Characterization of the Small Bowel Microbiome Reveals Different Profiles in Human Subjects Who Are Overweight or Have Obesity.

INTRODUCTION: Gut microbiome changes are linked to obesity, but findings are based on stool data. In this article, we analyzed the duodenal microbiome and serum biomarkers in subjects with normal weight, overweight, and obesity. METHODS: Duodenal aspirates and serum samples were obtained from subjects undergoing standard-of-care esophagogastroduodenoscopy without colon preparation. Aspirate DNAs were analyzed by 16S rRNA and shotgun sequencing. Predicted microbial metabolic functions and serum levels of metabolic and inflammatory biomarkers were also assessed. RESULTS: Subjects with normal weight (N = 105), overweight (N = 67), and obesity (N = 42) were identified. Overweight-specific duodenal microbial features include lower relative abundance (RA) of Bifidobacterium species and Escherichia coli strain K-12 and higher Lactobacillus intestinalis , L. johnsonii , and Prevotella loescheii RA. Obesity-specific features include higher Lactobacillus gasseri RA and lower L. reuteri (subspecies rodentium ), Alloprevotella rava , and Leptotrichia spp RA. Escalation features (progressive changes from normal weight through obesity) include decreasing Bacteroides pyogenes , Staphylococcus hominis , and unknown Faecalibacterium species RA, increasing RA of unknown Lactobacillus and Mycobacterium species, and decreasing microbial potential for biogenic amines metabolism. De-escalation features (direction of change altered in normal to overweight and overweight to obesity) include Lactobacillus acidophilus , L. hominis , L. iners , and Bifidobacterium dentium . An unknown Lactobacillus species is associated with type IIa dyslipidemia and overweight, whereas Alloprevotella rava is associated with type IIb and IV dyslipidemias. DISCUSSION: Direct analysis of the duodenal microbiome has identified key genera associated with overweight and obesity, including some previously identified in stool, e.g., Bifidobacterium and Lactobacillus . Specific species and strains exhibit differing associations with overweight and obesity, including escalation and de-escalation features that may represent targets for future study and therapeutics.

Defining Small Intestinal Bacterial Overgrowth by Culture and High Throughput Sequencing.

BACKGROUND& AIMS: Despite accelerated research in small intestinal bacterial overgrowth (SIBO), questions remain regarding optimal diagnostic approaches and definitions. Here, we aim to define SIBO using small bowel culture and sequencing, identifying specific contributory microbes, in the context of gastrointestinal symptoms. METHODS: Subjects undergoing esophagogastroduodenoscopy (without colonoscopy) were recruited and completed symptom severity questionnaires. Duodenal aspirates were plated on MacConkey and blood agar. Aspirate DNA was analyzed by 16S ribosomal RNA and shotgun sequencing. Microbial network connectivity for different SIBO thresholds and predicted microbial metabolic functions were also assessed. RESULTS: A total of 385 subjects with <103 colony forming units (CFU)/mL on MacConkey agar and 98 subjects with ≥103 CFU/mL, including ≥103 to <105 CFU/mL (N = 66) and ≥105 CFU/mL (N = 32), were identified. Duodenal microbial α-diversity progressively decreased, and relative abundance of Escherichia/Shigella and Klebsiella increased, in subjects with ≥103 to <105 CFU/mL and ≥105 CFU/mL. Microbial network connectivity also progressively decreased in these subjects, driven by the increased relative abundance of Escherichia (P < .0001) and Klebsiella (P = .0018). Microbial metabolic pathways for carbohydrate fermentation, hydrogen production, and hydrogen sulfide production were enhanced in subjects with ≥103 CFU/mL and correlated with symptoms. Shotgun sequencing (N = 38) identified 2 main Escherichia coli strains and 2 Klebsiella species representing 40.24% of all duodenal bacteria in subjects with ≥103 CFU/mL. CONCLUSIONS: Our findings confirm ≥103 CFU/mL is the optimal SIBO threshold, associated with gastrointestinal symptoms, significantly decreased microbial diversity, and network disruption. Microbial hydrogen- and hydrogen sulfide-related pathways were enhanced in SIBO subjects, supporting past studies. Remarkably few specific E coli and Klebsiella strains/species appear to dominate the microbiome in SIBO, and correlate with abdominal pain, diarrhea, and bloating severities.

Consuming artificial sweeteners may alter the structure and function of duodenal microbial communities.

Studies using stool samples suggest that non-sugar sweetener (NSS) consumption affects gut microbiome composition. However, stool does not represent the entire gut. We analyzed the duodenal luminal microbiome in subjects consuming non-aspartame non-sugar sweeteners (NANS, N = 35), aspartame only (ASP, N = 9), and controls (CON, N = 55) and the stool microbiome in a subset (N = 40). Duodenal alpha diversity was decreased in NANS vs. CON. Duodenal relative abundance (RA) of Escherichia, Klebsiella, and Salmonella (all phylum Proteobacteria) was lower in both NANS and ASP vs. CON, whereas stool RA of Escherichia, Klebsiella, and Salmonella was increased in both NANS and ASP vs. CON. Predicted duodenal microbial metabolic pathways altered in NANS vs. CON included polysaccharides biosynthesis and D-galactose degradation, whereas cylindrospermopsin biosynthesis was significantly enriched in ASP vs. CON. These findings suggest that consuming non-sugar sweeteners may significantly alter microbiome composition and function in the metabolically active small bowel, with different alterations seen in stool.

Coronavirus Disease 2019 (COVID-19) Pandemic Lifestyle Changes May Have Influenced Small Bowel Microbial Composition and Microbial Resistance.

BACKGROUND: The coronavirus disease 2019 (COVID-19) global pandemic necessitated many severe lifestyle changes, including lockdowns, social distancing, altered food consumption and exercise patterns, and extensive hygiene practices. These extensive changes may have affected the human gut microbiome, which is highly influenced by lifestyle. AIMS: To examine the potential effects of pandemic-related lifestyle changes on the metabolically relevant small bowel microbiome. METHODS: Adult subjects presenting for upper endoscopy without colonoscopy were identified and divided into two matched groups: pre-pandemic (February 2019-March 2020) and intra-pandemic (April 2021-September 2021, all COVID-19 negative). Duodenal aspirates and blood samples were collected. Duodenal microbiomes were analyzed by 16S rRNA sequencing. Serum cytokine levels were analyzed by Luminex FlexMap3D. RESULTS: Fifty-six pre-pandemic and 38 COVID-negative intra-pandemic subjects were included. There were no significant changes in duodenal microbial alpha diversity in the intra-pandemic vs. pre-pandemic group, but beta diversity was significantly different. The relative abundance (RA) of phylum Deinococcus-Thermus and family Thermaceae, which are resistant extremophiles, was significantly higher in the intra-pandemic vs. pre-pandemic group. The RA of several Gram-negative taxa including Bacteroidaceae (phylum Bacteroidetes) and the Proteobacteria families Enterobacteriaceae and Pseudomonadaceae, and the RA of potential disruptor genera Escherichia-Shigella and Rothia, were significantly lower in the intra-pandemic vs. pre-pandemic group. Circulating levels of interleukin-18 were also lower in the intra-pandemic group. CONCLUSIONS: These findings suggest the small bowel microbiome underwent significant changes during the pandemic, in COVID-19-negative individuals. Given the key roles of the small bowel microbiota in host physiology, this may have implications for human health.

Methanogens and Hydrogen Sulfide Producing Bacteria Guide Distinct Gut Microbe Profiles and Irritable Bowel Syndrome Subtypes.

INTRODUCTION: Irritable bowel syndrome (IBS) includes diarrhea-predominant (IBS-D) and constipation-predominant (IBS-C) subtypes. We combined breath testing and stool microbiome sequencing to identify potential microbial drivers of IBS subtypes. METHODS: IBS-C and IBS-D subjects from 2 randomized controlled trials (NCT03763175 and NCT04557215) were included. Baseline breath carbon dioxide, hydrogen (H 2 ), methane (CH 4 ), and hydrogen sulfide (H 2 S) levels were measured by gas chromatography, and baseline stool microbiome composition was analyzed by 16S rRNA sequencing. Microbial metabolic pathways were analyzed using Kyoto Encyclopedia of Genes and Genomes collection databases. RESULTS: IBS-C subjects had higher breath CH 4 that correlated with higher gut microbial diversity and higher relative abundance (RA) of stool methanogens, predominantly Methanobrevibacter , as well as higher absolute abundance of Methanobrevibacter smithii in stool. IBS-D subjects had higher breath H 2 that correlated with lower microbial diversity and higher breath H 2 S that correlated with higher RA of H 2 S-producing bacteria, including Fusobacterium and Desulfovibrio spp. The predominant H 2 producers were different in these distinct microtypes, with higher RA of Ruminococcaceae and Christensenellaceae in IBS-C/CH 4 + (which correlated with Methanobacteriaceae RA) and higher Enterobacteriaceae RA in IBS-D. Finally, microbial metabolic pathway analysis revealed enrichment of Kyoto Encyclopedia of Genes and Genomes modules associated with methanogenesis and biosynthesis of methanogenesis cofactor F420 in IBS-C/CH 4 + subjects, whereas modules associated with H 2 S production, including sulfate reduction pathways, were enriched in IBS-D. DISCUSSION: Our findings identify distinct gut microtypes linked to breath gas patterns in IBS-C and IBS-D subjects, driven by methanogens such as M. smithii and H 2 S producers such as Fusobacterium and Desulfovibrio spp, respectively.

Smoking has disruptive effects on the small bowel luminal microbiome.

Tobacco use is the leading preventable cause of cancer, and affects the respiratory, oral, fecal, and duodenal mucosa-associated microbiota. However, the effects of smoking on the duodenal luminal microbiome have not been studied directly. We aimed to compare the duodenal luminal microbiome in never-smokers, current smokers, and ex-smokers who quit ≥ 10 years ago. In a cross-sectional study, current smokers (CS, n = 24) were identified and matched to never-smokers (NS, n = 27) and ex-smokers (XS, n = 27) by age (± 5 years), body mass index (BMI, ± 3 kg/m2), and sex. Current antibiotic users were excluded. The duodenal luminal microbiome was analysed in 1 aspirate sample per subject by 16S rRNA gene sequencing. Relative abundances (RA) of families associated with increased duodenal microbial diversity, Prevotellaceae, Neisseriaceae, and Porphyromonadaceae, were significantly lower in CS vs. NS. This was driven by lower RA of unknown Prevotella and Porphyromonas species, and Neisseria subflava and N. cinerea, in CS. In contrast, RA of Enterobacteriaceae and Lactobacillaceae (associated with decreased diversity), were significantly higher in CS, due to higher RA of Escherichia-Shigella, Klebsiella and Lactobacillus species. Many of these changes were absent or less pronounced in XS, who exhibited a duodenal luminal microbiome more similar to NS. RA of taxa previously found to be increased in the oral and respiratory microbiota of smokers were also higher in the duodenal luminal microbiome, including Bulledia extructa and an unknown Filifactor species. In conclusion, smoking is associated with an altered duodenal luminal microbiome. However, ex-smokers have a duodenal luminal microbiome that is similar to never-smokers.

A Smartphone Application Using Artificial Intelligence Is Superior To Subject Self-Reporting When Assessing Stool Form.

INTRODUCTION: Stool form assessment relies on subjective patient reports using the Bristol Stool Scale (BSS). In a novel smartphone application (app), trained artificial intelligence (AI) characterizes digital images of users' stool. In this study, we evaluate this AI for accuracy in assessing stool characteristics. METHODS: Subjects with diarrhea-predominant irritable bowel syndrome image-captured every stool for 2 weeks using the app, which assessed images for 5 visual characteristics (BSS, consistency, fragmentation, edge fuzziness, and volume). In the validation phase, using 2 expert gastroenterologists as a gold standard, sensitivity, specificity, accuracy, and diagnostic odds ratios of subject-reported vs AI-graded BSS scores were compared. In the implementation phase, agreements between AI-graded and subject-reported daily average BSS scores were determined, and subject BSS and AI stool characteristics scores were correlated with diarrhea-predominant irritable bowel syndrome symptom severity scores. RESULTS: In the validation phase (n = 14), there was good agreement between the 2 experts and AI characterizations for BSS (intraclass correlation coefficients [ICC] = 0.782-0.852), stool consistency (ICC = 0.873-0.890), edge fuzziness (ICC = 0.836-0.839), fragmentation (ICC = 0.837-0.863), and volume (ICC = 0.725-0.851). AI outperformed subjects' self-reports in categorizing daily average BSS scores as constipation, normal, or diarrhea. In the implementation phase (n = 25), the agreement between AI and self-reported BSS scores was moderate (ICC = 0.61). AI stool characterization also correlated better than subject reports with diarrhea severity scores. DISCUSSION: A novel smartphone application can determine BSS and other visual stool characteristics with high accuracy compared with the 2 expert gastroenterologists. Moreover, trained AI was superior to subject self-reporting of BSS. AI assessments could provide more objective outcome measures for stool characterization in gastroenterology.

Duodenal microbiome changes in postmenopausal women: effects of hormone therapy and implications for cardiovascular risk.

OBJECTIVE: Hormone therapy (HT) is used to treat menopause-related conditions and symptoms. The small intestine plays key roles in metabolic and endocrine function, but the effects of HT on the small intestinal microbiome are unknown. Here, we characterize duodenal microbiome differences, and the effects of HT, in postmenopausal women. METHODS: Female participants undergoing esophagogastroduodenoscopy who were postmenopausal and taking HT (HT+), postmenopausal but not taking HT (HT-), or of reproductive age and not taking exogenous hormones (RA), were identified and matched for body mass index (±3 kg/m2). DNAs were isolated from duodenal aspirates obtained during upper endoscopy. V3 and V4 libraries were used for 16S rRNA sequencing. Serum hormone levels were analyzed by Luminex FlexMap. RESULTS: The core duodenal microbiome was different in HT- participants (n = 12) when compared with RA participants (n = 10), but more similar in HT+ (n = 13) and RA participants. HT- participants had increased Proteobacteria taxa, leading to greater microbial dysbiosis compared with HT+ participants, and had decreased prevalence of Bacteroidetes, which was associated with higher fasting glucose levels, lower duodenal microbial diversity, and lower testosterone levels. HT+ participants had significantly higher estradiol (P = 0.04) and progesterone (P = 0.04), and lower fasting glucose (P = 0.03), than HT- participants, and had increased relative abundance of Prevotella (P = 0.01), and decreased Escherichia (P = 1.12E-7), Klebsiella (P = 5.93E-7), and Lactobacillus (P = 0.02), all associated with lower cardiovascular disease risks. CONCLUSIONS: These findings support previous studies suggesting that HT may have beneficial effects following menopause, and although preliminary, may also support a beneficial effect of HT on the duodenal microbiome.

A Single Fasting Exhaled Methane Level Correlates With Fecal Methanogen Load, Clinical Symptoms and Accurately Detects Intestinal Methanogen Overgrowth.

INTRODUCTION: A 2-hour breath test is the gold standard for diagnosing intestinal methanogen overgrowth (IMO). This method can be cumbersome especially if used repetitively to monitor treatment response. Therefore, we aimed to assess the reliability of a fasting single methane measurement (SMM) in diagnosing IMO and its utility as a biomarker to monitor treatment response in subjects with IMO. METHODS: First, we calculated the test characteristics of SMM compared with lactulose and glucose breath test in 2 large-scale retrospective cohorts. Second, the symptomology associated with SMM using various cutoffs was analyzed. Third, in a double-blind randomized control trial, the temporal stability of SMM levels in subjects taking placebo was analyzed. Fourth, stool Methanobrevibacter smithii loads were quantified using quantitative polymerase chain reaction and compared with SMM levels. Last, the change in SMM over time during antibiotic therapy was analyzed. RESULTS: Using the cutoff of SMM ≥10 ppm, SMM had a sensitivity of 86.4% and specificity of 100% for diagnosing IMO on the glucose and lactulose breath tests and was associated with constipation (5.65 ± 3.47 vs 4.32 ± 3.62, P = 0.008). SMM remained stable for 14 weeks without treatment (P = 0.45), and antibiotics lead to a decrease in SMM after 2 days (P < 0.0001). SMM was positively associate with stool M. smithii load (R = 0.65, P < 0.0001). DISCUSSION: Fasting SMM ≥10 ppm seems to accurately diagnose IMO, is associated with constipation, and correlates with stool M. smithii. SMM seems to be stable without treatment and decreases after antibiotics. SMM may be a useful test to diagnose IMO and monitor treatment response.

The effect of chromium intake on oxidative stress parameters: A systematic review and meta-analysis.

BACKGROUND: Trivalent chromium is a trace element thought to have a beneficial effect on oxidative stress (OS) parameters and inflammation. This review aimed to investigate the dose-response of chromium and summarize the effects of chromium supplementation on OS parameters in the literature. METHODS: MEDLINE, Scopus, Web of Science and Cochrane CENTRAL databases were searched for RCTs published from inception to January 2021 evaluating the effect of chromium supplementation on OS parameters, namely MDA, TBARS, SOD, TAS, CAT, GPx, and GSH. A random-effects model was used to pool data and calculated standard mean difference and 95 % confidence intervals. Quantified heterogeneity among studies was assessed through Cochrane's I2 values. RESULTS: Nine studies enrolling 550 participants met the inclusion criteria. The obtained results indicate that chromium supplementation significantly increases TAC (SMD: 0.46; 95 % CI: 0.08, 0.84; I2 = 00.0 % n = 2) and significantly decreases MDA levels (SMD: -0.46; 95 % CI: -0.86, -0.07; I2 = 52.4 % n = 5). Supplementation did not significantly change CAT, GPx, GSH, SOD, TAS, and TBARS. CONCLUSION: Chromium supplementation may improve OS parameters, however, due to high heterogeneity observed in the included studies, these findings should be interpreted with caution. Large RCTs on various patient groups evaluating the impact of chromium supplementation are needed to allow an adequate generalization of the benefits of chromium on human health.

Exhaled Methane Is Associated with a Lower Heart Rate.

BACKGROUND: In humans, methane (CH4) is exclusively produced by the intestinal microbiota and has been implicated in several conditions including cardiovascular disease. After microbial production of CH4 in the gut, it steadily crosses into the systemic circulation and reaches the lungs where it can be detected in the exhaled breath, as a surrogate measure for intestinal CH4 production. Recent reports have shown an association between CH4 and vagal dysfunction as well as the inhibition of CH4 activity on ileal contractions with atropine, suggesting its action on the parasympathetic nervous system. Given these findings, we hypothesized that CH4 may be affecting resting heart rate (HR) based on the potential effect of CH4 on the vagus nerve. OBJECTIVES: Given its possible role in the parasympathetic nervous system, we aimed to study the relationship between breath CH4 and resting HR in humans. Additionally, we performed a longitudinal study analyzing the change in HR and its association with breath CH4 over time. METHODS: First, we reviewed 1,126 subjects and compared HR in subjects with detectable and undetectable breath CH4. Second, we performed a post hoc analysis of a randomized control trial to compare the change in HR for those who had an increase in breath CH4 versus those that had a decrease in breath CH4 over 14 weeks. Last, we assessed whether a larger decrease in CH4 is associated with a larger increase in HR over time. RESULTS: In the retrospective cohort, subjects with detectable CH4 had a lower HR compared to those with undetectable CH4 (73.0 ± 0.83 vs. 76.0 ± 0.44 beats/min, p = 0.01). In the post hoc analysis, a decrease in CH4 over time was associated with an increase in HR (median ∆ = 6.5 ± 8.32 beats/min, p = 0.0006). Last, we demonstrated a biological gradient whereby a larger drop in CH4 was associated with a greater increase in HR (R = -0.31, p = 0.03). CONCLUSION: Our findings suggest a potential role for the microbiome (and specifically CH4 from methanogens) to regulate HR. Considering these findings, mechanistic studies are warranted to further investigate this potential novel microbiome-neurocardiac axis.

Effect of saffron supplementation on oxidative stress parameters: A systematic review and meta-analysis of randomized placebo-controlled trials.

Oxidative stress (OS), the absence of equilibrium between prooxidants and antioxidants in the body, has been shown to play a pivotal role in the initiation and progression of many diseases. Saffron has been noted for its antioxidant capacity and can be used to improve OS parameters in unhealthy patients. Our aim was to evaluate the efficacy of saffron supplementation on OS parameters in unhealthy patients in randomized controlled trials (RCTs). We searched Medline, EMBASE, Cochrane CENTRAL, Scopus, and Web of Science without language restrictions for RCTs up until April 2021. Studies were included if they compared any form of saffron supplementation to placebo or no supplementation on OS parameters in unhealthy patients. Using a random-effects model with calculated standardized mean difference (SMD) and 95% confidence intervals (CI), we quantitatively synthesized the data. Heterogeneity was assessed using Cochrane's I 2 values. Ten randomized controlled trials were eligible for this review. Seven were included in the meta-analysis and indicated an association between saffron intake and a statistically significant decrease in malondialdehyde (MDA) levels (SMD: -0.40; 95% CI: -0.63, -0.17; I 2 = 32.6%) and a significant increase in total antioxidant capacity (TAC, SMD: 0.24; 95% CI: 0.05, 0.42; I 2 = 00.0%). Saffron intake was shown to significantly impact MDA and TAC, indicating its beneficial properties in improving OS in unhealthy patients. However, additional RCTs are required to evaluate the effect on other OS parameters.

Age and the aging process significantly alter the small bowel microbiome.

Gut microbial diversity decreases with aging, but existing studies have used stool samples, which do not represent the entire gut. We analyzed the duodenal microbiome in 251 subjects aged 18-35 (n = 32), 36-50 (n = 41), 51-65 (n = 96), and 66-80 (n = 82). Decreased duodenal microbial diversity in older subjects is associated with combinations of chronological age, number of concomitant diseases, and number of medications used, and also correlated with increasing coliform numbers (p < 0.0001). Relative abundance (RA) of phylum Proteobacteria increases in older subjects, with increased RA of family Enterobacteriaceae and coliform genera Escherichia and Klebsiella, and is associated with alterations in the RA of other duodenal microbial taxa and decreased microbial diversity. Increased RA of specific genera are associated with chronological age only (Escherichia, Lactobacillus, and Enterococcus), number of medications only (Klebsiella), or number of concomitant diseases only (Clostridium and Bilophila). These findings indicate the small intestinal microbiome changes significantly with age and the aging process.

Trigger point injection for post-mastectomy pain: a simple intervention with high rate of long-term relief.

Post-mastectomy pain syndrome (PMPS) is a common and often debilitating condition. The syndrome is defined by chest wall pain unresponsive to standard pain medications and the presence of exquisite point tenderness along the inframammary fold at the site of the T4 and T5 cutaneous intercostal nerve branches as they exit from the chest wall. Pressure at the site triggers and reproduces the patient's spontaneous or motion-evoked pain. The likely pathogenesis is neuroma formation after injury to the T4 and T5 intercostal nerves during breast surgery. We assessed the rate of long-term resolution of post-mastectomy pain after trigger point injections (2 mL of 1:1 mixture of 0.5% bupivacaine and 4 mg/mL dexamethasone) to relieve neuropathic pain in a prospective single-arm cohort study. Fifty-two women (aged 31-92) who underwent partial mastectomy with reduction mammoplasty or mastectomy with or without reconstruction, and who presented with PMPS were enrolled at the University of California San Francisco Breast Care Center from August 2010 through April 2018. The primary outcome was a long-term resolution of pain, defined as significant or complete relief of pain for greater than 3 months. A total of 91 trigger points were treated with mean follow-up 43.9 months with a 91.2% (83/91) success rate. Among those with a long-term resolution of pain, 60 trigger points (72.3%) required a single injection to achieve long-lasting relief. Perineural infiltration with bupivacaine and dexamethasone is a safe, simple, and effective treatment for PMPS presenting as trigger point pain along the inframammary fold.

HER2-Overexpressing Ductal Carcinoma In Situ Associated with Increased Risk of Ipsilateral Invasive Recurrence, Receptor Discordance with Recurrence.

The impact of HER2 status in ductal carcinoma in situ (DCIS) on the risk of progression to invasive ductal carcinoma (IDC) has been debated. We aim to use a national database to identify patients with known HER2 status to elucidate the effect of HER2 overexpression on ipsilateral IDC (iIDC) development. We performed survival analysis on patient-level data using the U.S. NCI's Surveillance Epidemiology and End Results program. We identified patients diagnosed with DCIS who underwent lumpectomy and had known HER2 status. Competing risks analysis was performed. A total of 1,540 patients had known HER2 status and met inclusion criteria. Median age at diagnosis was 60, median follow-up time was 44.5 months. A total of 417 (27.1%) patients were HER2 positive and 1,035 (67.2%) were HER2 negative. Twenty-two (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% for HER2-negative and borderline patients, and 3.9% for HER2-positive patients. On multivariate competing risks regression, two factors were significant for iIDC: radiation (protective) therapy within 24 months (HR, 0.05; P = 0.00006) and HER2 overexpression (increased likelihood; HR, 2.72; P = 0.044). Patients with HER2-positive DCIS were more likely to have recurrences with receptor discordance. HER2 may serve as a prognostic factor for invasive recurrence and was the only lesion-related factor to significantly relate to iIDC development. It may also be associated with receptor discordance of recurrences. Further large studies will be needed to confirm these results.

Worldwide ACE (I/D) polymorphism may affect COVID-19 recovery rate: an ecological meta-regression.

With the emergence of the Novel Coronavirus (2019-nCoV), researchers worldwide have started detecting the probable pathogenesis of the disease. The renin-angiotensin system (RAS) and angiotensin-converting enzymes have received a good deal of attention as possible pathways involved in 2019-nCoV pathogenesis. As the experiments seeking to find potential medications acting on these pathways are being conducted in the early phases, having an ecological worldview on the relationship between the prevalence of COVID-19 disease and the genetic differences in the genes involved in the RAS system could be valuable for the field. In this regard, we conducted a meta-analysis study of the prevalence of ACE (I/D) genotype in countries most affected by the COVID-19. In the meta-analysis, 48,758 healthy subjects from 30 different countries were evaluated in 116 studies, using the Comprehensive Meta-analysis software. The I/D allele frequency ratio was pooled by a random-effect model. The COVID-19 prevalence data of death and recovery rates were evaluated as the latitudes for the meta-regression analysis. Our results demonstrated that with the increase of the I/D allele frequency ratio, the recovery rate significantly increased (point estimate: 0.48, CI 95%: 0.05-0.91, p = 0.027). However, there was no significant difference in the case of death rate (point estimate: 1.74, CI 95%: 4.5-1.04, p = 0.22). This ecological perspective coupled with many limitations does not provide a direct clinical relevance between the COVID-19 and RAS system, but it shows potential pathophysiological associations. Our results raise concerns about ethnic and genetic differences that could affect the effectiveness of the currently investigated RAS-associated medications in different regions.

Erector spinae plane versus paravertebral nerve blocks for postoperative analgesia after breast surgery: a randomized clinical trial.

BACKGROUND: Paravertebral nerve blocks (PVBs) are frequently used to treat pain during and following breast surgery, but have various undesirable risks such as pneumothorax. The erector spinae plane block (ESPB) also provides perioperative breast analgesia, but is purported to be easier to administer with a favorable safety profile. However, it remains unknown if the new ESPB provides comparable analgesia as the decades-old PVB technique. METHODS: Subjects undergoing unilateral or bilateral non-mastectomy breast surgery were randomized to a single-injection ESPB or PVB in a subject-blinded fashion (ropivacaine 0.5% with epinephrine; 20 mL unilateral or 16 mL/side for bilateral). We hypothesized that (1) analgesia would be non-inferior in the recovery room as measured on a Numeric Rating Scale (NRS) with ESPB, and (2) opioid consumption would be non-inferior in the operating and recovery rooms with ESPB. RESULTS: Both pain scores and opioid consumption were higher in subjects with ESPBs (n=50) than PVBs (n=50; median NRS 3.0 vs 0; 95% CI -3.0 to 0; p=0.0011; and median morphine equivalents 2.0 vs 1.5 mg; 95% CI -1.2 to -0.1; p=0.0043). No block-related adverse events occurred in either group. CONCLUSIONS: PVBs provided superior analgesia and reduced opioid requirements following non-mastectomy breast surgery. To compare the relatively rare complications between the techniques will require a sample size 1-2 orders of magnitude greater than the current investigation; however, without a dramatic improvement in safety profile for ESPBs, it appears that PVBs are superior to ESPBs for postoperative analgesia after non-mastectomy breast surgery. TRIAL REGISTRATION NUMBER: NCT03549234.

Ultrasound-guided percutaneous intercostal cryoanalgesia for multiple weeks of analgesia following mastectomy: a case series.

BACKGROUND: Acute post-mastectomy pain is frequently challenging to adequately treat with local anesthetic-based regional anesthesia techniques due to its relatively long duration measured in multiple weeks. CASE: We report three cases in which preoperative ultrasound-guided percutaneous intercostal nerve cryoneurolysis was performed to treat pain following mastectomy. Across all postoperative days and all three patients, the mean pain score on the numeric rating scale was 0 for each day. Similarly, no patient required any supplemental opioid analgesics during the entire postoperative period; and, no patient reported insomnia or awakenings due to pain at any time point. This was a significant improvement over historic cohorts. CONCLUSIONS: Ultrasound-guided percutaneous cryoanalgesia is a potential novel analgesic modality for acute pain management which has a duration that better-matches mastectomy than other currently-described techniques. Appropriately powered randomized, controlled clinical trials are required to demonstrate and quantify both potential benefits and risks.

Changes in mammographic density following bariatric surgery.

BACKGROUND: Obesity and high breast density both increase breast cancer risk but paradoxically are inversely related. Bariatric surgery decreases breast cancer risk, but its impact on mammographic breast density is not well understood. OBJECTIVES: We investigated how mammographic density changes after bariatric surgery and whether this change is related to weight loss. SETTING: University of California, San Francisco Medical Center. METHODS: We reviewed records from 349 prospectively collected patients who underwent bariatric surgery between 2013 and 2015 and identified 42 women with pre- and postoperative screening mammograms within 1.5 years of surgery. We recorded body mass index (BMI), height and Breast Imaging Reporting and Data System density and calculated BMI loss and total weight loss. Data were analyzed in Stata 14.2. RESULTS: Average age was 54.2 years, mean preoperative BMI was 43.8 kg/m2, mean BMI lost was 30.9%, and total weight loss was 31.1% at 1.3 years. Over one-third had a change in mammographic breast density, which increased 93.3% of the time (P < .001). Amount of weight loss was not associated with a density change. Patients with the lowest mammographic density preoperatively were most likely to have a density change (P = .02). CONCLUSIONS: Most women with a mammographic change had an increase in breast density, despite bariatric surgery being associated with reduced breast cancer risk. Baseline breast density was associated with a density change, but amount of weight loss was not. These findings suggest the metabolic effects of bariatric surgery have an effect on breast parenchyma independent of absolute BMI reduction or weight loss.

Tc-99m tilmanocept versus Tc-99m sulfur colloid in breast cancer sentinel lymph node identification: Results from a randomized, blinded clinical trial.

INTRODUCTION: No prior trials have compared sentinel lymph node (SLN) identification outcomes between Tc-99m tilmanocept (TcTM) and Tc-99m sulfur colloid (TcSC) in breast cancer (BC). METHODS: We report on the secondary outcomes from a randomized, double-blinded, single surgeon clinical trial comparing post-injection site pain between TcTM and TcSC. Patients were randomized to receive a preoperative single, peritumoral intradermal injection of TcTM or TcSC. The number of total, "hot", and blue nodes detected and removed were compared between groups. RESULTS: Fifty-two (27-TcSC and 25-TcTM) patients were enrolled and underwent definitive surgical treatment. At least one "hot" SLN was detected in all patients. Three (5.8%) patients had a disease positive-SLN. The total number of SLNs removed was 61 (mean 2.26 (standard deviation (SD) 0.90)) in the TcSC group and 54 (mean 2.16 (SD 0.90)) in the TcTM group, P = 0.69. The total number of "hot" nodes in the TcSC group was 1.96 (SD 0.76) compared to 2.04 (SD 0.73) in the TcTM group, P = 0.71. CONCLUSIONS: The number of identified SLNs did not differ significantly between TcTM and TcSC. Given that no significant technical advantages exist between the two agents, surgeons should choose a radiopharmaceutical based on cost and side effect profile.