Marker-free characterization of full-length transcriptomes of single live circulating tumor cells.

The identification and characterization of circulating tumor cells (CTCs) are important for gaining insights into the biology of metastatic cancers, monitoring disease progression, and medical management of the disease. The limiting factor in the enrichment of purified CTC populations is their sparse availability, heterogeneity, and altered phenotypes relative to the primary tumor. Intensive research both at the technical and molecular fronts led to the development of assays that ease CTC detection and identification from peripheral blood. Most CTC detection methods based on single-cell RNA sequencing (scRNA-seq) use a mix of size selection, marker-based white blood cell (WBC) depletion, and antibodies targeting tumor-associated antigens. However, the majority of these methods either miss out on atypical CTCs or suffer from WBC contamination. We present unCTC, an R package for unbiased identification and characterization of CTCs from single-cell transcriptomic data. unCTC features many standard and novel computational and statistical modules for various analyses. These include a novel method of scRNA-seq clustering, named deep dictionary learning using k-means clustering cost (DDLK), expression-based copy number variation (CNV) inference, and combinatorial, marker-based verification of the malignant phenotypes. DDLK enables robust segregation of CTCs and WBCs in the pathway space, as opposed to the gene expression space. We validated the utility of unCTC on scRNA-seq profiles of breast CTCs from six patients, captured and profiled using an integrated ClearCell FX and Polaris workflow that works by the principles of size-based separation of CTCs and marker-based WBC depletion.

Multisystem Inflammatory Syndrome in an Adolescent Following SARS-CoV-2 Exposure Despite Three Doses of a COVID-19 Vaccine.

The multisystem inflammatory syndrome in children (MIS-C) is a known complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the pediatric population. Recent studies have demonstrated high efficacy of a two-dose vaccine series in preventing MIS-C among adolescents. To date, such studies have only included children exposed to SARS-CoV-2 prior to the emergence of the Omicron variant (B.1.1.529). We report a case of an adolescent who received three doses of a vaccine yet developed MIS-C following known exposure to SARS-CoV-2. Given the uncertainty in whether current vaccines offer as much protection against MIS-C due to the Omicron variant or any potential new variants as they have for older variants, pediatric providers should maintain a high index of suspicion for MIS-C regardless of vaccination status.

Characteristics of Provider-Focused Research on Complementary and Integrative Medicine in Palliative Care: A Scoping Review.

BACKGROUND: The use of complementary and integrative medicine (CIM) continues to grow in palliative care. While research supports the use of many CIM therapies for symptom relief, the scope of provider-focused research on CIM remains poorly characterized. OBJECTIVES: We conducted a scoping review to characterize provider-focused research on CIM in palliative care in order to map existing evidence and identify knowledge gaps. METHODS: We developed a protocol outlining the study population, concept, and context; then used a validated approach per the JBI manual and searched MEDLINE, EMBASE, CINAHL, and AMED. RESULTS: We identified 34 studies that were conducted primarily in the US (n = 9) and UK (n = 6), focused mostly on nurse (n = 29) and physician (n = 22) providers, and employed questionnaires (n = 16) or qualitative (n = 15) methods. Studies investigated 58 CIM modalities, including massage (n = 13), music therapy (n = 12), and aromatherapy (n = 10), to address common symptoms including pain (n = 17), fatigue (n = 6), and nausea/vomiting (n = 6). Study outcomes included perceived benefits of CIM (n = 17) and types of CIM modalities that providers offer (n = 15). Uncommonly studied phenomena included referral patterns (n = 4), facilitators of provider recommendation of CIM (n = 3), and rates of CIM use (n = 3). CONCLUSION: Provider-focused research on CIM in palliative care can expand its scope by addressing perspectives of interdisciplinary providers, examining CIM modalities that patients report using, addressing symptoms commonly encountered in palliative care, and researching provider-use-focused outcomes. We identify these possibilities for future studies in addition to opportunities for systematic investigations to enhance the safe and efficacious delivery of CIM in the palliative care setting.

Do Palliative Care Providers Use Complementary and Integrative Medicine? A Nationwide Survey.

CONTEXT: Given the high prevalence of burdensome symptoms in palliative care (PC) and increasing use of complementary and integrative medicine (CIM) therapies, research is needed to determine how often and what types of CIM therapies providers recommend to manage symptoms in PC. OBJECTIVES: To document recommendation rates of CIM for target symptoms and assess if, CIM use varies by provider characteristics. METHODS: Nationwide survey's of physicians (MD and DO), physician assistants, and nurse practitioners in PC. RESULTS: Participants (N = 404) were mostly female (71.3%), physicians (74.9%), and cared for adults (90.4%). Providers recommended CIM an average of 6.82 times per-month (95% CI: 6.04-7.60) and used an average of 5.13 (95% CI: 4.90-5.36) out of 10 CIM modalities. Respondents recommended mind-body medicines (e.g., meditation, biofeedback) most, followed by massage, and acupuncture and/or acupressure. The most targeted symptoms included pain; followed by anxiety, mood disturbance, and distress. Recommendation frequencies for specific modality-for-symptom combinations ranged from little use (e.g., aromatherapy for constipation) to occasional use (e.g., mind-body interventions for psychiatric symptoms). Finally, recommendation rates increased as a function of pediatric practice, noninpatient practice setting, provider age, and proportion of effort spent delivering palliative care. CONCLUSION: To the best of our knowledge, this is the first national survey to characterize PC providers' CIM recommendation behaviors and assess specific therapies and common target symptoms. Providers recommended a broad range of CIM but do so less frequently than patients report using CIM. These findings should be of interest to any provider caring for patients with serious illness.

Long-Term Effects of Hearing Aids on Hearing Ability in Patients with Sensorineural Hearing Loss.

BACKGROUND: A frequent concern surrounding amplification with hearing aids for patients with sensorineural hearing loss is whether these devices negatively affect hearing ability. To date, there have been few studies examining the long-term effects of amplification on audiometric outcomes in adults. PURPOSE: In the present study, we examined how hearing aids affect standard audiometric outcomes over long-term periods of follow-up. RESEARCH DESIGN: We retrospectively collected audiometric data in adults with sensorineural hearing loss, constructing a model of long-term outcomes. STUDY SAMPLE: This retrospective cohort study included 802 ears from 401 adult patients with bilateral sensorineural hearing loss eligible for amplification with hearing aids at a single institution. INTERVENTION: Of the eligible patients, 88 were aided bilaterally, and 313 were unaided. DATA COLLECTION AND ANALYSIS: We examined the standard three-frequency pure-tone average (PTA3-Freq), a novel extended pure-tone average (PTAExt), and word recognition score (WRS) per-ear at each encounter. We then modeled the association between the use of hearing aids for 5 years and these audiometric outcomes using targeted maximum likelihood estimation. RESULTS: In comparing aided and unaided ears at the end of 5 years, there were discernible effects for all measurements. The PTA3-Freq was 5 dB greater in aided ears (95% CI: 1.37-8.64, p = 0.007), WRS was 4.5 percentage points lower in aided ears (95% CI: -9.14 to 0.15, p = 0.058), and PTAExt was 5 dB greater in aided ears (95% CI: 2.18-7.82, p < 0.001), adjusting for measured confounders. CONCLUSION: Our analysis revealed discernible effects of 5 years of hearing aid use on hearing ability, specifically as measured by the PTA3-Freq, novel PTAExt, and WRS, suggesting a greater decline in hearing ability in patients using hearing aids. Future studies are needed to examine these effects between treatment groups over longer periods of time and in more heterogeneous populations to improve clinical practice guidelines and safety of both prescriptive fitting nonprescriptive amplification.

AMIGO2 Scales Dendrite Arbors in the Retina.

The size of dendrite arbors shapes their function and differs vastly between neuron types. The signals that control dendritic arbor size remain obscure. Here, we find that in the retina, starburst amacrine cells (SACs) and rod bipolar cells (RBCs) express the homophilic cell-surface protein AMIGO2. In Amigo2 knockout (KO) mice, SAC and RBC dendrites expand while arbors of other retinal neurons remain stable. SAC dendrites are divided into a central input region and a peripheral output region that provides asymmetric inhibition to direction-selective ganglion cells (DSGCs). Input and output compartments scale precisely with increased arbor size in Amigo2 KO mice, and SAC dendrites maintain asymmetric connectivity with DSGCs. Increased coverage of SAC dendrites is accompanied by increased direction selectivity of DSGCs without changes to other ganglion cells. Our results identify AMIGO2 as a cell-type-specific dendritic scaling factor and link dendrite size and coverage to visual feature detection.

Elevating Growth Factor Responsiveness and Axon Regeneration by Modulating Presynaptic Inputs.

Despite robust effects on immature neurons, growth factors minimally promote axon regeneration in the adult central nervous system (CNS). Attempting to improve growth-factor responsiveness in mature neurons by dedifferentiation, we overexpressed Lin28 in the retina. Lin28-treated retinas responded to insulin-like growth factor-1 (IGF1) by initiating retinal ganglion cell (RGC) axon regeneration after axotomy. Surprisingly, this effect was cell non-autonomous. Lin28 expression was required only in amacrine cells, inhibitory neurons that innervate RGCs. Ultimately, we found that optic-nerve crush pathologically upregulated activity in amacrine cells, which reduced RGC electrical activity and suppressed growth-factor signaling. Silencing amacrine cells or pharmacologically blocking inhibitory neurotransmission also induced IGF1 competence. Remarkably, RGCs regenerating across these manipulations localized IGF1 receptor to their primary cilia, which maintained their signaling competence and regenerative ability. Thus, our results reveal a circuit-based mechanism that regulates CNS axon regeneration and implicate primary cilia as a regenerative signaling hub.

The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α.

BACKGROUND & AIMS: Rifaximin-α reduces the risk of recurrence of overt hepatic encephalopathy. However, there remain concerns regarding the financial cost of the drug. We aimed to study the impact of treatment with rifaximin-α on healthcare resource utilisation using data from seven UK liver treatment centres. METHODS: All seven centres agreed a standardised data set and data characterising clinical, demographic and emergency hospital admissions were collected retrospectively for the time periods 3, 6 and 12 months before and following initiation of rifaximin-α. Admission rates and hospital length of stay before and during therapy were compared. Costs of admissions and drug acquisition were estimated using published sources. Multivariate analyses were carried out to assess the relative impact of various factors on hospital length of stay. RESULTS: Data were available from 326 patients. Following the commencement of rifaximin, the total hospital length of stay reduced by an estimated 31-53%, equating to a reduction in inpatient costs of between £4858 and £6607 per year. Taking into account drug costs of £3379 for 1-year treatment with rifaximin-α, there was an estimated annual mean saving of £1480-£3228 per patient. CONCLUSIONS: Initiation of treatment with rifaximin-α was associated with a marked reduction in the number of hospital admissions and hospital length of stay. These data suggest that treatment of patients with rifaximin-α for hepatic encephalopathy was generally cost saving.

National survey of anticoagulation policy in endoscopy.

BACKGROUND: Anticoagulated patients who need to undergo endoscopy present unique challenges to the gastroenterologist. The continuation of anticoagulant therapy increases the risk of haemorrhagic complications of gastrointestinal endoscopy. Reversing the anticoagulation increases the risk of thromboembolism. In our experience in various endoscopy units, there are variable policies on the management of anticoagulated patients undergoing gastrointestinal endoscopy. METHODS: To study the current practice, survey questionnaires were sent to 2320 doctors, working in 231 hospitals across the United Kingdom. RESULTS: Responses were obtained from 219 hospitals (94.8%), but only from 434 doctors (18.7%). The results show 40.8% endoscopists continued the patients on warfarin when performing a planned upper gastrointestinal endoscopy, whereas 26% stopped it; 33.2% gave varying reports, that is, they used their own judgement according to the disease for which the anticoagulant was being given. For planned lower gastrointestinal endoscopy, 48.7% doctors preferred to stop warfarin; 53.3% of the endoscopists stated that they have a policy in place at their hospital for both upper and lower gastrointestinal endoscopy in anticoagulated patients; 5.5% had a policy for upper gastrointestinal endoscopy only and 6.2% for lower gastrointestinal endoscopy only. Thirty-five per cent doctors reported that they did not have any standard policy. We compared the responses from within a hospital to see whether the doctors were uniformly aware of an existing policy in their hospital. For upper gastrointestinal endoscopy, the responses were the same (either yes or no) by 51% of the doctors, whereas they were different by 49%. For lower gastrointestinal endoscopies, the same response was given by 49% of the doctors, whereas 51% gave different answers. The poor response rate from the doctors, however, makes firm interpretation of the data difficult. CONCLUSIONS: A wide variation in practice is seen across the country. A robust national guideline to streamline the endoscopy practice in anticoagulated patients is needed.