The Role of Human-Centered Design in Healthcare Innovation: a Digital Health Equity Case Study.

Healthcare delivery has become more complicated, particularly with the addition of digital tools and advanced technologies that can further exacerbate existing disparities. New approaches to solve complex, multi-faceted problems are needed. Human-centered design (HCD), also known as design thinking, is an innovative set of methods to develop solutions to these types of issues using collaborative, team-based, and empathetic approaches focused on end user experiences. Originally advanced in technology sectors, HCD has garnered growing attention in quality improvement, healthcare redesign, and public health and medical education. During the COVID-19 pandemic, our healthcare organization recognized notable differences in utilization of virtual (video-based) services among specific patient populations. In response, we mobilized, and using HCD, we collectively brainstormed ideas, rapidly developed prototypes, and iteratively adapted solutions to work toward addressing this digital divide and clinic and systems-level struggles with improving and maintaining digital health access. HCD approaches create a cohesive team-based structure that permits the dismantling of organizational hierarchies and departmental silos. Here we share lessons learned on implementing HCD into clinical care settings and how HCD can result in the development of site-specific, patient-centered innovations to address access disparities and to improve digital health equity.

Multimodal single-cell analysis of cutaneous T-cell lymphoma reveals distinct subclonal tissue-dependent signatures.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of mature T-cell neoplasms characterized by the accumulation of clonal malignant CD4+ T cells in the skin. The most common variant of CTCL, mycosis fungoides (MF ), is confined to the skin in early stages but can be accompanied by extracutaneous dissemination of malignant T cells to the blood and lymph nodes in advanced stages of disease. Sézary syndrome (SS), a leukemic form of disease, is characterized by significant blood involvement. Little is known about the transcriptional and genomic relationship between skin- and blood-residing malignant T cells in CTCL. To identify and interrogate malignant clones in matched skin and blood from patients with leukemic MF and SS, we combine T-cell receptor clonotyping with quantification of gene expression and cell surface markers at the single cell level. Our data reveal clonal evolution at a transcriptional and genetic level within the malignant populations of individual patients. We highlight highly consistent transcriptional signatures delineating skin- and blood-derived malignant T cells. Analysis of these 2 populations suggests that environmental cues, along with genetic aberrations, contribute to transcriptional profiles of malignant T cells. Our findings indicate that the skin microenvironment in CTCL promotes a transcriptional response supporting rapid malignant expansion, as opposed to the quiescent state observed in the blood, potentially influencing efficacy of therapies. These results provide insight into tissue-specific characteristics of cancerous cells and underscore the need to address the patients' individual malignant profiles at the time of therapy to eliminate all subclones.

Translocation detection from Hi-C data via scan statistics.

Recent Hi-C technology enables more comprehensive chromosomal conformation research, including the detection of structural variations, especially translocations. In this paper, we formulate the interchromosomal translocation detection as a problem of scan clustering in a spatial point process. We then develop TranScan, a new translocation detection method through scan statistics with the control of false discovery. The simulation shows that TranScan is more powerful than an existing sophisticated scan clustering method, especially under strong signal situations. Evaluation of TranScan against current translocation detection methods on realistic breakpoint simulations generated from real data suggests better discriminative power under the receiver-operating characteristic curve. Power analysis also highlights TranScan's consistent outperformance when sequencing depth and heterozygosity rate is varied. Comparatively, Type I error rate is lowest when evaluated using a karyotypically normal cell line. Both the simulation and real data analysis indicate that TranScan has great potentials in interchromosomal translocation detection using Hi-C data.

Outpatient Management of COVID-19: Rapid Evidence Review.

New COVID-19 variants of concern continue to develop. Incubation period, transmissibility, immune escape, and treatment effectiveness differ by variants of concern. Physicians should be aware that the characteristics of the predominant variants of concern determine aspects of diagnosis and treatment. Multiple testing modalities exist; the most appropriate testing strategy varies depending on the clinical scenario, with factors of test sensitivity, turnaround time, and the expertise required for specimen collection. Three types of vaccines are available in the United States, and all people six months and older should be encouraged to receive one because vaccination is effective in reducing the incidence of and hospitalizations and deaths associated with COVID-19. Vaccination may also reduce the incidence of post-acute sequelae of SARS-CoV-2 infection (i.e., long COVID). Consider medications, such as nirmatrelvir/ritonavir, as first-line treatment for eligible patients diagnosed with COVID-19 unless logistical or supply constraints occur. National Institutes of Health guidelines and local health care partner resources can be used to determine eligibility. Long-term health effects of having COVID-19 are under investigation.

Multiplexed detection of proteins, transcriptomes, clonotypes and CRISPR perturbations in single cells.

Multimodal single-cell assays provide high-resolution snapshots of complex cell populations, but are mostly limited to transcriptome plus an additional modality. Here, we describe expanded CRISPR-compatible cellular indexing of transcriptomes and epitopes by sequencing (ECCITE-seq) for the high-throughput characterization of at least five modalities of information from each single cell. We demonstrate application of ECCITE-seq to multimodal CRISPR screens with robust direct single-guide RNA capture and to clonotype-aware multimodal phenotyping of cancer samples.

Long COVID: Rapid Evidence Review.

Postacute sequelae of COVID-19, also known as long COVID, affects approximately 10% to 30% of the hundreds of millions of people who have had acute COVID-19. The Centers for Disease Control and Prevention defines long COVID as the presence of new, returning, or ongoing symptoms associated with acute COVID-19 that persist beyond 28 days. The diagnosis of long COVID can be based on a previous clinical diagnosis of COVID-19 and does not require a prior positive polymerase chain reaction or antigen test result to confirm infection. Patients with long COVID report a broad range of symptoms, including abdominal pain, anosmia, chest pain, cognitive impairment (brain fog), dizziness, dyspnea, fatigue, headache, insomnia, mood changes, palpitations, paresthesias, and postexertional malaise. The presentation is variable, and symptoms can fluctuate or persist and relapse and remit. The diagnostic approach is to differentiate long COVID from acute sequelae of COVID-19, previous comorbidities, unmasking of preexisting health conditions, reinfections, new acute concerns, and complications of prolonged illness, hospitalization, or isolation. Many presenting symptoms of long COVID are commonly seen in a primary care practice, and management can be improved by using established treatment paradigms and supportive care. Although several medications have been suggested for the treatment of fatigue related to long COVID, the evidence for their use is currently lacking. Holistic treatment strategies for long COVID include discussion of pacing and energy conservation; individualized, symptom-guided, phased return to activity programs; maintaining adequate hydration and a healthy diet; and treatment of underlying medical conditions.

Advancing Telemedicine Within Family Medicine's Core Values.

Telemedicine adoption has been gradual but accelerated during the COVID-19 pandemic. It is important for us to pause and consider how this impacts family medicine. How do we ground ourselves so that we use technology to enhance our practice while maintaining fundamental family medicine values? In this article, we explore how telemedicine interacts with five family medicine tenants: contextual care, continuity of care, access to care, comprehensive care, and care coordination. Keeping this framework in mind and using a health equity lens can help us retain fundamental family medicine values as we adapt to rapid technological change.

Redesigning Primary Care to Address the COVID-19 Pandemic in the Midst of the Pandemic.

During a pandemic, primary care is the first line of defense. It is able to reinforce public health messages, help patients manage at home, and identify those in need of hospital care. In response to the COVID-19 pandemic, primary care scrambled to rapidly transform itself and protect clinicians, staff, and patients while remaining connected to patients. Using the established public health framework for addressing a pandemic, we describe the actions primary care needs to take in a pandemic. Recommended actions are based on observed experiences of the authors' primary care practices and networks. Early in the COVID-19 pandemic, tasks focused on promoting physical distancing and encouraging patients with suspected illness or exposure to self-quarantine. Testing was not available and contract tracing was not possible. As the pandemic spread, in-person care was converted to virtual care using telehealth. Practices remained connected to patients using registries to reach out to those at risk for infection, with uncontrolled chronic conditions, or were socially vulnerable. Practices managed most patients with suspected COVID-19 at home. As the pandemic decelerates, practices are now preparing to address the direct and indirect consequences-complications from COVID-19 infections, missed treatment for acute problems, inadequate prevention, uncontrolled chronic disease, mental illness, and greater social needs. Throughout, practices bore tremendous financial burden, laying off staff or even closing at a time when most needed. Primary care must learn from this experience and be ready for the next pandemic. Policymakers and payers cannot fail primary care during their next time of need.

Outpatient Management of COVID-19: Rapid Evidence Review.

Common presenting symptoms of coronavirus disease 2019 include fever, dry cough, shortness of breath, and fatigue. However, patients may have a wide range of symptoms representing a spectrum of mild to severe illness. Symptoms in children tend to be milder and may include fever, cough, and feeding difficulty. The incubation period is two to 14 days, although symptoms typically appear within five days of exposure. Multiple testing modalities exist, but infection should be confirmed by polymerase chain reaction testing using a nasopharyngeal swab. There are no evidence- based treatments appropriate for use in the outpatient setting; management is supportive and should include education about isolation. In hospitalized patients, remdesivir should be considered to reduce time to recovery, and low-dose dexamethasone should be considered in patients who require supplemental oxygen. Overall, 85% of patients have mild illness, whereas 14% have severe disease requiring hospitalization, including 5% who require admission to an intensive care unit. Predictors of severe disease include increasing age, comorbidities, lymphopenia, neutrophilia, leukocytosis, low oxygen saturation, and increased levels of C-reactive protein, d-dimer, transaminases, and lactate dehydrogenase.

Neutrophilic Dermatosis of the Hands: A Review of 17 Cases.

PURPOSE: Neutrophilic dermatosis of the hands is an inflammatory skin condition related to Sweet syndrome that responds to corticosteroids. It commonly affects the dorsum of the hand and often mimics infection, with violaceous inflammatory papules and plaques that may ulcerate. The aim of this study was to review the clinical presentation of neutrophilic dermatosis of the hands. METHODS: A retrospective review was undertaken of all cases of neutrophilic dermatosis of the hands seen at a tertiary hospital in New South Wales, Australia, over a 5-year period. RESULTS: Seventeen cases were identified. The mean time to diagnosis was 9 days after lesion onset. Most cases were older adults (mean age, 71 years). The most common referral diagnoses were infection or a nonhealing wound and 65% of cases reported a history of trauma. The dorsal index finger was the site of involvement in 41% of cases. One case involved the palm. Histopathology reports were available for skin punch biopsy for 14 of 17 cases, which showed dermal neutrophilic infiltrate (93%) and epidermal involvement with necrosis, ulceration, or pustulation (64%). Six cases were treated surgically prior to the correct diagnosis and management being introduced. CONCLUSIONS: Neutrophilic dermatosis of the hands was often misdiagnosed as infection. A history of trauma is common and may be misleading. Dermatological consultation and skin punch biopsy are useful in confirming the diagnosis, ideally prior to surgical management. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

Association between dehydration on admission and postoperative complications in older persons undergoing orthopaedic surgery.

AIM AND OBJECTIVES: To examine the prevalence of dehydration upon hospital admission and its association with postoperative complications in older persons undergoing orthopaedic surgery. BACKGROUND: Ageing-related physiological and pathological changes, as well as suboptimal care quality, can render older persons vulnerable to dehydration. However, few empirical studies have been conducted to examine the association between dehydration and care outcomes in this population. DESIGN: Retrospective documentary review. METHODS: The medical records of patients who were aged 65 years or above and admitted for orthopaedic surgery at an acute hospital in Hong Kong over the period of January 2013 to June 2013 were reviewed. The sociodemographic characteristics, health conditions, laboratory results during index hospitalisation, postoperative care and 1-month survival were analysed. Dehydration status was defined on the basis of the ratio of blood urea nitrogen to creatinine upon admission. RESULTS: Of 310 reviewed records, 216 records were included in the analysis. A total of 21.8% of the patients in the included cases were defined as dehydrated and 35.2% were defined as at risk of dehydration. There were significantly more patients in the dehydrated group were female, having diuretic medication, swallowing difficulty, oedema, tube feeding, diaper or urinary catheter use, with postoperative complications in respiratory, gastrointestinal and haematological systems, and died within 30 days than those in the euhydrated group. CONCLUSIONS: The findings of this study reveal that dehydration is highly prevalent among older persons on admission. Female gender and swallowing difficulty were found to be significantly associated with dehydration, although causal inference could not be delineated through this retrospective study. RELEVANCE TO CLINICAL PRACTICE: Given its significant influence on care outcomes and postoperative recovery, hydration care that promotes early recognition and timely management of dehydration is an integral part of fundamental care for older persons.

Insights into the genetic structure and diversity of 38 South Asian Indians from deep whole-genome sequencing.

South Asia possesses a significant amount of genetic diversity due to considerable intergroup differences in culture and language. There have been numerous reports on the genetic structure of Asian Indians, although these have mostly relied on genotyping microarrays or targeted sequencing of the mitochondria and Y chromosomes. Asian Indians in Singapore are primarily descendants of immigrants from Dravidian-language-speaking states in south India, and 38 individuals from the general population underwent deep whole-genome sequencing with a target coverage of 30X as part of the Singapore Sequencing Indian Project (SSIP). The genetic structure and diversity of these samples were compared against samples from the Singapore Sequencing Malay Project and populations in Phase 1 of the 1,000 Genomes Project (1 KGP). SSIP samples exhibited greater intra-population genetic diversity and possessed higher heterozygous-to-homozygous genotype ratio than other Asian populations. When compared against a panel of well-defined Asian Indians, the genetic makeup of the SSIP samples was closely related to South Indians. However, even though the SSIP samples clustered distinctly from the Europeans in the global population structure analysis with autosomal SNPs, eight samples were assigned to mitochondrial haplogroups that were predominantly present in Europeans and possessed higher European admixture than the remaining samples. An analysis of the relative relatedness between SSIP with two archaic hominins (Denisovan, Neanderthal) identified higher ancient admixture in East Asian populations than in SSIP. The data resource for these samples is publicly available and is expected to serve as a valuable complement to the South Asian samples in Phase 3 of 1 KGP.

Assessing single nucleotide variant detection and genotype calling on whole-genome sequenced individuals.

MOTIVATION: Whole-genome sequencing (WGS) is now routinely used for the detection and identification of genetic variants, particularly single nucleotide polymorphisms (SNPs) in humans, and this has provided valuable new insights into human diversity, population histories and genetic association studies of traits and diseases. However, this relies on accurate detection and genotyping calling of the polymorphisms present in the samples sequenced. To minimize cost, the majority of current WGS studies, including the 1000 Genomes Project (1 KGP) have adopted low coverage sequencing of large number of samples, where such designs have inadvertently influenced the development of variant calling methods on WGS data. Assessment of variant accuracy are usually performed on the same set of low coverage individuals or a smaller number of deeply sequenced individuals. It is thus unclear how these variant calling methods would fare for a dataset of ∼100 samples from a population not part of the 1 KGP that have been sequenced at various coverage depths. AVAILABILITY AND IMPLEMENTATION: Using down-sampling of the sequencing reads obtained from the Singapore Sequencing Malay Project (SSMP), and a set of SNP calls from the same individuals genotyped on the Illumina Omni1-Quad array, we assessed the sensitivity of SNP detection, accuracy of genotype calls made and variant accuracy for six commonly used variant calling methods of GATK, SAMtools, Consensus Assessment of Sequence and Variation (CASAVA), VarScan, glfTools and SOAPsnp. The results indicate that at 5× coverage depth, the multi-sample callers of GATK and SAMtools yield the best accuracy particularly if the study samples are called together with a large number of individuals such as those from 1000 Genomes Project. If study samples are sequenced at a high coverage depth such as 30×, CASAVA has the highest variant accuracy as compared with the other variant callers assessed.

Electric vehicle battery chemistry affects supply chain disruption vulnerabilities.

We examine the relationship between electric vehicle battery chemistry and supply chain disruption vulnerability for four critical minerals: lithium, cobalt, nickel, and manganese. We compare the nickel manganese cobalt (NMC) and lithium iron phosphate (LFP) cathode chemistries by (1) mapping the supply chains for these four materials, (2) calculating a vulnerability index for each cathode chemistry for various focal countries and (3) using network flow optimization to bound uncertainties. World supply is currently vulnerable to disruptions in China for both chemistries: 80% [71% to 100%] of NMC cathodes and 92% [90% to 93%] of LFP cathodes include minerals that pass through China. NMC has additional risks due to concentrations of nickel, cobalt, and manganese in other countries. The combined vulnerability of multiple supply chain stages is substantially larger than at individual steps alone. Our results suggest that reducing risk requires addressing vulnerabilities across the entire battery supply chain.

Direct RNA sequencing coupled with adaptive sampling enriches RNAs of interest in the transcriptome.

Abundant cellular transcripts occupy most of the sequencing reads in the transcriptome, making it challenging to assay for low-abundant transcripts. Here, we utilize the adaptive sampling function of Oxford Nanopore sequencing to selectively deplete and enrich RNAs of interest without biochemical manipulation before sequencing. Adaptive sampling performed on a pool of in vitro transcribed RNAs resulted in a net increase of 22-30% in the proportion of transcripts of interest in the population. Enriching and depleting different proportions of the Candida albicans transcriptome also resulted in a 11-13.5% increase in the number of reads on target transcripts, with longer and more abundant transcripts being more efficiently depleted. Depleting all currently annotated Candida albicans transcripts did not result in an absolute enrichment of remaining transcripts, although we identified 26 previously unknown transcripts and isoforms, 17 of which are antisense to existing transcripts. Further improvements in the adaptive sampling of RNAs will allow the technology to be widely applied to study RNAs of interest in diverse transcriptomes.

KARR-seq reveals cellular higher-order RNA structures and RNA-RNA interactions.

RNA fate and function are affected by their structures and interactomes. However, how RNA and RNA-binding proteins (RBPs) assemble into higher-order structures and how RNA molecules may interact with each other to facilitate functions remain largely unknown. Here we present KARR-seq, which uses N3-kethoxal labeling and multifunctional chemical crosslinkers to covalently trap and determine RNA-RNA interactions and higher-order RNA structures inside cells, independent of local protein binding to RNA. KARR-seq depicts higher-order RNA structure and detects widespread intermolecular RNA-RNA interactions with high sensitivity and accuracy. Using KARR-seq, we show that translation represses mRNA compaction under native and stress conditions. We determined the higher-order RNA structures of respiratory syncytial virus (RSV) and vesicular stomatitis virus (VSV) and identified RNA-RNA interactions between the viruses and the host RNAs that potentially regulate viral replication.

Viral quasispecies inference from 454 pyrosequencing.

BACKGROUND: Many potentially life-threatening infectious viruses are highly mutable in nature. Characterizing the fittest variants within a quasispecies from infected patients is expected to allow unprecedented opportunities to investigate the relationship between quasispecies diversity and disease epidemiology. The advent of next-generation sequencing technologies has allowed the study of virus diversity with high-throughput sequencing, although these methods come with higher rates of errors which can artificially increase diversity. RESULTS: Here we introduce a novel computational approach that incorporates base quality scores from next-generation sequencers for reconstructing viral genome sequences that simultaneously infers the number of variants within a quasispecies that are present. Comparisons on simulated and clinical data on dengue virus suggest that the novel approach provides a more accurate inference of the underlying number of variants within the quasispecies, which is vital for clinical efforts in mapping the within-host viral diversity. Sequence alignments generated by our approach are also found to exhibit lower rates of error. CONCLUSIONS: The ability to infer the viral quasispecies colony that is present within a human host provides the potential for a more accurate classification of the viral phenotype. Understanding the genomics of viruses will be relevant not just to studying how to control or even eradicate these viral infectious diseases, but also in learning about the innate protection in the human host against the viruses.

Patient-Facing Clinical Decision Support for High Blood Pressure Control: Patient Survey.

BACKGROUND: High blood pressure (HBP) affects nearly half of adults in the United States and is a major factor in heart attacks, strokes, kidney disease, and other morbidities. To reduce risk, guidelines for HBP contain more than 70 recommendations, including many related to patient behaviors, such as home monitoring and lifestyle changes. Thus, the patient's role in controlling HBP is crucial. Patient-facing clinical decision support (CDS) tools may help patients adhere to evidence-based care, but customization is required. OBJECTIVE: Our objective was to understand how to adapt CDS to best engage patients in controlling HBP. METHODS: We conducted a mixed methods study with two phases: (1) survey-guided interviews with a limited cohort and (2) a nationwide web-based survey. Participation in each phase was limited to adults aged between 18 and 85 years who had been diagnosed with hypertension. The survey included general questions that assessed goal setting, treatment priorities, medication load, comorbid conditions, satisfaction with blood pressure (BP) management, and attitudes toward CDS, and also a series of questions regarding A/B preferences using paired information displays to assess perceived trustworthiness of potential CDS user interface options. RESULTS: We conducted 17 survey-guided interviews to gather patient needs from CDS, then analyzed results and created a second survey of 519 adults with clinically diagnosed HBP. A large majority of participants reported that BP control was a high priority (83%), had monitored BP at home (82%), and felt comfortable using technology (88%). Survey respondents found displays with more detailed recommendations more trustworthy (56%-77% of them preferred simpler displays), especially when incorporating social trust and priorities from providers and patients like them, but had no differences in action taken. CONCLUSIONS: Respondents to the survey felt that CDS capabilities could help them with HBP control. The more detailed design options for BP display and recommendations messaging were considered the most trustworthy yet did not differentiate perceived actions.

The Carbon Footprint and Cost of Virtual Residency Interviews.

Background: The shift from in-person to virtual residency interviews may impact greenhouse gas emissions (GHGE) and costs but the direction and amount of this change is not yet clear. Objective: To estimate GHGE and financial impacts of virtual interviews among applicants and programs. Methods: In 2020-2021 we sent a postinterview survey to 1429 applicants from 7 residency programs and 1 clinical psychology program at 1 institution. The survey collected origin of travel and transit type if in-person interviews had been held and excluded responses if the applicant would not have participated in an in-person interview, or if travel type or original city was missing. We used the International Civil Aviation Organization calculator to estimate flight-related GHGE in metric tons of carbon dioxide equivalent (MTCO2e) and Google Maps to estimate ground travel, with a standard CO2e per mile. Flight, hotel, and airport taxi costs were estimated using Expedia.com, Hotels.com, Uber, and Lyft. We aggregated these data and calculated median and interquartile ranges (IQRs) for applicant GHGE and cost savings, and assumed no cost or GHGE from virtual interviews. We used Wilcoxon signed rank sum tests to compare in-person 2019-2020 and virtual 2020-2021 GME program interview budgets. Results: The survey response rate was 565, or 40% of applicants; 543 remained after the exclusion criteria were applied. Reduction in applicant travel due to virtual interviews led to median estimated GHGE savings of 0.47 (IQR 0.30-0.61) MTCO2e and $490 (IQR $392-$544) per applicant, per interview. Programs savings ranged from $7,615 to $33,670 for the interview season. Conclusions: Virtual interviews in 8 GME programs were associated with lower estimated GHGE and costs, for applicants and programs, compared with in-person interviews.