United States

Bladder cancer (BC) accounts for over 500,000 cases diagnosed yearly worldwide and about 83,700 new cases diagnosed in USA in 2021. It is estimated that 17,200 patients will die each year in the USA, due to high rates of tumor recurrence and cancer progression. In early stages, (noninvasive), BC is associated with a favorable course, but 20% of the cases are aggressive and have dismal prognosis[1]. The purpose of our study is to identify biomarkers that
will help in the diagnosis of the disease in early stages to improve survival.
Exosomes are extracellular vesicles that bud off the cell membrane that can be secreted in most body fluids including blood, urine and CSF. Exosomes carry markers of the secretory cells of origin, including those of endosome origin, those involved in intracellular transport, those of cell membrane origin as well as RNA and double stranded DNAs. MicroRNA contained within the exosome has been implicated in modulating recipient cell functions. Tumor cells release exosomes into the extracellular space which has led to increased use of liquid biopsy to identify biomarkers that can aid in early detection of cancer[2]. We studied exosomal miRNA expression from urine samples in patients with BC to evaluate their possible role as tumor markers.
Urine samples were collected from 14 patients with BC at different stages seen in a protocol approved, at the UOB in the NIH. Exosomal RNAs isolated from urine samples were extracted and quantified. RNA was amplified for miRNA expression profile using 384-SeraMir profile qPCR array.
Significant and highly expressed microRNAs were selected for analysis. MicroRNAs commonly dysregulated in urine BC samples were: has-125b-5p, hsa-Let-7b, hsa-148a-5p, hsa- 30da-5p, hsa-423-5p, hsa-16-5p and hsa-191-5p. MicroRNA profiles from the urine samples will
be matched with the tumor tissues in each case. From the total of MicroRNAs obtained, 274 were known microRNAs and 334 were novel predicted microRNAs.
Our study demonstrates the potential of exosomal microRNAs as a useful biomarker to detect non- and invasive bladder cancer. The biomarkers have great potential not only for diagnosis, but also for early detection, detection of tumor recurrence and progression, and treatment response.

References
Key statistics for Bladder Cancer. American Cancer Society. https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html. Accessed June 27, 2022.
Piao XM, Cha EJ, Yun SJ, Kim WJ. Role of Exosomal miRNA in Bladder Cancer: A Promising Liquid Biopsy Biomarker. Int J Mol Sci. 2021;22(4):1713. Published 2021 Feb 8. doi:10.3390/ijms22041713


2022 AMA Research Challenge

Urinary Exosomal miRNAs Can Be Utilized as Biomarkers to Detect Early and Invasive Bladder Cancer

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Charles Lopresto, DO

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poster

OBJECTIVE: Postoperative infection after surgical nephrolithiasis procedures is a significant morbidity concern. Preoperative antibiotics are recommended by multiple professional guidelines to prevent life-threatening infection. However, the efficacy of different antibiotic approaches continues to be poorly understood. The primary objective of this study was to investigate the relationship between perioperative antibiotic regimens and incidence of postoperative urinary tract infection (UTI), systemic inflammatory response syndrome (SIRS), and urosepsis.

METHODS: A retrospective analysis of prospectively collected data from the Registry for Stones of the Kidney and Ureter (ReSKU) was conducted in this case-cohort study of patients who underwent nephrolithiasis surgery. Subjects whose stone surgery occurred between 2015 and 2021, had a definitive preoperative urine culture, received perioperative antibiotics, and completed a postoperative follow-up visit were included. 25 subjects experienced postoperative UTI, SIRS, or sepsis. 240 did not have any infection-related postoperative issues. Chi-Square tests were performed to determine if there was a relationship between categorical variables of interest [sex, urine culture results, antibiotic regimen, and route of antibiotic administration (oral or intravenous)] and a postoperative infectious outcome.

RESULTS: Postoperative infection was found to be significantly associated with sex [χ2 (1, N=265) = 4.73, p=0.030] but not with urine culture results [χ2 (1, N=265) = 1.86, p=0.17], antibiotic regimen [χ2 (29, N=265) = 44.59, p=0.77], or route of antibiotic administration [χ2 (3, N=265) = 2.22, p=0.53]. A likelihood ratio of 6.9 was seen between positive urine culture and postoperative infection.

CONCLUSION: The risk for postoperative infection after stone surgery is higher among women compared to men. Our data demonstrate no basis for specificity of antibiotic regimen to prevent postoperative infections after surgical nephrolithiasis treatment. To reduce risk of postoperative infection, more important than type of antibiotic, route of administration, or urine culture is simply the importance of consistently giving preoperative antibiotics. These data support AUA and EUA guidelines on the importance of preoperative antibiotics to reduce infectious morbidity after surgery.

Urologic perioperative infection outcomes and prescribed antibiotics

Background
The Brain Injury Guidelines (BIG) provide an approach to stratify TBI patients into 3 categories of severity (BIG 1 to 3) by variables including anatomic size, location, and the use of antiplatelet agents (APA) and anticoagulants (AC). The BIG classify patients on APA or AC as BIG 3 regardless of injury severity, indicating a therapeutic plan involving hospitalization, neurosurgery consultation, and repeat head CT (RHCT). Current evidence is controversial when comparing hematoma progression rates in TBI patients on APA/AC therapies. We evaluated whether pre-injury antiplatelet or anticoagulant use in TBI patients alone should disqualify them from BIG 1 consideration, and if appropriate reclassification could help conserve hospital resources without compromising patient safety.

Methods 
This retrospective study investigated TBI patients presenting to the ED of an urban Level I trauma center from January 2018 until March 2022. Patients categorized as BIG 3 due to prehospital APA/AC use but otherwise fitting all requirements of a BIG 1 injury classification (“Anatomical BIG 1”) were compared to patients with similar anatomic injuries (“True BIG 1”). Head CT progression rates between these two groups were compared.

Results
271 TBI patient records were examined. 27 patients were sorted as true BIG 1, 49 patients as BIG 2, and 195 patients as BIG 3. Thirty five “anatomic BIG 1” patients classified as BIG 3 due to APA/AC status were identified. 19 patients were on APA therapy, 5 were on a DOAC, 3 were on clopidogrel, 3 were on dual APA therapy, 2 were on warfarin, 2 were on dual APA/DOAC therapy, and 1 was on dual APA/AC therapy. All 35 patients showed no progression on RHCT.

Conclusion
Antithrombotic (AT) use in patients with anatomic BIG 1 brain injuries does not appear to increase risk of progression. Pre-hospital AT use consequently does not appear to warrant escalation of care to BIG 3 in patients with such injuries. This could increase patient savings on hospitalization costs as well as reduce exposure to radiation as current practice guidelines indicate that an RHCT not necessary for BIG 1 brain injuries.

Antithrombotic Use In Patients with Mild Brain Injury May Not Mandate Brain Injury Guidelines (BIG) Elevation

Abstract Title: Perceptions Toward Secure Text Messaging Immediately After Hospital Discharge: An Exploratory Study

Authors: Nicholas R. Piniella, OMS-III1,2, Michael Pardo, MD2, Theresa Fuller, MS2, Nathaniel Bessa, BS2, Anuj K Dalal, MD2,3

Institutional Affiliation: 1New York Institute of Technology College of Osteopathic Medicine; 2Division of General Internal Medicine and Primary Care, Brigham and Women’s Hospital; 3Harvard Medical School

Background: Patients remain uniquely vulnerable after hospital discharge. Readmissions within seven days may be preventable, especially if patient-reported concerns are quickly addressed by their inpatient physicians. However, few data exist regarding patient and physician attitudes toward post-discharge communication. This exploratory study aims to assess patients’ and physicians’ perceptions regarding direct, secure text messaging during the early discharge period.

Methods: This IRB-approved, prospective, observational study was conducted on patients hospitalized on the general medicine service at a large academic hospital in Boston, MA from 04/01/2018 through 10/31/2018. Subjects were recruited from a convenience sample of English-speaking adult patients who owned a smartphone and were willing to participate in secure text messaging. Subjects were administered a 15-item survey assessing attitudes toward post-discharge communication. The patients’ inpatient physician was instructed on using a HIPAA-compliant mobile messaging application upon discharge; the message thread would terminate after seven days. Physicians were administered surveys assessing post-discharge communication upon patient discharge and after seven days. Data were collected using REDCap. Descriptive statistics were used to analyze responses.

Results: Of 36 patients approached, 29 eligible subjects completed the survey (19 female, 51.8y ± 16.6). Twenty-eight respondents (97%) indicated they were likely to contact their hospital team post-discharge: 27 (96%) by secure text message; 20 (71%) by calling the provider, 18 (64%) by email, 16 (57%) via patient portal, and 15 (54%) by calling the hospital. Of the 29 physicians surveyed, 12 (41%) completed both surveys. Two of nine respondents to the question (22%) believed their patient would want to contact them. Six (50%) physicians were willing to initiate secure messaging. Three (25%) physicians initiated secure messaging; of these, 2 (67%) physicians reported that the time involved was less than 15 minutes. All three physicians reported a favorable experience.

Conclusion: This exploratory study found that patients have a strong desire to text their hospital physicians immediately after discharge, but physicians may underestimate this interest. While the few physicians who participated seemed to favorably rate their experience, larger studies are required to substantiate this finding and thoroughly understand the perceived barriers to adoption.

Perceptions Toward Secure Text Messaging Immediately After Hospital Discharge: An Exploratory Study

Background: The Achilles Tendon is difficult to visualize because it yields a low signal-to-noise ratio that precludes MRI visualization. While ultrasound yields competent qualitative images, it provides limited quantitative measures. Recent studies, however, have shown aligning the Achilles at a 55-degree angle to the MRI’s primary axis, denoted “the magic angle,” boosts signal-to-noise ratio. Wengler et al., applied diffusion tensor imaging (DTI), an MRI measure that creates images by leveraging the movement of water, to visualize and quantify diffusivity within the Achilles tendons of participants. This paper promoted DTI as a visualization tool for Achilles pathologies, and we further built upon its findings by studying whether DTI yields reproducible results.

Methods: Participants (n=10) with healthy Achilles were included. The right Achilles was imaged in an MRI with the ankle placed at a 55-degree angle relative to the magnet in a 3T MRI. 6-mm transverse slice images were obtained with the following parameters: 1 mm2 isotropic resolution, 2 signal averaging, 5000/58 ms repetition/echo times, 500s/mm2 diffusion strength, 30 gradient directions, and 5 mins scan time. Participants were then given a 5–10-minute break and had the same Achilles re-imaged, following the same steps as before. The MRI images were post-processed with DSI Studio, an open-source diffusion analysis software (http://dsi-studio.labsolver.org). Fractional anisotropy (FA) along with mean (MD), radial (RD), and axial diffusivity (AD) were measured, and reliability was assessed by visualizing Bland-Altman plots. Scan and rescan values were averaged within-participant and mean (SD) were reported for the group. Average differences between scan and rescan values are also reported descriptively.

Results: Average diffusivity of scan and rescan images were, FA: (mean (SD)) 0.419(0.092); RD: 0.893(0.304) mm2/s; AD: 1.663(0.545) mm2/s; and MD: 1.150 (0.371) mm2/s. Average difference between scan and rescan were, FA: 0.008(0.072); RD: 0.075(0.267) mm2/s; AD: 0.114(0.455) mm2/s; and MD: 0.088 (0.323) mm2/s. Bland-Altman plots showed the difference between each scan and rescan was within 95% confidence interval for all four diffusivity measures.

Conclusion: Our preliminary study demonstrates that DTI of the AT produces results that are unbiased (bias less than 10% for all metrics), however, consistency between values suggests the need for further optimization (30% inconsistency between scans).

Preliminary Reproducibility Analysis of Diffusion Tensor Imaging of the Achilles Tendon

Abstract Title: Qualitative Interviews with Primary Care and Gynecological Providers about Obesity Treatment 

Matta K, McCabe C, Bailey-Davis L

Background

To reduce the rates of obesity, the United States Preventive Services Task Force (USPSTF) guidelines recommend that clinicians offer/refer any patient with a BMI of 30 kg/m2 or higher to an intensive, multicomponent behavioral intervention. Despite this recommendation, obesity remains a pervasive concern. The purpose of this study was to evaluate the perceived use of USPSTF guidelines in treating obesity by community medicine physicians (CMPs) and gynecologists. The 5 A’s model (e.g., assess, advice, agree, assist, and arrange) was used to organize the process of obesity treatment.

Methods

Semi-structured interviews of CMPs and gynecologists at Geisinger Health were conducted in March-May 2022. Telephone interviews were completed by trained interviewers using an internal service that transcribed the data verbatim. The study team reviewed the transcripts independently in their entirety to identify initial codes using an open coding approach. These preliminary codes were then organized using the 5 A’s model for obesity treatment as themes. Data were further divided into the subthemes of “facilitators,” “barriers,” or “existing” practice within each 5 A theme.

Results

Recruitment response was 36%; 22 physicians contacted, 4 gynecologists and 4 CMPs were interviewed. Overall, physicians indicated that assessment and advice were routinely practiced and aligned with guidelines but agree, assist, and arrange were areas of weakness. By each A, the facilitators include: Assess: medical jargon in conversation Advice: personalizing advice; Agree: shared-decision making about referrals; Assist: none; and Arrange: specialty referrals. Conversely, barriers include: Assess: patient discomfort; Advice: lacking education; Agree: none; Assist: anti-obesity medications; Arrange: referrals out of Geisinger/referral results.


Conclusion

Physicians are adopting practices to advance Agreement, perceive barriers to Assisting and Arranging, and although Assessment and Advice were commonly practiced, there is discomfort with starting conversations and management strategies. These findings are mixed relevant to prior 5 As research. Our finding that Assess and Advice are practiced and that physicians struggle with the Assist and Arrange is consistent, however greater facilitation of Agreement is novel. These findings are useful for understanding why obesity treatment practices are not aligned with the guidelines, and where improvements could be made to support physicians and patients.

Qualitative Interviews with Primary Care and Gynecological Providers about Obesity Treatment

Background
The literature finds that 70% of transgender people report healthcare discrimination, along with radically increased rates of MDD, AUD, SI, SA, and mental illness. 41% self-reported a history of SA, with nonaccess to gender-affirming surgery equating a 71% higher odds.

Case Presentation
Joshua, a 16 year-old transgender male, using he/him/his pronouns, with no known psychiatric history, was admitted to the children's hospital for intentional Tylenol overdose, presenting with severe abdominal pain, somnolence, and nonbilious emesis, with elevated LFTs and INR, but metabolic panel and CBC otherwise within normal limits. The patient was promptly treated with N-acetylcysteine, showing improved alertness the next day, along with quiet but appropriate affect and mood. The patient admitted to two years of depression and two suicide attempts. Inpatient PHQ-9 was 29. Joshua reported a supportive household, but consistent bullying and misgendering at school, with peers and teachers refusing to use his chosen name and continuing to refer to him as “a girl”, harassing him any time that he uses male restrooms. Joshua has never followed with a psychiatrist or received gender-affirming treatment, but desires hormone therapy. While inpatient, Joshua's senior resident was adamant that she and her team use Joshua's chosen name and consistently use male pronouns, presenting Joshua as a "16 year-old male". 

Discussion
The hospital used a standard EMR, allowing for SOGIE data to be put into charts, but not allowing names or genders to be changed. The team was intentional about using accurate pronouns and Joshua's chosen name in documentation, and on a virtual "post-it". However, when running the list at the end of the day, the senior resident incorrectly named Joshua as "Allison", misgendering him. Despite the team's efforts, this was the name and sex printed from the EMR.

A survey of 204 transgender children found an overwhelming preference to use their chosen names in documentation, even when considering safety concerns. Even when SOGIE data is available, it is rarely automated into documentation. This case study presents a common barrier to affirmative care for transgender patients through limits in the EMR, necessitating a conscious effort by providers and recognition of their shortcomings.

Barrier to Care for Gender Minority Patients

Background:
Miliary TB is an aggressive infection in the setting of lymphohematogenous distribution of the bacilli of M. tuberculosis, that can be potentially fatal if left untreated. Drug-resistant TB may occur in the setting of patient non-compliance, concomitant HIV infection, inability to receive the correct duration and dose of medications, or patients in high-risk areas such as China or India.

Methods:
We describe a young immigrant patient who presented with electrolyte derangement and was found to have a complicated combination of infections including acute disseminated miliary TB, syphilis, and HIV. Our goal is to discuss this rare case and address risk factors associated with his immigrant status and barriers to treating these three serious infections together.

Results: 
A 33 YO Hispanic M immigrant from Mexico with PMH of prior COVID-19 infection presented with cough, fever, and weakness. He was tachycardic and tachypneic with sufficient oxygen saturation on room air. Labs demonstrated hypoNa of 122mEq/dL (ref range 135-145) and he was admitted to the MICU for severe electrolyte derangement. CXR showed R lobe infiltrates. CT CAP suggestive of diffuse disseminated TB with severe PNA and several cavitary lesions involving the mediastinum. Sputum AFB cultures were positive. ID and Pulmonology teams were consulted and the patient began RIPE therapy. Admission was complicated by diagnoses of HIV and Syphilis. HAART therapy was deferred and the patient received Penicillin injections for Syphilis as well as prophylactic Bactrim DS (CD4 count 57). HypoNa improved and the patient was transferred to the floors. Despite >20d of RIPE therapy and the patient remaining asymptomatic, he remained AFB sputum culture positive, attributed to his concomitant HIV status or drug resistance.

Conclusion:
A high prevalence of HIV, syphilis, and TB exists in immigrant populations. It is imperative to screen for rapid diagnosis and management. Given high mortality rate of miliary TB, initiation of RIPE therapy is essential. Our patient’s HAART initiation was held to prevent immune reconstitution syndrome in the setting of multiple infections. There is limited randomized control trial data regarding optimal treatment guidelines and duration for patients with drug-resistant TB, especially with concomitant HIV.

Disseminated Miliary Tuberculosis with Drug Resistance & Concomitant Syphilis & HIV Infections

The risk of assumptions when approaching abdominal pain

Introduction
In the summer of 2022, the Rainy River Basin in Northern Minnesota and nearby Ontario Canada experienced historic flooding with the highest levels in over 70 years, and with water levels peaking on June 15th. This flooding caused unusually large amounts of standing water in the region and resulted in an atypical year for mosquitos in the region, particularly the Summer Floodwater mosquito, or Aedes vexans.

Mosquito bite hypersensitivity is characterized by edema and skin reactions. There are some known causes of hypersensitivity reactions to mosquito bites. Epstein Barr Virus, natural killer (NK) cell lymphocytosis, and chronic urticaria are conditions known to be associated with mosquito hypersensitivity. Children with atopy, and grass allergies are more likely to have mosquito hypersensitivity. However, the exact cause of these associations is unknown.

Methods
We observed mosquito bite reactions in a camp of 108 campers and 52 staff located in the Rainy River Basin, and with wilderness trips throughout Northern Minnesota and Southern Ontario, Canada. We tracked reactions throughout 3.5-week sessions for campers and over 9 weeks for staff.

Results
Unusual hypersensitivity reactions were observed in the Rainy River Basin near Rainy Lake at a sleep away summer camp among staff and campers. These reactions were indicative of allergic reactions or “skeeter syndrome.” Skeeter syndrome is a rare allergic and often severe allergic reaction to mosquito bites resulting in blistering and swelling at the site of the bite, and in less severe cases bruising. Reactions that were observed at the camp included periorbital edema, ulcerative lesions, blistering, and ecchymosis. One case in particular resulted in swelling at the joint of multiple mosquito bites, resulting in movement restriction and pain. Some reactions were observed on international staff who had no previous exposure to mosquito bites while others were observed on individuals with previous mosquito exposure. Some reactions that cause breaks in skin continuity are of concern due to increased risk of complications such as cellulitis and, in rare cases, systemic infection and sepsis. 

Conclusions
As natural disasters become increasingly common with climate change, preventative measures should be taken in areas experiencing lake and river flooding to avoid mosquito hypersensitivity reactions. Best practices include using permethrin on clothing and applying products with 20-50% DEET concentrations every 6 hours to exposed skin. Children and pregnant women can use Picaridin and IR3535 as safe alternatives to DEET. In cases where hypersensitive reactions did occur, treatment was initiated with diphenhydramine cream and bandages to prevent skin breakdown or infection from itching. We also used 0.1% hydrocortisone cream and wrapped extremities to prevent swelling.

“Skeeter Syndrome” and other mosquito hypersensitivity reactions at a sleepaway summer camp in flooded Rainy River Basin

It is estimated that there are more than 250 million Hepatitis B virus (HBV) carriers in the world, causing approximately 600,000 deaths annually from complications. Hepatitis B vaccines are highly effective. Hepatitis B surface antigen (HBsAg) is a marker of current infection, which can be either acute or chronic. We describe a rare case of HBsAg positivity in a patient who was immunized for the first time with the HBV vaccination (Recombivax) 15 days earlier, with all other HBV serological markers being negative, but with markedly elevated initial liver enzymes , which ultimately was related to ischemic hepatitis. It was thought initially that HBV antigenemia post vaccination was short lived. In the literature, the longest case described with transient positive HBsAg in patients for up to 52 days after HBV vaccination. It can be hypothesized that HBsAg positivity post vaccination could be due to regular screening, ESRD patients receiving vaccine boosters, immunization with double dose of vaccine and diminished ability to make HbsAb for neutralization/clearance of inoculate HBsAg. Our case underscores the importance of being aware of vaccination status in patients whom HBsAg comes back positive with negative rest of the serology. This will help avoid the high cost involved in assessing these healthy adults for hepatitis B infection with unnecessary testing. This case highlights that vaccine induced HBsAg reactivity remains a problem, therefore other causes of liver injury must be sought if they present with elevated liver enzymes.

Urinary Exosomal miRNAs Can Be Utilized as Biomarkers to Detect Early and Invasive Bladder Cancer

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