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Abstract Organic solvents host the synthesis of high-value crystals used as pharmaceuticals and optical devices, among other applications. A knowledge gap persists on how replacing the hydrogen bonds and polar attraction that dominate aqueous environments with the weaker van der Waals forces affects the growth mechanism, including its defining feature, whether crystals grow classically or nonclassically. Here we demonstrate a rare dual growth mode of etioporphyrin I crystals, enabled by liquid precursors that associate with crystal surfaces to generate stacks of layers, which then grow laterally by incorporating solute molecules. Our findings reveal the precursors as mesoscopic solute-rich clusters, a unique phase favored by weak bonds such as those between organic solutes. The lateral spreading of the precursor-initiated stacks of layers crucially relies on abundant solute supply directly from the solution, bypassing diffusion along the crystal surface; the direct incorporation pathway may, again, be unique to organic solvents. Clusters that evolve to amorphous particles do not seamlessly integrate into crystal lattices. Crystals growing fast and mostly nonclassically at high supersaturations are not excessively strained. Our findings demonstrate that the weak interactions typical of organic systems promote nonclassical growth modes by supporting liquid precursors and enabling the spreading of multilayer stacks.

Niklas Kahr Rasmussen,1 Birgitte Berg,2 Anne Sia Louise Christiansen,3 Jesper Skov Neergaard,1 Gitte Ter-Borch,2 Emily A Hildebrand,4 Maya Gonczi,4 Thomas Sparre1 1Medical & Science Innovation, Novo Nordisk A/S, Søborg, Denmark; 2Clinical Operations, Novo Nordisk A/S, Søborg, Denmark; 3Biostatistics, Novo Nordisk A/S, Søborg, Denmark; 4Research Collective LLC, Tempe, AZ, USACorrespondence: Niklas Kahr Rasmussen, Medical & Science Innovation, Novo Nordisk A/S, Søborg, Denmark, Tel +45 3075 5040, Email NKHR@novonordisk.comIntroduction: Concizumab is a once-daily prophylactic treatment developed for patients with hemophilia A or B (HA/HB) with or without inhibitors. It is the first treatment for hemophilia patients to be delivered subcutaneously using a pre-filled, multi-dose pen-injector with a 4 mm, 32 G needle.Aim: To investigate patient and caregiver handling and preference for the concizumab pen-injector compared with current injection systems used to treat hemophilia.Methods: This preference and handling study was conducted in accordance with authority guidelines for approval of new devices and included adults and adolescents with HA/HB with or without inhibitors and caregivers currently administering factor replacement therapy or factor VIII mimetic (emicizumab) therapy. All participants underwent a training session, followed by a test session during which participants independently administered a single pen-injection into an injection pad or manikin. Time to train, time to prepare and inject, and number of complete independent injections handling the pen were assessed. Participants evaluated handling and preference via the Hemophilia Device Handling and Preference Assessment Questionnaire.Results: 80 participants (44 adults, 21 adolescents, 15 caregivers) currently using factor replacement therapy (n=41, 51%) or emicizumab (n=39, 49%) participated. Average training time and time to complete an injection were 7 min 49s and 1 min 21s. In total, 98% of independent complete injections were achieved at first attempt. 98% (n=78; 95% confidence interval [CI] 91– 100%) of participants assessed the pen-injector as either “easy” or “very easy” to use. 88% of participants preferred the pen-injector (n=70; 95% CI 78– 94%) over their current injection system, and 9% (n=7) reported “no preference”.Conclusion: Participants found the concizumab pen-injector easy to learn and easy to use and preferred it over their current injection systems.Plain Language Summary: People with hemophilia lack clotting factors that help stop bleeding after an injury. If left untreated, it can lead to life-threatening bleeding episodes. Treatment such as replacement therapy with clotting factors needs to be administered at regular intervals to prevent bleeding. The administration of intravenous (inside the vein) medication can be challenging due to the required skills, injection pain and availability of a good vein to inject into. Factor VIII mimetic therapy now allows people to inject medication under the skin (subcutaneously). However, using vials and syringes still poses challenges with the time to prepare and inject medication. Pen-injectors have been developed to address these challenges and provide additional benefits, including increased dose accuracy, portability, reduced discomfort, and less administration time. Concizumab is a medication developed for once-daily subcutaneous injection for people with hemophilia A or hemophilia B, with or without inhibitors, using a pen-injector. The objective of this preference and handling study was to understand patient and caregiver pen-injector handling experiences, and device preferences compared to their existing devices. In this study, most participants found it easy to learn to use the pen-injector. 98% of participants reported that the pen-injector was easy or very easy to use compared with their current device. 88% of participants reported a preference for the concizumab pen-injector over their current device. This shows that the pen-injector can easily and effectively be used to inject concizumab, providing more control and independence in patients’ treatment while reducing the burden caused by intravenous modes of administration.Keywords: concizumab, pen-injector, subcutaneous, preference and handling study, questionnaire

ObjectivesThe purpose of the systematic review was to synthesize literature on eating disorders (ED) and non-interpersonal traumatic events (NTE) and consolidate the reported prevalence of NTE in patients with an ED.MethodsThe literature search was performed in Embase, PsycInfo, and PubMed. The keywords in the search were “eating disorder,” “trauma” and “non-interpersonal,” using index-terms and free-search keywords related to NTE and ED. The PRISMA guidelines were followed. Relevant studies were screened using Rayyan.ResultsOf the 16 studies included in the quantitative synthesis, five overall types of NTE were identified: accidents, illness, injury, natural disaster and war. Findings provided tentative evidence for illness and injury being more prevalent in patients suffering from an ED compared to controls. The remaining subtypes of NTE did not show a higher prevalence in patients with an ED when compared to controls. Findings also suggest that those with binge/purge subtype of anorexia nervosa (AN) had a higher prevalence of non-interpersonal traumatic events compared to the restrictive subtype of AN.DiscussionThis systematic review provided a clear synthesis of previous findings related to NTE among patients with an ED. Noteworthy, is that many studies do not take into account if the trauma happened prior or after to ED onset, which may affect the association. Furthermore, the body of research on NTE in patients with ED is exceedingly limited, and more research is needed.

IntroductionSARS-CoV-2 infection affects the cardiopulmonary system in the acute as well as long-term phase. The aim of the present study was to comprehensively assess symptoms and possible long-term impairments 6 and 18 months after hospitalization for severe COVID-19 infection.MethodsThis prospective registry included patients with PCR-confirmed COVID-19 infection requiring hospitalization. Follow-up approximately 6 months post discharge comprised a detailed patient history, clinical examination, transthoracic echocardiography, electrocardiogram, cardiac magnetic resonance imaging (cMRI), chest computed tomography (CT) scan, pulmonary function test (PFT), six-minute walk test (6MWT) and a laboratory panel. At the time of the second follow-up visit at 18 months, patients without pathologic findings during the first study visit were contacted by phone to inquire about the course of their symptoms. In all other patients all initial examinations were repeated.ResultsTwo hundred Patients, who were hospitalized for COVID-19, were contacted by phone and were recruited for the study. Due to dropouts the second study visit was performed in 170 patients. A comparison between the two study visits at 6 and 18 months post discharge showed the following results: Six months after discharge, 73% and 18 months after discharge 52% fulfilled the criteria for Long COVID with fatigue being the most common symptom (49%). Echocardiography at 6 months post discharge showed an impaired left ventricular function in 8% of which 80% returned to normal. Six months post discharge, cMRI revealed pericardial effusion in 17% which resolved in 47% of the 15 patients who underwent a control cMRI. Signs of peri- or myocarditis were present in 5% of the patients and were resolved in all 4 patients who attended control studies. At 6 months, chest CT scans identified post-infectious residues in 24%. In the 25 repeated chest CT scans 20% showed full recovery. Length of in-hospital stay was identified as a significant predictor for persisting Long COVID (95% CI: 1.005–1.12, p = 0.03).ConclusionComparing 6 to 18 months, the prevalence of Long COVID decreased over time, but a high symptom burden remained. Structural and functional abnormalities were less frequent than the portrayed symptoms, and it thus remains a challenge to substantiate the symptoms.

Multiplex sampling, so far mainly used as a tool for S/N ratio improvement in spectroscopic applications and separation techniques, has been investigated here for its potential suitability for time-resolved monitoring where chromatograms of transient signals are recorded at intervals much shorter than the chromatographic runtime. Different designs of multiplex sample introduction were developed and utilized to analyze lithium-ion battery degradation products under normal or abuse conditions to achieve fast and efficient sample introduction. After comprehensive optimization, measurements were performed on two different GC systems, with either barrier discharge ionization detection (BID) or mass spectrometric detection (MS). Three different injector designs were examined, and modifications in the pertinent hardware components and operational conditions used. The shortest achievable sample introduction time was 50 ms with an interval of 6 s. Relative standard deviations were lower than 4% and 10% for the intra- and inter-day repeatability, respectively. The sample introduction system and column head pressure had to be carefully controlled, as this parameter most critically affects the amount of sample introduced and, thus, detector response. The newly developed sample introduction system was successfully used to monitor volatile degradation products of lithium-ion batteries and demonstrated concentration changes over the course of time of the degradation products (e.g., fluoroethane, acetaldehyde and ethane), as well as for solvents from the battery electrolyte like ethyl carbonate.