Changes in the Vaginal Microbiome and Associated Toxicities Following Radiation Therapy for Gynecologic Cancers

Postmenopausal women often suffer from vaginal symptoms associated with atrophic vaginitis. Additionally, gynecologic cancer survivors may live for decades with additional, clinically significant, persistent vaginal toxicities caused by cancer therapies, including pain, dyspareunia, and sexual dysfunction. The vaginal microbiome (VM) has been previously linked with vaginal symptoms related to menopause (i.e. dryness). Our previous work showed that gynecologic cancer patients exhibit distinct VM profiles from healthy women, with low abundance of lactobacilli and prevalence of multiple opportunistic pathogenic bacteria. Here we explore the association between the dynamics and structure of the vaginal microbiome with the manifestation and persistence of vaginal symptoms, during one year after completion of cancer therapies, while controlling for clinical and sociodemographic factors. We compared cross-sectionally the vaginal microbiome in 134 women, 64 gynecologic patients treated with radiotherapy and 68 healthy controls, and we longitudinally followed a subset of 52 women quarterly (4 times in a year: pre-radiation therapy, 2, 6 and 12 months post-therapy). Differences among the VM profiles of cancer and healthy women were more pronounced with the progression of time. Cancer patients had higher diversity VMs and a variety of vaginal community types (CTs) that are not dominated by Lactobacilli, with extensive VM variation between individuals. Additionally, cancer patients exhibit highly unstable VMs (based on Bray-Curtis distances) compared to healthy controls. Vaginal symptoms prevalent in cancer patients included vaginal pain (40%), hemorrhage (35%), vaginismus (28%) and inflammation (20%), while symptoms such as dryness (45%), lack of lubrication (33%) and dyspareunia (32%) were equally or more prominent in healthy women at baseline. However, 24% of cancer patients experienced persistent symptoms at all time points, as opposed to 12% of healthy women. Symptom persistence was strongly inversely correlated with VM stability; for example, patients with persistent dryness or abnormally high pH have the most unstable microbiomes. Associations were identified between vaginal symptoms and individual bacterial taxa, including: Prevotella with vaginal dryness, Delftia with pain following vaginal intercourse, and Gemillaceaea with low levels of lubrication during intercourse. Taken together our results indicate that gynecologic cancer therapy is associated with reduced vaginal microbiome stability and vaginal symptom persistence.

COVEVOL: Natural Evolution at 6 Months of COVID-19

Many studies have investigated post-COVID symptoms, but the predictors of symptom persistence remain unknown. The objective was to describe the natural course of the disease at 6 months and to identify possible factors favoring the resurgence or persistence of these symptoms. COVEVOL is a retrospective observational descriptive study of 74 patients. All patients with positive SARS-CoV-2 PCR from March 2020 were included. We compared a group with symptom persistence (PS group) with another group without symptom persistence (no-PS group). Fifty-three out of seventy-four patients (71.62%) described at least one persistent symptom at 6 months of SARS-CoV-2 infection. In the PS group, 56.6% were women and the average age was 54.7 years old [21-89.2] ±16.9. The main symptoms were asthenia (56.6%, n = 30), dyspnea (34%, n = 18), anxiety (32.1% n = 17), anosmia (24.5%, n = 13) and agueusia (15.1% n = 8). Ten patients (13.51%) presented a resurgence in symptoms. Patients in the PS group were older (p = 0.0048), had a higher BMI (p = 0.0071), and were more frequently hospitalized (p = 0.0359) compared to the no-PS group. Odynophagia and nasal obstruction were less present in the inaugural symptoms of COVID-19 in the PS group (p = 0.0202 and p = 0.0332). Persistent post-COVID syndromes are common and identification of contributing factors is necessary for understanding this phenomenon and appropriate management.

Efficacy of Adenoidectomy for the Management of Chronic Rhinosinusitis in Children Older Than 7 Years of Age

Objectives: While adenoidectomy is the first-line surgical management of chronic rhinosinusitis (CRS) in young children, evidence regarding its utility in older children is lacking. This study aimed to assess the efficacy of adenoidectomy in children 7 to 18 years old with regard to symptom control, postoperative medication use, and the need for additional surgery. Methods: Single-institution retrospective chart review of patients ages 7 to 18 undergoing adenoidectomy for CRS from 2009 to 2019. Patients with cystic fibrosis and ciliary disorders were excluded. Comorbidities, preoperative and postoperative symptoms (rhinorrhea, congestion, anosmia, and facial pain), medication use (antibiotics, antihistamines, nasal steroids, and irrigations), and Lund-Mackay scores were extracted. McNemar’s or Wilcoxon Rank Sum Tests were used to assess rates of symptom control and medication use. Fisher’s exact or Chi-square tests were used to assess for factors associated with symptom persistence. Results: Ninety-seven patients with a mean age of 9 years (range 7-18) were identified. Patients were shown to experience significantly decreased rates of rhinorrhea (64.9% vs 20.6%, <.001), congestion (95.9% vs 26.8%, <.001), facial pain (17.5% vs 3.1%, .001), use of nasal steroids (79.4% vs 36.1%, <.001), antihistamines (47.4% vs 20.6%, <.001), and number of antibiotics (median 1 vs 0, <.001) after adenoidectomy. No patient or disease factors were associated with symptom persistence. Nine patients (9.3%) required additional nasal surgery. Conclusion: In this cohort of older children with CRS with limited follow up, additional surgery is not routinely done following adenoidectomy, the results suggest that adenoidectomy alone may provide adequate symptom control and medication reduction.

Possible clustering and/or drug switching confounding obscures up to 56% reduction of symptom persistence by ivermectin. Data Summary for comment posted to JAMA re: Lopez-Medina et al.

This is a summary of our analysis of the dataset obtained from the study by López-Medina et al. (Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial, JAMA, 2021) supporting our comment posted to the JAMA web site: "Possible clustering and/or drug switching confounding obscures up to 56% reduction of symptom persistence by ivermectin."

Heart rate variability interacts with recovery of resting-state connectivity in amygdala circuitry and the persistence of symptoms after sport-related concussion

ObjectiveWe investigated longitudinal trajectories of resting-state fMRI (rsfMRI), autonomic function, and graded symptoms after sport-related concussion (SRC).BackgroundLimbic circuitry may be particularly vulnerable to traumatic brain injury, which could explain the affective and autonomic dysfunction that some patients develop. Relatively few studies have performed longitudinal rsfMRI analyses in concussion and fewer have combined imaging with autonomic and symptom data. We leveraged published limbic rsfMRI networks centered on the amygdala that include core affective and autonomic structures to test whether athletes with SRC would have altered connectivity, and that network recovery would be related to measures of autonomic function and symptom persistence.Design/MethodsWe compared rsfMRI connectivity of amygdala networks in college athletes with SRC (N = 31, female = 14) at three time points after concussion (T1 = 4 days, T2 = 10–14 days, T3 = 2–3 months) and matched controls with no concussion (in-sport control [ISC] N = 36, female = 17).ResultsSRCs show greater amygdala network connectivity as compared to ISCs (T1 p = 0.003, T2 p = 0.014) that normalizes over time (T3 p = 0.182). However, SRCs with higher versus lower heart rate variability (HRV), as measured by pNN50 at T1, have opposing trajectories of connectivity. That is, SRCs with higher HRV have connectivity that starts high and normalizes over time (T1 p = 0.001, T2 p = 0.055, T3 p = 0.576) whereas SRCs with lower HRV have connectivity that increases over time (T1 p = 0.429, T2 p = 0.050, T3 p = 0.002). Furthermore, SRCs with greatest connectivity at T3, presumably the least recovered, have the most symptoms on the Graded Symptom Checklist at ∼3 months (r = 0.635, p = 0.001).ConclusionsHeightened connectivity of amygdala circuitry acutely after a concussion and its normalization over time may be protective, and with HRV, may be a biomarker of symptom persistence.

Obesity Worsens Gulf War Illness Symptom Persistence Pathology by Linking Altered Gut Microbiome Species to Long-Term Gastrointestinal, Hepatic, and Neuronal Inflammation in a Mouse Model

Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1β in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1β, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life.