Long-term outcomes of glued (sutureless) amniotic membrane transplantation in acute Stevens-Johnson syndrome/toxic epidermal necrolysis: a comparative study.

PURPOSE: To compare the effectiveness and efficiency of a glued (sutureless) technique for amniotic membrane transplantation (AMT) with a traditional sutured one in the setting of acute Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). METHODS: This retrospective cohort study evaluated all patients diagnosed with SJS/TEN between 2008 and 2020 within our hospital network who received AMT in the acute phase according to our protocol and had at least one ophthalmic follow-up in the chronic phase. Primary outcomes included best-corrected visual acuity (BCVA) at the most recent visit, presence of a severe ocular complication (SOC) via predefined criteria, time to procedure and duration of procedure. Random effects model analysis was used to evaluate the impact of potential covariates on outcome measures. RESULTS: A total of 23 patients (45 eyes) were included: 14 patients (27 eyes) in the AMT suture group and 9 patients (18 eyes) in the AMT glue group. There was no difference between the two groups in BCVA at the most recent visit (p=0.5112) or development of a SOC (p=1.000). The glue method was shorter in duration than the suture method (p<0.001). Random effects model additionally indicated that there was no difference in BCVA at most recent follow-up between patients who had received glued versus sutured AMT (p=0.1460). CONCLUSIONS: Our glued technique for AMT is as effective as our sutured technique in stabilising the ocular surface and mitigating chronic ocular complications in SJS/TEN. The glued technique is also shorter in duration and performed more expediently than the sutured technique.

Efficient sonochemical catalytic degradation of tetracycline using TiO2 fractured nanoshells.

Overexposure to antibiotics originating in wastewater has profound environmental and health implications. Conventional treatment methods are not fully effective in removing certain antibiotics, such as the commonly used antibiotic, tetracycline, leading to its accumulation in water catchments. Alternative antibiotic removal strategies are garnering attention, including sonocatalytic oxidative processes. In this work, we investigated the degradation of tetracycline using a combination of TiO2 fractured nanoshells (TFNs) and an advanced sonochemical reactor design. The study encompassed an examination of multiple process parameters to understand their effects on the degradation of tetracycline. These included tetracycline adsorption on TFNs, reaction time, initial tetracycline concentration, solvent pH, acoustic pressure amplitude, number of acoustic cycles, catalyst dosage, TFNs' reusability, and the impact of adjuvants such as light and H2O2. Though TFNs adsorbed tetracycline, the addition of ultrasound was able to degrade tetracycline completely (with 100% degradation) within six minutes. Under the optimal operating conditions, the proposed sonocatalytic system consumed 80% less energy compared to the values reported in recently published sonocatalytic research. It also had the lowest CO2 footprint when compared to the other sono-/photo-based technologies. This study suggests that optimizing the reaction system and operating the reaction under low power and at a lower duty cycle are effective in achieving efficient cavitation for sonocatalytic reactions.

Cavitation-Enhanced Drug Delivery and Immunotherapy.

Welcome to this special issue on Cavitation-Enhanced Drug Delivery and Immunotherapy-a rapidly evolving area that has been buoyed in recent years by the development of methods harnessing the activity of ultrasound-stimulated bubbles known as cavitation [...].

Enhancement of sonochemical production of hydroxyl radicals from pulsed cylindrically converging ultrasound waves.

Sonochemistry is the use of ultrasound to generate highly reactive radical species through the inertial collapse of a gas/vapour cavity and is a green alternative for hydrogen production, wastewater treatment, and chemical synthesis and modifications. Yet, current sonochemical reactors often are limited by their design, resulting in low efficacy and yields with slow reaction kinetics. Here, we constructed a novel sonochemical reactor design that creates cylindrically converging ultrasound waves to create an intense localised region of high acoustic pressure amplitudes (15 MPaPKPK) capable of spontaneously nucleating cavitation. Using a novel dosimetry technique, we determined the effect of acoustic parameters on the yield of hydroxyl radicals (HO), HO production rate, and ultimately the sonochemical efficiency (SE) of our reactor. Our reactor design had a significantly higher HO production rate and SE compared to other conventional reactors and across literature.

Papilledema and retinopathy lead to diagnosis of IgA nephropathy: a case report.

This case features a young healthy male who was diagnosed with immunoglobulin A (IgA) nephropathy after presenting with blurry vision that was caused by hypertensive retinopathy and papilledema. In this report, we examine the relationship between hypertension and increased intracranial pressure (ICP), along with the ocular signs of IgA nephropathy that may present in the setting of kidney disease.

Immunoglobulin A (IgA) nephropathy is an immune-mediated inflammatory condition that affects the kidneys and is characterized by deposits of IgA antibodies across the body. Nephropathy in general is defined as the deterioration of kidney function. Hypertension is a common complication because of the resultant kidney damage. IgA can also deposit widely across the body, including within the eyes, and may lead to various inflammatory manifestations affecting the front and back of the eyes. We present a case of a 38-year-old male with 2 weeks of worsening vision and headaches. His blood pressure was extremely high (206/116 mmHg) and he was found to have acute kidney injury. Examination of his eye revealed hypertensive retinopathy but also significant swelling of both of his optic discs, concerning for increased intracranial pressure (ICP), which is unusual in a young, otherwise healthy male. The investigation for the cause of increased ICP led to the diagnosis of IgA nephropathy. Treatment of his increased ICP and blood pressure resulted in improvement of his vision. It is important to consider increased ICP as a cause of optic disc swelling in patients with very high blood pressures. Prompt evaluation and management of elevated ICP is important to preserve vision, prevent brain complications and diagnose the underlying disease process. Especially important is the communication and coordination across medical specialties to ensure safe treatment given the multisystem organ involvement. In this article, we also review the eye findings associated with IgA nephropathy, as well as other immune-mediated complications of this rare disease.

Heat shock transcription factors demonstrate a distinct mode of interaction with mitotic chromosomes.

A large number of transcription factors have been shown to bind and interact with mitotic chromosomes, which may promote the efficient reactivation of transcriptional programs following cell division. Although the DNA-binding domain (DBD) contributes strongly to TF behavior, the mitotic behaviors of TFs from the same DBD family may vary. To define the mechanisms governing TF behavior during mitosis in mouse embryonic stem cells, we examined two related TFs: Heat Shock Factor 1 and 2 (HSF1 and HSF2). We found that HSF2 maintains site-specific binding genome-wide during mitosis, whereas HSF1 binding is somewhat decreased. Surprisingly, live-cell imaging shows that both factors appear excluded from mitotic chromosomes to the same degree, and are similarly more dynamic in mitosis than in interphase. Exclusion from mitotic DNA is not due to extrinsic factors like nuclear import and export mechanisms. Rather, we found that the HSF DBDs can coat mitotic chromosomes, and that HSF2 DBD is able to establish site-specific binding. These data further confirm that site-specific binding and chromosome coating are independent properties, and that for some TFs, mitotic behavior is largely determined by the non-DBD regions.

Fluorescence-based chemical tools for monitoring ultrasound-induced hydroxyl radical production in aqueous solution and in cells.

We report the synthesis of hydroxyl-radical (˙OH) responsive fluorescent probes that utilise the 3,5-dihydroxybenzyl (DHB) functionality. 4-Methylumbeliferone-DHB (Umb-DHB) and resorufin-DHB (Res-DHB) in the presence of ˙OH radicals resulted in significant increases in their respective fluorescent emission intensities at 460 nm and 585 nm. The incubation of Res-DHB in HeLa cells followed by therapeutic ultrasound (1 MHz) resulted in a significant increase in fluorescence emission intensity thus permitting the ability to monitor ultrasound-induced ˙OH production in live cells.

RNA Polymerase II transcription independent of TBP in murine embryonic stem cells.

Transcription by RNA Polymerase II (Pol II) is initiated by the hierarchical assembly of the pre-initiation complex onto promoter DNA. Decades of research have shown that the TATA-box binding protein (TBP) is essential for Pol II loading and initiation. Here, we report instead that acute depletion of TBP in mouse embryonic stem cells has no global effect on ongoing Pol II transcription. In contrast, acute TBP depletion severely impairs RNA Polymerase III initiation. Furthermore, Pol II transcriptional induction occurs normally upon TBP depletion. This TBP-independent transcription mechanism is not due to a functional redundancy with the TBP paralog TRF2, though TRF2 also binds to promoters of transcribed genes. Rather, we show that the TFIID complex can form and, despite having reduced TAF4 and TFIIA binding when TBP is depleted, the Pol II machinery is sufficiently robust in sustaining TBP-independent transcription.

Relationship between Atopic Disease and Acute Ocular and Systemic Outcomes in Patients with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

OBJECTIVE: To describe the relationship between history of atopic disease on systemic and ocular manifestations of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN). METHODS: Retrospective chart review of patients with SJS/TEN patients. Those with and without prior atopic diagnosis were compared. RESULTS: In total, 200 patients with SJS/TEN were identified. A total of 23 patients also had an atopic diagnosis. Four, 10, and 18 had atopic dermatitis, allergic rhinitis, and asthma respectively. Acute ocular severity was significantly worse in the atopic cohort. No significant differences in overall systemic severity of SJS or mortality were found between the atopic and non-atopic cohorts. Compared to our hospital system's general population, prevalence of an atopic diagnosis was significantly higher in those with SJS/TEN. CONCLUSION: Patients with a history of an atopic diagnosis appear to have more significant acute ocular involvement during their SJS/TEN hospitalization. Atopic conditions appear to occur more frequently in the SJS/TEN population compared to the general population.

Multimodal image alignment aids in the evaluation and monitoring of sector retinitis pigmentosa.

PURPOSE: To present a semi-automated method of image alignment to aid in monitoring the progression of inherited retinal degenerations (IRDs). RESULTS: A 22-year-old woman presented with nyctalopia and a family history of retinitis pigmentosa (RP), but with no prior genetic testing. Fundus examination showed a sectoral retinal degeneration involving the inferior and nasal retina with rare, pigmented deposits. Goldmann kinetic perimetry demonstrated corresponding superotemporal visual field defects. The best-corrected visual acuity was 20/20 in both eyes. Multimodal imaging delineated geographically restricted peripheral retinal degeneration extending to the inferior edge of the macula. Central visual function remained intact with normal multifocal electroretinography findings. Optical coherence tomography (OCT) through the leading edge of the retinal degeneration confirmed loss of the photoreceptor layer and associated retinal pigment epithelium. In the region of retinal degeneration, loss of vascular flow density was noted on optical coherence tomography angiography (OCTA). Genetic testing identified a pathologic sequence variant in RHO (c.68C>A, p.Pro23His), confirming autosomal dominant sector retinitis pigmentosa (SRP). Image alignment allowed for precise measurement of the progression of SRP over a period of 18 months. CONCLUSION: SRP is a rare subtype of RP characterized by focal, typically inferior and nasal, retinal degeneration of the peripheral retina. Although the onset and extent of peripheral retinal degeneration varies, compared with RP, SRP typically progresses more slowly to involve the macula. In this report, we highlight the utility of image registration and alignment to aid in monitoring disease progression in IRDs by means of multimodal imaging.

Ocular involvement in Mycoplasma induced rash and mucositis: A systematic review of the literature.

Mycoplasma pneumoniae induced rash and mucositis (MIRM) is a relatively newly identified clinical entity which is characterized by mucocutaneous manifestations in the setting of Mycoplasma infection. Though a clinically distinct disease, MIRM exists on a diagnostic continuum with entities including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and the recently described reactive infectious mucocutaneous eruption (RIME). In this systematic review, we discuss published findings on the epidemiology, clinical manifestations, diagnosis, and management of MIRM, with an emphasis on ocular disease. Lastly, we discuss some of the most recent developments and challenges in characterizing MIRM with respect to the related diagnosis of RIME.

Keeping an eye on the diabetic foot: The connection between diabetic eye disease and wound healing in the lower extremity.

Diabetic eye disease is strongly associated with the development of diabetic foot ulcers (DFUs). DFUs are a common and significant complication of diabetes mellitus (DM) that arise from a combination of micro- and macrovascular compromise. Hyperglycemia and associated metabolic dysfunction in DM lead to impaired wound healing, immune dysregulation, peripheral vascular disease, and diabetic neuropathy that predisposes the lower extremities to repetitive injury and progressive tissue damage that may ultimately necessitate amputation. Diabetic retinopathy (DR) is caused by cumulative damage to the retinal mic-rovasculature from hyperglycemia and other diabetes-associated factors. The severity of DR is closely associated with the development of DFUs and the need for lower extremity revascularization procedures and/or amputation. Like the lower extremity, the eye may also suffer end-organ damage from macrovascular compromise in the form of cranial neuropathies that impair its motility, cause optic neuropathy, or result in partial or complete blindness. Additionally, poor perfusion of the eye can cause ischemic retinopathy leading to the development of proliferative diabetic retinopathy or neovascular glaucoma, both serious, vision-threatening conditions. Finally, diabetic corneal ulcers and DFUs share many aspects of impaired wound healing resulting from neurovascular, sensory, and immunologic compromise. Notably, alterations in serum biomarkers, such as hemoglobin A1c, ceruloplasmin, creatinine, low-density lipoprotein, and high-density lipoprotein, are associated with both DR and DFUs. Monitoring these parameters can aid in prognosticating long-term outcomes and shed light on shared pathogenic mechanisms that lead to end-organ damage. The frequent co-occurrence of diabetic eye and foot problems mandate that patients affected by either condition undergo reciprocal comprehensive eye and foot evaluations in addition to optimizing diabetes management.

An alternative model for assessing mortality risk in Stevens Johnson syndrome/toxic epidermal necrolysis using a random forests classifier: A pilot study.

Introduction: Mortality risk prediction is an important part of the clinical assessment in the Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) patient. The SCORTEN and ABCD-10 scoring systems have been used as predictive clinical tools for assessing this risk. However, some of the metrics required in calculating these scores, such as the total body surface area (TBSA) involvement, are difficult to calculate. In addition, TBSA involvement is calculated in a variety of ways and is observer dependent and subjective. The goal of this study was to develop an alternative method to predict mortality in patients with SJS/TEN. Methods: Data was split into training and test datasets and preprocessed. Models were trained using five-fold cross validation. Out of several possible candidates, a random forests model was evaluated as being the most robust in predictive power for this dataset. Upon feature selection, a final random forests model was developed which was used for comparison against SCORTEN. Results: The differences in both accuracy (p = 0.324) and area under the receiver operating characteristic curve (AUROC) (p = 0.318) between the final random forests model and the SCORTEN and ABCD-10 models were not statistically significant. As such, this alternative method performs similarly to SCORTEN while only requiring simple laboratory tests from the day of admission. Discussion: This new alternative can make the mortality prediction process more efficient, along with providing a seamless implementation of the patient laboratory tests directly into the model from existing electronic health record (EHR) systems. Once the model was developed, a web application was built to deploy the model which integrates with the Epic EHR system on the Fast Healthcare Interoperability Resources (FHIR) Application Programming Interface (API); this only requires the patient medical record number and a date of the lab tests as parameters. This model ultimately allows clinicians to calculate patient mortality risk with only a few clicks. Further studies are needed for validation of this tool.

Corneal stromal deposits in connective tissue disease, a case series.

PURPOSE: We report two cases of refractile, peripheral, corneal stromal deposition in two patients with arterial tortuosity syndrome (ATS) and Ehlers-Danlos syndrome (EDS), two closely related connective tissue diseases (CTDs). OBSERVATIONS: Patient 1: A 21-year-old man with history of ATS and keratoectasia presented with bilateral peripheral corneal neovascularization with numerous whitish brown, refractile, deep stromal opacities that were circumferential along the inferotemporal cornea. After 3 years of follow-up, the corneal deposits did not progress, but the ectasia did, with significant bilateral corneal steepening and thinning for which the patient was recommended to undergo repeat corneal collagen cross linking. Patient 2: A 26-year-old man with presumed diagnosis of EDS presented with numerous whitish brown, refractile, deep stromal opacities that were circumferential along the temporal cornea in the right eye, and superiorly in the left eye. The left eye had a pseudopterygium involving 50% of the cornea. After 2 years of follow-up, the corneal opacities did not progress; however, the patient underwent primary excision of the pseudopterygium and subsequently had conjunctivalization of the entire cornea. The lesions in both cases resembled those seen in Terrien's marginal degeneration. CONCLUSIONS AND IMPORTANCE: Peripheral corneal stromal deposits have never been reported before in EDS or ATS or other connective tissue diseases. This case series may prompt further inquiry and characterization of these findings in patients with CTDs.

Unsupported gold nanocones as sonocatalytic agents with enhanced catalytic properties.

Gold catalysts have attracted attention for enabling sustainable chemical processes under ambient conditions. This reactivity is attributed to the small size of the catalysts (<5 nm); however, their size also creates difficulty when removing from product streams and often require rare-metal additives to enhance reaction rate kinetics, thereby limiting the environmental benefits of these catalysts. Comparatively, submicron gold catalysts are easier to separate but are much less reactive under ambient conditions. In this study, we synthesized submicron gas-stabilising gold nanocones (gs-AuNCs) that are acoustically responsive to afford greater reaction rates than other conventional gold catalysts. We explore the catalytic performance of acoustically responsive gs-AuNCs exposed to focussed ultrasound at 5.0 MPa peak negative pressure and 1.1 MHz center frequency. Cavitation nucleated from gs-AuNCs significantly increased the sonocatalytic degradation of water pollutants without the need for co-catalysts. The ability to amplify catalysis with ultrasound by tailoring the morphology of the catalyst to control cavitation opens new paths for future designs of sonocatalysts that may enable a sustainable chemical approach needed for a broad range of industrial processes.

Ultrasonic Implantation and Imaging of Sound-Sensitive Theranostic Agents for the Treatment of Arterial Inflammation.

For site-specific diseases such as atherosclerosis, it is desirable to noninvasively and locally deliver therapeutics for extended periods of time. High-intensity focused ultrasound (HIFU) provides targeted drug delivery, yet remains unable to sustain delivery beyond the HIFU treatment time. Furthermore, methods to validate HIFU-enhanced drug delivery remain limited. In this study, we report on HIFU-targeted implantation of degradable drug-loaded sound-sensitive multicavity PLGA microparticles (mcPLGA MPs) as a theranostic agent for the treatment of arterial lesions. Once implanted into the targeted tissue, mcPLGA MPs eluted dexamethasone for several days, thereby reducing inflammatory markers linked to oxidized lipid uptake in a foam cell spheroid model. Furthermore, implanted mcPLGA MPs created hyperechoic regions on diagnostic ultrasound images, and thus noninvasively verified that the target region was treated with the theranostic agents. This novel and innovative multifunctional theranostic platform may serve as a promising candidate for noninvasive imaging and treatment for site-specific diseases such as atherosclerosis.

Chronic ocular complications in lamotrigine vs. trimethoprim-sulfamethoxazole induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

PURPOSE: The purpose of this study is to compare the severity of chronic ocular complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by lamotrigine (LT) vs. trimethoprim-sulfamethoxazole (TS). METHODS: This retrospective cross-sectional study evaluated all SJS/TEN patients treated within our hospital network from 2008 to 2018. Inclusion criteria included patients with reactions identified as caused by either LT or TS, and patients with at least one ophthalmology follow up in the chronic phase (≥3 months from disease onset). Primary outcome measures included LogMAR best-corrected VA at most recent visit and the presence or absence of severe ocular complications (SOC). Secondary outcome measures included chronic ocular complication severity scores using a modified Sotozono scoring system. RESULTS: Forty-eight eyes of 24 patients were included in the study. The mean duration of follow-up was 39.50 ± 35.62 vs. 48.17 ± 33.09 months, respectively (p = 0.482). The LT group had worse average VA at the most recent visit (LogMAR VA; 0.508 vs. 0.041, p < 0.0001) and had a higher prevalence of SOCs (66.7% vs. 8.3%, p = 0.0038). The LT group scored worse on Sotozono chronic complications scores for the cornea (1.875 vs. 0.5, p = 0.0018), eyelid margin (5.583 vs.3.083, p = 0.0010), and overall condition (8.500 vs. 4.833, p = 0.0015). Sub-analyses showed that a moderate or severe acute ocular severity score was a significant predictor of chronic outcomes. CONCLUSIONS: Compared to patients with TS-induced SJS/TEN, patients with LT-induced SJS/TEN developed worse chronic ocular complications on several parameters. Future prospective studies are warranted to provide additional insight into the drug type as a predictor of chronic ocular complications.

Detection of Chronic Hypoventilation Among Infants With Robin Sequence Using Capillary Blood Gas Sampling.

OBJECTIVES/HYPOTHESIS: To describe the use of capillary blood gas (CBG) sampling to detect and quantify hypoventilation in infants with Robin sequence (RS). METHODS: Case series with chart review at two institutions. Infants with RS presenting over a 10-year period were identified using departmental databases. CBG values obtained during infancy or until airway intervention (AI) were reviewed. RESULTS: From 2008 to 2018, 111 infants with RS were identified as having had been assessed and managed from birth or transfer until discharge home and having CBG data available. In most cases, CBG sampling was obtained every other day until intervention or discharge. A total of 81 (73%) infants required AI: 72 (89%) underwent mandibular distraction osteogenesis, five (6%) underwent tracheotomy, and four (5%) were discharged home with a nasopharyngeal airway. The mean PCO2 at day of life (DOL) 7-30 for the AI group was 52.7 mmHg (95% confidence interval: 51.7-53.7) and for the no AI group was 45.9 mmHg (44.8-47.0; P < .0001). The mean HCO3 at DOL 7-30 for the AI group was 29.8 mEq/L (29.4-30.1) and for the no AI group was 27.0 mEq/L (26.5-27.4; P < .0001). Receiver operating characteristic curves were created for maximum PCO2 and HCO3 values and cutoffs were established by optimizing a balance of sensitivity and specificity. Infants requiring AI surpassed the PCO2 and HCO3 cutoff at a median of DOL 9. CONCLUSIONS: Among infants with RS and hypoventilation, objective measures of respiratory acidosis may be apparent by DOL 9. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2789-2794, 2021.

Investigating the Acoustic Response and Contrast Enhancement of Drug-Loadable PLGA Microparticles with Various Shapes and Morphologies.

Polymer nanoparticles and microparticles have been used primarily for drug delivery. There is now growing interest in further developing polymer-based solid cavitation agents to also enhance ultrasound imaging. We previously reported on a facile method to produce hollow poly(lactic-co-glycolic acid) (PLGA) microparticles with different diameters and degrees of porosity. Here, we investigate the cavitation response from these PLGA microparticles with both therapeutic and diagnostic ultrasound transducers. Interestingly, all formulations exhibited stable cavitation; larger porous and multicavity particles also provided inertial cavitation at elevated acoustic pressure amplitudes. These larger particles also achieved contrast enhancement comparable to that of commercially available ultrasound contrast agents, with a maximum recorded contrast-to-tissue ratio of 28 dB. Therefore, we found that multicavity PLGA microparticles respond to both therapeutic and diagnostic ultrasound and may be applied as a theranostic agent.