A journey from omics to clinicomics in solid cancers: Success stories and challenges.

The word 'cancer' encompasses a heterogenous group of distinct disease types characterized by a spectrum of pathological features, genetic alterations and response to therapies. According to the World Health Organization, cancer is the second leading cause of death worldwide, responsible for one in six deaths and hence imposes a significant burden on global healthcare systems. High-throughput omics technologies combined with advanced imaging tools, have revolutionized our ability to interrogate the molecular landscape of tumors and has provided unprecedented understanding of the disease. Yet, there is a gap between basic research discoveries and their translation into clinically meaningful therapies for improving patient care. To bridge this gap, there is a need to analyse the vast amounts of high dimensional datasets from multi-omics platforms. The integration of multi-omics data with clinical information like patient history, histological examination and imaging has led to the novel concept of clinicomics and may expedite the bench-to-bedside transition in cancer. The journey from omics to clinicomics has gained momentum with development of radiomics which involves extracting quantitative features from medical imaging data with the help of deep learning and artificial intelligence (AI) tools. These features capture detailed information about the tumor's shape, texture, intensity, and spatial distribution. Together, the related fields of multiomics, translational bioinformatics, radiomics and clinicomics may provide evidence-based recommendations tailored to the individual cancer patient's molecular profile and clinical characteristics. In this chapter, we summarize multiomics studies in solid cancers with a specific focus on breast cancer. We also review machine learning and AI based algorithms and their use in cancer diagnosis, subtyping, prognosis and predicting treatment resistance and relapse.

Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury.

BACKGROUND: Rotator cuff muscle degeneration leads to poor clinical outcomes for patients with rotator cuff tears. Fibroadipogenic progenitors (FAPs) are resident muscle stem cells with the ability to differentiate into fibroblasts as well as white and beige adipose tissue. Induction of the beige adipose phenotype in FAPs has been shown to improve muscle quality after rotator cuff tears, but the mechanisms of how FAPs exert their beneficial effects have not been fully elucidated. PURPOSE: To study the horizontal transfer of mitochondria from FAPs to myogenic cells and examine the effects of ß-agonism on this novel process. STUDY DESIGN: Controlled laboratory study. METHODS: In mice that had undergone a massive rotator cuff tear, single-cell RNA sequencing was performed on isolated FAPs for genes associated with mitochondrial biogenesis and transfer. Murine FAPs were isolated by fluorescence-activated cell sorting and treated with a ß-agonist versus control. FAPs were stained with mitochondrial dyes and cocultured with recipient C2C12 myoblasts, and the rate of transfer was measured after 24 hours by flow cytometry. PdgfraCreERT/MitoTag mice were generated to study the effects of a rotator cuff injury on mitochondrial transfer. PdgfraCreERT/tdTomato mice were likewise generated to perform lineage tracing of PDGFRA+ cells in this injury model. Both populations of transgenic mice underwent tendon transection and denervation surgery, and MitoTag-labeled mitochondria from Pdgfra+ FAPs were visualized by fluorescent microscopy, spinning disk confocal microscopy, and 2-photon microscopy; overall mitochondrial quantity was compared between mice treated with ß-agonists and dimethyl sulfoxide. RESULTS: Single-cell RNA sequencing in mice that underwent rotator cuff tear demonstrated an association between transcriptional markers of adipogenic differentiation and genes associated with mitochondrial biogenesis. In vitro cocultures of murine FAPs with C2C12 cells revealed that treatment of cells with a ß-agonist increased mitochondrial transfer compared to control conditions (17.8% ± 9.9% to 99.6% ± 0.13% P < .0001). Rotator cuff injury in PdgfraCreERT/MitoTag mice resulted in a robust increase in MitoTag signal in adjacent myofibers compared with uninjured mice. No accumulation of tdTomato signal from PDGFRA+ cells was seen in injured fibers at 6 weeks after injury, suggesting that FAPs do not fuse with injured muscle fibers but rather contribute their mitochondria. CONCLUSION: The authors have described a novel process of endogenous mitochondrial transfer that can occur within the injured rotator cuff between FAPs and myogenic cells. This process may be leveraged therapeutically with ß-agonist treatment and represents an exciting target for improving translational therapies available for rotator cuff muscle degeneration. CLINICAL RELEVANCE: Promoting endogenous mitochondrial transfer may represent a novel translational strategy to address muscle degeneration after rotator cuff tears.

Outpatient human coronavirus associated conjunctivitis in India.

BACKGROUND: Viral conjunctivitis (pink eye) can be highly contagious and is of public health importance. There remains significant debate whether SARS-CoV-2 can present as a primary conjunctivitis. The aim of this study was to identify pathogens associated with outpatient infectious conjunctivitis during the COVID-19 Delta surge. METHODS: This prospective study was conducted in the spring and summer months of 2021. 106 patients with acute conjunctivitis who presented to the Aravind Eye Center in Madurai, India were included. One anterior nasal swab and one conjunctival swab of each eye were obtained for each enrolled patient. Samples were subsequently processed for unbiased metagenomic RNA deep sequencing (RNA-seq). Outcomes included clinical findings and codetection of other pathogens with SARS-CoV-2 in patients with conjunctivitis. RESULTS: Among the 13 patients identified with human coronavirus RNA fragments in their swabs, 6 patients had SARS-CoV-2 infection, 5 patients had coinfections of SARS-CoV-2 and human adenovirus (HAdV), 1 patient had a coinfection with human coronavirus OC43 and HAdV, and 1 patient had a coinfection of Vittaforma corneae and SARS-CoV-2. 30% had bilateral disease and symptoms on presentation. Petechial hemorrhage was noted in 33% of patients with SARS-CoV-2 infection. No patients with SARS-CoV-2 or SARS-CoV-2 and HAdV infections had subepithelial infiltrates on presentation. All patients denied systemic symptoms. CONCLUSIONS: Among the patients presented with conjunctivitis associated with human coronavirus infection, over 50% of the patients had co-infections with other circulating pathogens, suggesting the public-health importance of broad pathogen testing and surveillance in the outpatient conjunctivitis population.

Deep sequencing analysis of clinical samples from patients with acute infectious conjunctivitis during the COVID-19 delta surge in Madurai, India.

BACKGROUND: Seasonal outbreaks of infectious conjunctivitis remain a public health issue. Determination of outbreak etiologies in the context of a worldwide pandemic may provide useful information to guide public health strategies. The aim of this study was to identify pathogens associated with outpatient infectious conjunctivitis during the COVID-19 Delta surge. METHODS: This prospective study was conducted from April 2021 to September 2021. All outpatients presenting to the Aravind Eye Center (Madurai, India) with signs and symptoms consistent with acute infectious conjunctivitis were eligible. Three swabs were obtained from each participant: one from each conjunctiva and one from the anterior nares. Samples were processed for metagenomic RNA deep sequencing (RNA-seq). RESULTS: Samples from 106 study participants were sequenced. The most common presenting symptoms were tearing (86%) and itching (71%). Preauricular lymphadenopathy was present in 38% of participants. 20% of participants had close contacts with similar symptoms. Systemic symptoms such as coughing, runny nose, vomiting or diarrhea were uncommonly reported. 60% of all participants used some medicated eye drops upon enrollment. 75% of study participants demonstrated infection with human adenovirus D (HAdV-D). 11% of conjunctivitis was associated with SARS-CoV-2. 15% had no definitive pathogen detected. 8% of all participants had codetection of more than one pathogen on RNA-seq. CONCLUSIONS: During the COVID-19 Delta surge in India, HAdV-D was the most common pathogen associated with infectious conjunctivitis. SARS-CoV-2 was the second most common associated pathogen. Seasonal surveillance may be necessary for the determination of emerging and reemerging pathogens responsible for infectious conjunctivitis.

COVID mortality in India: National survey data and health facility deaths.

India's national COVID death totals remain undetermined. Using an independent nationally representative survey of 0.14 million (M) adults, we compared COVID mortality during the 2020 and 2021 viral waves to expected all-cause mortality. COVID constituted 29% (95%CI 28-31%) of deaths from June 2020-July 2021, corresponding to 3.2M (3.1-3.4) deaths, of which 2.7M (2.6-2.9) occurred in April-July 2021 (when COVID doubled all-cause mortality). A sub-survey of 57,000 adults showed similar temporal increases in mortality with COVID and non-COVID deaths peaking similarly. Two government data sources found that, when compared to pre-pandemic periods, all-cause mortality was 27% (23-32%) higher in 0.2M health facilities and 26% (21-31%) higher in civil registration deaths in ten states; both increases occurred mostly in 2021. The analyses find that India's cumulative COVID deaths by September 2021 were 6-7 times higher than reported officially.

The Utility of Routine Fundus Photography Screening for Posterior Segment Disease: A Stepped-wedge, Cluster-randomized Trial in South India.

PURPOSE: To assess whether routine fundus photography (RFP) to screen for posterior segment disease at community eye clinics (vision centers [VCs]) in India increases referral to centralized ophthalmolic care. DESIGN: Stepped-wedge, cluster-randomized trial. PARTICIPANTS: Patients aged 40 to 75 years and those aged 20 to 40 years with a known history of hypertension or diabetes mellitus presenting to 4 technician-run VCs associated with the Aravind Eye Care System in India. METHODS: VCs (clusters) were randomized to standard care or RFP across five 2-week study periods (steps). Patients in each cluster received standard care initially. At the start of each subsequent step, a randomly chosen cluster crossed over to providing RFP to eligible patients. All clusters took part in RFP during the last step. Standard care involved technician eye exams, optional fundus photography, and teleconsultation with an ophthalmologist. RFP involved eye exams, dilation and 40-degree fundus photography, and teleconsultation with an ophthalmologist. MAIN OUTCOME MEASURES: Standard care and RFP clusters were compared by the proportion of patients referred for in-person evaluation by an ophthalmologist because of fundus photography findings and urgency of referral (urgently in ≤ 2 weeks vs. nonurgently in > 2 weeks). Generalized linear mixed models adjusting for cluster and step were used to estimate the odds of referral due to fundus photography findings compared with standard care. RESULTS: A total of 1447 patients were enrolled across the VCs, including 737 in the standard care group and 710 in the RFP group. Compared with standard care, the RFP group had a higher proportion of referrals due to fundus photography findings (11.3% vs. 4.4%), nonurgent referrals due to fundus photography (9.3% vs. 3.3%), and urgent referrals due to fundus photography (1.8% vs. 1.1%). The RFP intervention was associated with a 2-fold increased odds of being referred because of photography findings compared with standard care (odds ratio, 2.07; 95% confidence interval, 0.98-4.40; P = 0.058). CONCLUSIONS: Adding RFP to community eye clinics was associated with an increased odds of referral compared with standard care. This increase in referral was mostly due to nonurgent posterior segment disease.

Role of redox iron towards an increase in mortality among patients: a systemic review and meta-analysis.

An increase in biochemical concentrations of non-transferrin bound iron (NTBI) within the patients with an increase in serum iron concentration was evaluated with the following objectives: (a) Iron overloading diseases/conditions with free radicle form of 'iron containing' reactive oxygen species (ROS) and its imbalance mediated mortality, and (b) Intervention with iron containing drugs in context to increased redox iron concentration and treatment induced mortality. Literature search was done within Pubmed and cochrane review articles. The Redox iron levels are increased during dys-erythropoiesis and among transfusion recipient population and are responsive to iron-chelation therapy. Near expiry 'stored blood units' show a significant rise in the ROS level. Iron mediated ROS damage may be estimated by the serum antioxidant level, and show reduction in toxicity with high antioxidant, low pro-oxidant levels. Iron drug therapy causes a significant increase in NTBI and labile iron levels. Hospitalized patients on iron therapy however show a lower mortality rate. Serum ferritin is a mortality indicator among the high-dose iron therapy and transfusion dependent population. The cumulative difference of pre-chelation to post chelation ROS iron level was 0.97 (0.62; 1.32; N=261) among the transfusion dependent subjects and 2.89 (1.81-3.98; N=130) in the post iron therapy 'iron ROS' group. In conclusion, iron mediated mortality may not be mediated by redox iron among multi-transfused and iron overloaded patients.

Retro iris suture fixation of a rigid intraocular lens.

We present an iris suture fixation technique for a rigid poly(methyl methacrylate) (PMMA) intraocular lens (IOL). A 10-0 polypropylene suture on a long curved needle is used to preplace 2 iris suture bites 180 degrees apart. The suture loops below the iris are retracted through the main scleral tunnel using a Kuglen hook and a McPherson forceps. The 2 suture loops are twirled twice around the corresponding haptics of a standard 3-piece PMMA IOL, and the IOL is placed in the sulcus. After it is confirmed that the loop surrounds the haptic, the suture knot is tied to secure the IOL to the iris. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.

Twin occlusion: a solution to rehabilitate hemimandibulectomy patient-a case report.

Loss of continuity of the mandible destroys the balance and symmetry of mandibular function, leading to altered mandibular movements and deviation of the residual fragment towards the resected side. Prosthodontic treatment along with physical therapy may be useful in reducing mandibular deviation and improving masticatory efficiency. Numerous prosthetic methods are employed to minimize deviation and improve masticatory efficiency which includes implant supported prosthesis, mandibular guide flange prosthesis, and palatal based guidance restoration. This article describes rehabilitation of hemimandibulectomy patient using twinned teeth (two rows of teeth) on the unresected side in the maxillary edentulous arch for whom implant supported prosthesis, mandibular guide flange prosthesis or palatal based guide flange prosthesis cannot be fabricated to improve the masticatory efficiency.