Hereditary pancreatitis: outcomes and risks

Pancreatitis is an inflammatory disease of the pancreas that was first identified in the 1600s. Symptoms for pancreatitis include intense abdominal pain, nausea, and malnutrition. Hereditary pancreatitis (HP) is a genetic condition in which recurrent acute attacks can progress to chronic pancreatitis, typically beginning in adolescence. Mutations in the PRSS1 gene cause autosomal dominant HP. The 1996 discovery of a PRSS1 mutation causative for hereditary pancreatitis was in direct contrast to much of the medical community’s long-held beliefs that pancreatitis is primarily caused by alcoholism and gallstones. HP strongly impacts quality of life and is a risk factor for pancreatic cancer, making it a public health concern. Our understanding of HP is still limited, and chronic pancreatitis remains a serious disease for which significant treatment options are lacking. Questions remain regarding the exact mechanism of cancer development and risk factors in families with HP. Furthermore, HP has unpredictable duration, severity, complications, and outcomes. It is often accompanied by systemic diseases and complications, such as diabetes mellitus. Therefore, research is needed to further define the natural history of HP, its psychosocial implications, and its interactions with other risk factors. The overall goal of this research is to improve quality of life, patient care, and treatment options for individuals with this debilitating disease by understanding more about the natural history of the condition and collecting information on attitudes, concerns, and perspectives. The Hereditary Pancreatitis Study at the University of Pittsburgh has collected genetic, medical, and environmental data from hundreds of American families with pancreatitis since the mid-1990s. I have described the natural history of HP in this American cohort, analyzed risks for pancreatic cancer and diabetes based on family history, and assessed large HP pedigrees with pancreatic cancer. My analysis indicates that this American cohort is similar to published studies on the French, Danish, and other European populations. I also created a follow-up questionnaire for these participants to gather information on attitudes, risks for pancreatic cancer, and views on a pancreatic center of excellence and its services. Data from this questionnaire will be relevant to improving patient care in future studies

Evaluation of Polymorphic Locus Sequence Typing for Candida glabrata Epidemiology.

The opportunistic yeastCandida glabratais increasingly refractory to antifungal treatment or prophylaxis and relatedly is increasingly implicated in health care-associated infections. To elucidate the epidemiology of these infections, strain typing is required. Sequence-based typing provides multiple advantages over length-based methods, such as pulsed-field gel electrophoresis (PFGE); however, conventional multilocus sequence typing (targeting 6 conserved loci) and whole-genome sequencing are impractical for routine use. A commercial sequence-based typing service forC. glabratathat targets polymorphic tandem repeat-containing loci has recently been developed. These CgMT-J and CgMT-M services were evaluated with 56 epidemiologically unrelated isolates, 4 to 7 fluconazole-susceptible or fluconazole-resistant isolates from each of 5 center A patients, 5 matched pairs of fluconazole-susceptible/resistant isolates from center B patients, and 7 isolates from a center C patient who responded to then failed caspofungin therapy. CgMT-J and CgMT-M generated congruent results, resolving isolates into 24 and 20 alleles, respectively. Isolates from all but one of the center A patients shared the same otherwise rare alleles, suggesting nosocomial transmission. Unexpectedly, Pdr1 sequencing showed that resistance arose independently in each patient. Similarly, most isolates from center B also clustered together; however, this may reflect a dominant clone since their alleles were shared by multiple unrelated isolates. Although distinguishable by their echinocandin susceptibilities, all isolates from the center C patient shared alleles, in agreement with the previously reported relatedness of these isolates based on PFGE. Finally, we show how phylogenetic clusters can be used to provide surrogate parents to analyze the mutational basis for antifungal resistance

Lunar and Lagrangian Point L1/L2 CubeSat Communication and Navigation Considerations

CubeSats have grown in sophistication to the point that relatively low-cost mission solutions could be undertaken for planetary exploration. There are unique considerations for lunar and L1/L2 CubeSat communication and navigation compared with low earth orbit CubeSats. This paper explores those considerations as they relate to the Lunar IceCube Mission. The Lunar IceCube is a CubeSat mission led by Morehead State University with participation from NASA Goddard Space Flight Center, Jet Propulsion Laboratory, the Busek Company and Vermont Tech. It will search for surface water ice and other resources from a high inclination lunar orbit. Lunar IceCube is one of a select group of CubeSats designed to explore beyond low-earth orbit that will fly on NASA’s Space Launch System (SLS) as secondary payloads for Exploration Mission (EM) 1. Lunar IceCube and the EM-1 CubeSats will lay the groundwork for future lunar and L1/L2 CubeSat missions. This paper discusses communication and navigation needs for the Lunar IceCube mission and navigation and radiation tolerance requirements related to lunar and L1/L2 orbits. Potential CubeSat radios and antennas for such missions are investigated and compared. Ground station coverage, link analysis, and ground station solutions are also discussed. This paper will describe modifications in process for the Morehead ground station, as well as further enhancements of the Morehead ground station and NASA Near Earth Network (NEN) that are being considered. The potential NEN enhancements include upgrading current NEN Cortex receiver with Forward Error Correction (FEC) Turbo Code, providing X-band uplink capability, and adding ranging options. The benefits of ground station enhancements for CubeSats flown on NASA Exploration Missions (EM) are presented. This paper also describes how the NEN may support lunar and L1/L2 CubeSats without any enhancements. In addition, NEN is studying other initiatives to better support the CubeSat community, including streamlining the compatibility testing, planning and scheduling associated with CubeSat missions

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Hereditary pancreatitis: a prototype of chronic pancreatitis to characterize variable genomic elements that impact disease features and family dynamics

Pancreatitis is a complex acute and chronic inflammatory disease of the pancreas. Patients with chronic pancreatitis (CP) typically experience severe pain and loss of pancreatic function, and similar clinical phenotypes are produced by multiple genetic and environmental etiologies. However, the etiology of inflammation and the mechanisms behind risk for progression and outcomes remain obscure across different etiologies. Hereditary Pancreatitis (HP) is an autosomal dominant form characterized by disease onset in adolescence and progression to CP by adulthood. No effective treatment or therapeutic options exist, and the most advanced surgical option is total pancreatectomy with islet autotransplantation (TPIAT). Existing patients and samples from the HP Study at the University of Pittsburgh were leveraged to evaluate disease outcomes and quality of life in the largest USA cohort. Phenotypic variability and co-existing risk variants for disease severity and pancreatic cancer were evaluated in HP pedigrees. Leftover TPIAT pancreatic tissue from patients with CP was used to investigate underlying gene expression profiles. Risk of pancreatic cancer was significantly greater than age- and sex-matched SEER data (SIR 59), but the cumulative risk was 7.2% (95% CI 0-15.4) at 70 years, which is much lower than previous reports. Mental and physical quality of life was found to be significantly reduced in individuals with HP compared to family controls. Expression of worry and impact on family dynamics was identified from qualitative data. Phenotypic variability within and between HP pedigrees was identified for age of onset, penetrance and pancreatic cancer, for which one pancreatic cancer family harbored a predicted risk modifying ATM variant. RNA-sequencing studies indicated the upregulation of immune-signaling pathways and identified a new dedifferentiated cell population indicative of a regeneration response. Accurately defining risk for pancreatitis and outcomes is critical to improving patient counseling and management, and for surgical decision making. Furthermore, RNA-Sequencing provides a new opportunity to understand molecular pathogenesis in CP tissue and identify possible therapeutic targets for future research. Improvements in risk classification, early diagnosis and counseling strategies, and the development of targeted treatment approaches has important public health implications for healthcare spending, pain management and health-related quality of life