cohort of healthy controls (HC, N: 26). CMT patients were further divided into subjects with clinically normal (group 1) or impaired hand (group 2) function. The SEGT parameters evaluated were touch duration, inter-tapping interval, and movement rate parameters of two different sequences: finger tapping (FT) and index-medium-ring-little (IMRL) performed at self-paced mode (SPM) and maximum velocity (MV). Hand function and strength were assessed by the 9-hole peg test (9HPT) and dynamometry. Disability of patients was measured by the CMT neuropathy score. CMT patients had significantly worst performances at SEGT than controls regarding the rate of execution of both FT (at MV) and IMRL sequences (at SPM and MV). The rate parameter at MV in IMRL sequence showed a significant trend of decreasing in its average between HC (n: 26, rate=3.08±0.52 Hz), group 1 (n: 9, rate=2.64±0.66 Hz) and group 2 (n: 17, rate=2.19±0.45 Hz) (p for trend <0.001). No correlations were found with either 9HPT, dynamometry, electrophysiology, and the CMT neuropathy score. The SEGT test is sensitive to show hand dysfunction in CMT patients, with and without clinically impaired hands. [ABSTRACT FROM AUTHOR]

Our patient is a 65-year-old woman presenting with bilateral pes cavus, pronounced distal muscle wasting, weakness and areflexia. Electrophysiological findings included diffuse unrecordable motor and sensory responses. While the CMT phenotype was evident, the lack of family history and the severe, but unspecific electrophysiological impairment, was a challenge for genetic diagnosis. A sural nerve biopsy was performed, showing a severe loss of myelinated fibers with residual axons surrounded by myelin outfoldings. Whereas myelin outfoldings are a pathological hallmark of autosomal recessive CMT4B1 and CMT4B2, due to mutations in myotubularin-related 2 ( MTMR2) and 13 ( MTMR13) genes respectively, they may also occur in nerve biopsies from CMT1B patients. By direct sequencing, a novel heterozygous transversion c. 410G>T in MPZ gene was demonstrated, producing an amino acid change from glycine to valine in position 108 (p. G108V). In HeLa cells the fusion P0G108V- EGFP was normally trafficked to the cell membrane, but with decreased P0 adhesion function, compared with wild-type P0, thus supporting a pathogenic role of the new variant. In conclusion this case highlights the relevance, in selected cases, of sural nerve biopsy to orient the genetic/molecular tests, while in vitro analyses may strengthen the pathogenic role of novel mutations. [ABSTRACT FROM AUTHOR]

BACKGROUND Earlier detection and diagnosis of head and neck squamous cell carcinoma (HNSCC) should lead to improved outcomes. However, to the authors' knowledge, no effective screening strategy has been identified to date. In the current study, the authors evaluated whether it would be useful to screen subjects targeted for lung cancer screening for HNSCC as well. METHODS Medical records, death certificates, and cancer registry and questionnaire data were used to determine the number of observed incident HNSCC cases in the Pittsburgh Lung Screening Study (PLuSS), a cohort of current and former smokers aged ≥50 years with a ≥12.5 pack-year smoking history. The expected number of cases was estimated using stratum-specific incidence rates obtained from Surveillance, Epidemiology, and End Results data for 2000 through 2011. The standardized incidence ratio was calculated to examine the difference between the observed and expected number of cases. RESULTS Of the 3587 at-risk participants in the PLuSS, 23 (0.64%) developed HNSCC over a total of 32,201 person-years of follow-up. This finding was significantly higher than expected based on incidence rates obtained from the Surveillance, Epidemiology, and End Results program (13.70 cases expected; standardized incidence ratio, 1.68 [95% confidence interval, 1.06-2.52]). The excess burden of HNSCC in the PLuSS was 28.9 cases per 100,000 person-years. Observed incident cases were significantly more often male, had started smoking at a younger age, smoked more per day, and had more pack-years of smoking than the rest of the PLuSS at-risk participants. CONCLUSIONS The results of the current study provide a rationale for offering head and neck cancer screening along with computed tomography screening for lung cancer. Randomized controlled trials that assess the effectiveness of adding examination of the head and neck area to lung cancer screening programs are warranted. Cancer 2015;121:1431-1435. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background and purpose Charcot−Marie−Tooth disease type 1X ( CMT1X) is an X-linked dominant hereditary motor-sensory peripheral neuropathy, which results from mutations in the Gap Junction B1 ( GJB1) gene. In a few cases, gene deletions have been linked to the disease, but their relative contribution in the pathogenesis of CMT1X has not been assessed yet. Herein a retrospective study to establish the incidence of gene deletions is described. Methods Copy number variation analysis was performed by multiplex ligation-dependent probe amplification, whilst the breakpoints were defined by Sanger sequencing. Results A novel GJB1 deletion was identified in a family presenting with a classical CMT1X phenotype. The rearrangement includes the coding and the regulatory regions of GJB1. Conclusions GJB1 deletions appear to be a rare but not insignificant cause of CMT1X and are associated with a typical disease phenotype. Accordingly, patients negative for point mutations whose pedigree and clinical records strongly suggest the possibility of CMT1X should be tested for GJB1 copy number variations. [ABSTRACT FROM AUTHOR]