Approach to sialadenitis.

OBJECTIVE: To provide family physicians with a practical evidence-based approach to the management of patients with sialadenitis. SOURCES OF INFORMATION: MEDLINE and PubMed databases were searched for English-language research on sialadenitis and other salivary gland disorders, as well as for relevant review articles and guidelines published between 1981 and 2021. MAIN MESSAGE: Sialadenitis refers to inflammation or infection of the salivary glands and is a condition that can be caused by a broad range of processes including infectious, obstructive, and autoimmune. History and physical examination play important roles in directing management, while imaging is often useful to establish a diagnosis. Red flags such as suspected abscess formation, signs of respiratory obstruction, facial paresis, and fixation of a mass to underlying tissue should prompt urgent referral to head and neck surgery or a visit to the emergency department. CONCLUSION: Family physicians can play an important role in the diagnosis and management of sialadenitis. Prompt recognition and treatment of the condition can prevent the development of complications.

Approche de la sialadénite.

OBJECTIF: Proposer aux médecins de famille une approche pratique fondée sur des données probantes pour la prise en charge de patients souffrant de sialadénite. SOURCES DE L'INFORMATION: Une recension a été effectuée dans les bases de données MEDLINE et PubMed pour trouver des recherches publiées en anglais sur la sialadénite et d'autres troubles des glandes salivaires, ainsi que des revues et des lignes directrices pertinentes, publiées entre 1981 et 2021. MESSAGE PRINCIPAL: La sialadénite désigne une inflammation ou une infection des glandes salivaires; elle peut être causée par un large éventail de processus de nature infectieuse, obstructive et auto-immune. L'anamnèse et l'examen physique jouent un rôle important pour orienter la prise en charge, tandis que l'imagerie est souvent utile pour établir un diagnostic. Des signaux d'alerte comme la formation suspectée d'un abcès, des signes d'obstruction respiratoire, une parésie faciale et la fixation d'une masse aux tissus sous-jacents devraient inciter à faire une demande de consultation urgente en chirurgie de la tête et du cou, ou à recommander une visite au service d'urgence. CONCLUSION: Les médecins de famille peuvent jouer un rôle important dans le diagnostic et la prise en charge de la sialadénite. Une reconnaissance et un traitement rapides du problème peuvent prévenir la survenance de complications.

Predicting Neoadjuvant Treatment Response in Rectal Cancer Using Machine Learning: Evaluation of MRI-Based Radiomic and Clinical Models.

BACKGROUND: Radiomics is an approach to medical imaging that quantifies the features normally translated into visual display. While both radiomic and clinical markers have shown promise in predicting response to neoadjuvant chemoradiation therapy (nCRT) for rectal cancer, the interrelationship is not yet clear. METHODS: A retrospective, single-institution study of patients treated with nCRT for locally advanced rectal cancer was performed. Clinical and radiomic features were extracted from electronic medical record and pre-treatment magnetic resonance imaging, respectively. Machine learning models were created and assessed for complete response and positive treatment effect using the area under the receiver operating curves. RESULTS: Of 131 rectal cancer patients evaluated, 68 (51.9%) were identified to have a positive treatment effect and 35 (26.7%) had a complete response. On univariate analysis, clinical T-stage (OR 0.46, p = 0.02), lymphovascular/perineural invasion (OR 0.11, p = 0.03), and statin use (OR 2.45, p = 0.049) were associated with a complete response. Clinical T-stage (OR 0.37, p = 0.01), lymphovascular/perineural invasion (OR 0.16, p = 0.001), and abnormal carcinoembryonic antigen level (OR 0.28, p = 0.002) were significantly associated with a positive treatment effect. The clinical model was the strongest individual predictor of both positive treatment effect (AUC = 0.64) and complete response (AUC = 0.69). The predictive ability of a positive treatment effect increased by adding tumor and mesorectal radiomic features to the clinical model (AUC = 0.73). CONCLUSIONS: The use of a combined model with both clinical and radiomic features resulted in the strongest predictive capability. With the eventual goal of tailoring treatment to the individual, both clinical and radiologic markers offer insight into identifying patients likely to respond favorably to nCRT.

How to identify balance disorders and reduce fall risk.

A multifactorial risk assessment, correction of hearing impairment, exercise, and an optimized home environment can help prevent imbalance-related falls.

Co-occupancy identifies transcription factor co-operation for axon growth.

Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that potentiate the effects of pro-regenerative Klf6 in vitro. High content screens of neurite outgrowth identified cooperative activity by 12 candidates, and systematic testing in a mouse model of corticospinal tract (CST) damage substantiated three novel instances of pairwise cooperation. Combined Klf6 and Nr5a2 drove the strongest growth, and transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics approach to detect TF cooperation.

Approach to hearing loss.

OBJECTIVE: To provide family physicians with a practical evidence-based approach to the management of patients with hearing loss. SOURCES OF INFORMATION: MEDLINE and PubMed databases were searched for English-language hearing loss research, review articles, and guidelines published between 1980 and 2020. Most of the retrieved articles provided level II or III evidence. MAIN MESSAGE: Hearing loss is one of the most common sensory impairments worldwide and causes great detriment to a patient's overall well-being by affecting physical health, finances, social inclusion, and mental health. A robust clinical assessment of hearing loss includes a history and physical examination that effectively characterizes the deficit as conductive, sensorineural, or mixed. Patients presenting with red flags (such as sudden unilateral sensorineural hearing loss) must be urgently referred to otolaryngology-head and neck surgery or immediately assessed in the emergency department. Many nonurgent presentations of hearing loss will also require referral for further audiological assessment, diagnosis, and management. CONCLUSION: As primary care providers, family physicians are well equipped to manage the psychological concerns associated with hearing loss and to reinforce conservative treatment strategies. Frequently, referral or urgent workup, including imaging, is necessary to confirm a patient's diagnosis and initiate management in order to prevent further complications.

Aborder la perte auditive.

OBJECTIF: Fournir aux médecins de famille une approche pratique et fondée sur des données probantes pour la prise en charge de la perte auditive. SOURCES D'INFORMATION: Une recherche dans les bases de données MEDLINE et PubMed a relevé les revues de synthèse, recherches et lignes directrices publiées en anglais de 1980 à 2020. Les données probantes étaient de niveau II ou III dans la plupart des articles relevés. MESSAGE PRINCIPAL: La perte auditive est l'une des déficiences sensorielles les plus fréquentes dans le monde, et elle est grandement préjudiciable au bien-être général du patient, affectant sa santé physique, ses finances, son inclusion sociale et sa santé mentale. Une solide évaluation clinique de la perte auditive comprend une anamnèse et un examen physique qui caractérisent efficacement la perte auditive comme étant de transmission, neurosensorielle ou mixte. Les patients qui présentent des signes alarmants (comme une perte auditive neurosensorielle unilatérale soudaine) doivent être aiguillés d'urgence en oto-rhino-laryngologie et chirurgie cervico-faciale ou être évalués immédiatement au service des urgences. Beaucoup de cas non urgents de perte auditive nécessitent également une évaluation audiologique plus poussée, un diagnostic et la prise en charge. CONCLUSION: À titre de fournisseurs de soins de première ligne, les médecins de famille sont bien placés pour gérer les préoccupations psychologiques liées à la perte auditive et pour renforcer les stratégies thérapeutiques prudentes. Il est fréquemment nécessaire d'aiguiller le patient ou d'effectuer un bilan urgent, dont l'imagerie, pour confirmer le diagnostic et instaurer la prise en charge afin de prévenir d'autres complications.

Pharyngitis: Approach to diagnosis and treatment.

OBJECTIVE: To provide family physicians with an updated approach to diagnosis and treatment of pharyngitis, detailing key symptoms, methods of investigation, and a summary of common causes. SOURCES OF INFORMATION: The approach described is based on the authors' clinical practice and peer-reviewed literature from 1989 to 2018. MAIN MESSAGE: Sore throat caused by pharyngitis is commonly seen in family medicine clinics and is caused by inflammation of the pharynx and surrounding tissues. Pharyngitis can be caused by viral, bacterial, or fungal infections. Viral causes are often self-limiting, while bacterial and fungal infections typically require antimicrobial therapy. Rapid antigen detection tests and throat cultures can be used with clinical findings to identify the inciting organism. Pharyngitis caused by Streptococcus pyogenes is among the most concerning owing to its associated severe complications such as acute rheumatic fever and glomerulonephritis. Hence, careful diagnosis of pharyngitis is necessary to provide targeted treatment. CONCLUSION: A thorough history is key to diagnosing pharyngitis. Rapid antigen detection tests should be reserved for concerns about antibiotic initiation. Physicians should exercise restraint in antibiotic initiation for pharyngitis, as restraint does not delay recovery or increase the risk of S pyogenes infections.

Pharyngite: Approche diagnostique et thérapeutique.

OBJECTIF: Offrir aux médecins de famille une approche diagnostique et thérapeutique actualisée de la pharyngite, en décrivant en détail les principaux symptômes, les méthodes d'investigation et un résumé des causes courantes. SOURCES D'INFORMATION: L'approche décrite est basée sur la pratique clinique des auteurs et sur les publications revues par les pairs de 1989 à 2018. MESSAGE PRINCIPAL: Le mal de gorge causé par la pharyngite est couramment observé dans les cliniques de médecine familiale; il est causé par l'inflammation du pharynx et des tissus environnants. La pharyngite est causée par une infection virale, bactérienne ou fongique. Les causes virales sont souvent spontanément résolutives, alors que les infections bactériennes et fongiques nécessitent habituellement l'antibiothérapie. Le test de détection rapide de l'antigène et la culture de gorge sont jumelés aux observations cliniques pour identifier l'organisme en cause. La pharyngite causée par streptococcus pyogenes fait partie des organismes les plus préoccupants en raison de ses complications graves, telles la fièvre rhumatismale aiguë et la glomérulonéphrite. Ainsi, il est nécessaire de poser un diagnostic attentif de pharyngite afin de pouvoir dispenser un traitement ciblé. CONCLUSION: L'anamnèse détaillée est la clé du diagnostic de pharyngite. Le test de détection rapide de l'antigène doit être réservé aux cas où l'instauration de l'antibiothérapie est préoccupante. Les médecins doivent user de retenue lorsqu'ils instaurent l'antibiothérapie contre la pharyngite, puisque la retenue ne retarde pas le rétablissement ni n'augmente le risque d'infection à s. pyogenes.

Cerumen Management: An Updated Clinical Review and Evidence-Based Approach for Primary Care Physicians.

Objective: To provide family physicians with a practical, evidence-based approach to managing patients with cerumen impaction. Methods: MEDLINE, The Cochrane Library, and the Turning Research Into Practice (TRIP) database were searched for English-language cerumen impaction guidelines and reviews. All such articles published between 1992 and 2018 were reviewed, with most providing level II and III evidence. Results: Cerumen impaction is a common presentation seen in primary care and cerumen removal is one of the most common otolaryngologic procedures performed in general practice. Cerumen impaction is often harmless but can be accompanied by more serious symptoms. Cerumenolytics and irrigation of the ear canal are reasonable first-line therapies and can be used in conjunction or isolation. If irrigation and cerumenolytics are contraindicated, manual removal is appropriate, but the tools necessary are not commonplace in primary care clinics and specialized training may be required to prevent adverse outcomes. Conclusion: Family physicians play a key role in the assessment and management of cerumen impaction and are well equipped to do so. Knowledge of the available techniques for cerumen removal as well as their contraindications ensures that cerumen is removed safely and effectively. When cerumen removal cannot be removed safely in a primary care setting, referral to Otolaryngology-Head and Neck Surgery is appropriate.

Use of Neoadjuvant Chemotherapy in the Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Current treatment for locally advanced rectal cancer includes neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. With neoadjuvant chemotherapy (NC), both chemoradiation and chemotherapy are given in the neoadjuvant setting. This study aims to assess patterns of NC utilization and differences in treatment response compared with standard treatment at our institution. MATERIALS AND METHODS: We performed a retrospective review of patients treated for stage II-III rectal cancer at our institution between 2008 and 2018, examining patient demographics, tumor characteristics, and treatment modality. The primary outcome of interest was complete response (CR) to treatment, including both pathologic and clinical CR. RESULTS: Of 184 patients, 134 (72.8%) received standard therapy, and 50 (27.2%) received NC. In the standard treatment group, 70.1% were node positive, and 9.0% had T4-disease, compared with 92.0% and 26.0% in the NC group, respectively (both P < 0.01). NC utilization increased over time, with 3.4% of patients receiving NC between 2008 and 2012, compared with 48.5% in 2013-2018 (P < 0.01). CR was achieved in 19.4% versus 34.0% (P < 0.01) of patients in standard versus NC groups. With multivariate analysis, NC (odds ratio = 3.02 [95% confidence interval 1.37-6.67], P = 0.01) was associated with increased likelihood of achieving CR, whereas higher T-stage was associated with decreased likelihood of CR (for cT4, odds ratio = 0.06 [95% confidence interval 0.01-0.56], P = 0.01). CONCLUSIONS: Use of NC was increasingly used at our institution from 2008 to 2018. Patients who received NC achieved higher rates of CR compared with those undergoing standard therapy, despite having more advanced disease. These data support trends from other institutions and provides rationale for further study regarding use of NC for locally advanced rectal cancer.

Approach to Ménière disease management.

OBJECTIVE: To provide family physicians with an updated approach to the diagnosis and management of Ménière disease (MD), detailing the natural course of MD and describing how to initiate medical therapy while awaiting consultation with otolaryngology-head and neck surgery. SOURCES OF INFORMATION: The approach is based on the authors' clinical practices and review articles from 1989 to 2018. Most of the cited studies provided level II or III evidence. MAIN MESSAGE: Ménière disease is an uncommon disorder of the inner ear causing vertigo attacks with associated unilateral hearing loss, tinnitus, and aural fullness. It has a degenerative course that often results in permanent sensorineural hearing loss. On average, MD stabilizes with no further vestibular attacks by about 8 years after the onset of symptoms; however, this is highly variable. Vertigo symptoms can be controlled through a combination of dietary salt restriction, stress reduction, and medical therapy (betahistine, diuretics, or both). These can be initiated by family physicians before consultation with otolaryngology-head and neck surgery. Symptoms refractory to such strategies can be treated using nonablative, and occasionally ablative, therapies. CONCLUSION: A thorough history is key to the approach to and management of MD and permits differentiating MD from other vestibular and nonvestibular conditions.

Approche à adopter pour la prise en charge de la maladie de Ménière.

OBJECTIF: Fournir aux médecins de famille une approche actualisée pour le diagnostic et la prise en charge de la maladie de Ménière, décrivant en détail l'évolution naturelle de la maladie de Ménière et la façon d'instaurer un traitement médical en attendant une consultation en otorhinolaryngologie­chirurgie cervico-faciale. SOURCES DE L'INFORMATION: L'approche se base sur les pratiques cliniques des auteurs et sur des articles de synthèse publiés entre 1989 et 2018. La plupart des études citées ont fourni des données probantes de niveau II ou III. MESSAGE PRINCIPAL: La maladie de Ménière est une affection peu fréquente de l'oreille interne, qui cause des crises de vertige et qui est associée à une perte auditive unilatérale, un acouphène et une sensation de plénitude auditive. La maladie est dégénérative et entraîne souvent une perte auditive neurosensorielle permanente. En moyenne, la maladie de Ménière se stabilise sans autre crise vestibulaire environ 8 ans après l'apparition des symptômes; cela est cependant très variable. Les symptômes de vertige peuvent être maîtrisés en combinant une alimentation hyposodée, une réduction du stress et un traitement médical (bétahistine, diurétiques ou les 2). Ces interventions peuvent être instaurées par le médecin de famille avant la consultation en otorhinolaryngologie­chirurgie cervico-faciale. Les symptômes réfractaires à ces interventions sont traités par l'entremise de traitements non ablatifs et, occasionnellement, ablatifs. CONCLUSION: Une anamnèse détaillée est la clé de l'approche à adopter pour la prise en charge de la maladie de Ménière et permet de différencier la maladie de Ménière des autres affections vestibulaires et non vestibulaires.

KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons.

The failure of axon regeneration in the CNS limits recovery from damage and disease. Members of the KLF family of transcription factors can exert both positive and negative effects on axon regeneration, but the underlying mechanisms are unclear. Here we show that forced expression of KLF6 promotes axon regeneration by corticospinal tract neurons in the injured spinal cord. RNA sequencing identified 454 genes whose expression changed upon forced KLF6 expression in vitro, including sub-networks that were highly enriched for functions relevant to axon extension including cytoskeleton remodeling, lipid synthesis, and bioenergetics. In addition, promoter analysis predicted a functional interaction between KLF6 and a second transcription factor, STAT3, and genome-wide footprinting using ATAC-Seq data confirmed frequent co-occupancy. Co-expression of the two factors yielded a synergistic elevation of neurite growth in vitro. These data clarify the transcriptional control of axon growth and point the way toward novel interventions to promote CNS regeneration.

Approach to tinnitus management.

OBJECTIVE: To provide family physicians with an evidence-based and practical approach to managing patients with tinnitus. SOURCES OF INFORMATION: MEDLINE was searched for English-language tinnitus guidelines and reviews. All such articles published between 1980 and 2016 were reviewed, with most providing level II and III evidence. MAIN MESSAGE: Tinnitus affects more than 40% of Canadians at least once in their lifetimes, most commonly older adults. Tinnitus is the perception of sound without external stimulation. It can greatly affect a patient's physical and psychological quality of life. Clinical history taking is directed at eliciting whether symptoms have a pulsatile or nonpulsatile quality, whether symptoms are unilateral or bilateral, and whether there is associated hearing loss. For tinnitus that is pulsatile or unilateral, referral to an otolaryngologist is recommended, as these qualities might be associated with more serious underlying conditions. Most patients with tinnitus can be managed with reassurance, conservative measures, and hearing aids if substantial hearing loss exists. CONCLUSION: Family physicians play the primary role in managing patients with tinnitus and are well situated to address both the physiologic and the psychological manifestations. As tinnitus is very common, helping patients cope with the symptoms through conservative measures and reassurance can prove to have the best outcomes.

Prise en charge de l'acouphène.

OBJECTIF: Présenter aux médecins de famille une approche pratique et fondée sur des données probantes pour prendre en charge les patients souffrant d'un acouphène. SOURCES DE L'INFORMATION: Une recension a été effectuée dans MEDLINE pour trouver des guides de pratique clinique et des revues en anglais portant sur les acouphènes. Tous les articles publiés entre 1980 et 2016 ont fait l'objet d'une revue, et la plupart des données probantes recueillies étaient de niveaux II et III. MESSAGE PRINCIPAL: Les acouphènes touchent plus de 40 % des Canadiens au moins une fois dans leur vie, le plus souvent chez les adultes plus âgés. L'acouphène désigne la perception de sons sans stimulation extérieure. Il peut nuire considérablement à la qualité de vie physique et psychologique des patients. L'anamnèse clinique vise à déterminer si les symptômes sont de nature pulsatile ou non, s'ils sont unilatéraux ou bilatéraux, et s'ils sont associés à une perte de l'ouïe. Si l'acouphène est pulsatile ou unilatéral, il est recommandé de demander une consultation en oto-rhino-laryngologie, parce que ces caractéristiques peuvent être associées à des problèmes sous-jacents plus graves. La prise en charge des patients souffrant d'un acouphène consiste à les rassurer, à adopter des mesures conservatrices et à recommander des appareils auditifs s'il y a une perte auditive importante. CONCLUSION: Les médecins de famille exercent le rôle principal dans la prise en charge des patients souffrant d'un acouphène et ils sont bien placés pour traiter les manifestations tant physiologiques que psychologiques. Parce que l'acouphène est très commun, il importe d'aider les patients à composer avec leurs symptômes en les rassurant et en adoptant des mesures conservatrices, ce qui semble produire les meilleurs résultats.

The application of CRISPR technology to high content screening in primary neurons.

Axon growth is coordinated by multiple interacting proteins that remain incompletely characterized. High content screening (HCS), in which manipulation of candidate genes is combined with rapid image analysis of phenotypic effects, has emerged as a powerful technique to identify key regulators of axon outgrowth. Here we explore the utility of a genome editing approach referred to as CRISPR (Clustered Regularly Interspersed Palindromic Repeats) for knockout screening in primary neurons. In the CRISPR approach a DNA-cleaving Cas enzyme is guided to genomic target sequences by user-created guide RNA (sgRNA), where it initiates a double-stranded break that ultimately results in frameshift mutation and loss of protein production. Using electroporation of plasmid DNA that co-expresses Cas9 enzyme and sgRNA, we first verified the ability of CRISPR targeting to achieve protein-level knockdown in cultured postnatal cortical neurons. Targeted proteins included NeuN (RbFox3) and PTEN, a well-studied regulator of axon growth. Effective knockdown lagged at least four days behind transfection, but targeted proteins were eventually undetectable by immunohistochemistry in >80% of transfected cells. Consistent with this, anti-PTEN sgRNA produced no changes in neurite outgrowth when assessed three days post-transfection. When week-long cultures were replated, however, PTEN knockdown consistently increased neurite lengths. These CRISPR-mediated PTEN effects were achieved using multi-well transfection and automated phenotypic analysis, indicating the suitability of PTEN as a positive control for future CRISPR-based screening efforts. Combined, these data establish an example of CRISPR-mediated protein knockdown in primary cortical neurons and its compatibility with HCS workflows.

Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo.

Axon regeneration in adult central nervous system (CNS) is limited in part by a developmental decline in the ability of injured neurons to re-express needed regeneration associated genes (RAGs). Adult CNS neurons may lack appropriate pro-regenerative transcription factors, or may display chromatin structure that restricts transcriptional access to RAGs. Here we performed epigenetic profiling around the promoter regions of key RAGs, and found progressive restriction across a time course of cortical maturation. These data identify a potential intrinsic constraint to axon growth in adult CNS neurons. Neurite outgrowth from cultured postnatal cortical neurons, however, proved insensitive to treatments that improve axon growth in other cell types, including combinatorial overexpression of AP1 factors, overexpression of histone acetyltransferases, and pharmacological inhibitors of histone deacetylases. This insensitivity could be due to intermediate chromatin closure at the time of culture, and highlights important differences in cell culture models used to test potential pro-regenerative interventions.