Meta-Analysis: Does Surgery Improve Leg Pain in Individuals with Sciatica?

BACKGROUND AND PURPOSE:

• Treatment for sciatica starts with non-surgical intervention, and can progress to surgical intervention if pain persists
• However, evidence supporting use of surgery in treating sciatica is limited
• Liu et al. (BMJ, 2023) investigated the effectiveness and safety of surgery compared with non-surgical treatment for sciatica

METHODS:

• Systematic review and meta-analysis
• Study inclusion criteria
  • Randomized controlled trials
  • Studies that compared any surgical treatment with non-surgical treatment, epidural steroid injections, or placebo or sham surgery
  • Studies in people with sciatica of any duration due to lumbar disc herniation diagnosed by radiological imaging
• Study design
  • Data were pooled using a random effects model
  • Risk of bias was assessed with the Cochrane tool | Certainty of evidence was assessed with GRADE criteria
  • Follow up was intermediate term (≤6 weeks) | Short term (>6 weeks and ≤3 months) | Medium term (>3 and <12 months) | Long term (at 12 months)
  • Pain and disability scores: 100 point scale ranging from 0 (no pain or disability) to 100 (worst pain or disability)
• Primary outcomes
  • Leg pain
  • Disability
• Secondary outcomes
  • Adverse events | Back pain | Quality of life | Satisfaction with treatment

RESULTS:

• 24 trials
  • 12 studies (1711 participants) investigated the effectiveness of discectomy compared with non-surgical treatment or epidural steroid injections
• Very low to low certainty evidence showed that discectomy, compared with non-surgical treatment, reduced leg pain
  • Immediate term: mean difference −12.1 (95% CI, −23.6 to −0.5)
  • Short term: MD −11.7 (95% CI, −18.6 to −4.7))
  • Medium term: MD −6.5 (95% CI, −11.0 to −2.1)
• Negligible effects of discectomy on leg pain were found at long term
  • Long term: MD −2.3 (95% CI, −4.5 to −0.2)
• For disability, small, negligible, or no effects were found
• A similar effect on leg pain was found when comparing discectomy with epidural steroid injections
• For disability, compared to epidural steroid injections, discectomy had
  • A moderate effect was found at short term
  • No effect was observed at medium and long term
• The risk of any adverse events was similar between discectomy and non-surgical treatment
  • RR 1.34 (95% CI, 0.91 to 1.98)

CONCLUSION:

• There is low to very low certainty evidence that discectomy can improve leg pain symptoms in individuals with sciatica, compared to non-surgical treatment
• However, effects waned over time and surgery had a negligible effect on leg pain long term
• The authors state

Discectomy might be an option for people who require rapid leg pain relief and disability improvement, when the benefits outweigh the risks and costs related to surgery

Learn More – Primary Sources:

Surgical versus non-surgical treatment for sciatica: systematic review and meta-analysis of randomised controlled trials

Cochrane Update: Do Cranberry Products Reduce the Risk of UTIs?

BACKGROUND AND PURPOSE:

• Cranberries for prevention of urinary tract infections (UTIs) is thought to be effective because they contain proanthocyanidins (PACs) which inhibit binding of some bacteria to cells lining the bladder
• Williams et al. (Cochrane Database of Systematic Review, 2023) provide an update on the efficacy of cranberries for preventing UTIs

METHODS:

• Systematic review and meta-analysis
• Study inclusion criteria
  • Randomized or quasi-randomized controlled trials
  • Studies that compared cranberry products with placebo, no specific treatment, or other intervention (antibiotics, probiotics) for the prevention of UTIs
• Study design
  • Study quality was assessed using the Cochrane risk of bias assessment tool
  • Confidence in the evidence was assessed using GRADE criteria
• Primary outcomes
  • Incidence of symptomatic UTIs
  • Positive culture results
  • Side effects
  • Adherence to therapy

RESULTS:

• 50 total studies (26 new studies added) | 8857 participants
  • The risk of bias was generally low

Cranberry Products vs Placebo or No Treatment

• 45 studies (26 studies included in meta-analysis)
• There is moderate certainty evidence that cranberry products reduced the risk of UTIs
  • Risk ratio (RR) 0.70 (95% CI 0.58 to 0.84) | I2=69% | 6211 participants
• Cranberry products probably reduced the risk of symptomatic, culture-verified UTIs in
  • Women with recurrent UTIs
    • RR 0.74 (95% CI, 0.55 to 0.99) | I2=54%
    • 8 studies | 1555 participants
  • Children
    • RR 0.46 (95% CI, 0.32 to 0.68) | I2=21%
    • 5 studies | 504 participants
  • People with a susceptibility to UTIs due to an intervention
    • RR 0.47 (95% CI, 0.37 to 0.61) | I2=0%
    • 6 studies | 1434 participants
• However, with low-certainty evidence, there may be little or no benefit of cranberry products among
  • Elderly institutionalized men and women
    • RR 0.93 (95% CI, 0.67 to 1.30) | I2=9%
    • 3 studies | 1489 participants
  • Pregnant women
    • RR 1.06 (95% CI, 0.75 to 1.50) | I2=3%
    • 3 studies | 765 participants
  • Adults with neuromuscular bladder dysfunction with incomplete bladder emptying
    • RR 0.97 (95% CI, 0.78 to 1.19) | I2=0%
    • 3 studies | 464 participants
• The number of participants with gastrointestinal side effects probably does not differ between those taking cranberry products and those receiving placebo or no specific treatment
  • RR 1.33 (95% CI, 1.00 to 1.77) | I2=0%
  • Moderate certainty evidence | 10 studies | 2166 participants

Cranberry Products vs Antibiotics

• 6 studies
• Compared to antibiotics, cranberry products may make little or no difference to the risk of
  • Symptomatic, culture-verified UTIs
    • RR 1.03 (95% CI, 0.80 to 1.33) | I2=0%
    • 2 studies | 385 participants
  • Clinical symptoms without culture
    • RR 1.30 (95% CI, 0.79 to 2.14) | I2=68%
    • 2 studies | 336 participants

Cranberry Products vs Probiotics

• 3 studies
• Compared to probiotics, cranberry products may reduce the risk of symptomatic, culture-verified UTIs
  • RR 0.39 (95% CI, 0.27 to 0.56) | I2=0%
  • 3 studies | 215 participants

Cranberry Tablets vs Juice

• 1 study
• It is unclear whether efficacy differs between cranberry juice and tablets as the certainty of the evidence was very low

Different Doses of PACs

• 2 studies
• It is unclear whether efficacy differs between different doses of PACs as the certainty of the evidence was very low
• No difference in the risk for UTIs could be demonstrated between low, moderate and high doses of PACs

CONCLUSION:

• Cranberry products reduce the risk of UTIs in women with recurrent UTIs, children, and those at risk due to a procedure
• The use of cranberry products is not supported in the elderly, pregnant women, or adults with neuromuscular bladder dysfunction

Learn More – Primary Sources:

Cranberries for preventing urinary tract infections

Cochrane Review: Is Obesity an Independent Risk Factor for COVID-19 Severity?

BACKGROUND AND PURPOSE:

• Tadayon Najafabadi et al. (Cochrane Database of Systematic Reviews, 2023) assess whether obesity as an independent prognostic factor for COVID-19 severity and mortality

METHODS:

• Systematic review and meta-analysis
• Study inclusion criteria
  • Case-control, case-series, prospective and retrospective cohort studies, secondary analyses of RCTs
  • Studies that evaluated associations between obesity and COVID-19 adverse outcomes
  • Studies needed to adjust for at least one factor other than obesity to be eligible
• Study design
  • Obesity classes
    • No obesity: BMI 18.5 to 24.9 kg/m2
    • Class I: BMI 30 to 35 kg/m2
    • Class II: BMI 35 to 40 kg/m2
    • Class III: BMI 40 kg/m2 and above
  • Random-effects meta-analyses were used to generate pooled estimated of association
    • Meta-analyses for each obesity class were conducted separately for the main comparison
    • Meta-analysis of unclassified obesity and obesity as a continuous variable (5 kg/m2 increase in BMI) was also performed
  • Risk of bias was assessed
  • Certainty of evidence was determined using GRADE criteria
• Primary outcome
  • COVID-19-related mortality and other severe adverse outcomes

RESULTS:

• 149 studies included in meta-analysis
• Compared to patients without obesity, patients with obesity class I or II were not at increased odds of mortality
  • Class I
    • OR 1.04 (95% CI, 0.94 to 1.16)High certainty evidence | 15 studies | 335,209 participants
  • Class II
    • OR 1.16, 95% CI, 0.99 to 1.36
    • High certainty | 11 studies | 317,925 participants
• Class III obesity may be at increased risk of COVID-19-related mortality
  • Class III
    • OR 1.67 (95% CI, 1.39 to 2.00)
    • Low certainty | 19 studies | 354,967 participants
• There was increased odds of mechanical ventilation with higher classes of obesity
  • Class I
    • OR 1.38 (95% CI, 1.20 to 1.59)
• • • Moderate certainty | 10 studies | 187,895 participants
    Class II
    • OR 1.67 (95% CI, 1.42 to 1.96)
• • • High certainty | 6 studies | 171,149 participants
  • Class III
    • OR 2.17 (95% CI, 1.59 to 2.97)
    • High certainty | 12 studies | 174,520 participants
• There was no dose-response relationship across increasing obesity classifications for ICU admission and hospitalization

CONCLUSION:

• Class III obesity may increase the risk of mortality related to COVID-19
• All classes of obesity appear to be associated with increased odds of mechanical ventilation in a dose-dependent manner

Learn More – Primary Sources:

Obesity as an independent risk factor for COVID‐19 severity and mortality

Are Uterine Cancer Rates Rising More Rapidly for Women of Hispanic Ethnicity? 

BACKGROUND AND PURPOSE:

• Liao et al. (Gynecologic Oncology, 2023) determined the rate of uterine cancer among Hispanic women

METHODS:

• Retrospective cohort study
  • Data derived from the United States Cancer Statistics (USCS) database and the Behavioral Risk Factors Surveillance System (BRFSS) survey from 2001 to 2018
• Population
  • ≥18 years
• Diagnosed with uterine cancer in the Exposures
  • Age: Divided into 5 to 10 year age groups
  • Ethnicity: Hispanic women and non-Hispanic White women
• Study design
  • Reproductive age definition: <50 years
  • Young reproductive age: 18 to 40 years
  • Obesity-related cancers: Classified according to the CDC
  • The average annual percent change (AAPC) calculated using joinpoint regression
• Primary outcomes
  • Incidence rates of overall uterine cancers and obesity-related uterine cancers
  • AAPC of uterine cancers

RESULTS:

• 843,116 patients with uterine cancer
  • In reproductive age women: 12.7% of cases
• In 2018, Hispanic women aged 35 to 39 years had the highest incidence of uterine cancer among young reproductive-age women
  • Hispanic women: 13.9 per 100,000
  • Non-Hispanic White women: 9.3 per 100,000
• The incidence of new uterine cancers increased annually for women aged 25 to 39 in both groups with Hispanic women experiencing a higher AAPC
  • Hispanic women: AAPC 4.0 to 4.5%
  • Non-Hispanic White women: AAPC 1.5 to 2.3%
• Hispanic women aged 35 to 39 living in the West specifically had higher incidences of uterine cancer and AAPCs
  • Incidence
    • Hispanic women: 14.93 per 100,000
    • Non-Hispanic White women: 6.61 per 100,000
  • AAPCs
    • Hispanic women: 5.24%
    • Non-Hispanic White women: 1.48%
• By the year 2026, the incidence of uterine cancer in 35 to 39 year old Hispanic women in the West will be three times that of White women
  • Hispanic women: estimated 22.4 per 100,000
  • Non-Hispanic White women: estimated 7.4 per 100,000
• In the BRFSS survey, Hispanic women aged 35 to 44 years reported an obesity rate of 30.1% in 2018
  • The rate of obesity in Hispanic women rose by 1.4% annually from 2001 to 2018

CONCLUSION:

• The overall incidence of uterine cancer continues to grow for women in the US with Hispanic women experiencing particularly high increases in incidence each year
• The authors state

The incidence of uterine cancer is rising rapidly in young reproductive-age Hispanic women compared to White women

These results may have public health implications towards the prevention and early detection of uterine cancer in this high-risk population 

Learn More – Primary Sources:

The rising rates of uterine cancer in Hispanic women of reproductive age in the United States (444)

For Rare Medullary Thyroid Cancer, Consider MEN2

SUMMARY:  

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant condition involving predisposition to distinct types of endocrine tumors. Associated tumors may develop at any age, but typically occur in early adulthood.  

Symptoms and Tumor Risks 

• Medullary thyroid carcinoma (MTC) or its precursor C-cell hyperplasia  
  • nearly 100% by age 35 
• Three clinical subtypes are distinguished based on additional features 
  • MEN2A 
    • Pheochromocytoma (typically adrenal): 50% 
    • Parathyroid adenoma or hyperplasia: 20% to 30% 
  • MEN2B 
    • Pheochromocytoma: 50% 
    • Marfanoid habitus (tall with long thin limbs) 
    • Mucosal neuromas  
    • Diffuse ganglioneuromatosis of the GI tract: 40% 
  • Familial Medullary Thyroid Cancer (FMTC) 
    • Typically later age of onset 

Genetics  

• Caused by pathogenic variants in the RET gene 
  • Specific variants can be used to predict subtype or associated clinical features 
• Autosomal dominant 
  • 5% of MEN2A are de novo 
  • 50% of MEN2B are de novo 

Diagnosis 

• MEN2 should be suspected in: 
  • Any individual with MTC 
  • Families with MEN2-related tumors in multiple close relatives 
  • Individuals with marfanoid features and mucosal neuromas (MEN2B) 
• Targeted genetic testing for the familial RET variant is appropriate when a close family member has been diagnosed with MEN2  

Management  

• Referral to cancer genetics and endocrinology for counseling and management 
• Treatment and surveillance generally include  
  • Prophylactic thyroidectomy OR annual measurement of plasma calcitonin (indicates presence of MTC or C-cell hyperplasia) 
  • Biochemical screening for pheochromocytomas and hyperparathyroidism  
    • plasma catecholamines and metanephrines 
    • serum calcium and parathyroid hormone 
• Genetic testing is appropriate for at-risk children | Prophylactic surgery and surveillance may be recommended as early as the first year of life, depending on the specific genetic variant 

Note: Because prompt medical interventions can prevent severe morbidity and mortality, MEN2 is on the ACMG list of secondary findings | In summary, the ACMG document on reporting such findings makes the following recommendations 

• In the course of genetic testing for research or clinical care, the laboratory may identify variants in genes unrelated to the initial indication for testing, but nevertheless may have important health implications 
• Results of such secondary findings should be communicated to the individuals who may benefit from this knowledge 
• An individual can ‘opt out’ of receiving secondary findings 

KEY POINTS: 

• Consider MEN2 and referral to genetics for patients who present with medullary thyroid carcinoma, pheochromocytoma, parathyroid adenoma, or diffuse intestinal ganglioneuromatosis 
• Management includes prophylactic thyroidectomy and regular surveillance for biomarkers associated with pheochromocytoma and hyperparathyroidism 

Learn More – Primary Sources:  

ACMG and NSGC Joint Practice Guidelines: Referral Indications for Cancer Predisposition Assessment

GeneReviews – Multiple Endocrine Neoplasia type 2

NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic

ACOG Committee Opinion 793: Hereditary cancer syndromes and risk assessment.  

Locate a Genetic Counselor or Genetics Services:   

Genetic Services Locator-ACMG 

Genetic Services Locator-NSGC   

Genetic Services Locator-CAGC   

RCT Results: Does Spironolactone Improve Acne for Women?

BACKGROUND AND PURPOSE:

• Spironolactone is often prescribed off-label for the treatment of acne, and may be useful in reducing antibiotic use in this setting
• Santer et al. (BMJ, 2023) assessed the effectiveness of oral spironolactone for acne vulgaris in adult women

METHODS:

• Pragmatic, multicenter, phase 3, double blind, randomized controlled trial
  • Spironolactone for women with acne vulgaris (SAFA) trial
  • England and Wales
• Participants
  • Women ≥18 years
  • Facial acne for ≥6 months
  • Appropriate to use oral antibiotics for acne treatment
• Interventions
  • Spironolactone
    • 50 mg/day until week 6, increasing to 100 mg/day until week 24
  • Placebo
• Study design
  • Acne-Specific Quality of Life (Acne-QoL) scores range from 0 to 30
    • Higher scores indicate improved QoL
• Primary outcomes
  • Acne-QoL symptom subscale score at week 12
• Secondary outcomes
  • Acne-QoL at week 24
  • Participant self-assessed improvement
  • Investigator’s global assessment (IGA) for treatment success
  • Adverse reactions

RESULTS:

• Spironolactone: 176 women | Placebo: 166 women
  • Mean age 29.2 years | Ethnicities other than White: 7%
  • Mild acne: 46% | Moderate acne: 40% | Severe acne: 13%
• Mean Acne-QoL symptom scores
  • Baseline
    • Spironolactone: 13.2 (SD, 4.9)
    • Placebo: 12.9 (SD, 4.5)
  • Week 12
    • Spironolactone: 19.2 (SD, 6.1)
    • Placebo: 17.8 (SD)
    • Difference 1.27 (95% CI 0.07 to 2.46)
  • Week 24
    • Spironolactone: 21.2 (SD, 5.9)
    • Placebo: 17.4 (SD, 5.8)
    • Difference 3.45 (95% CI, 2.16 to 4.75)
• More participants in the spironolactone group reported acne improvement
  • There was no significant difference at week 12
    • Spironolactone: 72% | Placebo: 68%
    • OR 1.16 (95% CI, 0.70 to 1.91)
  • There was a significant difference at week 24
    • Spironolactone: 82% | Placebo: 63%
    • OR 2.72 (95% CI, 1.50 to 4.93)
• Treatment success (IGA classified) at week 12 was greater in the spironolactone group
  • Spironolactone: 19% | Placebo: 6%
  • OR 5.18 (95% CI, 2.18 to 12.28)
• Adverse reactions were slightly more common in the spironolactone group
  • More headaches were reported (20% vs 12% | P=0.02)
• There were no serious adverse reactions

CONCLUSION:

• Compared to placebo, spironolactone improved acne symptoms at week 24
  • There was no difference from the placebo group at week 12
• That authors state

The findings from this trial show the effectiveness, safety, and tolerability of spironolactone in women with acne

Adopting a combined approach using oral spironolactone and topical agents has the potential to reduce the long term prescribing of oral antibiotics and therefore to reduce the likelihood of emerging bacterial resistance

Treatment courses of spironolactone over three months are likely of greater benefit than shorter treatment duration 

Learn More – Primary Sources:

Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial

Improvement in Cognitive Function in Older Adults Following Exercise

BACKGROUND AND PURPOSE:

• Aging is associated with a loss in functional connectivity (FC) between brain regions important for
  • Higher-order cognitive processes (region: FPN)
  • Introspection and self-generated thoughts (region: DMN)
  • Sensory information integration (region: SAL)
• Won et al. (Journal of Alzheimer’s Disease Reports, 2023) investigated the effects of exercise on within- and between-network functional connectivity of the DMN, FPN, and SAL in older adults with intact cognition (CN) and older adults diagnosed with mild cognitive impairment (MCI)

METHODS:

• Prospective intervention trial
  • Older adults recruited from in-person informational sessions at retirement communities and community recreation centers
• Participants
  • 60 to 88 years
• Intervention
  • Before and after implementation of an exercise intervention
    • 12-week walking program
• Study design
  • A resting state functional magnetic resonance imaging (fMRI) was performed after the 12-week exercise program
  • Changes in network connectivity and cognitive function after exercise were assessed using linear regression
• Primary outcomes
  • Measures of cognitive function
    • Controlled Oral Word Association Test (COWAT)
    • Rey Auditory Verbal Learning Test (RAVLT)
    • Narrative memory test (logical memory; LM)
  • Changes in within and between network connectivity

RESULTS:

• Intact cognition: 17 | Mild cognitive impairment: 16
• 78.0 (SD, 7.0) years
• The 12-week walking program led to a significant improvement in cardiorespiratory fitness among participants (P=0.005)
• Following exercise, all measures of cognitive function also increased
  • COWAT (P=0.041)
  • RAVLT (P=0.035)
  • LM (P=0.014)
• There were also significant increases in network connectivity following exercise
  • Within network connectivity
    • In the DMNW | SALW
  • Between network connectivity
    • Between the DMN-FPNB | DMN-SALB | FPN-SALB

CONCLUSION:

• Exercise training may improve cognition and memory performance by increasing between and within brain network connectivity in older adults both with normal cognition and with mild cognitive impairment
• The authors state

These findings suggest regular participation in simple aerobic exercise like moderate intensity walking may induce neuroplastic effects even in the face of Alzheimer’s disease-related neurodegenerative processes that have resulted in a diagnosis of MCI

Learn More – Primary Sources:

Large-Scale Network Connectivity and Cognitive Function Changes After Exercise Training in Older Adults with Intact Cognition and Mild Cognitive Impairment

Does Sjögren’s Syndrome Increase the Risk of Adverse Pregnancy Outcomes?

BACKGROUND AND PURPOSE:

• Sjögren’s syndrome is an autoimmune disorder affecting lacrimal and salivary glands, resulting in dry eyes and mouth, and may be associated with other autoimmune disorders (e.g., SLE)
• De Frémont et al. (The Lancet Rheumatology, 2023) described adverse pregnancy, delivery, and birth outcome risks in pregnant women with primary Sjögren’s syndrome

METHODS:

• Multicenter, prospective, cohort study
  • French registry
  • GR2 cohort (Groupe de Recherche sur la Grossesse et les Maladies Rares)
• Participants
  • Ongoing pregnancy at 12 weeks
  • Matched controls from the general population
• Exposures
  • Diagnosed primary Sjögren’s syndrome
• Study design
  • The GR2 cohort was used to assess outcomes and risk factors for flares
  • Matched controls used to assess outcomes vs patients without Sjögren’s syndrome
  • Flares defined using European Alliance of Associations for Rheumatology (EULAR) Disease Activity Index (ESSDAI) scores
• Primary outcomes
  • Factors associated with primary Sjögren’s syndrome flare
    • ≥3-point increase in ESSDAI score
  • Factors associated with adverse pregnancy outcomes
    • Fetal or neonatal death | Placental insufficiency leading to a preterm delivery | Small-for-gestational-age
  • Pregnancy | Delivery | Birth outcome rates

RESULTS:

• 96 women with primary Sjögren’s syndrome | 106 pregnancies
  • Median age at pregnancy: 33 (IQR, 31 to 36) years
  • White women: 83% | Black women: 17%
  • Previous systemic activity (ESSDAI score of ≥1): 90%
  • Systemic activity at inclusion: 45%
• Incidence of primary Sjögren’s syndrome flares in pregnancy: 13%
  • No baseline parameters were associated with these flares
• Incidence of adverse pregnancy outcomes: 7%
• Among pregnancies in women with data for antiphospholipid antibodies, antiphospholipid antibody positivity was more frequent among pregnancies with adverse outcomes (P=0.023)
  • Adverse outcomes: 50% of 4 pregnancies
  • No adverse outcomes: 4% of 51 pregnancies
• In the matched controlled study, there was no significant difference in adverse pregnancy outcomes in women with primary Sjögren’s syndrome vs matched controls
  • Primary Sjögren’s syndrome: 9%
  • Controls: 7%
  • Odds ratio 1.31 (95% CI, 0.53 to 2.98) | P=0.52

CONCLUSION:

• Among women with primary Sjögren’s syndrome, pregnancy prognoses were generally good, and the odds of adverse outcomes were no higher than in the general population
• Women with antiphospholipid antibodies may be at higher risk, and should be monitored more closely

Learn More – Primary Sources:

Pregnancy outcomes in women with primary Sjögren’s syndrome: an analysis of data from the multicentre, prospective, GR2 study

What Percentage of Breast Cancers May Be Overdiagnosed in Older Women?

BACKGROUND AND PURPOSE:

• Richman et al. (Annals of Internal Medicine, 2023) estimated the overdiagnosis rate associated with breast cancer screening among older women by age

METHODS:

• Retrospective cohort study
  • Data derived from SEER Medicare registry
• Population
  • Women ≥70 years
  • Recently received breast cancer screening
  • No breast cancer at baseline
• Exposures
  • Screening continuation in the next interval
  • Exit from screening
• Study design
  • Analyses used competing risk models, and were stratified by age
• Primary outcomes
  • Breast cancer diagnoses for up to 15 years of follow-up
  • Breast cancer deaths for the same period

RESULTS:

• 54,635 women
• For women aged 70 to 74, the rate of potential overdiagnosis was 31%
  • Cumulative incidence of breast cancer
    • Screened: 6.1 cases per 100 women (95% CI, 5.7 to 6.4)
    • Unscreened: 4.2 cases per 100 women (95% CI, 3.5 to 5.0)
• For women aged 75 to 84, the rate of potential overdiagnosis was 47%
  • Cumulative incidence of breast cancer for women aged 75 to 84
    • Screened: 4.9 cases per 100 women (95% CI, 4.6 to 5.2)
    • Unscreened: 2.6 per 100 women (95% CI, 2.2 to 3.0)
• For women 85 and older, the rate of potential overdiagnosis was 54%
  • Cumulative incidence of breast cancer for women aged 85 and older
    • Screened: 2.8 per 100 women (95% CI, 2.3 to 3.4)
    • Unscreened: 1.3 per 100 women (95% CI, 0.9 to 1.9)
• There was no significant reduction in breast cancer-specific death associated with screening
• Absolute risk for overdiagnosis did not differ regardless of age group
  • Range: 1.5 to 2.3 cases per 100 women screened

CONCLUSION:

• Women 70 years and older who continue breast cancer screening face a risk of overdiagnosis
• This increased risk became more marked with increasing age
• The authors state

The relative risk for overdiagnosis increases with age and is highest for the oldest women or those with lowest life expectancy

Overdiagnosis should be explicitly considered when making screening decisions, along with considering possible benefits of screening

Learn More – Primary Sources:

Estimating Breast Cancer Overdiagnosis After Screening Mammography Among Older Women in the United States

How Does Current Breast Cancer Prognosis Compare to the 1990s?

BACKGROUND AND PURPOSE:

• Taylor et al. (BMJ, 2023) described long-term breast cancer mortality among women with a past vs more recent diagnosis of breast cancer

METHODS:

• Population based observational cohort study
  • Data from the UK National Cancer Registration and Analysis Service
• Population
  • All women registered with early invasive breast cancer in England from 1993 to 2015
• Primary outcomes
  • Annual breast cancer mortality rates and cumulative risks by time since diagnosis
  • Calendar period of diagnosis
  • Characteristics of patients and tumors

RESULTS:

• Women registered: 512,447
• For women with a diagnosis made within each of the 5-year calendar periods starting in 1993
  • The crude annual breast cancer mortality rate was highest during the five years after diagnosis and then declined
• For any given time since diagnosis
  • Crude annual breast cancer mortality rates and risks decreased with increasing calendar period
  • Crude five-year breast cancer mortality risk
    • Diagnosis made during 1993 to 1999: 14.4% (95% CI, 14.2 to 14.6)
    • Diagnosis made during 2010 to 2015: 4.9% (95% CI, 4.8 to 5.0)
  • Adjusted annual breast cancer mortality rates also decreased with increasing calendar period in nearly all patient groups
• There was considerable variability in risk of death from breast cancer among those recently diagnosed
  • <3% for 62.8%
  • ≥20% in 4.6% of women

CONCLUSION:

• For women with early-stage breast cancer, prognoses have improved substantially since 1993
• The authors state

Since the 1990s, the five year risk of death from breast cancer has decreased from 14.4% to 4.9% overall, with reductions seen in nearly all patient groups

Learn More – Primary Sources:

Breast cancer mortality in 500 000 women with early invasive breast cancer in England, 1993-2015: population based observational cohort study

How Useful is ChatGPT at Evaluating Public Health Queries for Patients?

BACKGROUND AND PURPOSE:

• Ayers et al. (JAMA Netw Open, 2023) evaluated ChatGPT responses to public health questions from the non-professional community

METHODS:

• Cross-sectional study
• Questions
  • 23 questions in 4 categories
    • Addiction | Interpersonal violence | Mental health | Physical Health
  • Questions used a common help-seeking structure
• Response evaluation criteria (performed by two authors, independently)
  • Was the question responded to?
  • Was the response evidence-based?
  • Did the response refer the user to an appropriate resource?
• Study design
  • Interrater reliability was measured
  • The percentage corresponding to each outcome (overall and among categories) was calculated
  • The number of words in ChatGPT responses and its reading level were assessed using the Automated Readability Index

RESULTS:

• Median ChatGPT response length: 225 (IQR, 183 to 274) words
• Mode reading level: 9^th grade to 16^th grade
• ChatGPT recognized and responded to all 23 questions in 4 public health domains
  • Responses determined to be evidence based: 91% (95% CI, 71 to 98)
  • Responses that made referrals to specific resources: 22% (95% CI, 8 to 44)
    • Addiction: 2 of 14 queries
    • Interpersonal violence: 2 of 3 queries
    • Mental health: 1 of 3 queries
    • Physical health: 0 of 3 queries

CONCLUSION:

• The advice ChatGPT provided to public health queries was generally evidence-based but infrequently provided referrals to specific resources
• The authors state

Limitations of this study include relying on an abridged sample of questions whose standardized language may not reflect how the public would seek help (ie, asking follow-up questions)

Additionally, ChatGPT responses are probabilistic and in constant stages of refinement; hence, they may vary across users and over time

Learn More – Primary Sources:

Evaluating Artificial Intelligence Responses to Public Health Questions

RCT Results: Does Metformin Reduce the Risk of Long COVID?

BACKGROUND AND PURPOSE:

• Bramante et al. (The Lancet Infectious Diseases, 2023) examined whether treatment with metformin, ivermectin, or fluvoxamine reduced the risk of long COVID

METHODS:

• Randomized, phase 3 trial
  • 6 sites in the US
  • Trial’s original primary outcome was severe COVID-19 by day 14 (data published separately)
• Participants
  • 30 to 85 years
  • Overweight or obese
  • COVID-19 symptoms <7 days
  • Positive COVID test within 3 days before enrollment
  • Pregnant women were not excluded
  • Exclusions: Low risk of severe COVID-19 (Normal BMI and <30 years)
• Interventions
  • Metformin plus ivermectin
  • Metformin plus fluvoxamine
  • Metformin plus placebo
  • Ivermectin plus placebo
  • Fluvoxamine plus placebo
  • Placebo plus placebo
• Study design
  • Participants were randomly assigned to an intervention group (1:1:1:1:1:1)
  • Trial was blinded
• Primary outcome
  • Long COVID diagnosed by a medical provider

RESULTS:

• 1126 participants were assigned, received a dose of study treatments, and consented to long-term follow-up at day 180
  • Metformin: 564 | Placebo: 562
  • Female: 56.1% (Pregnant: 7.0%)
  • Median age: 45 (IQR, 37 to 54) years
  • Median BMI: 29.8 (IQR, 27.0 to 34.2) kg/m2
• Long COVID diagnoses by day 300: 8.3%
• The incidence of long COVID was reduced in the metformin group vs placebo
  • Metformin: cumulative incidence 6.3% (95% CI, 4.2 to 8.2)
  • Placebo: Cumulative incidence 10.4% (95% CI, 7.8 to 12.9)
  • HR 0.59 (95% CI, 0.39 to 0.89) | P=0.012
• The beneficial effect of metformin was consistent across prespecified subgroups
• When metformin was started within 3 days of symptom onset, the HR of long COVID was even lower
  • Hazard Ratio (HR) 0.37 (95% CI, 0.15 to 0.95)
• Compared to placebo, there was no effect on cumulative incidence of long COVID with
  • Ivermectin: HR 0.99 (95% CI, 0.59 to 1.64)
  • Fluvoxamine: HR 1.36 (95% CI, 0.78 to 2.34)

CONCLUSION:

• In this population of adults with overweight or obesity, metformin reduced the incidence of long COVID compared to placebo (note: pregnant women were not excluded)
• The authors state

In conclusion, early outpatient COVID-19 treatment with metformin decreased the subsequent risk of long COVID by 41.3% during 10-month follow-up

This finding is consistent with the 42.3% reduction in health-care utilisation for severe COVID-19 with metformin in the first 14 days of the trial 

Learn More – Primary Sources:

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial

RCT Results: Does Daily Low-Dose Aspirin Increase Incidence of Anemia?

BACKGROUND AND PURPOSE:

McQuilten et al. (Ann Intern Med, 2023) investigated the effect of low-dose aspirin on incident anemia, hemoglobin, and serum ferritin concentrations.

METHODS:

• Post hoc analysis of an RCT
  • ASPREE (ASPirin in Reducing Events in the Elderly) trial
• Participants
  • Community-dwelling ≥70 years or ≥65 years for Black and Hispanic persons
• Intervention
  • 100 mg of aspirin daily
  • Placebo
• Primary outcomes
  • Anemia incidence
  • Hemoglobin concentrations (measured annually)
  • Ferritin concentrations (measured at 3 years after assignment)

RESULTS:

• 19,114 individuals
• Anemia incidence was higher in the aspirin group
  • Placebo: 42.9 events per 1000 person-years | Aspirin: 51.2 events
  • Hazard ratio (HR) 1.20 (95% CI, 1.12 to 1.29)
• Both groups experienced declines in hemoglobin concentrations with steeper decline in the aspirin group
  • Placebo: 3.6 g/L per 5 years
  • Aspirin: 0.6 (95% CI, 0.3 to 1.0) g/L per 5 years
• Subgroup analysis: Aspirin group had
  • Greater prevalence of ferritin levels <45 µg/L at year 3
    • Placebo: 9.8% | Aspirin: 13%
  • Greater overall decline in ferritin
    • Aspirin: 11.5% (95% CI, 9.3 to 13.7)
• Similar results found in the absence of major bleeding

CONCLUSION:

• Even in the absence of major bleeding, daily aspirin led to increased incidence of anemia and reduced ferritin levels in healthy older adults
• The authors state

Low-dose aspirin increased incident anemia and decline in ferritin in otherwise healthy older adults, independent of major bleeding

Periodic monitoring of hemoglobin should be considered in older persons on aspirin 

Learn More – Primary Sources:

Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly: A Secondary Analysis of the Aspirin in Reducing Events in the Elderly Trial

Does Menopausal Hormone Therapy Contribute to Dementia Risk?

BACKGROUND AND PURPOSE:

• Pourhadi et al. (BMJ, 2023) assessed the association between use of menopausal hormone therapy and dementia

METHODS:

• Nationwide, nested case-control study
  • Danish national registries
• Participants
  • Danish women | 50 to 60 years on January 1, 2000
  • No history of dementia or contraindications for hormone therapy
  • Exclusion: Prior hysterectomy and bilateral oophorectomy
• Exposures
  • Menopausal hormone therapy
• Study design
  • Cases: Patients with dementia
  • Controls: Age-matched patients
• Primary outcome
  • All-cause dementia defined as
    • First-time diagnosis or
    • First-time use of dementia specific medication

RESULTS:

• Cases: 5589 | Controls: 55,890
• Estrogen-progestogen therapy was associated with increased rate for all-cause dementia
  • Hazard ratio (HR) 1.24 (95% CI, 1.17 to 1.33)
• Increasing durations of use yielded higher hazard ratios
  • ≤1 year of use: HR 1.21 (95% CI, 1.09 to 1.35)
  • >12 years of use: HR 1.74 (95% CI, 1.45 to 2.10)
• Estrogen-progestogen therapy was positively associated with development of dementia for both
  • Continuous regimens: HR 1.31 (95% CI, 1.18 to 1.46)
  • Cyclic regimens: HR 1.24 (95% CI, 1.13 to 1.35)
• Associations persisted in women who received treatment at ≤55 years
  • HR 1.24 (95% CI, 1.11 to 1.40)
• Findings persisted when restricted to
  • Late onset dementia (≥65 years): HR 1.21 (95% CI, 1.12 to 1.30)
  • Alzheimer’s disease: HR 1.22 (95% CI, 1.07 to 1.39)

CONCLUSION:

• Menopausal hormone therapy was associated with an increased risk of all-cause dementia, late onset dementia and Alzheimer’s disease
  • Risk persisted even in women who received hormone therapy at 55 years of age or younger
• Authors acknowledge that study is associative and not causative
  • Can not determine if actual effect of hormone therapy on dementia risk or underlying predisposition among women who need hormone therapy

Accompanying Editorial

• An accompanying editorial recognizes study strengths, including use of the entire population of Denmark
• The editorial provides multiple examples of confounding, including the possibility that women who have subjective cognitive changes and sleep disturbance during transition may be more likely to seek out hormone therapy
• RCTs that focused on younger women (50 to 55 years) did not show a negative impact
• The authors of the editorial conclude that

… the observed associations could be artefactual and should not be used to infer a causal relationship between hormone therapy and dementia risk

These findings cannot inform shared decision making about use of hormone therapy for menopausal symptoms 

Learn More – Primary Sources:

Menopausal hormone therapy and dementia: nationwide, nested case-control study

RCT Results: Once-Weekly vs Once-Daily Insulin for Type 2 Diabetes

BACKGROUND AND PURPOSE:

• Rosenstock et al. (NEJM, 2023) investigated the efficacy and long-term safety of once-weekly insulin icodec vs once-daily insulin glargine U100 in persons with type 2 diabetes

METHODS:

• Randomized, open-label phase 3a trial
  • 52-week main phase | 26-week extension phase | 5-week follow-up
• Participants
  • ≥18 years  Type 2 diabetes: Glycated hemoglobin level, 7 to 11%
  • Not previously received insulin
• Interventions
  • Once-weekly insulin icodec (700 U per milliliter)
  • Once-daily insulin glargine U100 (100 U per milliliter)
• Study design
  • 1:1 randomization
  • Medication given subQ
  • Starting dose
    • Icodec: 70 U per week
    • Glargine U100: 10 U per day
  • Treat-to-target trial
    • Insulin doses adjusted to target prebreakfast self-measured blood glucose target of 80 to 130 mg per deciliter (4.4 to 7.2 mmol per liter)
  • Hypoglycemic episodes (from baseline to weeks 52 and 83) were recorded
• Primary outcome
  • Change in the glycated hemoglobin level from baseline to week 52
• Secondary outcome
  • Percentage of time spent in the glycemic range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) in weeks 48 to 52

RESULTS:

• Once-weekly: 492 participants | Once-daily: 492 participants
  • Baseline characteristics were similar between the 2 groups
• Mean reduction in the glycated hemoglobin level at 52 weeks was greater with icodec
  • Icodec: 8.50% to 6.93% | Mean change −1.55 percentage points
  • Glargine U100: 8.44% to 7.12% | Mean change −1.35 percentage points
  • Estimated between-group difference: −0.19 (95% CI, −0.36 to −0.03) percentage points
  • Noninferiority: P<0.001 | Superiority of icodec: P=0.02
• Percentage of time spent in the glycemic range of 70 to 180 mg per deciliter was significantly higher with icodec
  • Icodec: 71.9% | Glargine U100: 66.9%
  • Estimated between-group difference: 4.27 (95% CI, 1.92 to 6.62) percentage points
  • Superiority: P<0.001
• Rates of combined clinically significant or severe hypoglycemia similar between the groups
  • At week 52
    • Icodec: 0.30 events per person-year of exposure
    • Glargine U100: 0.16 events
    • Estimated rate ratio (RR) 1.64 (95% CI, 0.98 to 2.75)
  • At week 83
    • Icodec: 0.30 events per person-year of exposure
    • Glargine U100: 0.16 events
    • Estimated RR 1.63 (95% CI, 1.02 to 2.61)
• Safety
  • There were no new safety signals detected
  • Incidences of adverse events were similar between the two groups

CONCLUSION:

• For patients with type 2 diabetes, better glycemic control was achieved with once-weekly insulin icodec compared to once-daily insulin glargine U100

Learn More – Primary Sources:

Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin

RCT Results: Is Intermittent Fasting Better Than Calorie Restriction for Long-Term Weight Loss?

BACKGROUND AND PURPOSE:

• Time-restricted eating (TRE), also called intermittent fasting, without calorie counting has become a popular weight loss method
• Lin et al. (Ann Intern Med, 2023) studied whether TRE is more effective for weight control and cardiometabolic risk reduction vs calorie restriction (CR) or control

METHODS:

• Randomized controlled trial
• Participants
  • Between 18 and 65 years
  • BMI between 30 and 50 kg/m2
• Intervention
  • 8-hour TRE
    • Eating between noon and 8:00 p.m. only, without calorie counting
  • CR
    • 25% energy restriction daily
  • Control
    • Eating over a period of 10 or more hours per day
• Study design
  • 1:1:1 randomization
  • Participants were not blinded
  • Physical habits unchanged
  • This study took place over 12 months
    • TRE and CR interventions: 6-month weight loss phase and 6-month maintenance phase
• Primary outcome
  • Change in body weight at 12 months
  • Change in metabolic markers at 12 months
  • Change in energy intake at 12 months

RESULTS:

• 77 participants
  • Mean age: 40 (SD, 11) years
  • Black: 33% | Hispanic: 46%
• Mean reduction in energy intake
  • TRE: −425 (SD, 531) kcal/d
  • CR: −405 (SD, 712) kcal/d
• Compared with the control group, weight loss by month 12 was higher with both intervention groups
  • TRE group
    • Absolute weight loss: −4.61 kg (95% CI, −7.37 to −1.85) | P≤0.01
    • Weight loss as a percentage of baseline body weight: −4.87% (95% CI, −7.61 to −2.13)
  • CR group
    • Absolute weight loss: −5.42 kg (95% CI, −9.13 to −1.71) | P≤0.01
    • Weight loss as a percentage of baseline body weight: −5.30% (95% CI, −9.06 to −1.54)
• There was no significant difference in weight loss at 12 months between the TRE and CR groups
  • Absolute weight loss: 0.81 kg (95% CI, −3.07 to 4.69) | P=0.68
  • Weight loss as a percentage of baseline body weight: 0.43% (95% CI, −3.48 to 4.34)

CONCLUSION:

• Both CR and TRE improves weight loss compared to control
• There was no difference in weight loss between the CR and TRE groups
• The authors state

TRE is effective for weight loss when compared with controls eating over a period of 10 or more hours but not more effective than daily CR in a racially diverse population

Future studies are needed to confirm our findings

Learn More – Primary Sources:

Time-Restricted Eating Without Calorie Counting for Weight Loss in a Racially Diverse Population: A Randomized Controlled Trial

How Often Does Low-Dose CT Lung Screening Uncover Other Significant Abnormalities?

BACKGROUND AND PURPOSE:

• Low-dose computed tomography (LDCT) lung screening reduces lung cancer mortality, but may reveal significant abnormalities that are not associated with lung cancer
• Gareen et al. (JAMA Intern Med, 2023) describe significant incidental findings (SIFs) reported in the LDCT arm of the National Lung Screening Trial

METHODS:

• Retrospective case series study
• Population
  • Participants in the National Lung Screening Trial who underwent at least 1 screening examination with LDCT
• Study design
  • Data were collected from 2002 to 2009 at 33 US medical centers
  • Participants were scheduled to undergo 3 screenings during the course of the trial
• Primary outcomes
  • SIFs, defined as either a
    • Final diagnosis of a negative screen result with significant abnormalities that were not suspicious for lung cancer
    • Positive screen result with emphysema, significant cardiovascular abnormality, or significant abnormality above or below the diaphragm

RESULTS:

• 26,455 participants | 75,126 LDCT screening examinations
  • Mean age: 61.4 (SD, 5.0) years
  • Women: 41.0%
  • Black: 4.5% | Hispanic/Latino: 1.8% | White: 91.2%
• Incidence of SIFs: 33.8% of participants
  • Incidence of SIFs considered reportable: 89.1%
• There was a higher incidence of reportable SIFs among those with a positive screen result for lung cancer, compared to those with a negative screen result
  • Positive screen result: 94.1% | Negative screen result: 81.8%
• The most common SIFs reported
  • Emphysema: 43.0% of SIFs reported
  • Coronary artery calcium: 12.2% of SIFs reported
  • Masses or suspicious lesions: 7.4% of SIFs reported
• Masses reported occurred in the
  • Kidney: 3.2%
  • Liver: 2.1%
  • Adrenal: 1.3%
  • Breast: 0.8%

CONCLUSION:

• SIFs were common with LDCT screening
  • Most SIFs were considered reportable and would likely require follow-up
• The authors state

In this case series study, slightly more than one-third of all NLST LDCT screening participants had a SIF detected

… the discovery of these SIFs can potentially present an opportunity for early detection of non–lung cancer conditions in a high-risk population

Learn More – Primary Sources:

Significant Incidental Findings in the National Lung Screening Trial