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.

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.

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.

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.

Current Expectations and Opinions on Single-port Robotic Surgery: A Survey Among European Experts by the SPARC Collaborative Group.

Single-port (SP) robotic surgery is a relatively new technology that is expected to become available on the European market within a year. We investigated the current expectations of robotic surgery experts and opinion leaders practicing in Europe. A 17-item online questionnaire was sent to 120 participants identified as "experts" on the basis of their general contributions to the field of robotic surgery. Overall, 90 responses were registered, with a response rate of 75%. Italy (30%), France (15%), and the UK (12%) provided the most participants, who worked mainly in academic-either public (60%) or private (20%)-hospitals. Most respondents (79%) had no previous experience with "single site" surgery, and attendance at scientific meetings (79%) and perusal of the literature (65%) were the sources of SP knowledge most frequently reported. The perceived advantages of SP robotic surgery included lower invasiveness (61%), easier access to the retroperitoneal or extraperitoneal space (53%), better cosmetic results (44%), and lower postoperative pain (44%). The most "appealing" SP procedures were retroperitoneal partial nephrectomy via an anterior approach (43%) and transvesical simple prostatectomy (43%). Within the limitations of this type of analysis, our findings suggest high interest and a positive attitude towards SP technology overall. Patient summary: Technology for single-port (SP) robotic surgery, in which just one skin incision is made in the abdomen to perform the operation, will soon be available in Europe. We conducted a survey on SP surgery among European experts in urological robotic surgery. The results show that there is high interest in and a positive attitude to SP surgery. The SP approach could result in better cosmetic results and lower postoperative pain for patients.

Recurrent MTOR Mutations in Renal Cell Carcinoma With Fibromyomatous Stroma: A Report of 2 Tumors.

Renal cell carcinoma with fibromyomatous stroma, recognized as a provisional entity in the current 2022 World Health Organization classification of renal neoplasms, is rare. Recent evidence suggests recurrent alterations in the mTOR pathway, supporting its recognition as a distinct entity. Herein, we report 2 renal cell carcinomas with fibromyomatous stroma with MTOR mutations occurring in 62- and 72-year-old women and review the literature to support its recognition as a distinct entity, focusing on the characteristic morphology, immunohistochemical staining patterns as well as genetic alterations.

Highly Regioselective Protecting-Group-Free Synthesis of the Antimalarial Drug MMV693183.

MMV693183 is a promising antimalarial drug candidate that works for uncomplicated malaria treatment and resistance management. Herein, we report an efficient and highly regioselective synthesis of MMV693183. This novel synthetic method highlights a three-step route with an overall yield of 46% from readily available starting materials. The key to the success lies in (1) utilizing the subtle difference of the two amino groups in the starting material (S)-propane-1,2-diamine dihydrochloride without amino protection and (2) identifying the L-(+)-tartaric acid as the counter acid for the organic salt formation, yielding the desired regioisomer up to 100:0. The efficient and scalable three-step protocol operates under mild conditions with a high chemo/regioselectivity, providing effective access to MMV693183.

Quantum octets in high mobility pentagonal two-dimensional PdSe2.

Two-dimensional (2D) materials have drawn immense interests in scientific and technological communities, owing to their extraordinary properties and their tunability by gating, proximity, strain and external fields. For electronic applications, an ideal 2D material would have high mobility, air stability, sizable band gap, and be compatible with large scale synthesis. Here we demonstrate air stable field effect transistors using atomically thin few-layer PdSe2 sheets that are sandwiched between hexagonal BN (hBN), with large saturation current > 350 µA/µm, and high field effect mobilities of ~ 700 and 10,000 cm2/Vs at 300 K and 2 K, respectively. At low temperatures, magnetotransport studies reveal unique octets in quantum oscillations that persist at all densities, arising from 2-fold spin and 4-fold valley degeneracies, which can be broken by in-plane and out-of-plane magnetic fields toward quantum Hall spin and orbital ferromagnetism.

What Do Psychiatrists Think About Caring for Patients Who Have Extremely Treatment-Refractory Illness?

Questions about when to limit unhelpful treatments are often raised in general medicine but are less commonly considered in psychiatry. Here we describe a survey of U.S. psychiatrists intended to characterize their attitudes about the management of suicidal ideation in patients with severely treatment-refractory illness. Respondents (n = 212) received one of two cases describing a patient with suicidal ideation due to either borderline personality disorder or major depressive disorder. Both patients were described as receiving all guideline-based and plausible emerging treatments. Respondents rated the expected helpfulness and likelihood of recommending each of four types of intervention: hospitalization, additional medication changes, additional neurostimulation, and additional psychotherapy. Across both cases, most respondents said they were likely to provide each intervention, except for additional neurostimulation in borderline personality disorder, while fewer thought each intervention would be helpful. Substantial minorities of respondents indicated that they would provide an intervention they did not think was likely to be helpful. Our results suggest that while most psychiatrists recognize the possibility that some patients are unlikely to be helped by available treatments, many would continue to offer such treatments.

Symptomatic idiopathic intracranial hypertension triggered by Ramadan intermittent fasting: a case report.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disorder that primarily affects obese women of reproductive age. The exact pathogenesis of IIH is unknown though multiple etiologies have been proposed. CASE PRESENTATION: We report a case of IIH triggered by first-time Ramadan intermittent fasting (RIF) in an 18-year-old woman. Our patient developed new onset headaches, diplopia, and pulsatile tinnitus with examination notable for bilateral papilledema and lumbar puncture revealing an elevated opening pressure. Her symptoms resolved after cessation of RIF, apart from persistent left sided tinnitus which later resolved with acetazolamide administration. CONCLUSION: This case report uniquely illustrates that RIF may provoke symptomatic IIH. We hypothesize that a decreased concentration of glucagon-like peptide-1 (GLP-1) induced by fasting results in decreased GLP-1 receptor activation in the choroid plexus, allowing for increased CSF secretion into the ventricles invoking increased intracranial pressure (ICP). This theoretical mechanism provides further insight as to the possible underlying pathophysiology of IIH.

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline.

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodology to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from d-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to a 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug.

Association between Prostate Carcinoma and Multiple Myeloma.

Synchronous or sequential development of multiple myeloma and prostate carcinoma is rare. It is not sure whether these two occur independently or if one influences the development of the other. We reviewed the cases published in the English literature; eight cases of myeloma developing after diagnosis and treatment for prostate carcinoma, five cases of simultaneous occurrence of myeloma and prostate carcinoma, and five cases where the patient with multiple myeloma later developed prostate carcinoma were found. This short review attempts to analyze the occurrence of these two diseases in the same patient and dissect whether there is a close association or it is just a mere coincidence.

Missing Voices: What Early Career Hospitalists View as Essential in Hospital Medicine-Focused Education.

OBJECTIVES: Acknowledging that a successful career in hospital medicine (HM) requires specialized skills, residency programs have developed hospital medicine-focused education (HMFE) programs. Surveys of Internal Medicine residency leaders have described HMFE curricula but are limited to that specialty and lack perspectives from early career hospitalists (ECHs) who recently completed this training. As such, we surveyed multispecialty ECHs to evaluate their preferences for HMFE and to identify gaps in standard residency training and career development that HMFE can bridge. The objectives of our study were to describe multispecialty ECH needs and preferences for HMFE and to identify gaps in standard residency training and career development that HMFE can bridge. METHODS: From February to March 2021, ECHs (defined as hospitalists within 0-5 years from residency) were surveyed using the Society of Hospital Medicine's listserv. Respondents identified as having participated in HMFE or not during residency (defining them as HMFE participants or non-HMFE participants). RESULTS: From 257 respondents, 84 (33%) ECHs met inclusion criteria. Half (n = 42) were HMFE participants. ECHs ranked clinical hospitalist career preparation (86%) and mentorship from HM faculty (85%) as the most important gaps in standard residency training and career development that HMFE can bridge. Other key components of HMFE included exposure to quality improvement, patient safety, and high-value care (67%); provision of autonomy through independent rounding (54%); and preparation for the job application process (70%). CONCLUSIONS: Multispecialty ECHs describe HMFE as positively influencing their decision to pursue a hospitalist career and increasing their preparedness for practice. HMFE may be particularly well suited to foster advanced clinical skills such as independent rounding, critical thinking, and self-reflection. We propose an organizing framework for HMFE in residency that may assist in the implementation and innovation of HMFE programs nationwide and in the development of standardized HMFE competencies.