Alaska Native (AN) people have the world’s highest recorded incidence of sporadic colorectal cancer (CRC) (∼91:100,000), whereas rural African (RA) people have the lowest risk (<5:100,000). Previous ...data supported the hypothesis that diet affected CRC risk through its effects on the colonic microbiota that produce tumor-suppressive or -promoting metabolites.
We investigated whether differences in these metabolites may contribute to the high risk of CRC in AN people.
A cross-sectional observational study assessed dietary intake from 32 AN and 21 RA healthy middle-aged volunteers before screening colonoscopy. Analysis of fecal microbiota composition by 16S ribosomal RNA gene sequencing and fecal/urinary metabolites by 1H-NMR spectroscopy was complemented with targeted quantification of fecal SCFAs, bile acids, and functional microbial genes.
Adenomatous polyps were detected in 16 of 32 AN participants, but not found in RA participants. The AN diet contained higher proportions of fat and animal protein and less fiber. AN fecal microbiota showed a compositional predominance of Blautia and Lachnoclostridium, higher microbial capacity for bile acid conversion, and low abundance of some species involved in saccharolytic fermentation (e.g., Prevotellaceae, Ruminococcaceae), but no significant lack of butyrogenic bacteria. Significantly lower concentrations of tumor-suppressive butyrate (22.5 ± 3.1 compared with 47.2 ± 7.3 SEM µmol/g) coincided with significantly higher concentrations of tumor-promoting deoxycholic acid (26.7 ± 4.2 compared with 11 ± 1.9 µmol/g) in AN fecal samples. AN participants had lower quantities of fecal/urinary metabolites than RA participants and metabolite profiles correlated with the abundance of distinct microbial genera in feces. The main microbial and metabolic CRC-associated markers were not significantly altered in AN participants with adenomatous polyps.
The low-fiber, high-fat diet of AN people and exposure to carcinogens derived from diet or environment are associated with a tumor-promoting colonic milieu as reflected by the high rates of adenomatous polyps in AN participants.
FOXN1 performs a pivotal role in the development of thymic epithelium. Homozygous FOXN1 deficiency results in T-B+NK+ SCID while FOXN1 haploinsufficiency is associated with T cell lymphopenia and ...nail dystrophy. We report two patients with variants of uncertain significance (VUS) in FOXN1 who presented with lymphopenia detected on newborn screening.
Patient A is a 17-month-old female born to non-consanguineous parents who presented with lowT-cell receptor excision circles (TRECs). At 2 weeks old, her lymphocyte subset panel revealed low T cells, but normal B and NK cells (Table 1). Follow up at 3 months revealed uptrending T cells and significantly decreased B cells. She had no concerning clinical features or infections at that time. By 6 months, her T cells were again downtrending, but her B cells had normalized. She required antibiotics for acute otitis media, which quickly resolved. At 15 months, T cell lymphopenia persisted (Figure 2). Her infection history was reassuring, developmental milestones met and physical exam notable only for spooned nails.
Patient B is a 4-month-old female also born to non-consanguineous parents presenting with low TRECs. Initial workup at 5 days revealed T cell lymphopenia, but normal B and NK cells (Table 1). At 2 months, CD4 lymphopenia persisted though CD8T cells normalized (Figure 2). She had a self-limiting upper respiratory infection, but otherwise unremarkable infection history. Development and physical exam were normal.
A targeted 429-gene panel for inborn errors of immunity revealed heterozygous FOXN1 VUSs in both Patient A (c.890T > G, p.Ile297Ser) and Patient B (c.890T > C, p.Ile297Thr). Patient A's variant was not present in population databases. Patient B's variant has been observed (gnomAD frequency of 0.007%) but not present in population databases for the patient's ethnicities. Surprisingly, both are located at the same position within the Forkhead domain (Figure 1). Algorithms to predict the effect of missense changes on FOXN1 protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all predicted these variants as likely to be disruptive. Further understanding of the phenotypes associated with heterozygous FOXN1 variants of uncertain significance is crucial to guiding diagnostics, treatment, and prognosis. Table 1Lymphocyte panel results at original presentation (Patient A: 2 weeks old, Patient B: 5 days old). Reference ranges obtained from J Allergy Clin Immunol, Volume 112, Number 5, pp 973–980, November 2003VariantCD4+ CD45RA+ (Naïve CD4+ T Cells, cells/μL)CD4+ CD45RO+ (Memory CD4+ T cells, cells/μL)CD8+ T Cells (cells/μL)CD19+ B Cells (cells/μL)CD16+ CD56+ (NK Cells, cells/μL)Patient Ac.890T>G (p.Ile297Ser)633100518423700Patient Bc.890T>C (p.Ile297Thr)569126122610311Ref range (0–3 months)1200–370060–900560–1700300–2000170–1700 Display omitted Display omitted
Paediatric mastocytosis is a rare clonal disorder characterized by the overproduction and organ infiltration of mast cells. Symptoms are due to mast cell mediator release. Cutaneous mastocytosis is ...the most common presentation in children with systemic disease being rare. Our aim is to provide a practical guideline in differentiating subtypes of paediatric mastocytosis while providing actionable recommendations on diagnosis, clinical management, follow-up and prognosis.
Longitudinal cohort studies of paediatric cutaneous mastocytosis have shown spontaneous remission with favourable prognosis. Hereditary alpha-tryptasemia may coexist with mastocytosis; thus, screening for this disorder is recommended. There is an emerging role for serum tryptase in asthma endotyping and potential for using therapeutic tryptase inhibitors.
Morbidity in paediatric mastocytosis typically arises from symptoms secondary to mast cell mediator release. Prognosis for nonaggressive disease is typically favourable; however, risks for anaphylaxis and psychosocial morbidity may be underestimated. Symptomatic management and anticipatory guidance may help support patients and families throughout the disease course.
There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19.
To determine the safety and efficacy of CCP compared with placebo in hospitalized ...patients with COVID-19 receiving noninvasive supplemental oxygen.
CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation.
A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline).
The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8.
Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval CrI, 0.75-1.18) with posterior probability (PcOR<1 = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; PcOR<1 = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; PcOR<1 = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; PcOR<1 = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06).
In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use.
ClinicalTrials.gov Identifier: NCT04364737.
Our center has adopted many evidence-based practices to improve outcomes for complex abdominal wall reconstruction with porcine dermal matrix. This study analyzed outcomes over time using porcine ...dermal matrix in complex abdominal wall reconstruction.
Prospective, tertiary hernia center data was examined for patients undergoing complex abdominal wall reconstruction with porcine dermal matrix. Early (2008–2014) and Recent (2015–2021) cohorts were defined by dividing the study interval in half. Multivariable analyses of wound complications and recurrence were performed.
Comparing 117 Early vs 245 Recent patients, both groups had high rates of previously repaired hernias (76.1% vs 67.4%; P = .110), Centers for Disease Control and Prevention class 3 or 4 wounds (76.0% vs 66.6%; P = .002), and very large hernia defects (320 ± 317 vs 282 ± 164 cm2; P = .640). Recent patients had higher rates of preoperative botulinum injection (0% vs 21.2%; P < .001), posterior component separation (15.4% vs 35.5%; P < .001), and delayed primary closure (23.1% vs 38.8%; P < .001), but lower rates of concurrent panniculectomy (32.3% vs 27.8%; P = .027) and similar anterior component separation (29.1% vs 18.2%; P = .060). Most mesh was placed preperitoneal (74.4% vs 93.3%; P < .001). Recent patients had less inlay (9.4% vs 2.1%; P < .01) and other mesh locations as fascial closure rate increased (88.0% vs 95.5%; P < .001). Over time, there was a decrease in wound complications (42.1% vs 14.3%; P < .001), length of stay (median interquartile range:8 6–13 vs 7 6–9; P = .003), and 30-day readmissions (32.7% vs 10.3%; P < .001). Hernia recurrence decreased (10.3% vs 3.7%; P = .016) with mean follow-up of 2.8 ± 3.2 and 1.7 ± 1.7 years, respectively.
Respective multivariable models(odds ratio, 95% confidence interval) demonstrated an increased risk of wound complications with diabetes (2.65, 1.16–5.98; P = .020), panniculectomy (2.63, 1.21–5.73; P = .014), and anterior component separation (5.1, 1.98–12.9; P < .001), with recurrence risk increased by wound complication (3.8, 1.4-2-7.62; P = .032).
Porcine dermal matrix in complex abdominal wall reconstruction performs well with low recurrence rates. Internal assessment and implementation of evidence-based practices improved outcomes such as length of stay, wound complications, and recurrence rate.
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