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Clostridium difficile infection (CDI) is characterized by dysbiosis of the intestinal microbiota and a profound derangement in the fecal metabolome. However, the contribution of specific gut microbes to fecal metabolites in C. difficile-associated gut microbiome remains poorly understood. Using gas-chromatography mass spectrometry (GC-MS) and 16S rRNA deep sequencing, we analyzed the metabolome and microbiome of fecal samples obtained longitudinally from subjects with Clostridium difficile infection (n = 7) and healthy controls (n = 6). From 155 fecal metabolites, we identified two sterol metabolites at >95% match to cholesterol and coprostanol that significantly discriminated C. difficile-associated gut microbiome from healthy microbiota. By correlating the levels of cholesterol and coprostanol in fecal extracts with 2,395 bacterial operational taxonomic units (OTUs) determined by 16S rRNA sequencing, we identified 63 OTUs associated with high levels of coprostanol and 2 OTUs correlated with low coprostanol levels. Using indicator species analysis (ISA), 31 of the 63 coprostanol-associated bacteria correlated with health, and two Veillonella species were associated with low coprostanol levels that correlated strongly with CDI. These 65 bacterial taxa could be clustered into 12 sub-communities, with each community containing a consortium of organisms that co-occurred with one another. Our studies identified 63 human gut microbes associated with cholesterol-reducing activities. Given the importance of gut bacteria in reducing and eliminating cholesterol from the GI tract, these results support the recent finding that gut microbiome may play an important role in host lipid metabolism.

A substantial proportion of patients with non-metastatic triple-negative breast cancer (TNBC) experience disease progression and death despite treatment. However, no tool currently exists to discriminate those at higher risk of death. To identify high-risk TNBC, we conducted a retrospective analysis of 749 patients from two independent cohorts. We built a prediction model that leverages breast magnetic resonance imaging (MRI) features to predict risk groups based on a 50-gene Transcriptomics Signature (TS). The TS distinguished patients with high-risk for death in multivariate survival analysis (Transcriptomic cohort: [HR] = 13.6, 95% confidence interval [CI] = 1.56-1, p  = 0.02; SCAN-B cohort: HR = 1.45, CI 1.04-2.03, p  = 0.02). The model identified a 20-feature radiomic signature derived from breast MRI that predicted the TS-based risk groups. This imaging-based classifier was applied to a validation cohort (log rank p  = 0.013, accuracy 0.72, AUC 0.71, F1 0.74, precision 0.67, and recall 0.82), detecting a 25% absolute survival difference between high- and low-risk groups after 5 years.

The aim was to describe the changes in body size and age at menarche in anthropologically distinct ethnic groups – Komi-Permyaks (KP) and Russians (RU) – of Permsky Krai that occurred in the last century, with a special concern to the urban-rural differences. The comparison of the 1861–1865 and 1990 birth cohorts (BiCo) revealed following results. In RU rural males the increase in stature (ST) was 10.8 cm (p < 0.001). The chest circumference has increased by 5.9 cm, but it is unsubstantial 0.25% when measured in relative to ST values. In RU urban males the overall increase in ST was 10.8 cm (p < 0.001), chest circumference increased by 10.5 cm. The peak increase in ST (+1.36 cm per decade) was attained between the 1964 and the 1990 BiCo. The data on body dimensions of RU females available only from the 1960s to 1990. The ST of rural females has not changed, but the absolute and the relative (to ST) values of pelvic width of the 1980–1989 BiCo are significantly (p < 0.05) lower than in the 1966–1975 and 1965 BiCo. The RU urban females of the 1985 BiCo are 3.6 cm taller than 1964 BiCo (p < 0.001), but over the next 5 years the ST decreased by 2 cm (p = 0.06). The relative pelvic width has decreased from 17.57% (BiCo 1965–1969) to 17.18% (BiCo 1980–1989; p < 0.05). Menarcheal age of Perm females declined from 14.5 yrs in the 1930–1939 BiCo to 13.3 yrs in 1950–1965 BiCo, then ceased to change. The changes across generations in rural KP were weak. The rural males born in 1885 were 2.1 cm teller than BiCo 1861–1865. From the 1925 to 1975 BiCo the average ST increased by 6.2 cm (1.24 cm/decade). KP rural females became 6.4 cm taller from the 1885 to 1985 BiCo. Pelvic width in the 1985 BiCo (27.4 cm) is significantly bigger (p < 0.05) than in the 1975 BiCo (26.9 cm). The changes in ST of urban KP females were more obvious than in rural groups. The 1985 BiCo of urban KP females (ST 161.8 cm) are taller than those born in 1965 (159.4 cm;p < 0.05), but their pelvic width does not differ. In urban and rural KP females age at menarche is earlier in the 1976–1985 than in the 1966–1975 BiCo (p < 0.01). In all the KP cohorts, urban females have earlier menarche than rural (p < 0.05).

Vitamin D status in groups of northern indigenous people of Russia leading close to traditional (seminomadic reindeer herding), post-traditional (in settlements) or \"modernized\" (in towns) way of life was analysed. The survey study groups consisted of 178 Nenets and Komi aged 18-60 living in the Arctic (66-67°N). Urban Komi, Udmurts and Komi-Permiaks (n=150) living in a non-Arctic area (57-61°N) formed a control group. The concentration of serum 25-hydroxyvitamin D (25OHD), as a transport form of vitamin D, was assessed by enzyme immunoassay analysis. The group average 25OHD levels in both rural and urban Arctic residents are within the range of values seen in the non-Arctic urban subjects adjusted for season: 39.7-47.7 nmol/l. Abandoning traditional lifestyle associates with lower vitamin D levels in indigenous Arctic people. Mean±standard deviation 25OHD values among Nenets were lower in those living in the administrative centre (a big settlement) with a population of 1,460 (32.2±12.90 nmol/l) than in the residents of small settlements (39.6±14.08 nmol/l), and in reindeer herders (42.4±13.45 nmol/l; p<0.05 in both cases). Komi townspeople had lower 25OHD concentrations (47.7±12.00 nmol/l) than Komi reindeer herders (68.7±25.20; p<0.01). The transition from seminomadic to post-traditional and \"modernized\" way of life has led to a decrease in the consumption of traditional foods among the indigenous people of the Russian Arctic. Our data support the notion that the traditional northern diet promotes healthy vitamin D levels, while adherence to the \"western\" type of diet correlates with a lower 25OHD concentration.

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.Neoadjuvant PD-1 blockade in patients with resectable melanoma followed by adjuvant maintenance results in early immunological effects driving clinical benefit and reveals transcriptional and genomic mechanisms of response.

Objectives The aim of this study was to determine whether lesion size metrics on consecutive screening mammograms could predict malignant invasive carcinoma versus benign lesion outcome. Methods We retrospectively reviewed suspicious screen-detected lesions confirmed by biopsy to be invasive breast cancers or benign that were visible on current and in-retrospect prior screening mammograms performed with digital breast tomosynthesis from 2017 to 2020. Four experienced radiologists recorded mammogram dates, breast density, lesion type, lesion diameter, and morphology on current and prior exams. We used logistic regression models to evaluate the association of invasive breast cancer outcome with lesion size metrics such as maximum dimension, average dimension, volume, and tumor volume doubling time (TVDT). Results Twenty-eight patients with invasive ductal carcinoma or invasive lobular carcinoma and 40 patients with benign lesions were identified. The mean TVDT was significantly shorter for invasive breast cancers compared to benign lesions (0.84 vs. 2.5 years; p = 0.0025). Patients with a TVDT of less than 1 year were shown to have an odds ratio of invasive cancer of 6.33 (95% confidence interval, 2.18–18.43). Logistic regression adjusted for age, lesion maximum dimension, and lesion volume demonstrated that shorter TVDT was the size variable significantly associated with invasive cancer outcome. Conclusion Invasive breast cancers detected on current and in-retrospect prior screening mammograms are associated with shorter TVDT compared to benign lesions. If confirmed to be sufficiently predictive of benignity in larger studies, lesions visible on mammograms which in comparison to prior exams have longer TVDTs could potentially avoid additional imaging and/or biopsy. Key Points • We propose tumor volume doubling time as a measure to distinguish benign from invasive breast cancer lesions. • Logistic regression results summarized the utility of the odds ratio in retrospective clinical mammography data.

Intra-abdominal abscesses are localized collections of pus, which generally arise from a breach in the normal mucosal defense barrier that allows bacteria from gastrointestinal tract, and less commonly from the gynecologic or urinary tract, to induce inflammation, resulting in an infection. The microbiology of these abscesses is usually polymicrobial, associated with the primary disease process. However, the microbial identity, diversity and richness in intra-abdominal abscesses have not been well characterized, due in part to the difficulty in cultivating commensal organisms using standard culture-based techniques. We used culture-independent 16S rRNA Illumina sequencing to characterize bacterial communities in intra-abdominal abscesses collected by percutaneous drainage. A total of 43 abscess samples, including 19 (44.2%) Gram stain and culture-negative specimens, were analyzed and compared with results from conventional microbiologic cultures. Microbial composition was determined in 8 of 19 culture-negative samples and 18 of 24 culture-positive samples, identifying a total of 221 bacterial taxa or operational taxonomic units (OTUs) and averaging 13.1 OTUs per sample (interquartile range, 8-16.5 OTUs). Microbial richness for monomicrobial and polymicrobial samples was significantly higher than culture-negative samples (17 and 15.2 OTUs vs 8 OTUs, respectively), with a trend toward a higher microbial diversity (Shannon diversity index of 0.87 and 1.18 vs 0.58, respectively). The bacterial consortia identified by cultures correlated poorly with the microbial composition determined by 16S rRNA sequencing, and in most cases, the cultured isolates were minority constituents of the overall abscess microbiome. Intra-abdominal abscesses were generally polymicrobial with a surprisingly high microbial diversity, but standard culture-based techniques failed to reveal this diversity. These data suggest that molecular-based approaches may be helpful for documenting the presence of bacteria in intra-abdominal abscesses where standard cultures are unrevealing, particularly in the setting of prior antibiotic exposure.

Northwest Siberia is geographically remote territory, which has been settled by indigenous human populations probably since the Upper Paleolithic. To investigate the genetic landscape of Northwest Siberians, we have analyzed mitochondrial and Y chromosome DNA polymorphisms of 169 unrelated individuals from Khanty and Mansi ethnic groups in Northwest Siberia. In addition, HVS-I sequences ( N =3522) and Y chromosome SNP data ( N =2175), obtained from the literature, were used to elucidate the genetic relationships among the North Eurasian populations. The results show clinal distributions of mtDNA and Y chromosome haplogroups along East–West axis of Northern Eurasia. In this context, the Ugric-speaking Khanty and Mansi appear as unique intermediate populations carrying Upper Paleolithic and more recent haplotypes typical for both West and East Eurasian gene pools. This admixture indicates that the Khanty and Mansi populations have resided in the contact zone of genetically distinguishable eastern and western Eurasia.

Abstract An analysis of changing diet patterns during the Soviet and post-Soviet periods was carried out among sea mammal hunters (villages of Lorino and Lavrentiya) and reindeer herders (village of Vaegi) of Chukotka. Economic and ethnic factors in the choice of food were investigated. The results show that both studied groups are developing diets that substantially differ from both the traditional and the “Soviet” ones.

Background Vitamin D status in groups of northern indigenous people of Russia leading close to traditional (seminomadic reindeer herding), post-traditional (in settlements) or \"modernized\" (in towns) way of life was analysed. Design The survey study groups consisted of 178 Nenets and Komi aged 18-60 living in the Arctic (66-67°N). Urban Komi, Udmurts and Komi-Permiaks (n=150) living in a non-Arctic area (57-61°N) formed a control group. The concentration of serum 25-hydroxyvitamin D (25OHD), as a transport form of vitamin D, was assessed by enzyme immunoassay analysis. Results The group average 25OHD levels in both rural and urban Arctic residents are within the range of values seen in the non-Arctic urban subjects adjusted for season: 39.7-47.7 nmol/l. Abandoning traditional lifestyle associates with lower vitamin D levels in indigenous Arctic people. Mean±standard deviation 25OHD values among Nenets were lower in those living in the administrative centre (a big settlement) with a population of 1,460 (32.2±12.90 nmol/l) than in the residents of small settlements (39.6±14.08 nmol/l), and in reindeer herders (42.4±13.45 nmol/l; p<0.05 in both cases). Komi townspeople had lower 25OHD concentrations (47.7±12.00 nmol/l) than Komi reindeer herders (68.7±25.20; p<0.01). Conclusions The transition from seminomadic to post-traditional and \"modernized\" way of life has led to a decrease in the consumption of traditional foods among the indigenous people of the Russian Arctic. Our data support the notion that the traditional northern diet promotes healthy vitamin D levels, while adherence to the \"western\" type of diet correlates with a lower 25OHD concentration.