Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib.

Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the etiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a therapeutic strategy that may effectively prevent life-changing morbidity caused by snakebite in rural Africa.

Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms.

Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, inhibit the cytotoxicity of a broad range of medically important snake venoms. Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.

Using Deep Learning to Predict Final HER2 Status in Invasive Breast Cancers That are Equivocal (2+) by Immunohistochemistry.

Invasive breast carcinomas are routinely tested for HER2 using immunohistochemistry (IHC), with reflex in situ hybridization (ISH) for those scored as equivocal (2+). ISH testing is expensive, time-consuming, and not universally available. In this study, we trained a deep learning algorithm to directly predict HER2 gene amplification status from HER2 2+ IHC slides. Data included 115 consecutive cases of invasive breast carcinoma scored as 2+ by IHC that had follow-up HER2 ISH testing. An external validation data set was created from 36 HER2 IHC slides prepared at an outside institution. All internal IHC slides were digitized and divided into training (80%), and test (20%) sets with 5-fold cross-validation. Small patches (256×256 pixels) were randomly extracted and used to train convolutional neural networks with EfficientNet B0 architecture using a transfer learning approach. Predictions for slides in the test set were made on individual patches, and these predictions were aggregated to generate an overall prediction for each slide. This resulted in a receiver operating characteristic area under the curve of 0.83 with an overall accuracy of 79% (sensitivity=0.70, specificity=0.82). Analysis of external validation slides resulted in a receiver operating characteristic area under the curve of 0.79 with an overall accuracy of 81% (sensitivity=0.50, specificity=0.82). Although the sensitivity and specificity are not high enough to negate the need for reflexive ISH testing entirely, this approach may be useful for triaging cases more likely to be HER2 positive and initiating treatment planning in centers where HER2 ISH testing is not readily available.

Deep learning for computer-assisted diagnosis of hereditary diffuse gastric cancer.

BACKGROUND: Patients with hereditary diffuse gastric cancer often undergo prophylactic gastrectomy to minimize cancer risk. Because intramucosal poorly cohesive carcinomas in this setting are typically not grossly visible, many pathologists assess the entire gastrectomy specimen microscopically. With 150 or more slides per case, this is a major time burden for pathologists. This study utilizes deep learning methods to analyze digitized slides and detect regions of carcinoma. METHODS: Prophylactic gastrectomy specimens from seven patients with germline CDH1 mutations were analyzed (five for training/validation and two for testing, with a total of 133 tumor foci). All hematoxylin and eosin slides containing cancer foci were digitally scanned, and patches of size 256×256 pixels were randomly extracted from regions of cancer as well as from regions of normal background tissue, resulting in 15,851 images for training/validation and 970 images for testing. A model with DenseNet-169 architecture was trained for 150 epochs, then evaluated on images from the test set. External validation was conducted on 814 images scanned at an outside institution. RESULTS: On individual patches, the trained model achieved a receiver operating characteristic (ROC) area under the curve (AUC) of 0.9986. This enabled it to maintain a sensitivity of 90% with a false-positive rate of less than 0.1%. On the external validation dataset, the model achieved a similar ROC AUC of 0.9984. On whole slide images, the network detected 100% of tumor foci and correctly eliminated an average of 99.9% of the non-cancer slide area from consideration. CONCLUSIONS: Overall, our model shows encouraging progress towards computer-assisted diagnosis of hereditary diffuse gastric cancer.

Does early antipsychotic response predict long-term treatment outcome?

OBJECTIVE: Early antipsychotic response within the first 2-3 weeks of treatment can predict short-term outcomes after several months. We conducted the current study to determine whether the predictive value of early antipsychotic response persists throughout long-term treatment over multiple years. METHODS: In this observational study, we conducted follow-up assessments of 64 patients with first-episode psychosis an average of 25 months after they began antipsychotic treatment. Patients were initially randomized to receive haloperidol or olanzapine, but treatment after the acute hospitalization period was not controlled. Regression analyses were used to determine whether early improvement on the Brief Psychiatric Rating Scale at 2 or 3 weeks predicted longer term improvement at follow-up. We conducted secondary analyses to determine whether early response could predict extrapyramidal side effects at follow-up. RESULTS: Early response to haloperidol at 2 weeks predicted Brief Psychiatric Rating Scale improvement on longer term follow-up (p = .002). Longer term improvement was not predicted by early response to olanzapine at 2 weeks (p = .726) or 3 weeks (p = .541). Rates of extrapyramidal side effects did not differ between treatment groups and were not predicted by early response. CONCLUSION: These results demonstrate the long-term prognostic value of early haloperidol response. The predictive value of early olanzapine response may be less robust.

The Relationship Between Early Haloperidol Response and Associated Extrapyramidal Side Effects.

BACKGROUND: Early response to antipsychotic medication within 2 weeks of initiating treatment can predict psychiatric outcomes. However, it is unclear whether early response is also predictive of extrapyramidal side effects (EPSs) associated with antipsychotic medications. METHODS: In this study, we investigated 136 consecutive antipsychotic-naive, first-episode psychosis patients naturalistically treated with haloperidol. Patients were assessed at baseline and weekly after treatment initiation using the Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale. Dystonia, parkinsonism, akathisia, and dyskinesia were also assessed weekly using standardized rating scales. Regression analyses were used to determine whether early response at week 2 of treatment predicted the incidence of EPS at any point during hospitalization. A secondary analysis was conducted to determine whether early response continued to predict EPS in patients who experienced no EPS within the first 2 weeks of treatment. RESULTS: The analyses demonstrated that greater Brief Psychiatric Rating Scale percent improvement at week 2 predicted a decreased risk of EPSs (P = 0.004), even in patients who did not show any EPSs within the first 2 weeks of treatment (P = 0.005). For specific EPS, early response predicted decreased incidences of parkinsonism (P = 0.028) and dyskinesia (P = 0.025), but not akathisia or dystonia. Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale improvement at week 2 did not predict EPSs. In addition, EPSs were not predicted by the maximum antipsychotic dose received during hospitalization. CONCLUSIONS: These results indicate that early antipsychotic response is valuable not only for predicting psychiatric outcomes, but also for predicting the risk of EPSs.

The predictive value of early treatment response in antipsychotic-naive patients with first-episode psychosis: Haloperidol versus olanzapine.

Early antipsychotic response predicts outcomes for psychotic patients, but recent evidence suggests that this may not be true for patients treated with olanzapine. In this study, we assessed the predictive value of early response to olanzapine or haloperidol in 75 antipsychotic-naive, first-episode psychosis inpatients. Patients were assessed weekly using the Brief Psychiatric Rating Scale (BPRS), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), and Young Mania Rating Scale (YMRS). Regression analyses were used to determine whether improvement at week 2 or week 3 predicted improvement at hospital discharge. The majority of patients in both groups experienced a decrease in symptom severity of ≥50% at week 2. In the haloperidol group, week 2 improvement predicted improvement at discharge for all measures except the HAM-A. In the olanzapine group, week 2 improvement only predicted improvement at discharge for HAM-D scores. However, week 3 improvement in the olanzapine group predicted improvement at discharge for all measures except the HAM-A. Olanzapine non-responders at week 3 (but not week 2) benefited from having olanzapine switched to another antipsychotic. These results suggest that a 2 week trial of haloperidol is sufficient to predict treatment outcomes, while a 3 week trial is required for olanzapine.

Catatonia: Our current understanding of its diagnosis, treatment and pathophysiology.

Catatonia is a psychomotor syndrome that has been reported to occur in more than 10% of patients with acute psychiatric illnesses. Two subtypes of the syndrome have been identified. Catatonia of the retarded type is characterized by immobility, mutism, staring, rigidity, and a host of other clinical signs. Excited catatonia is a less common presentation in which patients develop prolonged periods of psychomotor agitation. Once thought to be a subtype of schizophrenia, catatonia is now recognized to occur with a broad spectrum of medical and psychiatric illnesses, particularly affective disorders. In many cases, the catatonia must be treated before any underlying conditions can be accurately diagnosed. Most patients with the syndrome respond rapidly to low-dose benzodiazepines, but electroconvulsive therapy is occasionally required. Patients with longstanding catatonia or a diagnosis of schizophrenia may be less likely to respond. The pathobiology of catatonia is poorly understood, although abnormalities in gamma-aminobutyric acid and glutamate signaling have been suggested as causative factors. Because catatonia is common, highly treatable, and associated with significant morbidity and mortality if left untreated, physicians should maintain a high level of suspicion for this complex clinical syndrome. Since 1989, we have systematically assessed patients presenting to our psychiatry service with signs of retarded catatonia. In this paper, we present a review of the current literature on catatonia along with findings from the 220 cases we have assessed and treated.

Cushing Disease Presenting as Primary Psychiatric Illness: A Case Report and Literature Review.

We report the case of a woman with long-standing refractory depression and psychotic features who was eventually diagnosed with Cushing disease. After surgical treatment of a pituitary adenoma, she experienced gradual psychiatric recovery and was eventually able to discontinue all psychotropic medication. We review the psychiatric components of Cushing disease, implications of psychiatric illnesses for the treatment and prognosis of Cushing disease, and potential pathophysiological mechanisms linking glucocorticoid excess to psychiatric illness.