Efficacy and Safety of the Melanocortin Pan-Agonist PL9643 in a Phase 2 Study of Patients with Dry Eye Disease.

Purpose: The melanocortin receptor pan-agonist PL9643, a potential therapy for ocular diseases, was investigated in a phase 2, 12-week study in patients with dry eye disease (DED). Methods: This was a placebo-controlled study evaluating efficacy and safety of thrice-daily PL9643. Placebo (vehicle) was similar to tears. Primary endpoints were intra-patient changes in inferior corneal fluorescein staining and ocular discomfort after 12 weeks. Secondary endpoints were changes in additional DED signs or symptoms. Multiple secondary endpoints were not adjusted for multiplicity. Patients with moderate or severe DED were analyzed in addition to the overall intent-to-treat (ITT) population. Results: In the ITT population (n = 160) the PL9643 group did not demonstrate significant treatment difference versus placebo at week 12/day 85 for the primary endpoints (P > 0.05). In patients with moderate or severe DED (n = 53), PL9643 treatment demonstrated either nominally significant (P < 0.05) or trending (P < 0.1) improvement over placebo in mean change from baseline at week 12/day 85 in several sign endpoints, including fluorescein staining in inferior, superior, corneal sum, and total sum regions; Lissamine Green staining in temporal, nasal, conjunctival sum, and total sum regions; and tear film breakup time. Conjunctival redness also showed (nonsignificant) improvement at week 12/day 85. There were no drug-related adverse events (AEs) and no drug-related discontinuations. Conclusions: PL9643 showed no significant efficacy for the ITT population; however, efficacy results across several signs and symptoms in the subpopulation of moderate to severe DED patients, the low number of ocular AEs, and no tolerability issues suggest that PL9643 shows promise as a therapeutic for DED. Clinical Trial Registration number: NCT04268069.

Increasing use of sodium nitrite in suicides-an emerging trend.

Sodium nitrite (NaNO2) is a compound with broad practical applications in food preservation, automotive maintenance, and animal control. Sodium nitrite is also potentially fatal when ingested, as it interferes with the ability of red blood cells to transport oxygen. While incidents of accidental consumption have been reported in the literature, case reports of sodium nitrite being used as a pharmacological suicide agent are becoming more frequent. Therefore, a study was undertaken to evaluate trends in sodium nitrite deaths in South Australia between 2000 and 2019. All cases of fatal sodium nitrite ingestion were identified in the Toxicology database and autopsy reports at Forensic Science SA (FSSA). Ten cases of fatal sodium nitrite ingestion were identified, with the rate of cases increasing significantly over the study period (p > .001). Of the ten deaths attributed to sodium nitrite toxicity, eight were male, and two were female. The age range of decedents was 22-74 years (mean 51.9, SD 21.1), 22-74 years for males (mean 58.4, SD 18.2) and 23-29 years for females (mean 26.0, SD 4.2). Males (80%) and those with a history of depression and/or suicidal ideation (70%) were over-represented within the study population. While autopsy findings were generally consistent with the literature, scene findings emphasized the accessibility of sodium nitrite to the general public. This study highlights both a significant increasing trend in the use of sodium nitrite in suicides and important analytical limitations in the evaluation of suspected cases.

Lethal giant basal cell carcinoma.

Basal cell carcinomas are the most common malignancy in Caucasian populations with a very low predisposition to metastatic disease and an excellent prognosis if appropriately treated. Given the rarity of a lethal outcome two cases are reported. Case 1: A 61-year-old reclusive man who had an untreated facial basal cell carcinoma for 10 years died of hypothermia and sepsis complicating the extensively ulcerated and infected tumour. He also had underlying cardiomegaly, ischaemic heart disease and chronic obstructive pulmonary disease. Case 2: A 60-year-old man who had an untreated lower lumbar basal cell carcinoma for 14 years died of sepsis, inanition and pulmonary thromboembolism (due to a right-sided deep venous thrombosis) complicating the deeply ulcerated tumour. Untreated giant basal cell carcinoma may uncommonly present for medicolegal assessment with complex pathophysiological lethal mechanisms. The possibility of Diogenes syndrome should be considered.

Wischnewski spots in a case of accidental hypothermia.

Accidental hypothermia can be fatal, and is often associated with confusion and paradoxical undressing. Wischnewski spots are a classic manifestation of hypothermia at autopsy.

A risk-based approach to cognitive bias in forensic science.

Over the past decade, the potential impact of cognitive bias in forensic science has instigated much discussion and debate between academics, scientists and those in the justice sector. Evidence of bias influencing subjective decision-making across a range of forensic disciplines has been described in the literature. Forensic service organisations are being urged to address cognitive bias in subjective decision-making by designing processes or procedures to limit access to (irrelevant) contextual information or reduce dependence on cognitive functions. Although some laboratories have implemented bias mitigating strategies, with varying impact on operational efficiency, there has been no systematic assessment of the risk posed by cognitive bias. Forensic Science SA assessed the potential impact of bias on forensic interpretations across multiple disciplines, using a risk management framework. This process proved useful in assessing the effectiveness of existing bias mitigating strategies and identified the latent level of risk posed. While all forensic organisations should seek to implement bias limiting measures that are simple, cost-effective and do not adversely impact efficiency, using a risk-based approach has contextualised the limited benefit of introducing resource hungry measures, as postulated in the literature. That is not to suggest that forensic organisations should dismiss the potential influence of cognitive bias but they need to strike an appropriate balance between risk and return, as they do with any business risk.

Fatal methemoglobinemia complicating alkaptonuria (ochronosis): a rare presentation.

A 61-year-old female died in hospital with multiple organ failure 4 weeks following presentation with acute kidney injury, hemolytic anemia and methemoglobinemia. At autopsy, brown to black discoloration of cartilages was observed. Histology revealed brown pigmentation of the hyaline cartilage, with focal full-thickness erosion of the articular hyaline cartilage, characteristic of alkaptonuria (ochronosis). Although alkaptonuria is rarely fatal, this case illustrates a rare acute fatal complication. Accumulation of circulating homgentisic acid secondary to acute derangement of renal function is believed to have overwhelmed the endogenous antioxidant processes, resulting in hemolysis and methemoglobinemia, which were refractory to treatment. Small numbers of cases have previously been reported in the literature in patients known to suffer with the disease, all of which were preceded by acute kidney injury. Whilst the clinical diagnosis of alkaptonuria may be challenging, the autopsy findings of this rare condition are striking and this case illustrates the utility of the autopsy, albeit retrospectively, in arriving at a diagnosis. To our knowledge this is the first reported case where previously undiagnosed alkaptonuria has presented with methemoglobinemia.

A simple post mortem room angiography method for the investigation of traumatic basal subarachnoid hemorrhage.

Identifying the site of vascular bleeding in fatal cases of traumatic basal subarachnoid hemorrhage (TBSAH) is important, but can be very difficult to achieve when there is extensive blood clot in the posterior cranial fossa. Post mortem angiography in these circumstances has been reported previously but with mixed results, and is rarely used in current practice within the United Kingdom. We have developed a simple and effective post mortem angiography method, using fluoroscopy and clear modern contrast medium, suitable for use in the autopsy room. Contrast medium was injected through an angiographic catheter positioned (with water filled balloon) in the extracranial vertebral artery (ECVA) just behind the clavicle, whilst the base of the skull and upper cervical spine area was visualized by fluoroscopy following digital subtraction of the bony images. The procedure was developed over a series of 8 TBSAH cases and using unfixed cadaveric specimens. A clear leak point was identified in 3 cases and the likely site indicated in a further fatality (all with tears subsequently confirmed by histology). In 4 cases, the bleeding point was not identified by angiography. In 7 deaths, the anatomy of the upper cervical loops and intracranial course of the vertebral arteries were well delineated by angiography and several small loop segments were documented. In 1 case, with severe degenerative vascular disease, extracranial vessel wall trauma and luminal thrombosis, angiography was unsuccessful above the level of the first cervical (C1) vertebra. Injecting contrast through the internal carotid artery, just above the bifurcation, was also shown to visualize the anterior cerebral circulation well. This method is likely to identify the main site of vascular tearing in about 50% of cases of TBSAH and to delineate the important anatomy of the vessels, prior to dissection of the upper neck and posterior fossa, thus minimizing handling artefacts and guiding the histological sampling of the vessels.

Forensic Features of Lethal Late-Presenting Diaphragmatic Hernias.

Diaphragmatic defects are a relatively common and benign finding in adults which may be congenital or secondarily acquired. The case files at Forensic Sciences South Australia were reviewed over a 10-year period from July 2005 to June 2015 for all adult (>17 years) cases in which diaphragmatic hernias were identified at postmortem examination that had either caused or contributed to death. Five cases were found: age range 49-90 years (average 67.2 years); male:female ratio 2:3. Herniated organs included the stomach (N = 3), small (N = 3) and large intestines (N = 2). Mechanisms of death involved lung compression with respiratory failure and/or mediastinal shift, and vascular compromise with gastric or intestinal infarction and/or perforation. Diaphragmatic hernias may not be identified until the time of autopsy and may be quite complex entities to evaluate due to a lack of clinical history and to difficulties in determining their origin and possible contributions to mechanisms of death.

Homicidal smothering: vital histological confirmation of orofacial injury despite a prolonged post-mortem interval.

Homicidal smothering is the deliberate occlusion of the external airways, usually using the hands, pillows, or bedding. Victims are often those who are unable to resist, such as the young or the old. The limited resistance offered by these individuals may result in a comparative lack of injury. We present a case of a 72-year-old female, found deceased on her bed. The case was initially not considered suspicious and a coronial autopsy was performed. Concerns were subsequently raised and the body remained refrigerated. Six months after the initial examination, an opinion was requested as to whether further examination would be worthwhile to consider allegations of deliberate smothering. Review of the scene photographs showed deviation of the nose, eversion of the upper lip, and suspected intra-oral bruising. A bloodstained pillow was adjacent to the face. At the later autopsy, the body was found to show significant post-mortem deterioration and the facial tissues were mummified. The upper lip was excised and routinely processed for histology, sections showing remarkably good tissue preservation and extensive recent bruising, allowing the suspicious lip injuries in the scene photographs to be safely interpreted. This report illustrates the subtle pathological findings apparent in many of these cases and reinforces the need for thorough external examination and correlation with forensic scene investigation. Histological sampling of suspected injuries can be rewarding, even in the presence of severe post-mortem deterioration.