Humans

IgA Nephropathy in Adults: A Review

Author/s: 
Sinead Stoneman, Jia Wei Teh, Michelle Marie O’Shaughnessy

Importance IgA nephropathy (IgAN) is a chronic kidney disease involving deposition of IgA-containing immune complexes in the glomerulus, causing glomerular inflammation and scarring. It is the most common immune-mediated glomerular disease worldwide, and affects an estimated 198 887 to 208 184 persons in the US. Up to 50% of patients with IgAN develop kidney failure within 10 years of diagnosis.

Observations IgAN typically presents with nephritic syndrome and usually occurs in younger adults, with a mean age at diagnosis of 34 to 45 years. Incidence is highest in East Asia. Approximately 60% of cases are detected incidentally with hematuria or proteinuria on urinalysis. Up to 30% of patients present with episodic visible hematuria, often concomitantly with an upper respiratory or gastrointestinal tract infection (synpharyngitic hematuria). Less common presentations include nephrotic syndrome (<5%) and rapidly progressive glomerulonephritis (<5%). When IgAN is suspected (due to hematuria, proteinuria, or reduced kidney function), initial workup should include quantification of proteinuria and assessment for other causes of nephritic syndrome (eg, lupus nephritis). Adults with suspected IgAN and proteinuria greater than or equal to 0.5 g per day should undergo kidney biopsy. The diagnosis of primary IgAN is based on presence of IgA-dominant immune deposits in the glomerular mesangium after excluding other causes of this histologic appearance, ie, IgA vasculitis, IgA-dominant infection-related glomerulonephritis, and secondary IgAN from diseases such as cirrhosis, inflammatory bowel disease, celiac disease, infection (eg, viral hepatitis), and autoimmune diseases (eg, axial spondyloarthritis). Based on the Kidney Disease: Improving Global Outcomes 2025 clinical practice guideline for the management of IgAN, treatment for patients with proteinuria greater than 0.5 g per day includes behavioral modifications (eg, dietary sodium <2 g/d, smoking cessation, weight control, exercise), antihypertensive medications for goal blood pressure less than 120/70 mm Hg, and therapies to reduce the formation of IgA-containing immune complexes (eg, targeted-release budesonide), decrease glomerular injury (eg, systemic glucocorticoids, iptacopan), and manage existing IgAN-induced nephron loss (eg, renin-angiotensin system inhibitor or dual endothelin angiotensin receptor antagonist [eg, sparsentan] alone or in combination with a sodium-glucose cotransporter 2 inhibitor).

Conclusions and Relevance IgAN is the leading cause of immune-mediated glomerular disease worldwide. Patients with suspected IgAN and proteinuria greater than or equal to 0.5 g per day should undergo kidney biopsy to confirm the diagnosis. Treatment of IgAN includes behavioral modifications, blood pressure management, and therapies to decrease formation of IgA-containing immune complexes (eg, targeted-release budesonide), reduce immune complex–mediated glomerular injury (eg, systemic glucocorticoids, iptacopan), and manage IgAN-induced nephron loss (eg, renin-angiotensin system inhibitor, dual endothelin angiotensin receptor antagonist, and sodium-glucose cotransporter 2 inhibitor).

Does This Patient Have Volume Overload? The Rational Clinical Examination

Author/s: 
Benjamin Drum, Bryce La Course, Mark Kelly, Audrey York, Emily Worrall, Jennifer Martins, Stacy Johnson, Edmund A Liles Jr

Importance: Accurate assessment of intravascular volume facilitates management decisions about fluid management in patients with volume overload.

Objective: To identify the most accurate clinical examination, radiographic, and laboratory findings for assessing volume overload in nonintubated patients.

Data sources and study selection: MEDLINE was searched (1946 to January 6, 2026) to identify peer-reviewed English-language studies about the diagnostic accuracy of the clinical examination of spontaneously breathing patients with intravascular volume overload.

Data extraction and synthesis: Three authors independently extracted data for each finding and calculated sensitivity, specificity, and likelihood ratios (LRs). A 2-level mixed logistic regression model was used to pool estimates.

Results: Forty studies, involving 11 490 adult patients, were included, with a prevalence of volume overload of 35% to 69%. Thirty-three of those studies evaluated patients with dyspnea. Prevalence of volume overload was more likely when the physical examination revealed jugular venous distention with the highest point of pulsation more than 3 cm in a vertical line above the sternal angle (LR, 4.1 [95% CI, 2.9-5.6]; specificity, 92%), lower extremity edema (LR, 2.2 [95% CI, 1.5-3.1]; specificity, 80%), or crackles on auscultation (LR, 2.7 [95% CI, 1.7-4.5]; specificity, 81%). Vascular congestion on chest radiography increased the likelihood of intravascular volume overload (LR, 5.9 [95% CI, 2.9-12.0]; specificity, 91%). Point-of-care ultrasonography that identified bilateral pulmonary B-lines suggested volume overload (LR, 4.0 [95% CI, 2.6-6.1]; specificity, 77%), and absence of pulmonary B-lines made volume overload unlikely (LR, 0.09 [95% CI, 0.04-0.23]; sensitivity, 93%). Inferior vena cava collapsibility index of less than 50% increased the likelihood of volume overload (LR, 3.9 [95% CI, 2.5-6.1]; specificity, 79%), and a collapsibility index of at least 50% made it less likely (LR, 0.22 [95% CI, 0.11-0.45]; sensitivity, 82%). Point-of-care ultrasonographic measurement of jugular venous pressure (JVP; >8 cm) also increased the likelihood of volume overload (LR, 2.8 [95% CI, 2.2-3.5]; specificity, 71%), although JVP of 8 cm or less identified patients less likely to have volume overload (LR, 0.26 [95% CI, 0.20-0.33]; sensitivity, 81%). A plasma brain-type natriuretic peptide (BNP) level of 100 ng/mL or higher was the single best test to identify those most likely to have volume overload (LR, 6.9 [95% CI, 2.4-20.4]; specificity, 87%), and a normal value made it less likely (LR, 0.14 [95% CI, 0.08-0.24]; sensitivity, 87%).

Conclusions and relevance: A BNP level of 100 ng/mL or higher and presence of vascular congestion on chest radiography may be the most useful tests to identify patients with volume overload. Absence of pulmonary B-lines using point-of-care ultrasonography or BNP levels of less than 100 ng/mL may be most useful to exclude volume overload.

Pertussis Infection in Adults

Author/s: 
Paul B. Cornia, Benjamin A. Lipsky

Pertussis, or whooping cough, is a highly contagious respiratory illness caused by Bordetella pertussis, a fastidious gram-negative coccobacillus that is a human pathogen without known animal or environmental reservoirs. There are 8 additional known Bordetella species, 3 of which can cause respiratory illness in humans: B parapertussis (which causes infection clinically indistinguishable from pertussis), B bronchiseptica, and B holmesii.

Evidence-Based Footwear Recommendations for Older Adults: Enhancing Mobility, Comfort, and Fall Prevention

Author/s: 
C Ray Cheever, Hyoungjun Sim, Mohamed Y. Ahmidouch, Jaewon Moon, Anissa Powell, Rayad B. Shams, Matthew Wang, Madison Hunter, Samantha Kodikara, Lindsay A. Wilson, Michael T. Gross

Background: Older adults often struggle to find footwear suitable for their clinical needs, thus affecting mobility, safety, and quality of life. Proper footwear is important due to fall risk, balance impairments, knee osteoarthritis (OA), hallux rigidus, plantar fasciitis, diabetic neuropathy, and limb length discrepancies (LLDs). Barriers such as inadequate clinical guidance and limited patient understanding persist. This paper provides updated, evidence-based recommendations for these challenges.

Methods: A topic review was conducted to evaluate shoe wear characteristics that address geriatric needs. Recommendations were synthesized from more than 45 years of clinical experience in physical therapy and categorized by clinical conditions. Evidence identified effective shoe features, including sole stiffness, tread patterns, heel elevation, and orthotic modifications to improve function, reduce pain, and reduce fall risk.

Results: Balance and fall risk: Shoes with wide soles, medium-firm materials, low heels, and high collars improved stability and reduced postural sway. Cupped, rigid insoles enhanced dynamic control, while treaded rubber outsoles minimized slipping. Knee OA: Flexible shoes with laterally wedged insoles and minimal heel lift reduced medial knee loads and pain. Supportive shoes and medially wedged insoles decreased lateral knee loads and pain. Hallux rigidus/bunions: Rocker-bottom shoes and stiffer soles accommodate deformities, improving function and comfort. Plantar fasciitis: Orthoses, supportive therapies, and stretching regimens were efficacious. Diabetic neuropathy: Rigid rocker soles and custom insoles reduced plantar pressure and ulcer recurrence. LLDs: Gradual shoe lift introduction alleviated low back pain. General recommendations: Properly fitted, comfortable shoes with moderately firm insoles, slip-resistant outsoles, and secure fastening mechanisms improve safety and function.

Conclusions: Footwear significantly impacts the mobility, safety, and well-being of older adults. Tailored recommendations enhance pain management, independence, and fall prevention. Providers should involve patients in decisions and counsel against the use of slippers or excessively elevated heels.

Keywords: fall prevention; older adults; orthoses; pain; shoes.

Approach to mallet finger injury: Practical guide for Canadian primary care physicians

Author/s: 
Vincent Dinh, Marisa Market, Kevin Cheung

Objective: To provide primary care physicians with an evidence-based approach to recognizing and managing mallet finger injuries.

Sources of information: A literature search was conducted in PubMed and Google Scholar using relevant key words and subject headings. Recommendations were categorized based on clinical evidence and expert opinion using a 3-level classification system.

Main message: A mallet finger injury commonly occurs after an axial load, resulting in avulsion of the extensor tendon from the distal phalanx. This may occur with or without an avulsion fracture. Diagnosis is made clinically, with x-ray scans used to assess for an associated fracture and joint alignment. Nonsurgical management with continuous splinting for 6 to 8 weeks is the standard of care and achieves excellent outcomes even in cases of delayed presentation. Surgery referral may be considered for avulsion fractures resulting in joint subluxation, open injuries, and failure of conservative management. Untreated mallet finger injuries can lead to chronic swan-neck deformities, which may limit function.

Conclusion: Mallet finger injuries may be easily recognized and managed in the primary care settings, resulting in excellent patient outcomes without the need for specialist referral. This review should equip primary care physicians with confidence in diagnosing a mallet finger injury, initiating appropriate splinting, providing patient education, and recognizing indications for surgical referral.

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.

The association between medication use and vitamin B12 deficiency in the elderly population: a cross- sectional study

Author/s: 
Monique P H Tillemans, Thijs J Giezen, Toine C G Egberts, Kees J Kalisvaart

Background
Vitamin B12 deficiency is common in the elderly population and can cause severe complications. The use of certain medication has in previous studies been associated with vitamin B12 deficiency in the general population. To identify elderly patients at risk for vitamin B12 deficiency due to medication use, we evaluated the association between medication use and vitamin B12 deficiency in the elderly population.

Methods
Hospitalized geriatric patients 65 years of age or over with a serum vitamin B12 measurement within one week of the admittance date were included. Patients were classified as either B12 normal (258–635 pmol/L) or B12 deficient (< 148 pmol/L). Upon hospital admission patients’ medication use was verified. The association between vitamin B12 deficiency and the use of antacid, antiepileptic, antidiabetic, lipid lowering and other medication was evaluated by univariate and multivariate analyses.

Results
Of the 7132 patients included in the study, 532 (7.5%) had vitamin B12 deficiency and 3433 (48.1%) patients had normal vitamin B12 concentrations. Metformin use was significantly and independently (adjusted OR 2.5; 95% CI 1.7–3.6) associated with a dose-dependent higher risk of vitamin B12 deficiency. The use of other medication evaluated in this study was not associated with vitamin B12 deficiency.

Conclusions
Metformin use is significantly associated with vitamin B12 deficiency in the elderly, and this risk rises with higher metformin doses. Monitoring and timely start of vitamin B12 supplementation along with the lowest possible metformin dose are essential to prevent complications.

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.

Calcium pyrophosphate deposition disease

Author/s: 
Timothy S.H. Kwok, Gregory Choy

Calcium pyrophosphate deposition (CPPD) disease is caused by CPP crystal accumulation in musculoskeletal tissues, leading to inflammation
Symptomatic CPPD disease (formerly known as “pseudogout”) is more common in older than younger adults and typically affects joints with previous damage. Chondrocalcinosis visible on radiographs affects 10% of adults and 50% of those older than 80 years, but most people are asymptomatic and findings are noted incidentally.1

The most common presentation is acute inflammatory monoarthritis affecting the wrists or knees, which resolves within 4 weeks
Extra-articular structures can also be affected, leading to acute inflammatory tendinitis. Crowned dens syndrome comprises 5% of CPPD disease presentations and can mimic bacterial meningitis, manifesting with acute cervical neck pain, fever, and elevated inflammatory markers with CPPD at C1 to C2, seen on computed tomography. The chronic (> 3 mo) inflammatory phenotype presents with hand or wrist symmetric polyarthritis, or with recurrent flares, and can be misdiagnosed as seronegative rheumatoid arthritis. Calcium pyrophosphate deposition disease and osteoarthritis can co-exist — underlying CPPD disease should be considered in patients with osteoarthritis at atypical locations (e.g., metacarpophalangeal joints, wrists, ankles, shoulders, elbows).2

Diagnosis can be confirmed with CPP crystals identified from synovial fluid, or the presence of the crowned dens syndrome
Although used for research, the 2023 Classification Criteria have high sensitivity (99.2%) and specificity (92.5%), thereby providing a diagnostic framework.2 Supportive diagnostic features include acute knee or wrist inflammatory arthritis in an older adult, osteoarthritis at atypical areas, or CPPD on imaging.3

Patients younger than 60 years at diagnosis should be assessed for associated metabolic diseases
Investigations for secondary causes of CPPD disease include calcium (hypercalcemia), parathyroid hormone (hyperparathyroidism), ferritin, transferrin saturation (hemochromatosis), magnesium (hypomagnesemia), and alkaline phosphatase (hypophosphatasia).2

Corticosteroids, colchicine, and nonsteroidal antiinflammatory drugs can treat acute flares4
Inflammatory arthritis lasting more than 3 months or recurrent flares (> 2/yr) should prompt rheumatology referral for consideration of chronic suppressive colchicine, hydroxychloroquine, or methotrexate (Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.250933/tab-related-content).5

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