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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a worldwide challenge. There are an estimated 17–24 million patients worldwide, with an estimated 60 percent or more who have not been diagnosed. Without a known cure, no specific curative medication, disability lasting years to being life-long, and disagreement among healthcare providers as to how to most appropriately treat these patients, ME/CFS patients are in need of assistance. Appropriate healthcare provider education would increase the percentage of patients diagnosed and treated; however, in-school healthcare provider education is limited. To address the latter issue, the New Jersey Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Association (NJME/CFSA) has developed an independent, incentive-driven, learning program for students of the health professions. NJME/CFSA offers a yearly scholarship program in which applicants write a scholarly paper on an ME/CFS-related topic. The efficacy of the program is demonstrated by the 2024–2025 first place scholarship winner’s essay, which addresses the biological basis of ME/CFS and how the healthcare provider can improve the quality of life of ME/CFS patients. For the reader, the essay provides an update on what is known regarding the biological underpinnings of ME/CFS, as well as a medical student’s perspective as to how the clinician can provide care and support for ME/CFS patients. The original essay has been slightly modified to demonstrate that ME/CFS is a worldwide problem and for publication.

Significance The blood protein von Willebrand factor (VWF) is required for platelets to stop bleeding at sites of injury, and the metalloprotease ADAMTS13 limits platelet adhesion by cleaving VWF only when flowing blood stretches it, especially within a growing thrombus. This feedback inhibition is essential because ADAMTS13 deficiency causes fatal microvascular thrombosis. How ADAMTS13 recognizes VWF so specifically is not understood. We now find that ADAMTS13 is folded roughly in half so that its distal domains inhibit the metalloprotease domain. VWF relieves this autoinhibition and promotes its own destruction by allosterically activating ADAMTS13. Thus, VWF is both a substrate and a cofactor in this critical regulatory process. The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) within endovascular platelet aggregates, and ADAMTS13 deficiency causes fatal microvascular thrombosis. The proximal metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains of ADAMTS13 recognize a cryptic site in VWF that is exposed by tensile force. Another seven T and two complement C1r/C1s, sea urchin epidermal growth factor, and bone morphogenetic protein (CUB) domains of uncertain function are C-terminal to the MDTCS domains. We find that the distal T8-CUB2 domains markedly inhibit substrate cleavage, and binding of VWF or monoclonal antibodies to distal ADAMTS13 domains relieves this autoinhibition. Small angle X-ray scattering data indicate that distal T-CUB domains interact with proximal MDTCS domains. Thus, ADAMTS13 is regulated by substrate-induced allosteric activation, which may optimize VWF cleavage under fluid shear stress in vivo. Distal domains of other ADAMTS proteases may have similar allosteric properties.

There is often difficulty differentiating between psychosomatic, somatopsychic, multisystem illness, and different degrees of medical uncertainty. Uncommon, complex, and multisystem diseases are commonly misdiagnosed. Two case histories are described, and relevant terms differentiating psychosomatic, somatopsychic, and multisystem illnesses are identified, reviewed, and discussed. Adequate differentiation requires an understanding of the mind/body connection, which includes knowledge of general medicine, psychiatry, and the systems linking the body and the brain. A psychiatric diagnosis cannot be given solely based upon the absence of physical, laboratory, or pathological findings. Medically unexplained symptoms, somatoform disorder, and compensation neurosis are outdated and/or inaccurate terms. The terms subjective, nonspecific, and vague can be used inaccurately. Conversion disorders, functional disorders, psychogenic illness, factitious disorder imposed upon another (Munchausen’s syndrome by proxy), somatic symptom disorder, psychogenic seizures, psychogenic pain, psychogenic fatigue, and delusional parasitosis can be over-diagnosed. Bodily distress disorder and bodily distress syndrome are scientifically unsupported and inaccurate. Many “all in your head” conditions may be related to the microbiome and the immune system. Better education concerning the interface between medicine and psychiatry and the associated diagnostic nomenclature as well as utilizing clinical judgment and thorough assessment, exercising humility, and maintaining our roots in traditional medicine will help to improve diagnostic accuracy and patient trust.

The potential benefits of the scientific insights gleaned from years of treating ME/CFS for the emerging symptoms of COVID-19, and in particular Longhaul- or Longhauler-COVID-19 are discussed in this opinion article. Longhaul COVID-19 is the current name being given to the long-term sequelae (symptoms lasting beyond 6 weeks) of SARS-CoV-2 infection. Multiple case definitions for ME/CFS exist, but post-exertional malaise (PEM) is currently emerging as the ‘hallmark’ symptom. The inability to identify a unique trigger of ME/CFS, as well as the inability to identify a specific, diagnostic laboratory test, led many physicians to conclude that the illness was psychosomatic or non-existent. However, recent research in the US and the UK, championed by patient organizations and their use of the internet and social media, suggest underlying pathophysiologies, e.g., oxidative stress and mitochondrial dysfunction. The similarity and overlap of ME/CFS and Longhaul COVID-19 symptoms suggest to us similar pathological processes. We put forward a unifying hypothesis that explains the precipitating events such as viral triggers and other documented exposures: For their overlap in symptoms, ME/CFS and Longhaul COVID-19 should be described as Post Active Phase of Infection Syndromes (PAPIS). We further propose that the underlying biochemical pathways and pathophysiological processes of similar symptoms are similar regardless of the initiating trigger. Exploration of the biochemical pathways and pathophysiological processes should yield effective therapies for these conditions and others that may exhibit these symptoms. ME/CFS patients have suffered far too long. Longhaul COVD-19 patients should not be subject to a similar fate. We caution that failure to meet the now combined challenges of ME/CFS and Longhaul COVID-19 will impose serious socioeconomic as well as clinical consequences for patients, the families of patients, and society as a whole.

Purpose: The aim of this study was to compare the mutation frequency distribution for a 32-mutation panel and a 69-mutation panel used for cystic fibrosis carrier screening. Further aims of the study were to examine the race-specific detection rates provided by both panels and to assess the performance of extended panels in large-scale, population-based cystic fibrosis carrier screening. Although genetic screening for the most common CFTR mutations allows detection of nearly 90% of cystic fibrosis carriers, the large number of other mutations, and their distribution within different ethnic groups, limits the utility of general population screening. Methods: Patients referred for cystic fibrosis screening from January 2005 through December 2010 were tested using either a 32-mutation panel ( n = 1,601,308 individuals) or a 69-mutation panel ( n = 109,830). Results: The carrier frequencies observed for the 69-mutation panel study population (1/36) and Caucasian (1/27) and African-American individuals (1/79) agree well with published cystic fibrosis carrier frequencies; however, a higher carrier frequency was observed for Hispanic-American individuals (1/48) using the 69-mutation panel as compared with the 32-mutation panel (1/69). The 69-mutation panel detected ~20% more mutations than the 32-mutation panel for both African-American and Hispanic-American individuals. Conclusion: Expanded panels using race-specific variants can improve cystic fibrosis carrier detection rates within specific populations. However, it is important that the pathogenicity and the relative frequency of these variants are confirmed. Genet Med 16 7, 539–546.

Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas ( n =105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFN γ including IDO-1 , WARS (tRNA(trp)), GBP1 , GBP4 , GBP5 , PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas ( P <0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas ( P <0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups ( P <0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.

This collection of research papers addresses fundamental questions concerning the nature of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), the problem of disbelief and lack of knowledge and understanding of the condition among many doctors and the origins of this problem, and its impact on patients and their families. We report briefly the growing knowledge of the underlying pathological processes in ME/CFS, and the development of new organizations, including Doctors with ME, the US ME/CFS Clinical Coalition and EUROMENE, to address aspects of the challenges posed by the illness. We discuss the implications of COVID-19, which has much in common with ME/CFS, with much overlap of symptoms, and propose a new taxonomic category, which we are terming post-active phase of infection syndromes (PAPIS) to include both. This collection of papers includes a number of papers reporting similar serious impacts on the quality of life of patients and their families in various European countries. The advice of EUROMENE experts on diagnosis and management is included in the collection. We report this in light of guidance from other parts of the world, including the USA and Australia, and in the context of current difficulties in the UK over the promulgation of a revised guideline from the National Institute for Health and Care Excellence (NICE). We also consider evidence on the cost-effectiveness of interventions for ME/CFS, and on the difficulties of determining the costs of care when a high proportion of people with ME/CFS are never diagnosed as such. The Special Issue includes a paper which is a reminder of the importance of a person-centred approach to care by reviewing mind–body interventions. Finally, another paper reviews the scope for prevention in minimizing the population burden of ME/CFS, and concludes that secondary prevention, through early detection and diagnosis, could be of value.

ObjectiveTo review existing structured MRI reports for primary staging of rectal cancer and create a new, freely available structured report based on multidisciplinary expert opinion and literature review.MethodsTwenty abdominal imaging experts from the Society of Abdominal Radiology (SAR)’s Disease Focused Panel (DFP) on Rectal and Anal Cancer completed a questionnaire and participated in a subsequent consensus meeting based on the RAND-UCLA Appropriateness Method. Twenty-two items were classified via a group survey as “appropriate” or “inappropriate” (defined by ≥ 70% consensus), or “needs group discussion” (defined by < 70% consensus). Certain items were also discussed with multidisciplinary team members from colorectal surgery, oncology and pathology.ResultsAfter completion of the questionnaire, 16 (72%) items required further discussion (< 70% consensus). Following group discussion, consensus was achieved for 21 (95%) of the items. Based on the consensus meeting, a revised structured report was developed. The most significant modifications included (1) Exclusion of the T2/early T3 category; (2) Replacement of the term “circumferential resection margin (CRM)” with “mesorectal fascia (MRF)”; (3) A revised definition of “mucinous content”; (4) Creation of two distinct categories for suspicious lymph nodes (LNs) and tumor deposits; and (5) Classification of suspicious extra-mesorectal LNs by anatomic location.ConclusionThe SAR DFP on Rectal and Anal Cancer recommends using this newly updated reporting template for primary MRI staging of rectal cancer.

von Willebrand factor (VWF) is a multimeric protein that binds platelets and collagen, facilitating hemostasis at sites of vessel injury. Measurement of VWF multimer distribution is critical for diagnosis of variant von Willebrand disease (VWD), particularly types 2A and 2B, but the typical measurement by gel electrophoresis is technically difficult and time-consuming. A comparison of VWF collagen binding (VWF:CB) and VWF multimer distribution was performed to evaluate the utility of VWF:CB as a diagnostic test. Participants were enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD. VWF:CB was analyzed with type III collagen and multimer distribution by agarose gel electrophoresis. The study population included 146 healthy controls, 351 individuals with type 1 VWD, and 77 with type 2 VWD. Differences between individuals with multimer group results within (controls) and outside the reference intervals were assessed with Mann-Whitney tests. The mean VWF:CB/VWF antigen ratio was 1.10 for individuals with multimer distribution within the reference intervals and 0.51 for those with multimer distribution outside the reference intervals (P < 0.001). Sensitivity of VWF:CB for multimer abnormalities was 100% for healthy controls, 99% for patients with type 1, and 100% for patients with type 2A and type 2B VWD using a VWF:CB/VWF antigen cutoff ratio of 0.6, and decreased to 99% for all patients with a ratio of 0.7. With the exception of individuals with novel or unclassified mutations, the VWF:CB was able to correctly categorize participants with variant VWD. These findings suggest that VWF:CB may substitute for multimer distribution in initial VWD testing, although further studies are needed to validate the clinical utility of VWF:CB.

Patients with von Willebrand disease (VWD) often require treatment with supplemental von Willebrand factor (VWF) prior to procedures or to treat bleeding. Commercial VWF concentrates and more recently recombinant human VWF (rVWF) have replaced cryoprecipitate as the mainstay of therapy. In comparison with cryoprecipitate, the VWF content and multimer distribution under current manufacturing processes of these commercial products has not been reported. We measured the factor VIII (FVIII:C), VWF antigen (VWF:Ag), VWF collagen-binding activity (VWF:CB), VWF platelet-binding activity by GPIbM enzyme-linked immunosorbent assay (VWF:GPIbM), and percentage of high-molecular-weight (HMWM) VWF in 3 pools of group A and O cryoprecipitate, 3 vials of VWF concentrate (Humate-P), and 1 lot of rVWF (Vonvendi). We found that both group O and group A cryoprecipitate have significantly higher ratios of VWF:GPIbM activity and FVIII:C activity relative to VWF:Ag and have better preservation of HMWM than Humate-P. Although not compared statistically, rVWF appears to have more HMWM VWF and a higher ratio of VWF:GPIbM to VWF:Ag than Humate-P and cryoprecipitate. The estimated acquisition cost for our hospital for treating one major bleeding episode was more than 4-fold higher with Humate-P and 7- to 10-fold higher with rVWF than with cryoprecipitate.