The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without any observable adverse effects. Moreover, recent results from an open label clinical study suggested that daily oral dosing with CuATSM slows disease progression in patients with both sporadic and familial ALS, providing encouraging support for CuATSM in the treatment of ALS. Here, we assessed CuATSM in high copy SOD1G93A mice on the congenic C57BL/6 background, treating at 100 mg/kg/day by gavage, starting at 70 days of age. This dose in this specific model has not been assessed previously. Unexpectedly, we report a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3–51 days of treatment. Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day. At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates. This work provides the first evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1G93A mice on a congenic C57BL/6 background. Furthermore, results from the 100 mg/kg/day phase of the study support dose escalation determination of tolerability as a prudent step when assessing treatments in previously unassessed models or genetic backgrounds.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition associated with significant psychosocial comorbidity. To date, the relationship between HS and sexual dysfunction has not been assessed through meta‐analysis. A systematic review was performed by OVID Medline, EMBASE, Cochrane Central, PsycINFO via EBSCO, Web of Science, and LILACS. Original English language studies assessing HS and sexual function published prior to April 2020 were screened. Scores from the Female Sexual Function Index (FSFI), International Index of Erectile Function (IIEF), Arizona Sexual Experiences Scale (ASEX), Frankfurt Self‐Concept Scale for Sexuality (FKKS SEX), and Dermatology Life Quality Index (DLQI) were analyzed. Sixteen studies met inclusion criteria, and nine were eligible for meta‐analysis. Pooled mean FSFI score for female HS patients met criteria for sexual dysfunction (mean = 20.32, P < 0.001). Females with HS reported worse FSFI scores than controls (pooled mean difference = −5.704, P = 0.003, I2=0). Mean IIEF score among males with HS was 47.96 (P < 0.001). Males with HS also reported worse IIEF scores than controls (pooled mean difference = −18.77, P = 0.00, I2 = 0). Females with HS performed worse on sexual function inventories than males with HS (SMD = −0.72, P = 0.009, I2 = 0). Both male and female HS patients reported significantly more sexual impairment than same‐sex controls. Female HS patients also experience more sexual impairment than males and on average meet criteria for sexual dysfunction (FSFI <26.55). Clinicians should be aware that their patients with HS, especially females, may be suffering from sexual dysfunction and treated them appropriately.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. Abnormal accumulation of misfolded and aggregated proteins in the soma of motor neurons is one of the main pathological hallmarks of ALS. Hence, reducing the burden of misfolded protein in motor neurons has emerged as a promising therapeutic approach to control the disease. Antisense oligonucleotides (ASOs) carry the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, the extremely poor blood-brain barrier (BBB) penetration of ASOs and invasiveness of current intrathecal delivery methods, warrant the development of alternative strategies for the delivery of ASOs to the central nervous system (CNS). In the current study, we report the effective delivery of a next-generation SOD1 ASO (Tofersen) into the brain of mice using calcium phosphate lipid nanoparticles following systemic delivery. Most importantly, for the first time, we demonstrate the superior capability of transcranial focused ultrasound (FUS) with intravenously administered microbubbles to significantly improve the delivery of ASO-loaded nanoparticles into the mouse brain compared to control mice receiving FUS without microbubbles. Histological examination in combination with contrast enhanced MRI suggests that the opening of the BBB in this context is transient and without evidence of any perturbation in the neural micro environment, parenchymal injury or necrosis indicating the treatment is well tolerated. Further in vivo evaluation of this strategy could lead to the development of a promising new approach for therapeutic delivery to treat ALS in patients.

How we imagine our place within the structure of sociotechnical-human relationships—specifically, in domains of life affected by data-analytics and the probabilistic bets institutions and people in power make on the future of our credit worthiness, political leanings, shopping habits etc.—is our “algorithmic imagination.” The purpose of this panel is to explore the “algorithmic imagination” as it manifests in particular scholarly, historical, socio-cultural, and technical contexts. The panelists prioritize how social actors, situated in distinct settings, go about constructing an “algorithmic imagination” in conversation/opposition with how computational systems have “imagined” them; they will also reflect critically and self-reflexively on the implications of an algorithmic imagination, so conceived. Collectively, the panelists demure from monolithic understandings of the “algorithmic imagination” while also embracing algorithmic intersectionality. The primary contention of this panel is that the ways in which algorithms have been “thought,” or imagined, have made it difficult to conceive of practicable strategies for transforming algorithmic cultures and, indeed, for delinking them from both state and corporate control. The panel, thus, makes three primary contributions. First, we situate, define, and distinguish the concept, “algorithmic imagination.” Second, the panel provides analyses of key facets of the algorithmic imagination, in specific historical settings and life-worlds defined by intersectionality. Lastly, it aims to contribute, however provisionally, to a political theory that recognizes the deterministic power of computational systems but rejects the notion that power is inherently democratic or monolithically insurmountable.

CuATSM has repeatedly demonstrated to be therapeutically effective in SOD1 mouse models of amyotrophic lateral sclerosis (ALS), leading to current clinical trials. CuATSM acts to stabilize ALS-associated mutant SOD1 protein by supplying copper. However, in vitro work has demonstrated that CuATSM is only therapeutic for wild-type-like SOD1 mutants, not metalbinding-region mutants, suggesting that CuATSM may have genotype-specific effects. Furthermore, relatively high doses of CuATSM have been shown to produce adverse events in humans and mice. Here, we investigated the genotype-specific therapeutic window of CuATSM. NSC-34 cells transiently expressing copperbinding or non-binding mutations of SOD1 were treated with a broad range of CuATSM concentrations and examined for survival via time-lapse microscopy. Determination of the no-observed-adverse-effect level and the LC 50 suggest that CuATSM-associated toxicity is dependent on the amount of copper-depleted SOD1 available as well as the mutant's ability to bind copper. Our results suggest that the particular variant of SOD1 mutant is crucial in not only determining the level of efficacy achieved but also potential adverse events.

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