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Diagnosis and Management of Resistant Hypertension: A Review

Author/s: 
Michel Azizi, Wanpen Vongpatanasin, Naomi D. L. Fisher

Importance: Hypertension, defined as office systolic blood pressure (SBP) 130 mm Hg or greater and/or diastolic blood pressure 80 mm Hg or greater, affects 43.9% of women and 49.5% of men in the US. Approximately 19.7% of patients treated for hypertension have apparent resistant hypertension (blood pressure ≥130/80 mm Hg) despite using 3 or more antihypertensive medications, preferably a renin-angiotensin system blocker, a calcium channel blocker, and a thiazide-type diuretic, at maximally tolerated doses.

Observations: Approximately 10% of patients treated for hypertension have true resistant hypertension confirmed with home or 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension (approximately 37.5% of apparent resistant hypertension) and after excluding medication nonadherence (approximately 50%) and secondary hypertension such as primary aldosteronism (approximately 5%-25%). Conditions associated with resistant hypertension include obesity, diabetes, chronic kidney disease, and sleep apnea. Resistant hypertension is associated with increased risk of cardiovascular death vs controlled blood pressure at 5 years to 10 years (absolute risk increase, 10.3% [95% CI, 8.7%-12.1%]). Lifestyle modifications for resistant hypertension include a low-sodium diet (<1500 mg/d), reducing or avoiding alcohol, 150 min/wk or more of aerobic exercise, and weight loss. Illicit drugs (eg, cocaine) and medications that increase blood pressure (eg, nonsteroid anti-inflammatory drugs, serotonin-norepinephrine reuptake inhibitors) should be avoided. Sleep apnea should be treated when diagnosis is confirmed. Pharmacologic optimization includes use of combination tablets of antihypertensives; intensifying diuretic therapy by using chlorthalidone; and sequential addition of antihypertensive medications using evidence-based algorithms. In a meta-analysis of 20 studies (9 randomized clinical trials [RCTs] and 11 observational studies [331 participants]), use of antihypertensive therapies that combine 2 to 3 medications into a single formulation reduced SBP by -3.99 mm Hg (95% CI, -7.92 to -0.07) vs equivalent doses given separately. For patients with apparent or true resistant hypertension who have an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater and a serum potassium level of 4.5 mmol/L or less, adding spironolactone (25-50 mg/d) compared with placebo lowers office SBP by -13.3 mm Hg (95% CI, -17.89 to -8.72 [4 RCTs]) and 24-hour ambulatory SBP by -8.46 mm Hg (95% CI, -12.54 to -4.38 [2 RCTs]) in a network meta-analysis of 24 RCTs (3485 patients with resistant hypertension). A meta-analysis of 10 RCTs (2478 participants) reported that compared with a sham procedure, catheter-based renal denervation, which disrupts the sympathetic nerves in the renal artery walls, decreased 24-hour ambulatory SBP by -4.4 mm Hg (95% CI, -6.1 to -2.7) and office SBP by -6.6 mm Hg (95% CI, -9.7 to -3.6).

Conclusions and relevance: True resistant hypertension affects 10% of patients treated for hypertension and is diagnosed after excluding white-coat hypertension, medication nonadherence, and secondary hypertension such as primary aldosteronism. First-line treatment includes lifestyle modifications, diuretic therapy with chlorthalidone, and combination tablets of antihypertensives. Spironolactone and renal denervation decrease blood pressure in patients with true resistant hypertension.

2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

Author/s: 
Roger S. Blumenthal, Pamela B. Morris, Mario Gaudino, Heather M. Johnson, Timothy S. Anderson, Vera A. Bittner, Ron Blankstein, LaPrincess C. Brewer, Leslie Cho, Sarah D. de Ferranti, Eugenia Gianos, Ty J. Gluckman, Kristen F. Gradney, Ijeoma Isiadinso, Donald M. Lloyd-Jones, Joel C. Marrs, Seth S. Martin, Kellie H. McLain, Laxmi S. Mehta, Samia Mora, Wudeneh M. Mulugeta, Pradeep Natarajan, Ann Marie Navar, Carl E. Orringer, Tamar S. Polonsky, Harmony R. Reynolds, Joseph J. Saseen, Michael D. Shapiro, Daniel E. Soffer, Sheila A. Tynes, Chloé D. Villavaso, Salim S. Virani, John T. Wilkins

Aim: The "2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia" retires and replaces the "2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol."

Methods: A comprehensive literature search was conducted from October 2024 to December 2024 to identify clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline.

Structure: The focus of this clinical practice guideline is to address the evaluation, management, and monitoring of individuals with dyslipidemias, including high blood cholesterol, hypertriglyceridemia, and elevated lipoprotein(a).

Keywords: ACC/AHA clinical practice guideline; HDL; LDL; anticholesteremic agents; atherosclerosis; atherosclerotic disease; cardiovascular disease; cardiovascular diseases; cholesterol; drug interactions; dyslipidemia(s); hydroxymethylglutaryl-CoA reductase inhibitors; hypercholesterolemia; hyperlipid(a)emia/s; hyperlipoproteinemia type II; hypertriglyceridemia; hypolipidemic agents; lipids; lipoprotein(a); primary prevention; risk adjustment; risk assessment; risk factors; simvastatin; statin(s); triglycerides.

Secondary Prevention after Ischemic Stroke

Author/s: 
Karen L. Furie, Peter J. Kelly

The risk of recurrent ischemic stroke can be reduced by managing modifiable risk factors and instituting a regimen of mechanism-specific secondary stroke prevention. Strategies for secondary prevention should be instituted as early as possible. Poststroke monitoring of risk metrics, lifestyle behaviors, and medication recommendations is of key importance.

Hypertension and alcohol: a cross-sectional study comparing PEth with AUDIT and AUDIT-C in primary care

Author/s: 
Åsa Thurfjell, Maria Hagströmer, Charlotte Ivarsson, Anders Norrman, Johanna Adami, Lena Lundh, Jan Hasselström

Background: This cross-sectional study aimed to describe proportions of patients with indications of alcohol consumption using phosphatidylethanol (PEth), the Alcohol Use Disorders Identification Test (AUDIT), and its consumption-focused version (AUDIT-C), in relation to blood pressure (BP) control, overall and by sex.

Methods: A total of 270 hypertensive primary care patients (ICD-10: I10.9) were stratified into BP control groups: controlled (<140/90 mmHg), uncontrolled (≥140/90 mmHg), and apparent treatment-resistant hypertension (aTRH; ≥140/90 mmHg with ≥3 antihypertensive drugs). A randomized sample from each stratum was invited, baseline data were collected. Alcohol consumption using predefined categories for PEth and AUDIT, and hazardous use (PEth ≥ 0.122 µmol/L; AUDIT ≥ 8; AUDIT-C ≥ 5 for men, ≥4 for women), were analyzed in relation to BP control groups.

Results: Mean age was 67 ± 11 years; 42% were women. PEth indicated high and regular alcohol consumption in 6.4% of controlled, 5.3% of uncontrolled, and 19.2% of aTRH patients (controlled vs. aTRH, P = .027; uncontrolled vs. aTRH, P = .013). AUDIT showed no significant differences in hazardous use between BP groups (P = .865). AUDIT-C identified slightly higher proportions of hazardous use than PEth, across BP groups and sexes. No significant differences were found between BP groups for hazardous use by PEth (P = .339) or AUDIT-C (P = .150).

Conclusions: PEth revealed significantly higher alcohol use in the aTRH group, undetected by AUDIT. AUDIT-C and PEth identified more hazardous use than AUDIT, suggesting their potential to prompt alcohol-related discussions and support evidence-based hypertension care. PEth correlated more strongly with AUDIT-C than with AUDIT.

Clinical trial registration: Retrospectively registered in Clinical Trials, SLSO2022-0143, 2022-12-10.

Keywords: alcohol use disorder; cardiovascular disorders (hypertension/DVT/atherosclerosis); hypertension (high blood pressure); prevention; primary care; screening.

Risk Factors for the Development of Food Allergy in Infants and Children: A Systematic Review and Meta-Analysis

Author/s: 
Nazmul Islam, Alexandro W L Chu, Falana Sheriff, Farid Foroutan, Gordon H Guyatt, Romina Brignardello-Petersen, Paul Oykhman, Alfonso Iorio, Ariel Izcovich, Katherine M Morrison, Yetiani Roldan Benitez

Importance: The incidence and risk (predictive) factors for early life food allergy development remain uncertain.

Objective: To estimate the incidence and quantify risk factors for food allergy development.

Data sources: MEDLINE and Embase were systematically searched to January 1, 2025. Data were analyzed from June 1, 2025, to November 25, 2025.

Study selection: Incidence estimates included studies confirming food allergy via food challenge. Risk factor analyses included cohort, case-control, and cross-sectional studies in any language assessing children younger than 6 years using multivariable analyses.

Data extraction and synthesis: Paired reviewers independently extracted data. Random-effects meta-analyses pooled incidence and adjusted odds ratios (ORs). Risk of bias was assessed using the QUIPS tool, and certainty of evidence assessed using GRADE.

Main outcome and measure: The primary outcome was food allergy to age 6 years.

Results: A total of 190 studies involving 2.8 million participants across 40 countries were analyzed. Among studies using food challenge, overall food allergy incidence was likely 4.7% (moderate certainty). Among 176 studies identifying 342 risk factors with varying certainty, the strongest and most certain factors included prior allergic conditions (eg, atopic dermatitis [eczema] within the first year of life [OR, 3.88; risk difference [RD], 12.0%; 95% CI, 8.8%-15.7%], allergic rhinitis [OR, 3.39; RD, 10.1%; 95% CI, 6.7%-14.4%], and wheeze [OR, 2.11; RD, 5.0%; 95% CI, 2.1%-8.8%]), severity of atopic dermatitis (OR, 1.22; RD, 1.0%; 95% CI, 0.6%-1.6%), increased skin transepidermal water loss (OR, 3.36; RD, 10.0%; 95% CI, 6.3%-14.8%), filaggrin gene sequence variations (OR, 1.93; RD, 4.2%; 95% CI, 2.4%-6.4%), delayed solid food introduction (eg, peanut after age 12 months [OR, 2.55; RD, 6.8%; 95% CI, 1.9%-14.6%]), infant antibiotic use (first month [OR, 4.11; RD, 12.8%; 95% CI, 0.4%-40%], first year [OR, 1.39; RD, 1.8%; 95% CI, 0.8%-3.1%], during pregnancy [OR, 1.32; RD, 1.5%; 95% CI, 0.6%-2.5%]), male sex (OR, 1.24; RD, 1.1%; 95% CI, 0.7%-1.6%), firstborn child (OR, 1.13; RD, 0.6%; 95% CI, 0.3%-1.0%), family history of food allergy (eg, mother [OR, 1.98; RD, 4.4%; 95% CI, 2.5%-6.8%], father [OR, 1.69; RD, 3.2%; 95% CI, 1.3%-5.5%], both parents [OR, 2.07; RD, 4.8%; 95% CI, 1.3%-5.5%], siblings [OR, 2.36; RD, 6.0%; 95% CI, 4.4%-8.0%]), parental migration (OR, 3.28; RD, 9.7%; 95% CI, 4.9%-16.3%), self-identification as Black (vs White [OR, 3.93; RD, 12.1%; 95% CI, 5.2%-22.5%], vs non-Hispanic White [OR, 2.23; RD, 5.5%; 95% CI, 3.0%-8.7%]), and cesarean delivery (OR, 1.16; RD, 1.0%; 95% CI, 0.3%-1.2%). Factors like low birth weight, postterm birth, maternal diet, and stress during pregnancy showed no significant risk difference.

Conclusions and relevance: In this meta-analysis, the most credible risk factors associated with development of childhood food allergy are a combination of major and minor risk factors, including early allergic conditions (atopic march/diathesis), delayed allergen introduction, genetics, antibiotic exposure, demographic factors, and birth-related variables.

Exacerbation risk in patients with bronchiectasis receiving DPP-1 inhibitors vs placebo: A meta-analysis of RCTs

Author/s: 
Giulia Carvalhal, Júlia Moreira Diniz, Larissa Calixto Hespanhol, David Curi Barbosa Izoton Cabral, Jafar Aljazeeri

Background: No therapies have been approved to alter bronchiectasis progression. Dipeptidyl peptidase-1 (DPP-1) inhibitors, which target neutrophil serine protease activation, are under investigation as potential disease-modifying agents.

Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing DPP-1 inhibitors versus placebo in patients with non-cystic fibrosis bronchiectasis. PubMed, Cochrane, EMBASE, Web of Science, Scopus, ClinicalTrials.gov, and ICTRP were searched from inception until April 26, 2025. Primary outcomes included time to first exacerbation and proportion of patients remaining exacerbation-free. Secondary outcomes included post-bronchodilator % Forced Expiratory Volume in 1 s (FEV1), Quality of Life-Bronchiectasis (QoL-B) questionnaire scores, and rate of adverse events. Time-to-event outcome was analyzed using Kaplan-Meier (KM)-estimated individual patient data (IPD), whereas random-effects meta-analyses were performed for remaining outcomes.

Results: 2523 patients from four RCTs were included, of whom 1689 (66.9 %) received DPP-1 inhibitors. Compared with placebo, DPP-1 inhibitors prolonged the time to first exacerbation (HR 0.79; 95 % CI: 0.71 to 0.88) and increased the proportion of patients remaining exacerbation-free (RR 1.33; 95 % CI 1.12 to 1.58). A slower decline in post-bronchodilator % FEV1 was observed (MD 1.1 %; 95 % CI 0.05 to 2.15), but no difference in QoL-B scores (MD 1.35; 95 % CI -0.72 to 3.42). The safety profile of DPP-1 inhibitors was acceptable and comparable to placebo. Moderate certainty was found across endpoints.

Conclusions: DPP-1 inhibitors prolong time to first exacerbation and reduce exacerbation rates in patients with bronchiectasis, with an acceptable safety profile. These findings support their potential as a disease-modifying strategy.

Registration: PROSPERO (CRD420251042542).

Keywords: Bronchiectasis; DPP-1 inhibitor; Dipeptidyl-peptidases and tripeptidyl-peptidases; Meta-analysis; Randomized controlled trials; Systematic review.

Ann Arbor Guide to Triaging Adults With Suspected Urinary Tract Infection for In-Person and Telehealth Settings

Author/s: 
Jennifer Meddings, Kristin Chrouser, Karen E. Fowler

Importance: Urinary tract infection (UTI) is common in ambulatory care settings and the primary reason for antibiotic prescribing. Despite several guidelines focused on the type and duration of antibiotics prescribed for treating UTI, there is limited outpatient guidance on how to best triage patients with presumed UTI.

Objective: To assess the appropriateness of different triage and management recommendations involving empiric antibiotics, urine testing strategies, and visit types and how these recommendations vary by patient sex, age, presenting symptoms, and clinical history.

Evidence review: Using the RAND/UCLA Appropriateness Method, a 13-member multidisciplinary panel (physicians, advanced practice providers, and nurses) performed a scoping review of the literature publications from 2009 to June 2024 and rated the appropriateness of 136 clinical scenarios (48 for women, 49 for men, and 39 scenarios not specific to sex) with up to 9 management strategies per scenario for a total of 1094 scenarios. For each scenario, experts rated the appropriateness of empiric treatment, types of urine testing, and triage to visit type (in-person, virtual, or none) as appropriate (ie, benefits outweigh risks), inappropriate, or of uncertain appropriateness. Appropriateness ratings were summarized into 2 groups: nonpregnant adult women and adult men.

Findings: Major recommendations based on symptoms included (1) same-day in-person evaluation if symptoms were concerning for pyelonephritis, complicated cystitis, or urinary obstruction; (2) a visit if additional nonurinary symptoms were present (ie, diarrhea, genital discharge, or cough); (3) neither urine testing nor empiric treatment solely due to a change in urine color or appearance without other bladder (cystitis) symptoms; (4) empiric treatment without testing or a visit, for women, if there were new classic cystitis symptoms of dysuria, urinary frequency, urgency, or suprapubic pain without risks for antibiotic resistance; (5) urinalysis with culture (ideally reflexed to culture) before taking first antibiotic dose for women at risk of antibiotic resistance (eg, recent antibiotic treatment for UTI or recurrent UTIs) and all men; and (6) empiric treatment considered for patients with barriers to obtaining timely urine testing or visits.

Conclusions and relevance: The appropriateness of empiric antibiotics, urine testing, and different clinical evaluation options were defined for adults presenting with concerns for UTI in common ambulatory triage settings, including telehealth. These criteria for ambulatory triage of suspected UTI symptoms in adults are anticipated to help standardize and improve the appropriateness of empiric antibiotic prescribing, urine testing, and visit type triage.

Restless Legs Syndrome: A Review

Author/s: 
John W. Winkelman, Benjamin Wipper

Importance Restless legs syndrome (RLS) is a sleep-related movement disorder that affects approximately 3% of US adults to a clinically significant extent and can cause substantial sleep disturbance.

Observations Restless legs syndrome is characterized by an overwhelming urge to move the limbs, typically the legs, often accompanied by unpleasant limb sensations (eg, achiness, tingling). Symptoms, provoked by immobility, are relieved while moving and are typically present or most severe in the evening or at night. Restless legs syndrome symptoms may lead to difficulty falling asleep, staying asleep, or returning to sleep. According to population-based studies, approximately 8% of US adults experience RLS symptoms of any frequency annually and 3% experience moderately or severely distressing symptoms at least twice weekly. Patients with RLS have impaired quality of life and elevated rates of cardiovascular disease (29.6% with coronary artery disease, stroke, or heart failure), depression (30.4%), and suicidal ideation or self-harm (0.35 cases/1000 person-years). Restless legs syndrome is common among patients with multiple sclerosis (27.5%), end-stage kidney disease (24%), and iron deficiency anemia (23.9%); during pregnancy and especially in the third trimester (22%); with peripheral neuropathy (eg, diabetic, idiopathic; 21.5%); and with Parkinson disease (20%). Other risk factors include family history of RLS, northern European descent, female sex (2:1 vs male sex), and older age (RLS prevalence of 10% in adults ≥65 years). Restless legs syndrome is diagnosed based on clinical history; polysomnography is not recommended for diagnosis. Iron supplementation with ferrous sulfate (325-650 mg daily or every other day) or intravenous iron (1000 mg) should be initiated for serum ferritin level less than or equal to 100 ng/mL or transferrin saturation less than 20%. If possible, medications associated with RLS, including serotonergic antidepressants, dopamine antagonists, and centrally acting H1 antihistamines (eg, diphenhydramine), should be discontinued. Gabapentinoids (eg, gabapentin, gabapentin enacarbil, pregabalin) are first-line pharmacologic therapy. In randomized clinical trials, approximately 70% of patients treated with gabapentinoids had much or very much improved RLS symptoms vs approximately 40% with placebo (P < .001). Dopamine agonists (eg, ropinirole, pramipexole, rotigotine) are no longer recommended as first-line medications due to the risk of augmentation, an iatrogenic worsening of RLS symptoms, which has an annual incidence of 7% to 10% with these medications. Patients who do not improve with first-line treatment or have augmented RLS often benefit from low-dose opioids (eg, methadone 5-10 mg daily).

Conclusions and Relevance Restless legs syndrome affects approximately 3% of adults and can have negative effects on sleep and quality of life. Initial management includes cessation of exacerbating medications, as well as iron supplementation for patients with low-normal iron indices. If medication therapy is indicated, gabapentinoids are first-line treatment.

Intranasal Treatments for Children With Sleep-Disordered Breathing: The MIST+ Randomized Clinical Trial

Author/s: 
Gillian M. Nixon, Deborah Anderson, Alice Baker

Importance: Symptoms of obstructive sleep apnea are common in childhood and associated with significant comorbidity. Surgical treatment with adenotonsillectomy is first-line treatment but medical treatments show potential to improve symptoms and reduce the need for surgery.

Objective: To determine the efficacy of 6 weeks of intranasal steroid (INS) compared with saline in children with obstructive sleep-disordered breathing (OSDB) with persistent symptoms after a 6-week intranasal saline run-in.

Design, setting, and participants: This was a double-blind, placebo-controlled, randomized clinical trial involving specialist clinic waitlists at 2 sites in Australia. Included were children aged 3 to 12 years. Study data were analyzed from January to June 2025.

Interventions: All children received once-daily intranasal saline for 6 weeks (run-in). Those with persisting symptoms (SDB score ≥-1) were randomized to either once-daily intranasal mometasone furoate, 50 µg, (INS) or continued saline for a further 6 weeks.

Main outcomes and measures: The primary outcome was symptom resolution (SDB score <-1). Secondary outcomes included behavior, quality of life, and parental perception of need for surgery. Analyses were adjusted for site and baseline measures.

Results: A total of 150 children (mean [SD] age, 6.2 [2.3] years; 93 male [62%]) were recruited. Of 139 children who completed the run-in phase, 41 (29.5%) had symptom resolution after saline run-in. Among 93 children randomized to intervention groups (47 INS; 46 saline), symptom resolution occurred in 35.6% (95% CI, 22.9%-50.6%) and 36.4% (95% CI, 23.5%-51.6%) of the INS and saline group, respectively, with no evidence for a clinically significant difference between groups (risk difference, -0.9%; 95% CI, -20.7% to 19.0%; P = .93). No group differences were found in secondary outcomes. Subgroup analysis did not reveal a group more or less likely to respond to medical treatment.

Conclusions and relevance: Results of this randomized clinical trial show that 6 weeks of intranasal saline resolved OSDB symptoms in nearly one-third of children. An additional 6-week course of INS or saline led to resolution in another one-third (total resolution around 50%), with no added benefit from INS. Intranasal saline is an effective short-term first-line treatment for OSDB before consideration of polysomnography or surgical intervention. Results suggest that saline should be recommended for 3 months before assessing the need for specialist referral.

Trial registration: ClinicalTrials.gov Identifier: NCT05382494.

What Is Prostatitis?

Author/s: 
Rebecca Voelker

Prostatitis involves infection, inflammation, or pain in the prostate gland and affects about 9% of men during their lifetime.

What Is Acute Bacterial Prostatitis?
Acute bacterial prostatitis is a urinary tract infection that involves the prostate.1 Patients with acute prostatitis typically have fever, chills, pelvic pain, sudden onset of frequent urination, and pain or burning during urination. Some patients cannot empty their bladder adequately (urinary retention).

Risk factors include medical procedures such as cystoscopy, urethral catheterization, prostate biopsy, urinary obstruction such as benign prostatic hyperplasia and strictures, anal intercourse without condom use, immunosuppression, and certain neurological disorders such as multiple sclerosis, stroke, and spinal cord injury. Digital rectal examination often reveals prostate swelling and tenderness. The diagnosis of acute bacterial prostatitis is made based on symptoms, urinalysis, and urine culture. First-line treatment is 2 to 4 weeks of antibiotics. Men with urinary retention due to a swollen prostate should have a urinary catheter placed to relieve discomfort and to drain the infected urine.

What Is Chronic Bacterial Prostatitis?
Chronic bacterial prostatitis is a persistent bacterial infection of the prostate despite antibiotic therapy. Patients typically do not have fever or chills, and between episodes of infection they may have no symptoms or have persistent pelvic pain and/or lower urinary tract symptoms.

Risk factors include age 50 years or older, prior acute bacterial prostatitis, urethral surgery or catheterization, anal intercourse without condom use, and genitourinary tuberculosis. The diagnosis is made when multiple urine culture samples grow the same bacterial strain during episodes of urinary tract infection. First-line treatment for chronic bacterial prostatitis is at least 4 weeks of oral antibiotics such as ciprofloxacin or levofloxacin.

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