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Background & Aims The immunosuppressant rapamycin frequently causes non-infectious diarrhea in recipients of organ transplants. We investigated the mechanisms of this process. Methods We performed a retrospective analysis of renal transplant recipients treated with rapamycin from 2003 through 2010 at Albany Medical College, collecting data on serum levels of rapamycin. Levels of the Na+/H+ exchanger 3 (NHE3) were measured in human ileal biopsies from patients who did and did not receive rapamycin (controls), in ileum tissues from rats or mice given rapamycin, and in mice with intestine-specific disruption of Mtor (mTORf/f:Villin-cre mice) or Atg7 (Atg7flox/flox; Villin-Cre). Exchange activity and intestinal water absorption were measured using a pH-sensitive dye and small intestine perfusion, respectively. Results Episodes of non-infectious diarrhea occurred in organ recipients following increases in serum levels of rapamycin. Expression of NHE3 was reduced in the ileal brush border of patients with diarrhea. In rats and mice, continuous administration of low doses of rapamycin reduced levels of NHE3 in intestinal tissues; this effect was not observed in mice with intestinal deletion of ATG7, indicating that autophagy is required for the reduction. Administration of single high doses of rapamycin to mice, to model the spikes in rapamycin levels that occur in patients with severe diarrheal episodes, resulted in reduced phosphorylation of S6 and AKT in ileal tissues, indicating inhibition of the mTOR complex (mTORC1 and mTORC2). Intestines of mice with intestine-specific deletion of mTOR were dilated and contained large amount of liquid stools; they also had reduced levels of total NHE3 and NHERF1, compared with control mice. We observed a significant reduction in Na+/H+ exchange activity in ileum tissues from these mice. Conclusions Rapamycin inhibition of mTOR reduces levels of NHE3 and Na+/H+ exchange activity in intestinal tissues of patients and rodents. This process appears to require the autophagic activity mediated by ATG7. Loss of mTOR regulation of NHE3 could mediate the development of diarrhea in patients undergoing rapamycin therapy.

Specific oncogenes with driver mutations, such as the Epidermal Growth Factor Receptor (EGFR 1) gene can lead to non-small-cell lung cancer formation. Identification of these oncogenes, their driver mutations and downstream effects allow the targeting of these pathways by drugs. Such personalised therapy has become an important strategy in combating lung cancer and highlights the need to test for these mutations. Tyrosine Kinase Inhibitors (TKIs) against EGFR, such as Erlotinib, are able to halt these tumour promoting properties in non-small-cell lung cancers. Third generation EGFR TKIs, such as Osimertinib, are focussing on resulting acquired TKI resistance. Here we report the clinical course of a patient with metastatic non-small-cell lung cancer who has undergone EGFR targeted therapy and been further challenged by TKI acquired resistance. Her extended survival and maintained quality of life are a consequence of these modern, genotype-targeted, personalised metastatic non-small-cell lung cancer therapies.

Familial amyloidoses are a group of inherited disorders that cause deposition of misfolded amyloidogenic proteins in various tissues, resulting in organ dysfunction. Point mutations in the coding region of seven different genes are known to cause clinically significant systemic amyloid disease. We describe a new mutation in exon 2 of the lysozyme gene associated with amyloidosis (ALys) in a 61-year-old woman with a 7-year history of non-bloody, watery diarrhea, and weight loss. Biopsies of the duodenum and stomach were positive for amyloid deposits in the lamina propria and blood vessels. Direct DNA sequencing of the lysozyme gene revealed a single base nucleotide transversion from T to A at the first position of codon 54, resulting in replacement of Tyr by Asn in the mature lysozyme protein (pTyr54Asn). Immunoblot analysis of amyloid fibrils extracted from a fat tissue sample confirmed lysozyme as the amyloid protein. Clinically, the phenotype associated with this lysozyme mutation featured chronic abdominal pain, diarrhea, weight loss, malabsorption, and sicca syndrome. There was no associated nephropathy as has been reported for other ALys mutations. We describe a new mutant lysozyme that presents with abdominal discomfort, diarrhea, weight loss, and sicca syndrome.

The transition to adulthood can be a vulnerable period for certain population groups. In particular, young adults aged 18–25 years who have a parent with mental illness and/or substance use problems face increased risks to their mental health compared to same aged peers. Yet these young adults may not have access to age-appropriate, targeted interventions, nor engage with traditional face-to-face health services. To support this vulnerable group, services need to engage with them in environments where they are likely to seek help, such as the Internet. This paper describes the risk mechanisms for this group of young adults, and the theoretical and empirical basis, aims, features and content of a tailored online group intervention; mi.spot ( m ental i llness: s upportive, p reventative, o nline, t argeted). The participatory approach employed to design the intervention is described. This involved working collaboratively with stakeholders (i.e., young adults, clinicians, researchers and website developers). Implementation considerations and future research priorities for an online approach targeting this group of young adults conclude the paper.

BackgroundInferior vena cava filter complications can range from dislodgement to perforation. Patients who present with concomitant bacteremia have rarely been reported. Persistent bacteremia usually results from direct bacterial seeding from a source other than perforation of surrounding viscus. It is unclear if the risk of perforation is higher in patients who are bacteremic due to other causes.Case presentationWe report an interesting case of a 67-year-old white woman who presented with fever, chills, and right upper quadrant abdominal pain. Her blood cultures were positive for methicillin-sensitive Staphylococcus aureus with no obvious source. Upon further investigation, she was found to have an inferior vena cava filter perforating her duodenum. The cause of her abdominal pain was explained by the inferior vena cava filter penetrating the duodenum; however, the source of bacteremia could not be ascertained. The inferior vena cava filter was removed successfully, and she was discharged on an intravenous antibiotic. Her symptoms resolved soon after the filter was removed.ConclusionsThe use of inferior vena cava filters has increased significantly in recent years. This is likely due to their wider availability and safer placement techniques. With increasing use, the complications arising from these filters have been on the rise as well. It is very important for clinicians to be aware of these complications to avoid delays in diagnosis and patient care.

Background One in 5 young people grow up in a family where one parent has experienced a mental health problem or substance use concern. Compared with their same-aged peers, these youth are at a higher risk of academic failure and acquiring a substance abuse and/or mental health issue. There is a paucity of accessible, age-appropriate interventions that address their needs. Objective A 6-week, web-based intervention, “mental illness: supported, preventative, online, targeted” (mi.spot), was developed based on previous research and the competence enhancement model. This paper describes the protocol for a randomized controlled trial and details how the usage, safety, acceptability, and feasibility of the intervention will be determined. Methods Participants will be recruited through social media and clinician referral. A total of 70 Australians, aged 18 to 25 years, who grew up with parents with a mental illness or substance use concern will participate in a 2-arm parallel randomized controlled trial. The assessment will consist of a baseline measurement and 2 follow-up periods, posttest and 6-week follow-up, using the Mental Health Continuum short form; the Depression, Anxiety, and Stress Scale; the Coping Orientation to Problems Experienced inventory; the General Help Seeking Questionnaire; the Social Connectedness Scale; the Mental Health Literacy Scale; the General Self-Efficacy Scale; and the Attribution of Responsibility for Parental Mental Illness Measure. Impact will be examined at pre, post, and follow-up time periods using analyses of variance that will include a within-subjects factor (time) and a between-subjects factor (intervention/control). Facilitator interviews will ascertain intervention feasibility. Participant interviews will ascertain intervention acceptability. Interview data will be analyzed within a qualitative framework. Usage (data analytics) across site features and several indicators of clinical safety will also be reported. Results The impact of mi.spot will be examined at pre, post, and follow-up time periods using analyses of variance on each of the measures outlined above. There will be a within-subjects factor (time) and a between-subjects factor (intervention/control). Data analysis will employ the intention-to-treat principle by including all participants in the analyses. Qualitative interview data will be analyzed using interpretative phenomenological analysis along with respondent validation. The Monash University Human Research Ethics Committee (reference number: 2019-18660-30434) approved the trial on April 17, 2019. As of October 2, 2019, 30 participants were enrolled in the control group and 34 participants were enrolled in the intervention group. Result are expected to be submitted for publication in December 2020. Conclusions Study results will provide reliable evidence on a web-based intervention that has the potential to make a difference to the lives of many vulnerable young adults. Implementation guidelines are needed to embed the intervention in different service sectors. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12619000335190; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12619000335190 International Registered Report Identifier (IRRID) DERR1-10.2196/15626

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Immune alterations involving heightened T-helper-1 responses have been proposed to play a major role in the pathogenesis of sarcoidosis. Interferon-alpha therapy and hepatitis C infection have been implicated in the development of a variety of autoimmune diseases. However, despite the wide use of IFN-alpha therapy for hepatitis C, only a few cases of sarcoidosis have been reported in this context. We report the case of a 42-year-old white female with hepatitis C, who developed systemic sarcoidosis shortly after therapy with IFN-alpha2b. The disease was heralded by the appearance of a cutaneous sarcoid/ foreign body granulomatous reaction at the site of an old tattoo. The sarcoidosis responded to a short course of oral prednisone therapy. We also reviewed the other reported cases and discussed the possible immunological mechanisms involved.