Humans

Long-Acting Reversible Contraception With Contraceptive Implants and Intrauterine Devices

Author/s: 
Averbach, S., Hofler, L.

Long-acting reversible contraception (LARC), including contraceptive implants and intrauterine devices (IUDs), is highly effective, with typical-use failure rates of less than 1 pregnancy per 100 person-years of use.1 Fertility returns rapidly after discontinuation of LARC.

Cannabis-Based Products for Chronic Pain : A Systematic Review

Author/s: 
McDonah, M. S., Morasco, B. J., Wagner, J., Ahmed, A. Y., Fu, R., Kansagara, D., Chou, R.

Background: Contemporary data are needed about the utility of cannabinoids in chronic pain.

Purpose: To evaluate the benefits and harms of cannabinoids for chronic pain.

Data sources: Ovid MEDLINE, PsycINFO, EMBASE, the Cochrane Library, and Scopus to January 2022.

Study selection: English-language, randomized, placebo-controlled trials and cohort studies (≥1 month duration) of cannabinoids for chronic pain.

Data extraction: Data abstraction, risk of bias, and strength of evidence assessments were dually reviewed. Cannabinoids were categorized by THC-to-CBD ratio (high, comparable, or low) and source (synthetic, extract or purified, or whole plant).

Data synthesis: Eighteen randomized, placebo-controlled trials (n = 1740) and 7 cohort studies (n = 13 095) assessed cannabinoids. Studies were primarily short term (1 to 6 months); 56% enrolled patients with neuropathic pain, with 3% to 89% female patients. Synthetic products with high THC-to-CBD ratios (>98% THC) may be associated with moderate improvement in pain severity and response (≥30% improvement) and an increased risk for sedation and are probably associated with a large increased risk for dizziness. Extracted products with high THC-to-CBD ratios (range, 3:1 to 47:1) may be associated with large increased risk for study withdrawal due to adverse events and dizziness. Sublingual spray with comparable THC-to-CBD ratio (1.1:1) probably is associated with small improvement in pain severity and overall function and may be associated with large increased risk for dizziness and sedation and moderate increased risk for nausea. Evidence for other products and outcomes, including longer-term harms, were not reported or were insufficient.

Limitation: Variation in interventions; lack of study details, including unclear availability in the United States; and inadequate evidence for some products.

Conclusion: Oral, synthetic cannabis products with high THC-to-CBD ratios and sublingual, extracted cannabis products with comparable THC-to-CBD ratios may be associated with short-term improvements in chronic pain and increased risk for dizziness and sedation. Studies are needed on long-term outcomes and further evaluation of product formulation effects.

Palliative care: An update for internists

Author/s: 
Hayver, R. D., Abedini, N., Jayes, R. L., Matti-Orozco, B., Pomerantz, D. H., Ansari, A. A.

All clinicians should maintain basic skills in general palliative care to help address the needs of patients and families. Because keeping up with the information provided by the growing palliative care literature can be challenging, we conducted a detailed search via Medline for palliative care articles published in 2020 in top peer-reviewed medical journals. Using a consensus-driven process of selection, we reviewed and summarized 11 articles to enhance knowledge of the practice-changing palliative care literature for general internists.

Keywords 

Oral Antiviral Medications for COVID-19

Author/s: 
Petty, L. A., Malani, P. N.

Twonewantiviralmedications, ritonavir-boostednirmatrelvir (Paxlovid,
ie, nirmatrelvir-ritonavir) and molnupiravir (Lagevrio), are currently
available in theUS underemergency useauthorization. These 2 drugs
areauthorized for treatmentofpatientswithmild tomoderateCOVID19 who are not currently hospitalized but are at high risk of developingseveredisease.Nirmatrelvir-ritonavirandmolnupiravirareapproved
for use only within 5 days of onset of COVID-19 symptoms.
Nirmatrelvir-ritonavir andmolnupiravir should be considered for
patients with symptoms of COVID-19 who test positive for SARSCoV-2 and either are an older adult (aged 65 years or older) or are
aged 12 years or older with an underlying condition that increases
risk of severe outcomes of COVID-19 (such as cancer, heart disease,
diabetes, and obesity).

Olfactory Loss and Beyond: A Practical Review of Chemosensory Dysfunction

Author/s: 
Claus, L. E., Leland, E. M., Tai, K. Y., Schlosser, R. J., Kamath, V., Lane, A. P., Rowan, N. R.

Background: Our ability to smell and taste is dictated by 3 chemosensory systems with distinct physiologic mechanisms - olfaction, gustation, and chemesthesis. Although often overlooked, dysfunction of these special senses may have broad implications on multiple facets of patients' lives -including safety, nutritional status, quality of life, mental health, and even cognitive function. As "loss of smell or taste" emerged as a common symptom of coronavirus disease 2019 (COVID-19), the importance of intact chemosensory function has been thrust into the spotlight. Despite the growing recognition of chemosensory dysfunction, this already highly prevalent condition will increasingly impact a larger and more diverse population, highlighting the need for improved awareness and care of these patients.

Methods: Comtemporary review of chemosensory function and assessments.

Conclusions: Although patient-reported chemosensory function measures highlight the ease of screening of chemosensory dysfunction, self-reported measures underestimate both the prevalence and degree of chemosensory dysfunction and do not adequately distinguish between olfaction, gustation, and chemesthesis. Meanwhile, psychophysical assessment tools provide opportunities for more accurate, thorough assessment of the chemosenses when appropriate. Primary care providers are uniquely situated to identify patients burdened by chemosensory dysfunction and raise patient and provider awareness about the importance of chemosensory dysfunction. Identification of chemosensory dysfunction, particularly olfactory dysfunction, may raise suspicion for many underlying medical conditions, including early detection of neurodegenerative conditions. Furthermore, identification and awareness of patients with chemosensory dysfunction may help primary care providers to identify those who may benefit from additional therapeutic and safety interventions, or consultations with specialists for more detailed evaluations and management.

Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review

Author/s: 
Ruopp, N. F., Cockrill, B. A.

Importance: Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling. The prevalence of PAH is approximately 10.6 cases per 1 million adults in the US. Untreated, PAH progresses to right heart failure and death.

Observations: Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 20 mm Hg and is classified into 5 clinical groups based on etiology, pathophysiology, and treatment. Pulmonary arterial hypertension is 1 of the 5 groups of PH and is hemodynamically defined by right heart catheterization demonstrating a mean pulmonary artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg or lower, and a pulmonary vascular resistance of 3 Wood units or greater. Pulmonary arterial hypertension is further divided into subgroups based on underlying etiology, consisting of idiopathic PAH, heritable PAH, drug- and toxin-associated PAH, pulmonary veno-occlusive disease, PAH in long-term responders to calcium channel blockers, and persistent PH of the newborn, as well as PAH associated with other medical conditions including connective tissue disease, HIV, and congenital heart disease. Early presenting symptoms are nonspecific and typically consist of dyspnea on exertion and fatigue. Currently approved therapy for PAH consists of drugs that enhance the nitric oxide-cyclic guanosine monophosphate biological pathway (sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (epoprostenol or treprostinil), and endothelin pathway antagonists (bosentan and ambrisentan). With these PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. Current treatment consists of combination drug therapy that targets more than 1 biological pathway, such as the nitric oxide-cyclic guanosine monophosphate and endothelin pathways (eg, ambrisentan and tadalafil), and has shown demonstrable improvement in morbidity and mortality compared with the previous conventional single-pathway targeted monotherapy.

Conclusions and relevance: Pulmonary arterial hypertension affects an estimated 10.6 per 1 million adults in the US and, without treatment, typically progresses to right heart failure and death. First-line therapy with drug combinations that target multiple biological pathways are associated with improved survival.

Antiseizure Medications for Adults With Epilepsy: A Review

Author/s: 
Kanner, A. M., Bicchi, M. M.

Importance: Epilepsy affects approximately 65 million people worldwide. Persistent seizures are associated with a 20% to 40% risk of bodily injuries (eg, fractures, burns, concussions) over 12-month follow-up. The primary goal of epilepsy treatment is to eliminate seizures while minimizing adverse effects of antiseizure drugs (ASDs).

Observations: An epileptic seizure is defined as a sudden occurrence of transient signs and symptoms caused by abnormal and excessive or synchronous neuronal activity in the brain. Focal and generalized epilepsy are the 2 most frequent types of epilepsy; diagnosis is based on the type of seizures. There are 26 US Food and Drug Administration-approved medications for epilepsy, of which 24 have similar antiseizure efficacy for focal epilepsy and 9 have similar efficacy for generalized epilepsy. The decision to initiate an ASD should be individualized, but should be strongly considered after 2 unprovoked seizures or after 1 unprovoked seizure that occurred during sleep and/or in the presence of epileptiform activity on an electroencephalogram and/or in the presence of a structural lesion on the brain magnetic resonance imaging. The ASDs must be selected based on the seizure and epilepsy types, the epilepsy syndrome, and the adverse effects associated with the drug. For focal epilepsy, oxcarbazepine and lamotrigine are first-line therapy, while levetiracetam can be also considered if there is no history of psychiatric disorder. For generalized epilepsy, the selection of the ASD is based on the type of epilepsy syndrome and the patient's sex, age, and psychiatric history. Seizure freedom is achieved in approximately 60% to 70% of all patients. A total of 25% to 50% of patients also experience neurologic, psychiatric, cognitive, or medical disorders, such as mood, anxiety, and attention deficit disorders and migraines. For these patients, selecting an ASD should consider the presence of these disorders and concomitant use of medications to treat them. ASDs with cytochrome P450 enzyme-inducing properties (eg, carbamazepine, phenytoin) may worsen comorbid coronary and cerebrovascular disease by causing hyperlipidemia and accelerating the metabolism of concomitant drugs used for their treatment. They can also facilitate the development of osteopenia and osteoporosis.

Conclusions and relevance: Epilepsy affects approximately 65 million people worldwide and is associated with increased rates of bodily injuries and mortality when not optimally treated. For focal and generalized epilepsy, selection of ASDs should consider the seizure and epilepsy types and epilepsy syndrome, as well as the patient's age and sex, comorbidities, and potential drug interactions.

Mortality and Morbidity in Mild Primary Hyperparathyroidism: Results From a 10-Year Prospective Randomized Controlled Trial of Parathyroidectomy Versus Observation

Author/s: 
Pretorius, M., Lundstam, K., Heck, A., Fagerland, M. W., Godang, K., Mollerup, C., Fougner, S. L., Pernow, Y., Aas, T., Hessman, O., Rosen, T., Nordestrom, J., Jansson, S., Hellstrom, M., Bollerslev, J.

Background: Primary hyperparathyroidism (PHPT) is a common endocrine disorder associated with increased risk for fractures, cardiovascular disease, kidney disease, and cancer and increased mortality. In mild PHPT with modest hypercalcemia and without known morbidities, parathyroidectomy (PTX) is debated because no long-term randomized trials have been performed.

Objective: To examine the effect of PTX on mild PHPT with regard to mortality (primary end point) and key morbidities (secondary end point).

Design: Prospective randomized controlled trial. (ClinicalTrials.gov: NCT00522028).

Setting: Eight Scandinavian referral centers.

Patients: From 1998 to 2005, 191 patients with mild PHPT were included.

Intervention: Ninety-five patients were randomly assigned to PTX, and 96 were assigned to observation without intervention (OBS).

Measurements: Date and causes of death were obtained from the Swedish and Norwegian Cause of Death Registries 10 years after randomization and after an extended observation period lasting until 2018. Morbidity events were prospectively registered annually.

Results: After 10 years, 15 patients had died (8 in the PTX group and 7 in the OBS group). Within the extended observation period, 44 deaths occurred, which were evenly distributed between groups (24 in the PTX group and 20 in the OBS group). A total of 101 morbidity events (cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones) were also similarly distributed between groups (52 in the PTX group and 49 in the OBS group). During the study, a total of 16 vertebral fractures occurred in 14 patients (7 in each group).

Limitation: During the study period, 23 patients in the PTX group and 27 in the OBS group withdrew.

Conclusion: Parathyroidectomy does not appear to reduce morbidity or mortality in mild PHPT. Thus, no evidence of adverse effects of observation was seen for at least a decade with respect to mortality, fractures, cancer, cardiovascular and cerebrovascular events, or renal morbidities.

Evaluation of a Dragons' Den-inspired symposium to spread primary health care innovations in Quebec, Canada: a mixed-methods study using quality-improvement e-surveys

Author/s: 
Smithman, M. A., Dumas-Pilon, M., Campbell, M. J., Breton, M.

Background: On May 24, 2017, the Quebec College of Family Physicians held an innovation symposium inspired by the television show Dragons' Den, at which innovators pitched their innovations to Dragon-Facilitators (i.e., decision-makers) and academic family medicine clinical leads. We evaluated the effects of the symposium on the spread of primary health care innovations.

Methods: We conducted a mixed-methods evaluation of the symposium. We collected data related to Rogers' innovation-decision process using 3 quality-improvement e-surveys (distributed between May 2017 and February 2018). The first survey evaluated spread outputs (innovation discovery, intention to spread, improvements) and was sent to all participants immediately after the symposium. The second evaluated short-term spread outcomes (follow-ups, successes, barriers) and was sent to innovators 3 months after the symposium. The third evaluated medium-term spread outcomes (spread, perceived impact) and was sent to innovators and clinical leads 9 months after the symposium. We analyzed the data using descriptive statistics, content analysis and joint display.

Results: Fifty-one innovators, 66 clinical leads (representing 42 clinics) and 37 Dragon-Facilitators attended the symposium. The response rates for the surveys were 61% (82/134) for the immediate post-symposium survey of all participants; 68% (21/31) for the 3-month survey of innovators; and 49% (48/97) for the 9-month survey of clinical leads and innovators. Immediately after the symposium, clinical leads and Dragon-Facilitators reported a high likelihood of adopting an innovation (mean ± standard deviation 8.02 ± 1.63 on a 10-point Likert scale) and 87% (53/61) agreed that they had discovered innovations at the symposium. Nearly all innovators (95%, 20/21) intended to follow up with potential adopters. After 3 months, 62% (13/21) of innovators had followed up in some way. After 9 months, 72% of clinical leads (18/25) had implemented at least 1 innovation, and 52% of innovators (12/23) had spread or were in the process of spreading innovations.

Interpretation: The innovation symposium supported participants in achieving the early stages of spreading primary health care innovations. Replicating such symposia may help spread other health care innovations.

Evaluation of Budesonide-Formoterol for Maintenance and Reliever Therapy Among Patients With Poorly Controlled Asthma A Systematic Review and Meta-analysis

Author/s: 
Beasley, R., Harrison, T., Peterson, S., Gustafson, P., Hamblin, A., Bengtsson, T., Fageras, M.

Importance: The Global Initiative for Asthma (GINA) recommends 2 alternative treatments for patients receiving treatment at steps 3 to 5: single inhaler combination inhaled corticosteroid-formoterol as both maintenance and reliever (SMART) or inhaled corticosteroid-long-acting β2-agonist as maintenance plus short-acting β2-agonist as reliever.

Objective: To assess whether switching to SMART is associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever among patients with poorly controlled asthma.

Data sources: For this systematic review and meta-analysis, the literature, internal study databases at AstraZeneca and the Medical Research Institute of New Zealand, and references from a previous systematic review and meta-analysis on SMART were searched to identify randomized clinical trials published from January 1990 to February 2018, that compared budesonide-formoterol by SMART with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever.

Study selection: Trials of at least 24 weeks' duration were included if they reported baseline data on GINA treatment step, asthma control status, and efficacy measures of severe exacerbations. Included patients were adults and adolescents with asthma and baseline Asthma Control Questionnaire 5-item version scores of 1.5 or higher.

Data extraction and synthesis: Patient-level data were identified by independent extraction, and analyses were performed using a fixed-effect model. Data analysis was performed from August 2018 to November 2021.

Main outcomes and measures: The primary outcome was time to first severe asthma exacerbation associated with each treatment, analyzed by Cox proportional hazards regression.

Results: Overall, 4863 patients were included (3034 [62.4%] female; mean [SD] age, 39.8 [16.3] years). Switching patients with uncontrolled asthma at GINA step 3 (n = 1950) to SMART at either step 3 or 4 was associated with a prolonged time to first severe asthma exacerbation, with a 29% reduced risk compared with stepping up to step 4 inhaled corticosteroid-long-acting β2-agonist maintenance plus short-acting β2-agonist reliever (hazard ratio, 0.71; 95% CI, 0.52-0.97). For patients with uncontrolled asthma at step 3 and step 4 (n = 2913), switching to SMART was associated with a prolonged time to first severe asthma exacerbation and a 30% reduced risk compared with remaining at the same treatment step (hazard ratio, 0.70; 95% CI, 0.58-0.85).

Conclusions and relevance: In this systematic review and meta-analysis, for patients with poorly controlled asthma, SMART was associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever. These findings suggest that if an adult or adolescent receiving treatment at GINA step 3 or 4 has poorly controlled asthma, it is preferable to switch to the SMART regimen rather than to step up or continue the GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever therapy.

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