High-throughput transcriptomics of 409 bacteria-drug pairs reveals drivers of gut microbiota perturbation.

Many drugs can perturb the gut microbiome, potentially leading to negative health consequences. However, mechanisms of most microorganism-drug responses have not been elucidated at the genetic level. Using high-throughput bacterial transcriptomics, we systematically characterized the gene expression profiles of prevalent human gut bacteria exposed to the most frequently prescribed orally administered pharmaceuticals. Across >400 drug-microorganism pairs, significant and reproducible transcriptional responses were observed, including pathways involved in multidrug resistance, metabolite transport, tartrate metabolism and riboflavin biosynthesis. Importantly, we discovered that statin-mediated upregulation of the AcrAB-TolC efflux pump in Bacteroidales species enhances microbial sensitivity to vitamin A and secondary bile acids. Moreover, gut bacteria carrying acrAB-tolC genes are depleted in patients taking simvastatin, suggesting that drug-efflux interactions generate collateral toxicity that depletes pump-containing microorganisms from patient microbiomes. This study provides a resource to further understand the drivers of drug-mediated microbiota shifts for better informed clinical interventions.

Prospective Cohort Study to Compare Long-Term Lung Cancer-Specific and All-Cause Survival of Clinical Early Stage (T1a-b; ≤20 mm) NSCLC Treated by Stereotactic Body Radiation Therapy and Surgery.

INTRODUCTION: We aimed to compare outcomes of patients with first primary clinical T1a-bN0M0 NSCLC treated with surgery or stereotactic body radiation therapy (SBRT). METHODS: We identified patients with first primary clinical T1a-bN0M0 NSCLCs on last pretreatment computed tomography treated by surgery or SBRT in the following two prospective cohorts: International Early Lung Cancer Action Program (I-ELCAP) and Initiative for Early Lung Cancer Research on Treatment (IELCART). Lung cancer-specific survival and all-cause survival after diagnosis were compared using Kaplan-Meier analysis. Propensity score matching was used to balance baseline demographics and comorbidities and analyzed using Cox proportional hazards regression. RESULTS: Of 1115 patients with NSCLC, 1003 had surgery and 112 had SBRT; 525 in I-ELCAP in 1992 to 2021 and 590 in IELCART in 2016 to 2021. Median follow-up was 57.6 months. Ten-year lung cancer-specific survival was not significantly different: 90% (95% confidence interval: 87%-92%) for surgery versus 88% (95% confidence interval: 77%-99%) for SBRT, p = 0.55. Cox regression revealed no significant difference in lung cancer-specific survival for the combined cohorts (p = 0.48) or separately for I-ELCAP (p = 1.00) and IELCART (p = 1.00). Although 10-year all-cause survival was significantly different (75% versus 45%, p < 0.0001), after propensity score matching, all-cause survival using Cox regression was no longer different for the combined cohorts (p = 0.74) or separately for I-ELCAP (p = 1.00) and IELCART (p = 0.62). CONCLUSIONS: This first prospectively collected cohort analysis of long-term survival of small, early NSCLCs revealed that lung cancer-specific survival was high for both treatments and not significantly different (p = 0.48) and that all-cause survival after propensity matching was not significantly different (p = 0.74). This supports SBRT as an alternative treatment option for small, early NSCLCs which is especially important with their increasing frequency owing to low-dose computed tomography screening. Furthermore, treatment decisions are influenced by many different factors and should be personalized on the basis of the unique circumstances of each patient.

Comprehensive, Evidence-Based, Consensus Guidelines for Prescription of Opioids for Chronic Non-Cancer Pain from the American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. OBJECTIVES: In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. METHODS: The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed. The multidisciplinary panel finalized 20 guideline recommendations for prescription of opioids for chronic non-cancer pain. Summary of the results showed over 90% agreement for the final 20 recommendations with strong consensus. The consensus guidelines included 4 sections specific to opioid therapy with 1) ten recommendations particular to initial steps of opioid therapy; 2) five recommendations for assessment of effectiveness of opioid therapy; 3) three recommendations regarding monitoring adherence and side effects; and 4) two general, final phase recommendations. LIMITATIONS: There is a continued paucity of literature of long-term opioid therapy addressing chronic non-cancer pain. Further, significant biases exist in the preparation of guidelines, which has led to highly variable rules and regulations across various states. CONCLUSION: These guidelines were developed based upon a comprehensive review of the literature, consensus among expert panelists, and in alignment with patient preferences, and shared decision-making so as to improve the long-term pain relief and function in patients with chronic non-cancer pain. Consequently, it was concluded - and herein recommended - that chronic opioid therapy should be provided in low doses with appropriate adherence monitoring and understanding of adverse events only to those patients with a proven medical necessity, and who exhibit stable improvement in both pain relief and activities of daily function, either independently or in conjunction with other modalities of treatments.

Comprehensive, evidence-based, consensus guidelines for prescription of opioids for chronic non-cancer pain from the American Society of Interventional Pain Physicians (ASIPP)

Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed

Eradicating Pulmonary Mycobacterium abscessus: The Promise of Dual ß-Lactam Therapy.

Macrolide resistance has rendered the treatment of Mycobacterium abscessus extremely difficult and is fueling a crisis. Recently, there has been dramatically increased incidence of infections by M abscessus. Select dual ß-lactam combinations have shown promising in vitro results. Herein, we present a patient whose M abscessus infection cured using dual ß-lactams as part of multidrug regimen.

High-throughput microbial culturomics using automation and machine learning.

Pure bacterial cultures remain essential for detailed experimental and mechanistic studies in microbiome research, and traditional methods to isolate individual bacteria from complex microbial ecosystems are labor-intensive, difficult-to-scale and lack phenotype-genotype integration. Here we describe an open-source high-throughput robotic strain isolation platform for the rapid generation of isolates on demand. We develop a machine learning approach that leverages colony morphology and genomic data to maximize the diversity of microbes isolated and enable targeted picking of specific genera. Application of this platform on fecal samples from 20 humans yields personalized gut microbiome biobanks totaling 26,997 isolates that represented >80% of all abundant taxa. Spatial analysis on >100,000 visually captured colonies reveals cogrowth patterns between Ruminococcaceae, Bacteroidaceae, Coriobacteriaceae and Bifidobacteriaceae families that suggest important microbial interactions. Comparative analysis of 1,197 high-quality genomes from these biobanks shows interesting intra- and interpersonal strain evolution, selection and horizontal gene transfer. This culturomics framework should empower new research efforts to systematize the collection and quantitative analysis of imaging-based phenotypes with high-resolution genomics data for many emerging microbiome studies.

Resurrecting essential amino acid biosynthesis in mammalian cells.

Major genomic deletions in independent eukaryotic lineages have led to repeated ancestral loss of biosynthesis pathways for nine of the twenty canonical amino acids. While the evolutionary forces driving these polyphyletic deletion events are not well understood, the consequence is that extant metazoans are unable to produce nine essential amino acids (EAAs). Previous studies have highlighted that EAA biosynthesis tends to be more energetically costly, raising the possibility that these pathways were lost from organisms with access to abundant EAAs. It is unclear whether present-day metazoans can reaccept these pathways to resurrect biosynthetic capabilities that were lost long ago or whether evolution has rendered EAA pathways incompatible with metazoan metabolism. Here, we report progress on a large-scale synthetic genomics effort to reestablish EAA biosynthetic functionality in mammalian cells. We designed codon-optimized biosynthesis pathways based on genes mined from Escherichia coli. These pathways were de novo synthesized in 3 kilobase chunks, assembled in yeasto and genomically integrated into a Chinese hamster ovary (CHO) cell line. One synthetic pathway produced valine at a sufficient level for cell viability and proliferation. 13C-tracing verified de novo biosynthesis of valine and further revealed build-up of pathway intermediate 2,3-dihydroxy-3-isovalerate. Increasing the dosage of downstream ilvD boosted pathway performance and allowed for long-term propagation of second-generation cells in valine-free medium at 3.2 days per doubling. This work demonstrates that mammalian metabolism is amenable to restoration of ancient core pathways, paving a path for genome-scale efforts to synthetically restore metabolic functions to the metazoan lineage.

Comparison of lung cancer aggressiveness in patients who never smoked compared to those who smoked.

OBJECTIVES: To determine whether radiographic measures of tumor aggressiveness differ by smoking status. MATERIALS AND METHODS: All patients diagnosed with non-small-cell lung cancer(NSCLC) ≤ 30 mm in maximum diameter, without clinical evidence of metastasis who had both pre-treatment PET scans and two CT scans at least 90 days apart in a prospective cohort, the Initiative for Early Lung Cancer Research on Treatment(IELCART) at Mount Sinai between 2016 and 2020 were identified. Comparison of two measures of tumor aggressiveness, positron emission tomography(PET) SUVmax and tumor volume doubling time(VDT) by smoking status was performed. RESULTS: Of 417 patients identified, 158 patients had pre-treatment PET scans and at least two CT scans available. The two measures of tumor aggressiveness, SUVmax and VDT values were significantly different between patients who had never smoked and those who smoked: patients who never smoked had lower median SUVmax[2.5(IQR: 1.1-4.8) vs. 4.2(IQR:2.1-9.2),p = 0.002] and longer median VDT[(372.6 days vs. 225.6 days,p = 0.001)] compared to those who smoked. Using multivariable analyses, when adjusting for age and sex alone, SUVmax(p = 0.004) and VDT(p = 0.0001) remained significantly different by smoking status. The final multivariable analysis, adjusted for all three co-variates(sex, age and tumor histology) showed no significant difference in SUVmax and VDT by smoking status [SUVmax(p = 0.25) and VDT(p = 0.06)]. CONCLUSION: Smoking history does not influence VDT or PET SUVmax measures of lung cancer aggressiveness.

"When to Nuss? patient age as a risk factor for complications of minimally invasive repair of pectus excavatum: a systematic review and meta-analysis".

PURPOSE: The optimal age for minimally invasive repair of pectus excavatum (MIRPE) is unclear; this study investigates the differences in complication rates among different age groups undergoing repair. METHODS: PubMed and Embase databases were searched from inception to October 2020. To assess age as a risk factor for complications, odds ratios from relevant studies were analyzed using the Mantel-Haenszel method with a random-effects model for younger vs older patients. Specific complication rates were compared between the two cohorts using a chi-squared test. RESULTS: Of the 4448 studies retrieved, 25 studies stratified complication data by age groups. From these studies, ten studies compared groups at ages < 18 and ≥ 18 and four studies compared ages < 20 and ≥ 20, and one study compared ages < 19 and ≥ 19. These fifteen studies reported on 5978 patients, with 1188 complications, for a complication rate of 19.87%. Older patients were more likely to have complications in a pooled analysis of studies comparing older vs younger patients (OR = 1.66, 95% CI = 1.28-2.14, heterogeneity I2 = 49%). Specifically, older patients were significantly more likely to experience pneumothorax, pleural effusion, wound infection, bar displacement, and reoperations. CONCLUSION: Increased age is a risk factor for complications of MIRPE. This supports repair of pectus excavatum prior to late adolescence.

Engineering living and regenerative fungal-bacterial biocomposite structures.

Engineered living materials could have the capacity to self-repair and self-replicate, sense local and distant disturbances in their environment, and respond with functionalities for reporting, actuation or remediation. However, few engineered living materials are capable of both responsivity and use in macroscopic structures. Here we describe the development, characterization and engineering of a fungal-bacterial biocomposite grown on lignocellulosic feedstocks that can form mouldable, foldable and regenerative living structures. We have developed strategies to make human-scale biocomposite structures using mould-based and origami-inspired growth and assembly paradigms. Microbiome profiling of the biocomposite over multiple generations enabled the identification of a dominant bacterial component, Pantoea agglomerans, which was further isolated and developed into a new chassis. We introduced engineered P. agglomerans into native feedstocks to yield living blocks with new biosynthetic and sensing-reporting capabilities. Bioprospecting the native microbiota to develop engineerable chassis constitutes an important strategy to facilitate the development of living biomaterials with new properties and functionalities.

Single-stage long-segment tracheal transplantation.

Tracheal transplantation has been envisioned as a viable option for reconstruction of long-segment tracheal defects. We report the first human single-stage long-segment tracheal transplantation. Narrow-band imaging and bronchoscopic biopsies demonstrate allograft vascularization and viable epithelial lining. The recipient was immunosuppressed with Tacrolimus, Mycophenolate mofetil, and corticosteroids. Six months after transplantation, the trachea is both functional and the patient is breathing without the need of a tracheostomy or stent.

Major modifications to minimize thoracic esophago-gastric leak and eradicate esophageal stricture after Ivor Lewis esophagectomy.

BACKGROUND: The Ivor Lewis esophagectomy (ILE) remains the procedure of choice for localized middle or lower esophageal carcinoma. Nevertheless, anastomotic leak remains a common complication with rates from 3% to 25% and a stricture rate as high as 40%. The frequency of these complications suggests that the procedure itself may have inherent limitations including the use of potentially ischemic tissue for the esophagogastric anastomosis. We introduce a modified technique that reduces operative steps, preserves blood supply, and uses a modified esophagogastric anastomosis. METHODS: All consecutive patients undergoing ILE with the described modified technique were identified. An esophagram was performed on postoperative day six or seven. To ensure that all cases were identified, anastomotic leaks were defined as any radiographic evidence of contrast extravasation. RESULTS: A total of 110 patients underwent the modified esophagectomy with 2 anastomotic leaks (1.82%) and zero strictures. There was 1 late death but no early deaths (<30 or 90 days) or early re-admissions (<30 days). The average number of risk factors was 2.12, and 98 patients (90%) had at least 1 risk factor in their medical history. CONCLUSIONS: The modifications proposed simplify procedural steps, limit unnecessary dissection and introduce a technique that ends the practice of connecting ischemic tissue. We believe this technique contributes to surgical durability and reduces the rate of postoperative leak and eliminates stricture.

Correction: Taste loss with obesity in mice and men.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Are Opioids Needed to Treat Chronic Low Back Pain? A Review of Treatment Options and Analgesics in Development.

The continued prevalence of chronic low back pain (CLBP) is a testament to our lack of understanding of the potential causes, leading to significant treatment challenges. CLBP is the leading cause of years lived with disability and the fifth leading cause of disability-adjusted life-years. No single non-pharmacologic, pharmacologic, or interventional therapy has proven effective as treatment for the majority of patients with CLBP. Although non-pharmacologic therapies are generally helpful, they are often ineffective as monotherapy and many patients lack adequate access to these treatments. Noninvasive treatment measures supported by evidence include physical and chiropractic therapy, yoga, acupuncture, and non-opioid and opioid pharmacologic therapy; data suggest a moderate benefit, at most, for any of these therapies. Until our understanding of the pathophysiology and treatment of CLBP advances, clinicians must continue to utilize rational multimodal treatment protocols. Recent Centers for Disease Control and Prevention guidelines for opioid prescribing recommend that opioids not be utilized as first-line therapy and to limit the doses when possible for fear of bothersome or dangerous adverse effects. In combination with the current opioid crisis, this has caused providers to minimize or eliminate opioid therapy when treating patients with chronic pain, leaving many patients suffering despite optimal nonopioid therapies. Therefore, there remains an unmet need for effective and tolerable opioid receptor agonists for the treatment of CLBP with improved safety properties over legacy opioids. There are several such agents in development, including opioids and other agents with novel mechanisms of action. This review critiques non-pharmacologic and pharmacologic treatment modalities for CLBP and examines the potential of novel opioids and other analgesics that may be a useful addition to the treatment options for patients with chronic pain.

Pre-surgical assessment of mediastinal lymph node metastases in Stage IA non-small-cell lung cancers.

OBJECTIVE: Evaluation of sensitivity and specificity of CT and fluorodeoxyglucose-positron emission tomography for pre-surgical staging of mediastinal lymph node metastases (N2/N3) of non-small-cell-lung-cancers ≤30 mm. METHODS: We reviewed a total of 263 patients from a prospective cohort study, who underwent resection including mediastinal lymph nodes, for first primary non-small-cell-lung-cancer ≤30 mm in maximum diameter on pre-surgical CT. Cutoff criteria for short-axis diameter on CT of the largest N2/N3 node of 10, 15, and 20 mm and positron emission uptake of 2.5, 3.0, and 4.0 were evaluated using Area-Under-the-Curve (AUC) assessment. Accuracy criterion was used to determine the optimal cutoffs. RESULTS: Of 263 patients, 9 had nonsolid, 42 part-solid, and 212 solid non-small-cell-lung-cancers. Post-surgically, none of the 51 patients with nonsolid or part-solid cancers had mediastinal lymph node metastases. Among the 212 patients with solid cancers, 23 had N2 node metastases. For the 212 patients with solid cancers, the AUC for CT lymph node measurements was 0.67 (95% CI: 0.57-0.77), significantly higher (p = 0.001) than chance alone, while the AUC for SUVmax measurements, 0.56 (95% CI: 0.48-0.65), was not (p = 0.13). Optimal CT cutoff was >20 mm had low sensitivity of 30.4% (95% CI: 11.6%-49.2%) but high specificity of 99.5% (95% CI: 98.4%-100.0%). CONCLUSION: Based on these results, clinical Stage IA for non-small-cell-lung-cancers with nonsolid, part-solid, or solid consistency should be based on pre-surgical CT maximum tumor diameter and lymph node short-axis measurements on CT ≤20 mm. Further prospective evaluation of these clinical Stage IA staging criteria is needed.

COVID-19 ventilator barotrauma management: less is more.

BACKGROUND: COVID-19 patients requiring mechanical ventilation may develop significant pneumomediastinum and sub-cutaneous emphysema without associated pneumothorax (SWAP). Prophylactic chest tube placement or sub-fascial "blowholes" are usually recommended to prevent tension pneumothorax and clinical decline. Risk of iatrogenic lung injury and release of virus into the environment is high. Incidence and conservative management data of such barotraumatic complications during the COVID-19 pandemic are lacking. METHODS: All patients with mediastinal air and SWAP evaluated by the department of Thoracic Surgery at the Mount Sinai Hospital between March 30 and April 10, 2020 were identified. All patients without pneumothorax were treated conservatively with daily chest x-ray and observation. Three patients had prophylactic chest tube placement prior to the study period without thoracic surgery consultation. RESULTS: There were 29 cases of mediastinal air with SWAP out of 171 COVID positive intubated patients (17.0%) who were treated conservatively. Patients were intubated for an average of 2.4 days before SWAP was identified. 12 patients (41%) had improvement or resolution without intervention. Two patients progressed to pneumothorax 3 and 8 days following initial presentation. Both had chest tubes placed without incident before there were any changes in oxygenation, hemodynamics, supportive medications, or ventilator settings. There were 3 patients who had percutaneous tubes placed before the study period all of whom had significant worsening of their sub-cutaneous air and air leak. CONCLUSIONS: Conservative management of massive sub-cutaneous emphysema without pneumothorax in COVID-19 patients is safe and limits viral exposure to healthcare workers. Placement of chest tubes is discouraged unless a definite sizable pneumothorax develops.

Taste loss with obesity in mice and men.

BACKGROUND: Our sense of taste is critical in defining our food choices and habits. Located primarily in our tongue, taste buds are small assemblies of constantly renewing sensory cells, tasked with evaluating oral stimuli before the food we eat is consumed. METHODS: Using both mice and a free-living human population, we tracked taste papilla abundancy with weight gain, to test for deficiencies in the taste system of obese mice and humans with increased adiposity. RESULTS: Mice fed a high-fat diet for 8 weeks expressed markers for all subtypes of taste cells at a lower level than chow-fed counterparts. This came alongside the loss of markers for taste cell proliferation (Ki-67) and development (ß-catenin), as well as lower fungiform papillae density, consistent with earlier results showing lower circumvallate taste bud abundance in obese mice. Likewise, in a population of college students tracked through 4 years of college attendance, the change in density of fungiform papillae, which house taste buds in the anterior tongue, was negatively correlated with change in neck circumference, a marker of adiposity. CONCLUSIONS: These results highlight changes in taste during weight gain as a potentially important consideration in the study of obesity.