Our hands are tied: abortion bans and hesitant medicine.

Trained for decades to analyze risks, benefits, unique body compositions, and complex medical scenarios, healthcare providers are now faced with one of medicine's most trying obstacles: how to practice medicine when new abortion bans contradict best practice standards. Drawn from qualitative interviews with medical providers in Tennessee, USA conducted between October 2022 and December 2022, this study shows how medical providers often must make medical decisions based on legal risks as opposed to standards of care. This is particularly significant as malpractice insurance does not cover criminal charges. In states with abortion bans, often hastily implemented and subject to changes by lawmakers, medical providers are now practicing a new kind of defensive medicine in an effort to protect themselves from legal threats. We call this hesitant medicine, where providers often experience a tension between their own legal protection and the well-being of their patients, making them hesitant to provide necessary abortion care. This has serious, far-reaching consequences. We focus on three distinct arenas impacted by this new form of defensive medicine, specifically: providers' decision-making around patient care, impacts on patient relationships, and finally, what we call the ultimate defense, leaving states with abortion bans to move to states with fewer legal risks. We conclude with commentary on potential ways to reduce the negative impacts of these trends.

Decision-making for congenital anomalies diagnosed during pregnancy: a narrative review.

PURPOSE: The purpose of this narrative review was to assess the limited literature on fetal anomalies diagnosed in the second trimester of pregnancy and parental decision-making and identify sources of information deemed as facilitators and barriers to medical decisions. METHODS: This was a literature review of source material and information about fetal anomalies diagnosed in the second trimester of pregnancy, decision-making, decision tools or aids, and sources of information for anomalies. The search string used explored related peer-reviewed publications and systematic reviews between 2007 and 2024. We also reviewed references from publications meeting inclusion criteria. The search was conducted between June 2022 and February 2024. Exclusion criteria included conference abstracts, non-peer reviewed literature, and articles not available in English language. A total of 77 publications were identified by searching multiple databases using a predefined search string. The search encompassed full text articles from 2007 to 2024 and 11 full-text publications were ultimately included in the review. A list of 45 co-occurring keywords was generated from the included texts, with each keyword having a minimum of two co-occurrences. RESULTS: Key themes identified included (1) the role of the clinician and need for development of professional knowledge and empathy surrounding discussion of fetal anomalies with patients; (2) information gathering, with individuals reporting use of multiple strategies to obtain information; while the majority found information satisfying, they preferred more details on diagnosis, long-term outcomes of the fetus/child and management of the pregnancy or termination process; and (3) decision-making, the path and process of how individuals made decisions about the pregnancy including quality of life, future fertility, and seeking other people's experiences. CONCLUSION: Many factors contribute to an individual's decision-making after a diagnosis of a fetal anomalies diagnosed in the second trimester of pregnancy, ranging from personal beliefs and goals to shared experiences of others and access to care. Understanding how sources of information may be deemed both as facilitators and barriers to different individuals during the decision-making process is important for healthcare providers in order to understand how to most effectively support patients. There is a dearth of information on training healthcare professionals to provide support to patients facing these decisions.

An evolutionarily conserved phosphoserine-arginine salt bridge in the interface between ribosomal proteins uS4 and uS5 regulates translational accuracy in Saccharomyces cerevisiae.

Protein-protein and protein-rRNA interactions at the interface between ribosomal proteins uS4 and uS5 are thought to maintain the accuracy of protein synthesis by increasing selection of cognate aminoacyl-tRNAs. Selection involves a major conformational change-domain closure-that stabilizes aminoacyl-tRNA in the ribosomal acceptor (A) site. This has been thought a constitutive function of the ribosome ensuring consistent accuracy. Recently, the Saccharomyces cerevisiae Ctk1 cyclin-dependent kinase was demonstrated to ensure translational accuracy and Ser238 of uS5 proposed as its target. Surprisingly, Ser238 is outside the uS4-uS5 interface and no obvious mechanism has been proposed to explain its role. We show that the true target of Ctk1 regulation is another uS5 residue, Ser176, which lies in the interface opposite to Arg57 of uS4. Based on site specific mutagenesis, we propose that phospho-Ser176 forms a salt bridge with Arg57, which should increase selectivity by strengthening the interface. Genetic data show that Ctk1 regulates accuracy indirectly; the data suggest that the kinase Ypk2 directly phosphorylates Ser176. A second kinase pathway involving TORC1 and Pkc1 can inhibit this effect. The level of accuracy appears to depend on competitive action of these two pathways to regulate the level of Ser176 phosphorylation.

Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6).

In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.

Intrapancreatic fat, pancreatitis, and pancreatic cancer.

Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of pancreatic cancer is gradually increasing, linked to an aging population and increasing rates of obesity and pancreatitis, which are risk factors for this cancer. Sources of risk include adipokine signaling from fat cells throughout the body, elevated levels of intrapancreatic intrapancreatic adipocytes (IPAs), inflammatory signals arising from pancreas-infiltrating immune cells and a fibrotic environment induced by recurring cycles of pancreatic obstruction and acinar cell lysis. Once cancers become established, reorganization of pancreatic tissue typically excludes IPAs from the tumor microenvironment, which instead consists of cancer cells embedded in a specialized microenvironment derived from cancer-associated fibroblasts (CAFs). While cancer cell interactions with CAFs and immune cells have been the topic of much investigation, mechanistic studies of the source and function of IPAs in the pre-cancerous niche are much less developed. Intriguingly, an extensive review of studies addressing the accumulation and activity of IPAs in the pancreas reveals that unexpectedly diverse group of factors cause replacement of acinar tissue with IPAs, particularly in the mouse models that are essential tools for research into pancreatic cancer. Genes implicated in regulation of IPA accumulation include KRAS, MYC, TGF-ß, periostin, HNF1, and regulators of ductal ciliation and ER stress, among others. These findings emphasize the importance of studying pancreas-damaging factors in the pre-cancerous environment, and have significant implications for the interpretation of data from mouse models for pancreatic cancer.

Evaluation of the Small-molecule BRD4 Degrader CFT-2718 in Small-cell Lung Cancer and Pancreatic Cancer Models.

Targeted, catalytic degradation of oncoproteins using heterobifunctional small molecules is an attractive modality, particularly for hematologic malignancies, which are often initiated by aberrant transcription factors and are challenging to drug with inhibitors. BRD4, a member of the bromodomain and extraterminal family, is a core transcriptional and epigenetic regulator that recruits the P-TEFb complex, which includes Cdk9 and cyclin T, to RNA polymerase II (pol II). Together, BRD4 and CDK9 phosphorylate serine 2 (pSer2) of heptad repeats in the C-terminal domain of RPB1, the large subunit of pol II, promote transcriptional elongation. Small-molecule degraders of BRD4 have shown encouraging efficacy in preclinical models for several tumor types but less efficacy in other cancers including small-cell lung cancer (SCLC) and pancreatic cancer. Here, we evaluated CFT-2718, a new BRD4-targeting degrader with enhanced catalytic activity and in vivo properties. In vivo, CFT-2718 has significantly greater efficacy than the CDK9 inhibitor dinaciclib in reducing growth of the LX-36 SCLC patient-derived xenograft (PDX) model and performed comparably to dinaciclib in limiting growth of the PNX-001 pancreatic PDX model. In vitro, CFT-2718 reduced cell viability in four SCLC and two pancreatic cancer models. In SCLC models, this activity significantly exceeded that of dinaciclib; furthermore, CFT-2718 selectively increased the expression of cleaved PARP, an indicator of apoptosis. CFT-2718 caused rapid BRD4 degradation and reduced levels of total and pSer2 RPB1 protein. These and other findings suggest that BRD-mediated transcriptional suppression merits further exploration in the setting of SCLC.

"Medically unexplained" symptoms and symptom disorders in primary care: prognosis-based recognition and classification.

BACKGROUND: Many patients consult their GP because they experience bodily symptoms. In a substantial proportion of cases, the clinical picture does not meet the existing diagnostic criteria for diseases or disorders. This may be because symptoms are recent and evolving or because symptoms are persistent but, either by their character or the negative results of clinical investigation cannot be attributed to disease: so-called "medically unexplained symptoms" (MUS). MUS are inconsistently recognised, diagnosed and managed in primary care. The specialist classification systems for MUS pose several problems in a primary care setting. The systems generally require great certainty about presence or absence of physical disease, they tend to be mind-body dualistic, and they view symptoms from a narrow specialty determined perspective. We need a new classification of MUS in primary care; a classification that better supports clinical decision-making, creates clearer communication and provides scientific underpinning of research to ensure effective interventions. DISCUSSION: We propose a classification of symptoms that places greater emphasis on prognostic factors. Prognosis-based classification aims to categorise the patient's risk of ongoing symptoms, complications, increased healthcare use or disability because of the symptoms. Current evidence suggests several factors which may be used: symptom characteristics such as: number, multi-system pattern, frequency, severity. Other factors are: concurrent mental disorders, psychological features and demographic data. We discuss how these characteristics may be used to classify symptoms into three groups: self-limiting symptoms, recurrent and persistent symptoms, and symptom disorders. The middle group is especially relevant in primary care; as these patients generally have reduced quality of life but often go unrecognised and are at risk of iatrogenic harm. The presented characteristics do not contain immediately obvious cut-points, and the assessment of prognosis depends on a combination of several factors. CONCLUSION: Three criteria (multiple symptoms, multiple systems, multiple times) may support the classification into good, intermediate and poor prognosis when dealing with symptoms in primary care. The proposed new classification specifically targets the patient population in primary care and may provide a rational framework for decision-making in clinical practice and for epidemiologic and clinical research of symptoms.

Multiple somatic symptoms in primary care patients: a cross-sectional study of consultation content, clinical management strategy and burden of encounter.

BACKGROUND: Consultations involving patients with multiple somatic symptoms may be considered as challenging and time-consuming by general practitioners (GPs). Yet, little is known about the possible links between consultation characteristics and GP-experienced burden of encounter. We aimed to explore consultation content, clinical management strategies, time consumption and GP-experienced burden of encounters with patients suffering from multiple somatic symptoms as defined by the concept of bodily distress syndrome (BDS). METHODS: Cross-sectional study of patient encounters in primary care from December 2008 to December 2009; 387 GPs participated (response rate: 44.4 %). Data were based on a one-page registration form completed by the GP and a patient questionnaire including the 25-item BDS checklist for somatic symptoms. Using logistic regression analyses, we compared patients who met the BDS criteria with patients who did not. RESULTS: A total of 1505 patients were included (response rate: 55.6 %). Health problems were less frequently reported as 'new' in patients with BDS (odds ratio (OR) = 0.73, 95 % confidence interval (CI): 0.54; 0.97). Medical prescriptions and referral rates were comparable in the two patient groups. Consultations focusing on mainly biomedical aspects were less frequent among patients with BDS (OR = 0.31, 95 % CI: 0.22; 0.43), whereas additional biomedical and psychosocial problems were more often discussed. GPs were more likely to ensure continuity of care in BDS patients by watchful waiting strategies (OR = 2.32, 95 % CI: 1.53; 3.52) or scheduled follow-up visits (OR = 1.61, 95 % CI: 1.09; 2.37). Patients with BDS were found to be more time-consuming (OR = 1.77, 95 % CI: 1.26; 2.48) and burdensome (OR = 2.54, 95 % CI: 1.81; 3.55) than patients without BDS. However, after adjustments for biomedical and psychosocial content of the consultation, the identified differences for time consumption and burden were no longer statistically significant. CONCLUSIONS: Patients with BDS represent higher care complexity in terms of biomedical and psychosocial needs. GPs seem to allow space and time for discussing these issues and to aim at ensuring continuity in care through watchful waiting or scheduled follow-up consultations. However, the reported GP-experienced burden call for professional development.

Bodily distress syndrome: A new diagnosis for functional disorders in primary care?

BACKGROUND: Conceptualisation and classification of functional disorders appear highly inconsistent in the health-care system, particularly in primary care. Numerous terms and overlapping diagnostic criteria are prevalent of which many are considered stigmatising by general practitioners and patients. The lack of a clear concept challenges the general practitioner's decision-making when a diagnosis or a treatment approach must be selected for a patient with a functional disorder. This calls for improvements of the diagnostic categories. Intense debate has risen in connection with the release of the fifth version of the 'Diagnostic and Statistical Manual of Mental Disorders' and the current revision of the 'International Statistical Classification of Diseases and Related Health Problems'. We aim to discuss a new evidence based diagnostic proposal, bodily distress syndrome, which holds the potential to change our current approach to functional disorders in primary care. A special focus will be directed towards the validity and utility criteria recommended for diagnostic categorisation. DISCUSSION: A growing body of evidence suggests that the numerous diagnoses for functional disorders listed in the current classifications belong to one family of closely related disorders. We name the underlying phenomenon 'bodily distress'; it manifests as patterns of multiple and disturbing bodily sensations. Bodily distress syndrome is a diagnostic category with specific criteria covering this illness phenomenon. The category has been explored through empirical studies, which in combination provide a sound basis for determining a symptom profile, the diagnostic stability and the boundaries of the condition. However, as bodily distress syndrome embraces only the most common symptom patterns, patients with few but impairing symptoms are not captured. Furthermore, the current lack of treatment options may also influence the acceptance of the proposed diagnosis. Bodily distress syndrome is a diagnostic category with notable validity according to empirical studies. Nevertheless, knowledge is sparse on the utility in primary care. Future intervention studies should investigate the translation of bodily distress syndrome into clinical practice. A particular focus should be directed towards the acceptability among general practitioners and patients. Most importantly, it should be investigated whether the new category may provide the basis for better treatment and improved clinical outcome.

The prognosis of bodily distress syndrome: a cohort study in primary care.

OBJECTIVE: Bodily distress syndrome (BDS) is a newly proposed diagnosis for functional disorders. The diagnosis is based on empirical research, but little is known about the course of the disease. We aimed to study the prognosis in terms of diagnosis stability over time. METHOD: A longitudinal study of 1356 primary care patients with 2-year follow-up was conducted in the Central Denmark Region. Data were obtained from family physician registration forms, patient questionnaires (including a BDS checklist) and nationwide registries. Complete data were available for 1001 patients (73.8%). RESULTS: Overall, 146 persons [14.6%, 95% confidence interval (CI): 12.5-16.9] fulfilled the criteria for BDS at baseline and 142 persons (14.2%, CI: 12.1-16.5) at follow-up. Among study participants with BDS at baseline, 56.8% (CI: 48.4-65.0) also had BDS at follow-up. Multiorgan BDS tended to be more persistent (81.8%, CI: 48.2-97.7) than single-organ BDS (54.8%, CI: 46.0-63.4). Patients with BDS had fewer socioeconomic resources, experienced more emotional distress, and used more opioids and medical services. CONCLUSIONS: BDS is a common clinical condition being prone to chronicity; one in seven primary care patients met the criteria for BDS, and more than half of these patients still suffered from BDS 2 years later.

Patient characteristics and frequency of bodily distress syndrome in primary care: a cross-sectional study.

BACKGROUND: Bodily distress syndrome (BDS) is a newly proposed diagnosis of medically unexplained symptoms, which is based on empirical research in primary care. AIM: To estimate the frequency of BDS in primary care and describe the characteristics of patients with BDS. DESIGN AND SETTING: A cross-sectional study of primary care patients in urban and rural areas of Central Denmark Region. METHOD: Data were obtained from GP one-page registration forms, patient questionnaires (including a checklist for BDS), and national registers. RESULTS: A total of 1356 primary care patients were included, of whom 230 patients (17.0%, 95% confidence intervals [CI] = 15.0 to 19.1) fulfilled the BDS criteria. BDS was more common among primary care patients aged 41-65 years (odds ratio [OR] = 1.9, 95% CI = 1.3 to 3.0) and was equally frequent among males and females (female sex, OR 0.9, 95% CI = 0.6 to 1.3). Patients with BDS were characterised by poor health-related quality of life (HRQOL) on the 12-item Short-Form Health Survey, that is, physical component summary scores <40 (OR 20.5, 95% CI = 12.9 to 32.4) and mental component summary scores <40 (OR 3.5, 95% CI = 2.2 to 5.6). Furthermore, patients with BDS were more likely to have high scores on the Symptom Checklist for anxiety (OR 2.2, 95% CI = 1.4 to 3.4) and depression (OR 5.1, 95% CI = 3.3 to 7.9), but regression analyses showed that mental morbidity did not account for the poor HRQOL. CONCLUSION: BDS is common among primary care patients, and patients with BDS have a higher probability of poor HRQOL and mental health problems.

A new questionnaire to identify bodily distress in primary care: The 'BDS checklist'.

BACKGROUND: Functional symptoms and disorders are common in primary care. Bodily distress syndrome (BDS) is a newly proposed clinical diagnosis for functional disorders. The BDS diagnosis is based on empirical research, and the symptoms stated in the BDS criteria have been translated into a self-report questionnaire called the BDS checklist. The aim of the present study was to investigate the psychometric properties of the checklist and to test the construct of BDS. METHOD: The 30-item BDS checklist was completed by 2480 adult primary care patients in a cross-sectional study on contact and disease patterns in Danish general practice. We performed (internal) validation analyses of the collected checklist data. We also performed factor and latent class analyses to identify both BDS symptom groups and BDS patient groups. RESULTS: Internal validation analyses revealed acceptable and usable psychometric properties of the BDS checklist. The factor analyses identified the four distinct determining factors for BDS: cardiopulmonary, gastrointestinal, musculoskeletal and general symptoms. Results from factor and multi-trait analyses suggested a shortening of the BDS checklist (from 30 to 25 items). The latent class analyses resulted in three severity levels (no, moderate and severe BDS); the best fit index was found for a threshold of ≥4 symptoms in a symptom group. CONCLUSION: The results provide empirical support for the previously described construct of BDS with four symptom groups and three patient groups. The BDS checklist is a self-report instrument that may be used for case finding in both clinical practice and in research.