Is Suffering a Useless Concept?

"Suffering" is a central concept within bioethics and often a crucial consideration in medical decision making. As used in practice, however, the concept risks being uninformative, ambiguous, or even misleading. In this paper, we consider a series of cases in which "suffering" is invoked and analyze them in light of prominent theories of suffering. We then outline ethical hazards that arise as a result of imprecise usage of the concept and offer practical recommendations for avoiding them. Appeals to suffering are often getting at something ethically important. But this is where the work of ethics begins, not where it ends.

A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid.

Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for the API, which will limit the potential uptake of this treatment in lower income regions. In this work, an alternative, lower-cost synthetic strategy to a known p-phenylenediamine intermediate to sutezolid has been demonstrated. The key step in this process is the construction of the thiomorpholine ring by a nucleophilic sulfide ring closure on an activated bis(2-hydroxyethyl)-functionalized aniline, which was in turn made by reaction of 3,4-difluoronitrobenzene and diethanolamine. This sulfide treatment has the added benefit of affecting a Zinin reduction of the nitro functional group, which alleviates the need for the transition metal reduction used in previous routes. After optimization, this key reaction was able to provide the desired aniline intermediate in yields between 65 and 80% and, after a standard charcoal treatment, purity of >94%. Initial demonstrations of the full 3-step strategy were successfully conducted on scales up to 100 g with overall yields of 53-68%. This preliminary work will serve as the foundation for a broader low-cost redesign of the sutezolid synthetic process.

Single-Port Robotic-Assisted Excision of the Urachal Remnant in an Adult Female: A Case Report.

Urachal anomalies and their associated disease processes are quite rare in pediatric populations and even rarer in adults. Although often asymptomatic, patients with symptoms can be treated with a combination of surveillance, antibiotics, and sometimes surgical resection. In this case, we describe our experience using the single-port robotic approach for the excision of a symptomatic urachal remnant. The patient presented with a chief complaint of urinary frequency, dysuria, intermittent hematuria, and right flank pain. A CT scan of the abdomen and pelvis revealed a bladder wall thickening at the dome of the bladder measuring 2.6 x 3.6 x 1.5 cm with concerns for adenocarcinoma. The patient subsequently underwent a biopsy, which was benign. The patient's symptoms persisted, and she elected to undergo surgical resection. Postoperatively, her symptoms resolved, and she was satisfied with her treatment outcome. This case exemplifies the feasibility of the single-port robotic approach to urachal remnant excision, with further applicability to simple transabdominal robotic bladder surgery.

ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer.

Immune checkpoint blockade has yet to produce robust anti-cancer responses for prostate cancer. Sialyltransferases have been shown across several solid tumours, including breast, melanoma, colorectal and prostate to promote immune suppression by synthesising sialoglycans, which act as ligands for Siglec receptors. We report that ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) levels negatively correlate with androgen signalling in prostate tumours. We demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion through the synthesises of sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. Here, we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. These interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.

Integrating circulating T follicular memory cells and autoantibody repertoires for characterization of autoimmune disorders.

Introduction: Autoimmune diseases are heterogeneous and often lack specific or sensitive diagnostic tests. Increased percentages of CD4+CXCR5+PD1+ circulating T follicular helper (cTfh) cells and skewed distributions of cTfh subtypes have been associated with autoimmunity. However, cTfh cell percentages can normalize with immunomodulatory treatment despite persistent disease activity, indicating the need for identifying additional cellular and/or serologic features correlating with autoimmunity. Methods: The cohort included 50 controls and 56 patients with autoimmune cytopenias, gastrointestinal, pulmonary, and/or neurologic autoimmune disease. Flow cytometry was used to measure CD4+CXCR5+ T cell subsets expressing the chemokine receptors CXCR3 and/or CCR6: CXCR3+CCR6- Type 1, CXCR3-CCR6- Type 2, CXCR3+CCR6+ Type 1/17, and CXCR3- CCR6+ Type 17 T cells. IgG and IgA autoantibodies were quantified using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the control cohort defined normal limits for T cell subset percentages and total number (burden) of autoantibodies. Results: This study focused on CD4+CXCR5+ T cells because CXCR5 upregulation occurs after cognate T-B cell interactions characteristic of autoimmune diseases. We refer to these cells as circulating T follicular memory (cTfm) cells to acknowledge the dynamic nature of antigen-experienced CXCR5+ T cells, which encompass progenitors of cTfh or Tfh cells as well as early effector memory T cells that have not yet lost CXCR5. Compared to controls, 57.1% of patients had increased CXCR5+CXCR3+CCR6+ cTfm1/17 and 25% had increased CXCR5+CXCR3-CCR6+ cTfm17 cell percentages. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 44.6% had an increased burden of autoantibodies of either isotype. Unsupervised autoantibody clustering identified three clusters of patients with IgG autoantibody profiles distinct from those of controls, enriched for patients with active autoimmunity and monogenic diseases. An increased percentage of cTfm17 cells was most closely associated with an increased burden of high-titer IgG and IgA autoantibodies. A composite measure integrating increased cTfm1/17, cTfm17, and high-titer IgG and/or IgA autoantibodies had 91.1% sensitivity and 90.9% specificity for identifying patients with autoimmunity. Percentages of cTfm1/17 and cTfm17 percentages and numbers of high-titer autoantibodies in patients receiving immunomodulatory treatment did not differ from those in untreated patients, thus suggesting that measurements of cTfm can complement measurements of other cellular markers affected by treatment. Conclusions: This study highlights two new approaches for assessing autoimmunity: measuring CD4+CXCR5+ cTfm subsets as well as total burden of autoantibodies. Our findings suggest that these approaches are particularly relevant to patients with rare autoimmune disorders for whom target antigens and prognosis are often unknown.

Develop Your CORE2 for Career Flourishing: A Career Development Workshop for Hospitalists.

Introduction: Appreciative inquiry harnesses an individual's strengths to realize positive change, and a flourishing-focused mindset emphasizes engagement, social connectivity, and seeking meaningful work. Though the impact of these models on physician well-being and career planning has been evaluated in graduate medical education, their integration into career development initiatives for faculty has been limited. We designed a workshop to nurture hospitalist career development, based on our CORE2 conceptual framework (character strengths, overall vision, role assessment, explicit goals, and evaluation). Methods: We presented the workshop at the 2022 and 2023 Society of Hospital Medicine (SHM) annual conferences. This 1.5-hour workshop comprised four modules and three small-group activities designed to help participants identify their signature character strengths, draft a professional vision statement, prioritize professional roles, and develop SMART goals aligned with these roles. Results: At the 2023 SHM annual conference, 36 participants attended the workshop, and 32 (89%) completed pre- and postworkshop surveys. After workshop completion, participants' self-assessed familiarity with their signature character strengths, knowledge of evidence-based principles to develop SMART goals, and confidence in their ability to write a vision statement and SMART goals all increased significantly (p < .05). Discussion: This workshop provides a valuable framework for self-directed longitudinal career development and reflection. We build on prior curricula on educator identity formation by guiding participants from identity definition to professional vision development to professional role evaluation to aligned goal creation and iterative evaluation. Our workshop's principles are readily generalizable to clinician-educators across medical disciplines.

Pre-Admission Oral Clonidine to Reduce Severe Pre-Operative Anxiety in Pediatric Patients with Behavioral Disorders: A Case Series.

Controlling preoperative anxiety is necessary in pediatric patients to avoid adverse effects such as emergence delirium, behavioral problems, post-traumatic stress disorder, anxiety prior to future procedures, and increased analgesic doses in the recovery room. Some patients, especially ones with behavioral issues, have a difficult time arriving at the hospital. Medications given at home can be helpful. We describe a case series of six patients who received pre-admission oral clonidine prior to arrival to the hospital. The patients were all able to enter the hospital without difficulty and the families reported less anxiety and more cooperation subjectively compared with previous experiences. Transient intraoperative hypotension was a side effect of oral clonidine, with no long-term sequelae.