One-Week Kava Dietary Supplementation Increases Both Urinary N- and O-Glucuronides of NNAL, a Lung Carcinogen Major Metabolite, among Smokers.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is one of the most prevalent and potent pulmonary carcinogens in tobacco products that increases the human lung cancer risk. Kava has the potential to reduce NNK and tobacco smoke-induced lung cancer risk by enhancing urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major metabolite of NNK) and thus reducing NNK-induced DNA damage. In this study, we quantified N-glucuronidated NNAL (NNAL-N-gluc), O-glucuronidated NNAL (NNAL-O-gluc), and free NNAL in the urine samples collected before and after 1-week kava dietary supplementation. The results showed that kava increased both NNAL-N-glucuronidation and O-glucuronidation. Since NNAL-N-glucuronidation is dominantly catalyzed by UGT2B10, its representative single-nucleotide polymorphisms (SNPs) were analyzed among the clinical trial participants. Individuals with any of the four analyzed SNPs appear to have a reduced basal capacity in NNAL-N-glucuronidation. Among these individuals, kava also resulted in a smaller extent of increases in NNAL-N-glucuronidation, suggesting that participants with those UGT2B10 SNPs may not benefit as much from kava with respect to enhancing NNAL-N-glucuronidation. In summary, our results provide further evidence that kava enhances NNAL urinary detoxification via an increase in both N-glucuronidation and O-glucuronidation. UGT2B10 genetic status has not only the potential to predict the basal capacity of the participants in NNAL-N-glucuronidation but also potentially the extent of kava benefits.

Opportunities and Challenges of Kava in Lung Cancer Prevention.

Lung cancer is the leading cause of cancer-related deaths due to its high incidence, late diagnosis, and limited success in clinical treatment. Prevention therefore is critical to help improve lung cancer management. Although tobacco control and tobacco cessation are effective strategies for lung cancer prevention, the numbers of current and former smokers in the USA and globally are not expected to decrease significantly in the near future. Chemoprevention and interception are needed to help high-risk individuals reduce their lung cancer risk or delay lung cancer development. This article will review the epidemiological data, pre-clinical animal data, and limited clinical data that support the potential of kava in reducing human lung cancer risk via its holistic polypharmacological effects. To facilitate its future clinical translation, advanced knowledge is needed with respect to its mechanisms of action and the development of mechanism-based non-invasive biomarkers in addition to safety and efficacy in more clinically relevant animal models.

Vocal Cord Dysfunction: Rapid Evidence Review.

Vocal cord dysfunction (i.e., vocal cords closing when they should be opening, particularly during inspiration) should be suspected in patients presenting with inspiratory stridor or wheezing; sudden, severe dyspnea (without hypoxia, tachypnea, or increased work of breathing); throat or chest tightness; and anxiety, particularly in females. Common triggers include exercise, asthma, gastroesophageal reflux disease, postnasal drip, upper or lower respiratory tract infection, and irritants. Nasolaryngoscopy and pulmonary function testing, with provocative exercise and methacholine, can help diagnose vocal cord dysfunction and are helpful to evaluate for other etiologies. Conditions that can trigger vocal cord dysfunction should be optimally treated, particularly asthma, gastroesophageal reflux disease, and postnasal drip, while avoiding potential irritants. Therapeutic breathing maneuvers and vocal cord relaxation techniques are first-line therapy for dyspnea that occurs with vocal cord dysfunction. A subset of vocal cord dysfunction leads to dysphonia, as opposed to dyspnea, secondary to abnormal laryngeal muscle spasms (vocal cord closure is less severe). OnabotulinumtoxinA injections may be helpful for spasmodic dysphonia and for treating dyspnea in certain cases, although evidence is limited.

Comparison of Factors Identified by Patients and Physicians Associated with Hospital Readmission (COMPARE2).

OBJECTIVE: Factors contributing to hospital readmission have rarely been sought from the patient perspective. Furthermore, it is unclear how patients and physicians compare in identifying factors contributing to readmission. The objective of the study was to identify and compare factors contributing to hospital readmission identified by patients and physicians by surveying participants upon hospital readmission to a teaching medicine service. METHODS: Patients 18 years and older who were discharged and readmitted to the same service within 30 days and the physicians caring for these patients were surveyed to identify factors contributing to readmission. Secondary outcomes included comparing responses between groups and determining level of agreement. Patients could be surveyed multiple times on subsequent readmissions; physicians could be surveyed for multiple patients. RESULTS: A total of 131 patients and 37 physicians were consented. The mean patient age was 60.1 years (standard deviation 16.8 years) and 55.6% were female; 56.4% were white, and 42.1% were black/African American. In total, 179 patient surveys identified "multiple medical problems" (48.6%), "trouble completing daily activities" (45.8%), and "discharged too soon" (43.6%) most frequently as contributing factors; 231 physician surveys identified "multiple medical problems" (45.0%) and "medical condition too difficult to care for at home" (35.6%) most frequently as contributing factors. Paired survey results were available for 135 readmissions and showed fair agreement for only 1 factor but no agreement for 5 factors. CONCLUSIONS: Patients identified previously unknown factors contributing to readmission. Little agreement existed between patients and physicians. Additional research is needed to determine how best to address patient-identified factors contributing to readmission.

Associations Between National Board Exam Performance and Residency Program Emphasis on Patient Safety and Interprofessional Teamwork.

OBJECTIVE: Several aspects of medical training may contribute to the ultimate goal of producing excellent physicians whose patients will have the best possible outcomes. However, the relative importance of education, evaluation and feedback, duty hours, practice structure, and program culture in achieving this goal is unclear. This study assessed associations among in-training exam performance, Accreditation Council for Graduate Medical Education (ACGME) Resident Survey responses, and American Board of Medical Specialties (ABMS) national board exam performance. METHODS: Residency training programs at a university teaching hospital were classified as having 5-year first-time ABMS pass rates above (n=12) or below (n=3) the national average for their specialty. These groups were compared by ACGME Resident Survey data and in-training exam performance. RESULTS: Surveys were collected from 484/543 eligible residents (89%), including 177 surveys from programs with below-average board pass rates and 307 surveys from programs with aboveaverage board pass rates. In-training exam performance was similar between groups. Aboveaverage programs had stronger agreement with statements that their culture reinforced patient safety (4.72 vs. 4.30, p=0.006) and that information was not lost during transitions of care (4.14 vs. 3.63, p=0.001). Although the occurrence of interprofessional teamwork was similar between groups, above-average programs had stronger agreement with the statement that interprofessional teamwork was effective (4.60 vs. 4.17, p=0.003). CONCLUSION: Residency programs emphasizing patient safety and effective interprofessional teamwork had above-average first-time national board pass rates.

Cerumen Impaction: Diagnosis and Management.

Cerumen production is a normal and protective process for the ear canal. However, cerumen should be removed when it causes symptoms (e.g., hearing loss, itching, pain, tinnitus) or prevents assessment of the external auditory canal, the tympanic membrane, or audiovestibular system. Cerumen should also be removed when it limits examination in patients who cannot communicate their symptoms, such as those with dementia or developmental delay, nonverbal patients with behavioral changes, and young children with fever, speech delay, or parental concerns. Patients with coagulopathies, hepatic failure, thrombocytopenia, or hemophilia, and those taking antiplatelet or anticoagulant medications, should be counseled about the increased risk of bleeding in the external auditory canal when cerumen is removed. Effective treatment options include cerumenolytic agents, irrigation with or without cerumenolytic pretreatment, and manual removal. Home irrigation with a bulb syringe may be appropriate for selected adults. Cotton-tipped swabs, ear candling, and olive oil drops or sprays should be avoided. If multiple attempts to remove the impacted cerumen-including a combination of treatments-are ineffective, clinicians should refer the patient to an otolaryngologist. Persistent symptoms despite resolution of the impaction should also prompt further evaluation for an alternative diagnosis.

Chronic Cough: Evaluation and Management.

Although chronic cough in adults (cough lasting longer than eight weeks) can be caused by many etiologies, four conditions account for most cases: upper airway cough syndrome, gastroesophageal reflux disease/laryngopharyngeal reflux disease, asthma, and nonasthmatic eosinophilic bronchitis. Patients should be evaluated clinically (with spirometry, if indicated), and empiric treatment should be initiated. Other potential causes include angiotensin-converting enzyme inhibitor use, environmental triggers, tobacco use, chronic obstructive pulmonary disease, and obstructive sleep apnea. Chest radiography can rule out concerning infectious, inflammatory, and malignant thoracic conditions. Patients with refractory chronic cough may warrant referral to a pulmonologist or otolaryngologist in addition to a trial of gabapentin, pregabalin, and/or speech therapy. In children, cough is considered chronic if present for more than four weeks. In children six to 14 years of age, it is most commonly caused by asthma, protracted bacterial bronchitis, and upper airway cough syndrome. Evaluation should focus initially on these etiologies, with targeted treatment and monitoring for resolution.

Otology: Vertigo.

Vertigo, an unexpected feeling of self-motion, is no longer characterized simply by symptom quality but by using triggers and timing. Evaluating vertigo by triggers and timing not only distinguishes serious central causes from benign peripheral causes, but also narrows the differential diagnosis by further classifying vertigo as spontaneous episodic vestibular syndrome, triggered episodic vestibular syndrome, or acute vestibular syndrome. A targeted physical examination can then be used to further delineate the cause within each of these three vestibular categories. Neuroimaging and vestibular testing are not routinely recommended. In the management of vertigo, vestibular hypofunction can be treated with vestibular rehabilitation, which can be self-administered or directed by a physical therapist. Pharmacotherapy sometimes is indicated for vertigo based on triggers, timing, and the specific condition, but it is not always beneficial and is used more often for symptom reduction than as a cure. Transtympanic corticosteroid or gentamicin injections are recommended for patients who do not benefit from nonablative therapy. Surgical ablative therapy is reserved for patients who have not benefited from less definitive therapy and have nonusable hearing.

Otology: Cerumen Impaction and Aural Foreign Bodies.

Cerumen lubricates and protects the external auditory canal, but excess accumulation can lead to ear fullness, itching, otalgia, discharge, hearing loss, and tinnitus. Cerumen should be treated whenever symptoms are present or if it limits diagnosis by preventing a needed otoscopic examination. Clinicians should evaluate for cerumen impaction in those using hearing aids and patients with intellectual disability. Cerumen impaction can be treated with cerumenolytics, ear irrigation, and manual removal with instrumentation. Aural foreign bodies can cause ear fullness, otalgia, discharge, and hearing loss. They are more common in children than adults. The most common type of aural foreign bodies in children is jewelry, followed by paper products, parts of pens or pencils, desk supplies (eg, erasers), BBs or pellets, and earplugs or earphones. In adults, the most common aural foreign bodies are cotton swabs or cotton, followed by hearing aid parts and jewelry or ear accessories. Patients should avoid using cotton tip applicators in the external auditory canal. Alligator forceps, small right angle hooks, and ear irrigation commonly are used to remove aural foreign bodies in an outpatient clinic setting, but the choice depends on the type of foreign body. Soft and irregularly shaped objects can be removed without referral to an otolaryngologist. Patients with hard, spherical, or cylindrical objects should be referred to an otolaryngologist if previous removal attempts have failed or if there is ear trauma to avoid worsening its position in the ear canal.

Otology: Hearing Loss.

Hearing loss is the cause of significant morbidity throughout the United States and the world. Because of numerous factors, such as ongoing noise exposure, poorly controlled chronic disease, and an aging population, the burden of hearing loss is expected to continue to increase. Hearing loss commonly is categorized as conductive, sensorineural, or mixed. The type of hearing loss can be determined through a combination of patient history and physical examination, and then confirmed with audiometry and tympanometry. Advanced imaging is not typically necessary, but it may be helpful in specific instances. The presentation of sudden sensorineural hearing loss should prompt urgent referral to an otolaryngologist and audiologist. Management of this condition is selective but may initially include oral corticosteroids. Management for chronic hearing loss involves the use of hearing aids, which can offer a large benefit to users but historically have been expensive and not covered by many insurance plans. Recent US legislation has made hearing aids more accessible and affordable by allowing direct-to-consumer marketing and offering over-the-counter hearing aids without a clinical evaluation.

Otology: Ear Infections.

Acute otitis media (AOM) is a common diagnosis in children who present with symptoms of otalgia, fever, or irritability and is confirmed by a bulging tympanic membrane or otorrhea on physical examination. It often is preceded by a viral infection, but the bacterial pathogens isolated most commonly are Streptococcus pneumonia, Haemophilus influenzae, and Moraxella catarrhalis. Watchful waiting may be appropriate in children 6 months or older with uncomplicated unilateral AOM. When antibiotics are indicated, amoxicillin is the first-line treatment in those without recent treatment with or allergy to this drug. Otitis media with effusion (OME) is fluid in the middle ear without symptoms of AOM and typically resolves within 3 months. Tympanostomy tube placement is the most common ambulatory surgery for children in the United States. It is used to ventilate the middle ear space and may be performed to treat recurrent AOM, persistent AOM, or chronic OME. Acute otitis externa is inflammation of the external ear canal, often due to infection. On examination, the ear canal is red and inflamed, with patients typically experiencing discomfort with manipulation of the affected ear. It is treated with a topical antibiotic with or without topical corticosteroid.

Feasibility of preemptive pharmacogenetic testing and improvement of medication treatment satisfaction among medically underserved patients.

Previous findings suggest that medically underserved patients are prescribed medications with pharmacogenetic (PGx) guidelines at a high frequency. Thus, underserved patients may especially benefit from PGx testing, but little evidence exists regarding the effect of testing in this population. This pilot study aimed to generate key feasibility data and explore clinical outcomes of PGx implementation in underserved populations. Black and Latino patients were recruited from an outpatient clinic and underwent PGx testing. Feasibility measures included enrollment metrics and actionable genotype frequencies. The primary clinical outcome was patient medication treatment satisfaction 6 months after testing. Implementation outcomes included the number of healthcare provider encounters and medication changes within the 6-month follow-up. Effectiveness outcomes included medication adherence, patient-perceived test value, and time spent discussing medications with providers. Ninety-nine patients completed the study. Proton-pump inhibitors were the most frequent PGx drug class prescribed at baseline (61%) followed by nonsteroidal anti-inflammatory drugs (36%). Patients with an actionable genotype constituted 96% of the population, whereas 28% had an actionable genotype related to their PGx drug. Patient treatment satisfaction significantly increased over the 6 months after PGx testing. In addition, medication adherence and the number of provider encounters significantly increased over the study period. In a pilot study, preemptive PGx testing was feasible in primary care clinics, improved patient treatment satisfaction and adherence, and increased the number of provider encounters in medically underserved patients. Future clinical trials are warranted to assess the long-term effects of PGx testing in a larger diverse patient population.

Advanced Practice Providers in Departments of Family Medicine: Status, Supervision, and Services.

BACKGROUND: Nurse practitioners (NP), physician assistants (PA), and other advanced practice providers (APP) are one solution to meet health care workforce shortage. Our study examined clinical workforce decisions and perceptions of APPs and family physicians (FPs) from the perspective of a national survey chairs of Departments of Family Medicine. METHODS: A survey was developed and distributed to family medicine department chairs as identified by the Association of Departments of Family Medicine (ADFM). In addition to demographic information, respondents were asked if their department directly employs APPs, major factors influencing departments of family medicine to hire APPs, services to patients currently being provided by APPs, and services preferentially provided by APPs. Descriptive statistics were reviewed. Bivariate analyses and Chi-square were computed comparing perceptions of APPs and FPs by how these types of health care providers are currently used in the respondent's clinical operation. RESULTS: The overall response rate for the survey was 48.4% (109/225). Most departments of family medicine (62.4%) use APPs. Access to care and filing gaps in team-based care are the primary factors for APP employment. Although most departments have APPs provide services that include complex chronic conditions complicated by coexisting conditions or not yet controlled, most department chairs do not prefer APPs provide these services. DISCUSSION: The role APPs in terms of specific patient care activities and services in the health care team of departments of family medicine is often in conflict with preferred roles as delineated by the chair.

Pursuing Scholarship: Creating Effective Conference Submissions.

Medical educators are expected to disseminate peer-reviewed scholarly work for academic promotion and tenure. However, developing submissions for presentations at national meetings can be confusing and sometimes overwhelming. Awareness and use of some best practices can demystify the process and maximize opportunities for acceptance for a variety of potential submission categories. This article outlines logistical steps and best practices for each stage of the conference submission process that faculty should consider when preparing submissions. These include topic choice, team composition, consideration of different submission types, and strategies for effectively engaging participants.

Smell and taste disorders in primary care.

Smell and taste disorders can be challenging to diagnose because of the large number of potential etiologies. Patients are often unable to provide a clear history of symptoms, because they frequently cannot distinguish between difficulties with smell and taste. Standardized questionnaires may be helpful in diagnosis. Smell and taste dysfunction have been implicated in loss of appetite, unintended weight loss, malnutrition, and reduced quality of life. Taste dysfunction may be complete or partial, and affect one or more aspects of taste (sweetness, bitterness, sourness, saltiness, and umami [savory]). An estimated 95% of taste disorders are caused by impairment of smell rather than gustatory loss. The most common causes of olfactory dysfunction include allergic rhinitis, chronic rhinosinusitis (with or without sinonasal polyps), and upper respiratory infection. Other potential causes include head trauma, neurodegenerative diseases (including Parkinson disease and cognitive impairments), and medications. Examination of the nose, mouth, and oropharynx as well as neurologic examination (focusing on cranial nerves I, VII, IX, and X) is essential. Additional assessment such as cognitive testing, nasal endoscopy, computed tomography of the sinuses or nose, or brain magnetic resonance imaging may be indicated. Up to one-half of patients with olfactory dysfunction improve over time. Improvement in olfactory function is inversely correlated with severity and duration of loss, age, smoking, and male sex.

Incidental seromucinous hamartoma of the anterior nasal cavity presenting after episode of vestibular neuritis.

A woman in her 70s presented to primary care clinic complaining of acute onset dizziness for 1 day that was initially diagnosed as vestibular neuritis and treated with steroids. The next day, she presented to the emergency department with worsening symptoms. Imaging revealed no intracranial process; however, non-contrast CT imaging revealed a soft-tissue mass in the posterior ethmoid sinus. The vertigo completely resolved before an otolaryngologist surgically removed the nasal mass, which actually originated from the right cribriform plate and extended to the anterior middle turbinate head. The final pathology was consistent with seromucinous hamartoma.

Reducing tobacco-associated lung cancer risk: a study protocol for a randomized clinical trial of AB-free kava.

BACKGROUND: Tobacco use is the leading cause of many preventable diseases, resulting in premature death or disease. Given that the majority of adult who smoke want to stop, this health burden could be significantly reduced if the success rate of tobacco cessation can be improved. In addition, most adults planning to quit were interested in trying complementary approaches to facilitating tobacco cessation, which is currently lacking. Therefore, there is an unmet and urgent need for novel interventions to improve the success of tobacco cessation. If such an intervention can reduce tobacco-associated lung carcinogenesis, that will be more desirable. The goal of this project is to develop a safe and effective kava-based intervention to enable tobacco cessation and reduce lung cancer risk, which will improve the health of smokers. METHODS: A randomized controlled trial will enroll 80 adults who currently smoke at least 10 cigarettes daily and randomize 1:1 into the placebo and AB-free kava arms, being exposed for 4 weeks, with a total of six visits (weeks 0, 1, 2, 4, 8, and 12) to evaluate the compliance and potential issues of AB-free kava use among the participants, explore the potential effect of the AB-free kava intervention on tobacco dependence, tobacco use, and lung carcinogenesis biomarkers. Participants will be enrolled during their primary care clinic visit. DISCUSSION: Primary care settings play a critical role in tobacco-related disease screening, counseling, and early intervention, as the majority of adults who smoke visit their physicians annually. Building upon our promising pilot human trial results in conjunction with ample compelling lab animal results, and consistent with evidence of kava's benefits from epidemiological data, this trial will evaluate the compliance of AB-free kava among adults who currently smoke with no intention to quit. The other exploratory aims include (1) whether AB-free kava intervention can reduce tobacco use and tobacco dependence; (2) whether AB-free kava use suppresses tobacco-induced carcinogenesis; and (3) the potential of the mechanism-based noninvasive biomarkers in precision AB-free kava intervention. The positive results from this study are expected to provide a great opportunity to effectively reduce smoking rates and tobacco-related diseases. TRIAL REGISTRATION: ClinicalTrials.gov with the identifier: NCT05081882. Registered on October 18, 2021.

Adipose Tissue Insulin Resistance Predicts the Severity of Liver Fibrosis in Patients With Type 2 Diabetes and NAFLD.

CONTEXT: Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown. OBJECTIVE: Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipose tissue insulin resistance index [adipo-IR]) and liver (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) IR in people with T2D and NAFLD. DESIGN: Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (a marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/adipo-IR. SETTING: University ambulatory care practice. PARTICIPANTS: A total of 483 participants with T2D. INTERVENTION: Screening for steatosis and fibrosis with elastography. MAIN OUTCOME MEASURES: Liver steatosis (controlled attenuation parameter), fibrosis (liver stiffness measurement), and measurements of IR (adipo-IR, HOMA-IR) and fibrosis (cytokeratin-18). RESULTS: Clinically significant liver fibrosis (stage F ≥ 2 = liver stiffness measurement ≥8.0 kPa) was found in 11%, having more features of the metabolic syndrome, lower adiponectin, and higher aspartate aminotransferase (AST), alanine aminotransferase, liver fat, and cytokeratin-18 (P < 0.05-0.01). In multivariable analysis including just clinical variables (model 1), obesity (body mass index [BMI]) had the strongest association with fibrosis (odds ratio, 2.56; CI, 1.87-3.50; P < 0.01). When metabolic measurements and cytokeratin-18 were included (model 2), only BMI, AST, and liver fat remained significant. When fibrosis stage was adjusted for BMI, AST, and steatosis (model 3), only Adipo-IR remained strongly associated with fibrosis (OR, 1.51; CI, 1.05-2.16; P = 0.03), but not BMI, hepatic IR, or steatosis. CONCLUSIONS: These findings pinpoint to the central role of dysfunctional, insulin-resistant adipose tissue to advanced fibrosis in T2D, beyond simply BMI or steatosis. The clinical implication is that targeting adipose tissue should be the priority of treatment in NAFLD.

Feasibility of a primary care patient decision aid for smoking cessation with information about e-cigarettes.

Decision aids can promote shared decision making and behavior change and may be effective in helping patients quit smoking. Patients are increasingly using e-cigarettes for smoking cessation; however, little is known about the impact of including e-cigarette information in smoking cessation decision aids. Our objective was to assess the feasibility and acceptability of a smoking cessation decision aid including e-cigarette information. This study was conducted at one family medicine clinic in the United States. We used a pre-post design. In Phase I, the decision aid presented information about approved cessation methods. In Phase II, current e-cigarette users and patients with no intention of quitting received additional information on switching to e-cigarettes. We assessed the impact of the decision aids on quit attempts and abstinence, confidence and readiness to quit, confidence and readiness to switch to e-cigarettes, and patient satisfaction. We enrolled 60 patients in each phase (N = 120). Patients reported higher confidence and readiness to quit after viewing the decision aids and consulting with their physician (p < 0.01). Patients reported the decision aid helped prepare them to make a decision about quitting smoking and expressed satisfaction with the decision aid and clinician consultation. We did not observe an impact of including e-cigarette information. Smoking cessation decision aids are acceptable to patients and may promote behavior change. Future studies should explore the impact of providing patients e-cigarette information using larger sample sizes and rigorous designs. Further research is needed to identify strategies to promote shared decision-making regarding e-cigarettes.

Dysosmia and drug tolerance with use of venlafaxine.

A 57-year-old woman presented with a 1-year history of major depressive disorder. She was started on venlafaxine XR 75 mg orally daily and a few days later developed severe dysosmia to foods she used to enjoy. She never had previous problems with smell or taste. At her 1-month follow-up, her depressive symptoms had improved, but she reported persistent dysosmia and was found to have associated weight loss due to decreased oral intake. She was advised to switch medications, but due to financial constraints she continued taking the same dose. At follow-up 48 days later, she reported complete resolution of her dysosmia and was eating normally again, but she had persistence of some depressive symptoms so her dose was gradually increased to venlafaxine XR 225 mg orally daily until her depressive symptoms and postmenopausal hot flashes were well controlled. There were no changes with continued use over the following 8 years.