Genome-wide screening reveals the genetic basis of mammalian embryonic eye development.

BACKGROUND: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. RESULTS: Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. CONCLUSIONS: Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus.

Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify potential inhibitors of replication or gene expression. From this work we identified isonicotinic acid inhibitors of the histone lysine demethylase 5 (KDM5) with potent anti-HBV activity. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) an ester prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as an increased H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes reduced the levels of HBV RNA, DNA and antigen. Evaluation of GS-5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious from the in vitro model. Here we discuss potential reasons for the disconnect between in vitro and in vivo efficacy, which highlight the translational difficulties of epigenetic targets for viral diseases.

Ultrasound-Guided Scalp Blocks for an Awake Craniotomy: A Case Report.

Ultrasound-guided scalp blocks may revolutionize regional anesthesia for neurosurgery. In this report, we demonstrate that ultrasound-guided scalp blocks can be used effectively for a craniotomy. A 48-year-old patient with a brain tumor at the motor cortex was scheduled for an awake craniotomy. Ultrasound-guided scalp blocks targeting the bilateral supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, greater auricular, lesser occipital, greater occipital, and third occipital nerves were performed. A total of 29 mL of levobupivacaine 0.3% was used. No additional local anesthetic agent was given for skull pinning, skin incision, or the craniotomy. Postoperatively, the patient remained pain-free, and she was discharged without complications.

Case Vignettes in Transplant Psychiatry Ethics.

The demand for liver transplants continues to far exceed the number of available viable donor organs; hence, it is of utmost importance to determine those individuals who are best able to care for these valuable, limited resources as potential recipients. At the same time, psychiatric comorbidity is common in the course of end-stage liver disease and can be mutually complicating. This article focuses on liver transplant candidacy from a psychiatric perspective, using illustrative cases to underscore the foundational facets of medical ethics that serve as the guide to these complex medical and ethical decisions.

Acute pericarditis as a clinical manifestation in COVID-19 infection in a district hospital setting.

The global outbreak of coronavirus disease 2019(COVID-19) pandemic has heavily impacted the health service, leading to increased mortality and morbidity. Although known to manifest primarily as a respiratory illness, there are reports of cardiac involvement as extrapulmonary manifestation. We are reporting a case of pericarditis in a young patient who presented with only cardiac symptoms in COVID-19. He was admitted to the hospital for observation and treated with oral colchicine and oral ibuprofen. His conditions improved and subsequently discharged well. Acute pericarditis can present as part of the COVID-19 extrapulmonary spectrum. Therefore, it is important and challenging for clinicians to recognise the atypical presentations of COVID-19 to reduce morbidity and mortality.

Drowning incidents and conditions due to hidden flash rips in Lake Michigan.

Flash rips are episodic bursts of water jetting offshore, which can lead to drowning incidents by sweeping swimmers offshore without warning, thus posing a hidden and unrecognized danger to beachgoers. This study reveals hazards of flash rips by investigating a series of drowning incidents along coasts of Lake Michigan during a series of storm events on July 18-21, 2019. Occurrences and causes of flash rips were depicted through webcam image observations, storm features of atmospheric disturbances, hydrodynamic circumstances of wind waves and meteorologically induced water level fluctuations, and model-reconstructed nearshore circulations. Results shows that flash rips were generated during or after storms through nearshore processes of storm-induced wind waves and meteorologically induced water level fluctuations. With small wind waves, low water level fluctuations, and a timing delay of rip occurrences relative to the causative convective storms, flash rips pose a hidden hazard to unaware swimmers. Historical observations for incidents in Lake Michigan between 2002 and 2019 further show that dry conditions or fair weathers and a calm water signature at the beach can likely generate unexpected hidden flash rips, resulting in the highest drowning risks. There is an urgent need for communication, education, and prediction/forecast of hidden flash rips to the Laurentian Great Lakes and worldwide coastal communities.

Neurotoxicity of an Hepatitis B Virus (HBV) Transcript Inhibitor in 13-Week Rat and Monkey Studies.

The nonclinical safety profile of GS-8873, a hepatitis B virus RNA transcript inhibitor was evaluated in rat and monkey 13-week toxicity studies with 8-week recovery phases. Vehicle or GS-8873 was dosed orally for 13 weeks at 2, 6, 20, and 60 mg/kg/day to Wistar Han rats and at 0.5, 1.5, 3, and 6 mg/kg/day to cynomolgus monkeys. In vitro and in vivo screening results from an analog discovered prior to GS-8873 informed the 13-week toxicology study designs. Neuroelectrophysiology and neurobehavioral evaluations were included at weeks 4 and 13 of the dosing and recovery phases for GS-8873. No adverse neurobehavioral effects were observed. Significant nerve conduction velocity (NCV) decreases and latency increases occurred at the high doses after 4 weeks of dosing. By week 13, dose-responsive NCV reductions and latency increases worsened across all dose groups compared with controls. Some reversal occurred 8 weeks after the last dose administered, but not to vehicle control levels. A minimal, axonal degeneration was observed in rat spinal and peripheral nerves across dose groups compared with controls. No monkey nervous system microscopic findings were observed. No-observed-adverse-effect-levels could not be determined for either species due to the neuroelectrophysiology findings and development was halted in the interest of safety. A retrospective risk assessment approach utilizing benchmark dose (BMD) modeling contributed 13-week NCV BMDL estimates (lower limits of the 95% confidence interval) in lieu of no-observed-adverse-effect-levels. The best-fitted models extrapolated NCV BMDLs for the rat caudal and monkey sural nerve at 0.3 and 0.1 mg/kg/day, respectively.

A retrospective cross-sectional study on the risk factors and survival outcome of End Stage Kidney Disease patients receiving regular maintenance haemodialysis with COVID-19 infection in Hospital Enche' Besar Hajjah Khalsom, Kluang.

INTRODUCTION: COVID-19 pandemic has affected healthcare services around the globe as hospitals were turned into designated hospitals to accommodate high risk groups of patients with COVID-19 infection including end stage kidney disease (ESKD) patients. In Malaysia, there was insufficient data on COVID-19 infection among ESKD patients. This study aims to determine factors and survival outcomes associated with COVID-19 infection among ESKD patients in a designated COVID-19 hospital in Malaysia. METHODS AND MATERIALS: A retrospective cross-sectional study involving 80 haemodialysis (HD) patients recruited from March 2020 till March 2021. Patients' information and results was retrieved and evaluated. Risk factors affecting the COVID-19 mortality were analysed using a one-way analysis of variance (ANOVA) and binary logistic regression. RESULTS: The mean age of the patients was 54 years who were predominantly Malays (87.5%) and living in rural areas. Majority of them had comorbidities such as diabetes mellitus (71%) and hypertension (90%). The most common presentations were fever (46%) and cough (54%) with chest radiographs showing bilateral lower zone ground glass opacities (45%). A quarter of the study population were admitted to the intensive care unit, necessitating mechanical ventilation. This study found that 51% of the patients were given steroids and 45% required oxygen supplementation. The COVID-19 infection mortality among the study population was 12.5%. Simple logistic regression analysis showed that albumin, Odd Ratio, OR=0.85 (95% Confidence Interval, 95%CI: 0.73, 0.98)) and absolute lymphocyte count OR=0.08 (95%CI: 0.11, 0.56) have inverse association with COVID-19 mortality. C-reactive protein OR=1.02 (95%CI: 1.01, 1.04), lactate dehydrogenase OR=1.01 (95%CI: 1.00, 1.01), mechanical ventilation OR=17.21 (95%CI: 3.03, 97.67) and high dose steroids OR=15.71 (95%CI: 1.80, 137.42) were directly associated with COVID-19 mortality. CONCLUSION: The high mortality rate among ESKD patients receiving HD was alarming. This warrants additional infection control measures to prevent the spread of COVID- 19 infection among this vulnerable group of patients. Expediting vaccination efforts in this group of patients should be advocated to reduce the incidence of complications from COVID-19 infection.

A rare presentation of ectopic thyroid gland at right axilla.

The thyroid gland and its hormones play important roles in organ development and in the homeostatic control of physiological mechanisms in human beings. As a result of embryogenic descent of thyroid gland, it commonly resides along the midline - from tongue to mediastinum (90%). Ectopic thyroid gland is a rare occurrence, with extra-lingual ectopic thyroid gland being even rarer. Thus, there is a concern for malignant metastasis. Madam H, a 56-year-old healthy woman presented to the Hospital Sultanah Nora Ismail, Johor, Malaysia in April 2020 with an increasing size of right axilla mass and history of weight loss. She was having right axilla mass for the previous 7 years but only noticed the increase in size about 1 year ago. She has no other constitutional symptoms. A tru-cut biopsy performed demonstrated a benign ectopic thyroid tissue. Thyroid function test showed primary hypothyroidism. Serum Chromogranin A and other thyroid antibodies were within the normal value. Further radiological imaging showed the normal thyroid gland at neck, with no signs of distant malignancy. There was no other axillary, mediastinal or hilar lymph node enlargement. She was started on regular T. L Thyroxine 100mcg daily and given regular follow-up in endocrine clinic. Benign ectopic thyroid gland is an unusual finding. As such, follow up is needed with possibility of carcinomatous transformation such as papillary carcinoma should be considered.

Hypothalamic-pituitary fungal infection causing panhypopituitarism.

Madam LPS, a 69 years old lady complained of left eye blurring of vision since January 2017. It was associated with left orbital swelling with chemosis, eye redness, epiphora, several episodes of self-limiting epistaxis and bilateral ophthalmoplegia. Other neurological examinations and cerebellar systems were intact. Magnetic Resonance Imaging (MRI) Brain and Orbit were performed, depicting a sellar mass with suprasellar extension with blood investigations results showed panhypopituitarism. She underwent bilateral orbital decompression. Trans-nasal endoscopic biopsy showed suppurative granulomatous lesion, which cultured Candida Albicans and Candida Galbrata. She was started on antifungal and hormonal replacement therapy for panhypopituitarism. Unfortunately, she did not respond well to treatment as repeated MRI Brain on December 2018 showed increase in size of sellar mass causing obstructive hydrocephalus and increasing size of left orbital lesion. She was counselled for another debulking surgery with a ventriculoperitoneal (VP) shunt. HPE taken were reported as chronic inflammatory process in favour to fungal infection. Pituitary infections may mimic pituitary mass. Some may exhibit symptoms of panhypopituitarism as well. Thus, physical examination, MRI brain imaging as well as HPE of biopsy are important aids to achieve diagnosis. Optimal treatment of fungal pituitary abscess includes transsphenoidal surgery combined with antifungal therapy.

Telepsychiatry in the Age of COVID: Some Ethical Considerations.

The COVID-19 pandemic has necessitated a rapid escalation in the use of telepsychiatry. Herein we revisit some of the ethical issues regarding its use, including patient benefice, distributive justice, privacy, and autonomy. Based on these considerations we would hold that telepsychiatry is a vital aspect of providing psychiatric care, and ethically should be offered as a format for treatment, likely beyond the pandemic period. Investigative and advocacy efforts will need to continue to determine its exact role within psychiatric care, and expand its availability for those most in need.

Adult metaplastic hutch diverticulum with robotic-assisted diverticulectomy and reconstruction: A case report.

BACKGROUND: Hutch diverticulum arises from the compromised muscular development at the ureteral orifice. It is a congenital disease and extremely rare in adult, only accounting for about 3% occurrence worldwide. It can be either symptomatic or asymptomatic, and relies on image tools for diagnosis and preoperative planning. Indications for surgery are dependent on the complications from the diverticulum. Metaplasia is about 10% among those with hutch diverticulum, and it still has chances turning into malignancy, especially urothelial cell carcinoma. CASE SUMMARY: A 27-year-old man was presented with frequently recurrent urinary tract infection for one year, and had suffered from intermittent right flank pain for 3 mo. No past medical histories were recorded before. No obvious abnormalities on laboratory data and urine examination were found. Under ultrasound, right hydronephrosis was seen and an anatomical abnormality was observed on intravenous pyelography. Further computed tomography urogram showed one diverticulum seated at superolateral side of right ureteral orifice. Cystoscopy was done and biopsy results showed focal metaplasia. After discussing with him, robotic-assisted diverticulectomy with reconstruction was performed. Right hydronephrosis was greatly improved after surgery. He has completed his 1.5-year follow-ups, and no malignancies were seen from urine cytology and image of intravenous pyelography. CONCLUSION: Robotic-assisted diverticulectomy and reconstruction to hutch diverticulum is a safe and efficient operation, providing several advantages over open and laparoscopic ones.

Eight-year follow-up of locally advanced lymphoepithelioma-like carcinoma at upper urinary tract: A case report.

BACKGROUND: Urinary tract lymphoepithelioma-like carcinoma is rarely seen. Although it is termed after lymphoepithelioma at the nasopharynx, it behaves more like high grade urothelial carcinoma by immunohistochemical features. Most published literatures focused on its rarity but few discussed results of long-term follow-ups. As no available guidelines are applicable, we postulated that principles should be similar to that of urothelial carcinoma at urinary tract. As of now, this work features the longest follow-up of this cancer at the upper urinary tract. CASE SUMMARY: A 63-year-old female had a chief complaint of intermittent left flank pain for 2 mo, along with accompanying symptoms including vomiting and body weight loss, about 7 kg over 2 mo. Laboratory data showed normocytic anemia, mildly poor renal function, and hyperparathyroidism. Urine analysis showed mild hematuria. Computed tomography showed a 4.2-cm-width irregular mass over left renal pelvic and enlarged lymph node at the left renal hilum. Whole-body bone scan was negative of active bone lesions. Biopsy from ureteroscopy showed urothelial carcinoma. Specimen from laparoscopic nephroureterectomy with bladder cuff resection showed lymphoepithelioma-like carcinoma with muscular invasion (pT3). She took adjuvant chemotherapies of 2 cycles and full courses of radiation therapy. No recurrence was observed with designed investigative programs. CONCLUSION: Locally advanced urinary tract lymphoepithelioma-like carcinoma could benefit from nephroureterectomy and bladder cuff excision in terms of recurrence-free survival.

Using on-demand dry ice production as an alternative cryogenic cold chain for bovine artificial insemination outreach in low-resource settings.

Artificial insemination (AI) is widely used in livestock industries to breed for desirable characteristics and increase yields. The standard practice of storing and transporting bovine semen uses liquid nitrogen (LN), a scarce commodity in many regions of the world. This study explored the feasibility of using dry ice, a more readily available alternative. We developed equipment that dispenses dry ice from widely available liquid carbon dioxide (LCO2) tanks into an easily transportable device. In vivo fertility results with a dry ice cold chain showed no statistical difference to the conventional LN method. In vitro bovine semen analyses also showed that storage under these conditions minimally affects characteristics associated with fertility. A dry ice cold chain system could leverage the global availability of LCO2 to expand the reach of AI and other cold storage applications of biological materials in low-resource settings.

Granzyme B PET Imaging of Immune Checkpoint Inhibitor Combinations in Colon Cancer Phenotypes.

PURPOSE: Immune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes. PROCEDURES: We have assessed the ability of a fluorine-labelled peptide, [18F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. In vivo tumour uptake of [18F]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations. RESULTS: [18F]AlF-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours. CONCLUSIONS: [18F]AlF-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation.

Transplant outcomes in kidney recipients with lupus nephritis, and systematic review.

BACKGROUND: Despite improved survival of patients with lupus nephritis (LN), some require kidney transplantation because of progression to end-stage renal disease (ESRD). However, the transplant outcomes of these patients and other recipients have not been thoroughly compared. METHODS: In total, 1848 Korean kidney recipients who underwent transplantation from 1998 to 2017 at two tertiary referral centers were evaluated retrospectively. Among them, 28 recipients with LN, and 50 control recipients matched by age, sex, and donor type, were compared with respect to graft and patient survival. We pooled our data with 17 previous cohort studies in which the graft survival of recipients with LN was described in detail. RESULTS: During the median follow-up period of 9.5 years (maximum 21 years), graft failure (GF) occurred in 10.7% and 16.0% of LN and control recipients, respectively. No differences were found in the rates of GF and death-censored graft failure or patient survival between the two groups. The risks of acute T cell-mediated and antibody-mediated rejection were also similar between the two groups. The pooled analysis showed similar 1- and 5-year graft survival rates between LN and control recipients. CONCLUSIONS: Kidney transplantation is an acceptable option in patients with concurrent LN and ESRD.

Detention, Capacity, and Treatment in the Mentally Ill-Ethical and Legal Challenges.

For individuals whose mental illness impair their ability to accept appropriate care-the depressed, acutely suicidal mother, or the psychotic lawyer too paranoid to eat any food-statutes exist to permit involuntary hospitalization, a temporary override of paternalistic benefice over personal autonomy. This exception to the primacy of personal autonomy at the core of bioethics has the aim of restoring the mental health of the temporarily incapacitated individual, and with it, their autonomy.

Unexpected rip currents induced by a meteotsunami.

A tragic drowning event occurred along southeastern beaches of Lake Michigan on a sunny and calm July 4, 2003, hours after a fast-moving convective storm had crossed the lake. Data forensics indicates that a moderate-height (~0.3 m) meteotsunami was generated by the fast-moving storm impacting the eastern coast of the lake. Detailed Nearshore Area (DNA) modeling forensics on a high-resolution spatial O(1 m) grid reveals that the meteotsunami wave generated unexpected rip currents, changing the nearshore condition from calm to hazardous in just a few minutes and lasting for several hours after the storm. Cross-comparison of rip current incidents and meteotsunami occurrence databases suggests that meteotsunamis present severe water safety hazards and high risks, more frequently than previously recognized. Overall, meteorological tsunamis are revealed as a new generation mechanism of rip currents, thus posing an unexpected beach hazard that, to date, has been ignored.