Severe coronavirus disease 2019 (COVID-19) is characterised by pneumonia with excessive systemic inflammation, referred to as a “cytokine storm” [1–3]. Dexamethasone treatment decreases mortality in patients with COVID-19 receiving respiratory support and is standard of care for severe COVID-19 [4, 5]. However, pulmonary inflammation, which drives COVID-19 morbidity and mortality [3], can persist despite corticosteroid use [6, 7]. Janus kinase (JAK) inhibition blocks signalling by many cytokines in diverse cell types, offering broad immunomodulation [8]. The oral JAK-1/2 inhibitor baricitinib combined with the antiviral remdesivir shows clinical efficacy in patients with severe COVID-19 [9]. Direct delivery of JAK inhibition to the lung via inhalation could overcome corticosteroid-resistant pulmonary inflammation [10], offering the potential for improved responses while minimising risk of excessive systemic immunosuppression. The novel inhaled pan-JAK inhibitor nezulcitinib (TD-0903) was designed to target all JAK isoforms (JAK1, JAK2, JAK3, TYK2; −log inhibition constant ≥9.2) and optimise delivery to the lungs while limiting systemic exposure (R. Sana and co-workers; unpublished results: abstract submitted to ERS International Congress, 2021). We report results from the completed part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19.

There is little literature to guide therapy in children and young adults with intracranial germ cell tumors. We present 17 consecutively diagnosed intracranial germ cell tumors at The Children's Hospital, Denver, from 1995 to 2001. Of 17 patients, 3 had considerable delay in diagnosis. Two with suprasellar tumors presented with dementia, blindness and pan-hypopituitarism and another with recurrent subarachnoid hemorrhage. Seven had germinoma, three were metastatic at diagnosis. Ten had non-germinomatous germ cell tumors (NGGCT), 5/10 were alpha feto-protein (AFP) positive only, one beta-human chorionic growth (betaHCG) factor positive only, 3 positive for AFP and betaHCG, and 1 malignant teratoma. Therapy for metastatic patients consisted of chemotherapy followed by craniospinal radiation (CSI). Patients with localized disease received chemotherapy followed by focal radiation. Two patients received chemotherapy only, one because she died of sepsis while receiving chemotherapy and one because of neurologic injury incurred during surgery parents elected for no therapy. Three patients have died, one of tumor recurrence, one from a remote complication of surgery and one of sepsis. Twelve patients are alive without evidence of disease from 10 to 68 months (median 31.5 months). All five children with only AFP positivity, treated with chemotherapy and focal radiation are alive without evidence of disease at 10, 16, 22, 41 and 41 months. Thus, there is little evidence that CSI is necessary in non-metastatic germinomas and AFP positive NGGCTs when combined chemotherapy and radiation therapy is used. However, complications of delayed diagnosis, surgery and chemotherapy are important causes of mortality, with only one patient dying of tumor.

We present CELER (Corpus of Eye Movements in L1 and L2 English Reading), a broad coverage eye-tracking corpus for English. CELER comprises over 320,000 words, and eye-tracking data from 365 participants. Sixty-nine participants are L1 (first language) speakers, and 296 are L2 (second language) speakers from a wide range of English proficiency levels and five different native language backgrounds. As such, CELER has an order of magnitude more L2 participants than any currently available eye movements dataset with L2 readers. Each participant in CELER reads 156 newswire sentences from the Wall Street Journal (WSJ), in a new experimental design where half of the sentences are shared across participants and half are unique to each participant. We provide analyses that compare L1 and L2 participants with respect to standard reading time measures, as well as the effects of frequency, surprisal, and word length on reading times. These analyses validate the corpus and demonstrate some of its strengths. We envision CELER to enable new types of research on language processing and acquisition, and to facilitate interactions between psycholinguistics and natural language processing (NLP).

Background: Lung-targeted anti-inflammatory therapy could potentially improve outcomes in patients with COVID-19. The novel inhaled pan-Janus kinase (JAK) inhibitor TD 0903 was designed to optimise delivery to the lungs while limiting systemic exposure. Here, we report results from the completed Part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19. Methods: Part 1 explored 3 doses of TD-0903 (1, 3, and 10 mg once-daily for 7 days) and placebo in a randomised, double-blind, ascending-dose study. Each dose cohort comprised 8 hospitalized patients (6:2 TD-0903:placebo) with PCR-confirmed COVID-19 requiring supplemental oxygen and receiving background standard-of-care therapy. Key objectives included safety and tolerability, pharmacokinetics, and oxygen saturation/fraction of inspired oxygen ratio; clinical outcomes were also explored. Data were summarised as descriptive statistics. Results: Twenty-five patients were randomised to receive TD 0903 1 mg (n = 6), 3 mg (n = 7), 10 mg (n = 6), or placebo (n = 6). Almost all patients (92%) received background dexamethasone; 3 (12%) received remdesivir. TD-0903 was generally well tolerated with no drug-related serious adverse events. Low plasma concentrations of TD-0903 were observed at all doses. Clinically favourable numerical trends in patients receiving TD-0903 vs placebo included improved 8-point clinical status, shortened hospitalisation, improved oxygenation, and fewer deaths. Conclusions: In Part 1 of this phase 2 trial, the novel inhaled JAK inhibitor TD-0903 showed potential for treatment of patients with severe COVID-19. TD-0903 3 mg is being evaluated in Part 2 of the randomised, double-blind, parallel-group trial in 198 hospitalized patients with COVID-19.

Colonic perforation is an uncommon but known and feared complication of colonoscopy, which carries a high mortality rate. We present an uncommon case of extensive intra-and extraperitoneal air following colonic perforation in a patient undergoing inpatient colonoscopy for evaluation of unintentional weight loss and constipation. During colonoscopy, a splenic flexure stricture was identified and dilated. Postprocedural hemodynamic instability prompted further imaging which revealed pneumoperitoneum, bilateral pneumothorax, pneumomediastinum, pneumopericardium, and severe subcutaneous emphysema. Emergent exploratory laparotomy found perforation of the proximal transverse colon which required resection and transverse colostomy placement. The patient also underwent bilateral chest tube placement and was treated with antibiotics for peritonitis. The patient was eventually diagnosed with Crohn's disease and discharged to an extended care facility with outpatient follow-up. Extraperitoneal colonic perforations are fairly rare, and to our knowledge, we present the most severe case that has been published in recent years.