Efficacy of complementary treatment with autologous platelet concentrates and/or mesenchymal stem cells in chemical osteonecrosis of the jaw. Systematic review of the literature.

The aim of this systematic review was to establish the current status of the subject and find out what scientific evidence we have on the use of autologous plasma concentrates (APCs) and mesenchymal stem cells (MSCs) as complementary therapies at the management of Medication-related Osteonecrosis of the jaw (MRONJ). We performed a literature search of articles published between December 2019 to January 2020 in electronic databases, in accordance to PRISMA system. The variables analyzed were: the number of patients, age, sex, medical history, origin of MRONJ, imaging studies, treatment performed, and evolution of MRONJ. The articles included in the review were grouped into two groups (Group A "Therapy with APCs" and Group B "Therapy with APCs and MSCs"). Newcastle-Ottawa scale (NOS) was used to assess the quality of the articles. Fisher's exact test was used to evaluate eventual differences between groups. Of the 306 patients who were included, 297 belonged to Group A and 9 to Group B. In our sample, women predominated against men and no significant differences in age were observed. Osteoporosis was the most frequent underlying disease in both groups. The most common origin of MRONJ was oral surgery in group A. Conservative surgery was performed in all patients, but complementary treatment was applied in different ways in each group. The resolution of the pathology was achieved in 90% of cases in both groups without significant differences between them. The mean score of the reviewed studies at NOS was 4. There are currently no published scientific data that can sufficiently support the use of APCs and MSCs for the treatment of established MRONJs.

Mediastinitis of odontogenic origin. A serious complication with 80 years of history.

We performed a systematic review of the literature about descending necrotising mediastinitis (DNM) of odontogenic origin. In parallel, a retrospective review of this pathology was carried out in an Oral and Maxillofacial Surgery Service of a reference hospital for a population of 1,100,000 inhabitants. The main objectives were to determine changes in mortality and prevalence of this serious complication. The systematic review included 51 articles with 89 patients and our study comprised seven patients. The period of time with the highest number of cases was between 2000-2009 (38 patients). The percentage of mortality observed was 20.2% in diffuse DNM and 4.9% in localised DNM. Thirty-one patients with DNM in our review were admitted for more than 41 days. Despite evidence of a decrease in DNM cases, publications have increased over the years, but it does not appear to be due to an increase in those of odontogenic origin. The survival of DNM has improved since 1998 and remained stable since then. Despite the low prevalence of this disease, multicentre control studies are needed to achieve better evidence about this entity.

The juxta-oral organ of Chievitz (organum yuxtaorale) updated: Embryology, anatomy, function and pathology.

BACKGROUND: The Chievitz's organ or juxta-oral organ is a mysterious bilateral structure, phylogenetically preserved, which develops from the mouth epithelium as an invagination that loses connection to it in the prenatal period. It is located laterally to the walls of the oral cavity in an imprecise anatomical location and receives abundant innervation from the buccal nerve. Structurally it consists of non-keratinizing squamous-like neuroepithelial cells surrounded by two layers of connective tissue with nerve fibers and different morphotypes of sensory corpuscles. Its function is completely unknown although based on its rich innervation it is assumed that works as a mechanoreceptor. METHODS: We have performed immunohistochemistry for axonal and Schwann cells, and the putative mechanoproteins ASIC2, TRPV4 and Piezo2 in sections of fetal juxta-oral organ. RESULTS: Intraparenchymatous nerve fibers and sensory corpuscles were observed as well as immunoreactivity for Piezo2 in both nerve fibers and epithelial parenchymatous cells. CONCLUSIONS: We add indirect evidence that the juxtaoral organ is a mechanoreceptor because in addition to its dense innervation, the epithelial cells and sensory nerve fibers display immunoreactivity for the mechanogated ion channel Piezo2. Based on current knowledge, the functional and clinical importance of the juxta-oral organ should be further investigated.

Medication-related osteonecrosis of the jaw. Implant presence-triggered osteonecrosis: Case series and literature review.

PURPOSE: The aim of this study was to review the characteristics of 'implant presence-triggered osteonecrosis' (IPTO) in the literature and identify possible differences between IPTOs and 'implant surgery-triggered osteonecrosis' (ISTO). MATERIALS AND METHODS: Reviews using PubMed and the Cochrane Database of Systematic Reviews were performed from 2009-2018; the focus was on medication-related osteonecrosis of the jaw (MRONJ) and dental implants. In addition, the hospital records of all patients presented in our department with IPTO were retrospectively reviewed. In both studies, the following data were collected: the number of patients with ISTO or IPTO, age, gender, location, stage of MRONJ, number of implants involved in MRONJ, the elapsed time between the placement of the implants and the development of MRONJ, applied treatment and the presence of mandibular fractures and progress. RESULTS: The literature review provided 111 articles. Nine of the articles were selected for bibliographic review. The number of osteonecrosis cases was significantly higher in the IPTO group (74 cases) compared with the ISTO group (27 cases). The duration of the anti-resorptive treatment (oral and intravenous) was also longer in the IPTO group. In our centre, seven patients with IPTO were chosen; however, no patients with ISTO were selected. The significant differences between the patients in our series and the information collected in the literature for the IPTO group were the time of ingestion of alendronate, the elapsed time from the placement of the implants to the development of the MRONJ and the number of implants linked to the development of a complication. CONCLUSIONS: The use of antiresorptives causes osteonecrosis in patients with implants that are subjected to functional loading, and this occurs at a higher frequency than what is observed after implant placement surgery.

Molecular basis of dental sensitivity: The odontoblasts are multisensory cells and express multifunctional ion channels.

Odontoblasts are the dental pulp cells responsible for the formation of dentin. In addition, accumulating data strongly suggest that they can also function as sensory cells that mediate the early steps of mechanical, thermic, and chemical dental sensitivity. This assumption is based on the expression of different families of ion channels involved in various modalities of sensitivity and the release of putative neurotransmitters in response to odontoblast stimulation which are able to act on pulp sensory nerve fibers. This review updates the current knowledge on the expression of transient-potential receptor ion channels and acid-sensing ion channels in odontoblasts, nerve fibers innervating them and trigeminal sensory neurons, as well as in pulp cells. Moreover, the innervation of the odontoblasts and the interrelationship been odontoblasts and nerve fibers mediated by neurotransmitters was also revisited. These data might provide the basis for novel therapeutic approaches for the treatment of dentin sensibility and/or dental pain.

In vivo behavior of complete human oral mucosa equivalents: characterization in athymic mice.

BACKGROUND AND OBJECTIVE: The interest in tissue engineering as a way to achieve repair of damaged body tissues has led to the carrying out of many studies whose results point to the potential effectiveness of these methods. In a previous study, we reported the obtaining of complete autologous oral mucosa equivalents (CAOMEs), characterized by oral immature keratinocytes and stem cells on an autologous plasma and fibroblast scaffold. The purpose of this study is to show their behavior in vivo, by using them as free grafts in experimental animals, and to demonstrate their potential capacity to regenerate oral mucosa. MATERIAL AND METHODS: We engineered CAOMEs, as previously described. All CAOMEs thus obtained were used as free grafts in nu/nu mice. To assess their evolution in vivo, we studied their histological and immunohistochemical features by using AE1/AE3 pancytokeratin, the 5/6 cytokeratin pair, cytokeratin 13, laminin 5, collagen IV, vimentin, p-63 and Ki-67, at 7, 14 and 21 d. RESULTS: The structure became progressively closer to that of oral mucosa samples. Cytokeratin 5/6 staining became increasingly intense in the basal and suprabasal layers, and cytokeratin 13 was exclusively positive in the superficial layers. The basal membrane was completed in 21 d. Vimentin showed a correct formation of the chorion. The increasingly positive staining of p-63 and Ki-67 indicated that the regeneration process was taking place. CONCLUSION: The present study shows the potential regenerative capacity of the CAOMEs by their ability to reach maturity similar to that seen in oral mucosa.

In vitro engineering of complete autologous oral mucosa equivalents: characterization of a novel scaffold.

BACKGROUND AND OBJECTIVE: Restoration of oral mucosa defects by means of in vitro-cultured equivalents has become a valid alternative in the field of oral and periodontics surgery. Although different techniques have been described, none has been able to provide an equivalent with an autologous scaffold for the epithelium. The purpose of this study was to obtain complete autologous oral mucosa equivalents (CAOME) using the patient's own fibroblasts and plasma and to characterize these equivalents both morphologically and immunohistochemically. MATERIAL AND METHODS: We acquired cell types (keratinocytes and fibroblasts) from the same mucosal samples, which were taken from healthy patients who underwent oral surgery. To construct the CAOME, a small sample of blood was obtained from the patient and subsequently processed to obtain a fibrin glue scaffold. All CAOME thus obtained were stained using the standard hematoxylin and eosin method to study their morphological characteristics. To establish the type of cells in the epithelial layer, CAOME were stained with pancytokeratin AE1/AE3, cytokeratins 5/6 and 13, p-63 and Ki-67. Finally, laminin 5 and collagen IV were used to reveal the presence of a basal membrane. RESULTS: The CAOME featured a monolayer of cube-shaped epithelial cells similar to that found on the basal layer of the oral mucosa. Close to the epithelial layer lay the fibrin and fibroblasts-embedded scaffold. The CAOME was positive to pancytokeratin AE1/AE3, cytokeratin 5/6 and p-63. No reaction was found to cytokeratin 13 and Ki-67. There was staining to laminin 5 but not to collagen IV. CONCLUSIONS: It is possible to engineer a CAOME with an epithelium of basal-like and immature keratinocytes, which could potentially reconstruct in vivo loss of tissue.

Diagnóstico, prevención y tratamiento de la osteonecrosis de los maxilares por bisfosfonatos. Recomendaciones de la sociedad española de cirugía oral y maxilofacial (SECOM) / Diagnosis, prevention and treatment of bisphosphonate-associated osteonecrosis of the jaw. Recommendations of the Spanish Society of Oral and Maxillofacial Surgery (SECOM)

Los bisfosfonatos son análogos estables de los pirofosfatos inorgánicos que han demostrado su eficacia para el tratamiento de diversas patologías, como las lesiones osteolíticas asociadas ametástasis óseas o al mieloma múltiple, la hipercalcemia maligna, la enfermedad de Paget y la osteoporosis. En la actualidad se podría hablar, al menos académicamente, de dos entidades con diferentes grados de información científica: lasosteonecrosis en relación con la administración intravenosa de estos medicamentos y lasosteonecrosis en relación con la administración oral de los mismos. Para el primer grupo las estrategias de prevención y tratamiento empiezan a estar consolidadas, mientras que para el segundo se precisará de una mayor documentación científica para alcanzar este objetivo. Facilitar el diagnóstico clínico y complementario de lasosteonecrosis por bisfosfonatos por parte de los especialistas de la salud oral (cirujanos orales y maxilofaciales, odontólogos y estomatólogos).Los objetivos del presente artículo son explicitarlas medidas preventivas más apropiadas para limitar el número de casos de esta patología, a la luz de los conocimientos actuales, detallar la forma de tratamiento más reconocida para los diferentes estadios de la osteonecrosis, una vez establecida así como proporcionar un documento para la buena praxis médica y odontológica en los pacientes que padecen esta enfermedad o estén en riesgo de sufrirla. Este documento ha sido aprobado por la Comisión Científica de la SECOM (AU)

The bisphosphonates are stable inorganic pyrophosphate analogs that have demonstrated their efficacy in the treatment of a variety of pathologies, such as osteolytic lesions associated with bony metastases or multiple myeloma, malignant hypercalcemia, Paget’s disease, and osteoporosis. Currently, two disease entities supported by different degrees of scientific evidence can be characterized, at least academically: osteonecrosis associated with intravenous bisphosphonate administration and osteonecrosis associated with oral bisphosphonate administration. Prevention and treatment strategies are being consolidated for jaw necrosis associated with intravenous bisphosphonateuse, but more scientific documentation isneeded for the condition associated with oralbisphosphonate use. Our aim is to facilitate the clinical and complementary diagnosis of bisphosphonate associated osteonecrosis byoral health specialists(oral and maxillofacial surgeons, dentists, and stomatologists). The objectives of the present article were to describe the most appropriate preventive measures for limiting the number of cases of this pathologyin the light of current knowledge, to detail the best recognized form of treatment for different stages of jaw osteonecrosis, and, for established jaw osteonecrosis, to describe good medical and dentistry practice for patients who suffer this disease or are at risk of suffering it. This document was approved by the SECOM Scientific Commission (AU)

Diagnóstico, prevención y tratamiento de la osteonecrosis de los maxilares por bisfosfonatos. Recomendaciones de la Sociedad Española de Cirugía Oral y Maxilofacial (SECOM) / Diagnosis, prevention, and treatment of bisphosphonate-associated osteonecrosis of the jaw. Recommendations of the Spanish Society of Oral and Maxillofacial Surgery (SECOM)

Los bisfosfonatos son análogos estables de los pirofosfatos inorgánicosque han demostrado su eficacia para el tratamiento de diversas patologías,como las lesiones osteolíticas asociadas a metástasis óseas o al mielomamúltiple, la hipercalcemia maligna, la enfermedad de Paget y la osteoporosis.En la actualidad se podría hablar, al menos académicamente, de dosentidades con diferentes grados de información científica: las osteonecrosisen relación con la administración intravenosa de estos medicamentos y lasosteonecrosis en relación con la administración oral de los mismos. Para elprimer grupo las estrategias de prevención y tratamiento empiezan a estarconsolidadas, mientras que para el segundo se precisará de una mayor documentacióncientífica para alcanzar este objetivo. Facilitar el diagnóstico clínicoy complementario de las osteonecrosis por bisfosfonatos por parte delos especialistas de la salud oral (cirujanos orales y maxilofaciales, odontólogosy estomatólogos). Los objetivos del presente artículo son explicitar lasmedidas preventivas más apropiadas para limitar el número de casos de estapatología, a la luz de los conocimientos actuales, detallar la forma de tratamientomás reconocida para los diferentes estadios de la osteonecrosis,una vez establecida así como proporcionar un documento para la buena praxismédica y odontológica en los pacientes que padecen esta enfermedad oestén en riesgo de sufrirla. Este documento ha sido aprobado por la ComisiónCientífica de la SECOM(AU)

The bisphosphonates are stable inorganic pyrophosphateanalogs that have demonstrated their efficacy in the treatment ofa variety of pathologies, such as osteolytic lesions associated withbony metastases or multiple myeloma, malignant hypercalcemia,Paget’s disease, and osteoporosis. Currently, two disease entitiessupported by different degrees of scientific evidence can becharacterized, at least academically: osteonecrosis associated withintravenous bisphosphonate administration and osteonecrosisassociated with oral bisphosphonate administration. Preventionand treatment strategies are being consolidated for jaw necrosisassociated with intravenous bisphosphonate use, but more scientificdocumentation is needed for the condition associated with oralbisphosphonate use. Our aim is to facilitate the clinical andcomplementary diagnosis of bisphosphonate associated osteonecrosisby oral health specialists (oral and maxillofacial surgeons, dentists,and stomatologists). The objectives of the present article were todescribe the most appropriate preventive measures for limiting thenumber of cases of this pathology in the light of current knowledge,to detail the best recognized form of treatment for different stagesof jaw osteonecrosis, and, for established jaw osteonecrosis, todescribe good medical and dentistry practice for patients who sufferthis disease or are at risk of suffering it. This document was approvedby the SECOM Scientific Commission(AU)

Histomorphometric evaluation of guided bone regeneration around implants with SLA surface: an experimental study in beagle dogs.

The aim of this study was to evaluate the efficacy of collagen membranes, either alone or combined with a human demineralized freeze-dried bone allograft (DFDBA) or natural bovine bone graft, in bone defects around dental implants with an SLA (sand-blasted, large grit, acid-etched) surface. The experiments were carried out in three beagle dogs using a split-mouth design. On one side of the jaw, three implants were placed and intra-bony defects were created and covered with a collagen membrane, randomly combined in two of the defects with human DFDBA or inorganic bovine bone graft. A control implant, without membrane covering or defect filling, was also placed. On the other side of the jaw, three implants were placed and the bone defects were treated in a similar fashion, but without membrane covering. The studied variables were the percentage of bone-to-implant contact within the limits of the initial bony defect and percentage of the original bony defect occupied by bone tissue. Although no statistically significant differences were found in this study between the membrane and nonmembrane groups, bone defects augmented with anorganic bovine bone and membranes showed the most promising results from a histological and histomorphometric perspective.

Vascularization of the peroneal muscles. Critical evaluation in fibular free flap harvesting.

This anatomical study was carried out in order to discover the etiology of partial necrosis of the peroneus longus and brevis muscles after fibular osteocutaneous flap harvest. The vascular supply to the lateral compartment peroneal muscles was investigated in 10 fresh cadaveric lower limbs. The peroneal muscles are supplied by two principal sources arteries, the anterior tibial artery (ATA) and the peroneal artery (PA). The ATA is the dominant artery and supplies the proximal and middle thirds of these muscles. The PA is considered to be a supplementary vascular source and supplies the distal thirds of these muscles. After harvesting the PA in a fibular flap, regions of the peroneal muscles preoperatively vascularized by its branches become supplied through the anastomotic "choke" vessels between the ATA and the PA. Primary closure of the cutaneous defect increases the possibility of developing a pseudo-compartment syndrome with necrosis of the more precariously vascularized portions of the peroneal muscles. This complication is difficult to diagnosis early and the reason why we advocate that direct skin closure following composite harvest must be avoided. Moreover, conservation of the inferior and superior lateral branches of the ATA is imperative in order to preserve the peroneal muscles vascularization.

Medicina basada en la evidencia (MBE). Ventajas / Evidence Based Medicine (EBM). Advantages

La Medicina basada en la Evidencia (MBE) se define como un proceso cuyo objetivo es la selección de los mejores argumentos científicos para la resolución de los problemas que la práctica médica cotidiana plantea. Filosóficamente es un nuevo paradigma (verificacionista), que se ha extendido a todas las profesiones sanitarias (Cirugía Basada en la Evidencia, Odontología Basada en la Evidencia, etc.), soportado por los avances tecnológicos. Aunque sus ventajas son evidentes, también se han reconocido limitaciones, especialmente en lo concerniente a la práctica quirúrgica. En el presente trabajo se revisan los fundamentos y principales ventajas de la MBE. (AU)

Effect of occlusal splint and transcutaneous electric nerve stimulation on the signs and symptoms of temporomandibular disorders in patients with bruxism.

A crossed-design experimental study has been made involving simple blind paired data and random assignment to treatment, with the aim of evaluating the action of an occlusal splint with transcutaneous electric nerve stimulation (TENS) upon the manifestations of temporomandibular disorders (TMD) in patients with bruxism. The prevalence of TMD in the 24 patients with bruxism was 62.5%%; the corresponding severity, as determined by the pantographic reproducibility index (PRI), was mild (mean value: 20.71). Clicking and pain in the lateral pterygoid muscle were the most frequent clinical manifestations. The occlusal splint and TENS did not significantly improve the signs and symptoms of TMD in these patients with bruxism.

Concordancia entre la exploración clínica y la imagen artroscópica en el diagnóstico de los desórdenes internos de la articulación temporomandibular / Concordance between clinical examination and arthroscopy image for the diagnosis of the temporomandibular joint internal derangements

Objetivos: 1. Determinar el grado de concordancia entre el diagnóstico clínico y el artroscópico en el diagnóstico de la disfunción temporomandibular (DTM). 2 Determinar la sensibilidad y especifidad de la exploración clínica en el diagnóstico de los desordenes internos de la articulación temporomandibular (ATM) Diseño. Se ha realizado un estudio experimental no randomizado, tipo ensayo clínico de efidencia a simple ciego. La muestra estaba constituida por 3O enfermos diagnosticados de DTM y sometidos a una artroscopia. Los diagnósticos clínicos y artroscópicos se emitieron según criterios internacionalmente consensuados. La concordancia entre los diagnósticos se evaluó mediante el índice Kappa de Cohen. La relación entre las variables investigadas (cualitativas) se analizó mediante la prueba de la X. Se consideraron diferencias significativas aquellas en las que el valor de p < 0,05. Resultados. La edad media de los enfermos fue de 34,7 años. El 86.1 por ciento de los pacientes eran mujeres. El diagnóstico clínico y artroscópico de desplazamiento discal con reducción, presento una concordancia importante (Kappa = 0,645), mostrando el diagnostico clínico una sensibilidad de 0,71 y una especificidad de 0,93. La concordancia observada entre el diagnóstico clínico de desplazamiento discal sin reducción y, el atroscópico fue casi completa (Kappa - 0,833) con una sensibilidad de 0,83 y una especificidad de 1. Conclusiones. En pacientes con DTM subsidiarios de tratamiento artroscópico el diagnóstico clinico es concordante con el artroscópico en la filiación de los desplazamientos discales (con o sin reduccion). La presencia de chasquidos y el tipo de trayecto de abertura oral son los dos mejores parametros clínicos para el disnóstico (AU)

Maxillary undifferentiated carcinoma with rhabdoid features.

The rhabdoid malignant tumor was individualized by Haas et al. as an independent entity within the kidney malignant neoplasms in 1981. From its histopathological characteristics, different cases of rhabdoid extra-renal tumor were documented. This aspect has been also recognized in a wide heterogeneous group of tumors (carcinoma, melanoma, mesothelioma and mesenchymal tumors). The diagnosis of extrarenal rhabdoid tumor is based on the presence of a proliferation of epithelioid cells with large nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and conspicuous cytoplasmic intermediate filaments, which compress the nuclei. In this article we present the case of a 50-year-old male patient with a malignant maxillary tumor with characteristic rhabdoid features. Its differential diagnosis will be discussed. The literature will also be reviewed.

Injertos óseos en cirugía implantológica: aspectos generales. Principios y fundamentos / Bone grafts in implantologic surgery. General aspects. Principles and fundaments (Part 1)

Los injertos óseos constituyen una de las técnicas de más frecuente uso en la cirugía reconstructiva implatológica. El material de elección para el reemplazo del hueso perdido por atrofia, traumatismo, procesos patológicos congénitos o adquiridos son los injertos óseos autógenos. En la curación del injerto óseo pueden intervenir fenómenos de osteogénesis, osteoconducción y osteoinducción. Los injertos óseos esponjosos se revascularizan antes que los injertos corticales. Los injertos de hueso de origen membranoso se reabsorben menos que los de origen endocondral. Los injertos óseos pueden ser colocados como bloques (corticales o corticoesponjosos) o particulados. Los injertos en bloque deben ser fijados con tornillos de oseosíntesis. Las tasas de éxito de los implantes superan el 80 por ciento en el maxilar superior y el 90 por ciento en la mandíbula. La causa más frecuente de complicaciones con los injertos en bloque es consecuencia de la dehiscencia de la mucosa, con exposición del injerto al medio intraoral. La instalación de las fijaciones en un segundo tiempo (diferidas a la reconstrucción ósea), permite la colocación más precisa de los implantes para su posterior rehabilitación prostodóntica (AU)

Injertos óseos en cirugía implantológica: técnicas quirúrgicas en el maxilar y la mándíbula / Bone grafts in implantologic surgery. Surgical techniques in the maxilla and mandible (Part II)

Los injertos óseos constituyen una de las técnicas de más frecuente uso en la cirugía reconstructiva implantológica. El material de elección para el reemplazo del hueso perdido son los injertos óseos autógenos. En los últimos 20 años se han publicado diferentes técnicas de reconstrucción ósea combinadas con implantes. Los injertos en bloque pueden colocarse por aposición a la cresta alveolar ("onlay graft"), interposición bajo el suelo del seno, de las fosas nasales, o de la cresta alveolar desdoblada con escoplos ("inlay graft"), por vestibular de la cresta atrófica ("veneer graft") o en silla de montar ("saddle graft", para tratar simultáneamente los problemas de deficiente altura y anchura). Los injertos esponjosos pueden colocarse bajo membranas de regeneración ósea guiada (ROG), mallas de titanio, en el suelo del seno o en el interior de cavidades óseas. La causa más frecuente de complicaciones con los injertos en bloque es consecuencia de las dehiscencia de la mucosa, con exposición del injerto al medio intraoral. La instalación de las fijaciones en un segundo tiempo (diferidas a la reconstrucción ósea), permite la colocación más precisa de los implantes para su posterior rehabilitación prostodóntica. (AU)

Intracranial placement of a nasogastric tube after severe craniofacial trauma.

Complications of intracranial placement of a nasogastric tube in patients with complex facial and skull base fractures are infrequent, though the associated morbidity and mortality are high. In such situations some authors advocate craniotomy to allow removal of the tube in several linear segments under direct visualization. Others advise tube removal nasally under antibiotic coverage. We present a case of complex craniofacial fracture in which a nasogastric tube was positioned intracranially 48 hours after admission. The tube was quickly removed through the nose, and the patient was discharged without neurologic problems.