Deep reinforcement learning in chemistry: A review.

Reinforcement learning (RL) has been applied to various domains in computational chemistry and has found wide-spread success. In this review, we first motivate the application of RL to chemistry and list some broad application domains, for example, molecule generation, geometry optimization, and retrosynthetic pathway search. We set up some of the formalism associated with reinforcement learning that should help the reader translate their chemistry problems into a form where RL can be used to solve them. We then discuss the solution formulations and algorithms proposed in recent literature for these problems, the advantages of one over the other, together with the necessary details of the RL algorithms they employ. This article should help the reader understand the state of RL applications in chemistry, learn about some relevant actively-researched open problems, gain insight into how RL can be used to approach them and hopefully inspire innovative RL applications in Chemistry.

Patient and health-care provider experience of a person-centred, multidisciplinary, psychosocial support and harm reduction programme for patients with harmful use of alcohol and drug-resistant tuberculosis in Minsk, Belarus.

BACKGROUND: Tuberculosis (TB) often concentrates in groups of people with complex health and social issues, including alcohol use disorders (AUD). Risk of TB, and poor TB treatment outcomes, are substantially elevated in people who have AUD. Médecins sans Frontières and the Belarus Ministry of Health have worked to improve treatment adherence in patients with multi-drug or rifampicin resistant (MDR/RR)-TB and harmful use of alcohol. In 2016, a person-centred, multidisciplinary, psychosocial support and harm reduction programme delivered by TB doctors, counsellors, psychiatrists, health-educators, and social workers was initiated. In 2020, we described patient and provider experiences within the programme as part of a wider evaluation. METHODS: We recruited 12 patients and 20 health-care workers, using purposive sampling, for in-depth individual interviews and focus group discussions. We used a participant-led, flexible, exploratory approach, enabling participants and the interviewer to shape topics of conversation. Qualitative data were coded manually and analysed thematically. As part of the analysis process, identified themes were shared with health-care worker participants to enable their reflections to be incorporated into the findings. RESULTS: Key themes related to the patients' and practitioners experience of having and treating MDRTB with associated complex health and social issues were: fragility and despair and guidance, trust and health. Prejudice and marginalisation were global to both themes. Counsellors and other health workers built a trusting relationship with patients, enabling guidance through a multi-disciplinary approach, which supported patients to achieve their vision of health. This guidance was achieved by a team of social workers, counsellors, doctors and health-educators who provided professional and individualised help for patients' illnesses, personal or interpersonal problems, administrative tasks, and job searches. CONCLUSIONS: Patients with MDR/RR-TB and harmful use of alcohol faced complex issues during treatment. Our findings describe how person-centred, multi-disciplinary, psychosocial support helped patients in this setting to cope with these challenges and complete the treatment programme. We recommend that these findings are used to: i) inform programmatic changes to further boost the person-centred care nature of this program; and ii) advocate for this type of person-centred care approach to be rolled out across Belarus, and in contexts that face similar challenges.

Diagnosis and management of pemphigus: Recommendations of an international panel of experts.

BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus.

Patients with pemphigus vulgaris (PV) harbor antibodies reactive against self-antigens expressed at the surface of keratinocytes, primarily desmoglein (Dsg) 3 and, to a lesser extent, Dsg1. Conventionally, only antibodies targeting these molecules have been thought to contribute to disease pathogenesis. This notion has been challenged by a growing pool of evidence that suggests that antibodies toward additional targets may play a role in disease. The aims of this study were to (i) establish high-throughput protein microarray technology as a method to investigate traditional and putative autoantibodies (autoAbs) in PV and (ii) use multiplexed protein array technology to define the scope and specificity of the autoAb response in PV. Our analysis demonstrated significant IgG reactivity in patients with PV toward the muscarinic acetylcholine receptor subtypes 3, 4, and 5 as well as thyroid peroxidase. Furthermore, we found that healthy first- and second-degree relatives of patients with PV express autoAbs toward desmoglein and non-Dsg targets. Our analysis also identified genetic elements, particularly HLA, as key drivers of autoAb expression. Finally, we show that patients with PV exhibit significantly reduced IgM reactivity toward disease-associated antigens relative to controls. The use of protein microarrays to profile the autoAb response in PV advanced the current understanding of disease and provided insight into the complex relationship between genetics and disease development.

Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets.

BACKGROUND: Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. METHODS: We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. RESULTS: Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. CONCLUSIONS: We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address a major gap in knowledge regarding the systemic changes underlying skin-specific manifestation of vitiligo. Several transcriptional "hot spots" observed in both environments offer prioritized targets for identifying disease risk genes. Finally, within the transcriptional framework of VL, we identify five novel molecules (STAT1, PRKCD, PTPN6, MYC and FGFR2) that lend themselves to being targeted by drugs for future potential VL-therapy.

Six-Month Response to Delamanid Treatment in MDR TB Patients.

Delamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from 7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.

Genomic Investigation of Lupus in the Skin.

Lupus erythematosus is a chronic autoimmune disorder with a protean clinical manifestation affecting virtually every organ including skin, with tremendous variation between patients. This makes it vital to stratify patients on a molecular basis. We used gene microarray technology for large-scale screening combined with bioinformatics to investigate global patterns of gene expression in cutaneous lupus erythematosus to allow further insights into disease heterogeneity. Unbiased clustering exposed a clear separation between cutaneous lupus erythematosus skin and blood samples. Pathway-based analyses of the differentially expressed genes from sample groups within skin and blood showed prominent apoptosis and interferon response signals. Given their well-known role in systemic lupus, the two processes are potentially critical to cutaneous lupus erythematosus as well. We found both coincident and distinct features between systemic lupus and cutaneous lupus erythematosus, as well as several pathways and processes that are specific to the cutaneous disease that offer potential therapeutic choices in the future. Finally, we identified shared cutaneous lupus erythematosus-skin and -blood transcriptional "hot spots" located on the genome that include several differentially expressed genes previously associated with the systemic disease. The differentially expressed genes included in the hot spots with no systemic lupus associations can potentially be targeted in future studies aimed at identifying risk genes related to cutaneous disease.

Longitudinal Tracking of Autoantibody Levels in a Pemphigus Vulgaris Patient: Support for a Role of Anti-Desmoglein 1 Autoantibodies as Predictors of Disease Progression.

Anti-desmoglein (Dsg) 1 and -Dsg3 antibody titers have an established role in the diagnosis of the autoimmune blistering skin disease pemphigus vulgaris (PV). However, their usefulness for disease monitoring has been controversial. A recent large-scale immunoprofiling study by our group indicated that anti-Dsg1 levels may be a better predictor of disease activity than anti-Dsg3 levels, with declining levels predicting progression from active phase of disease to early remission, irrespective of lesional subtypes. Here, we report an illustrative case of a PV patient with mucocutaneous disease that was followed longitudinally for >2.5 years clinically and by serum serology. Autoantibody levels directed against both Dsg1 and -3 showed a moderate correlation with PDAI scores, supporting a correlation of Dsg1 and 3 levels with disease severity. However, while both anti-Dsg3 and -Dsg1 antibody levels demonstrated a steady parallel decline after initiation of rituximab therapy, only anti-Dsg1 antibodies fell to levels below detectability with the progression to remission, while anti-Dsg3 levels remained elevated. This case illustrates the potential key role and clinical benefit of tracking anti-Dsg1 levels to monitor and conceivably predict disease activity in patients with PV. J Drugs Dermatol. 2017;16(2):135-139..

Monopathogenic vs multipathogenic explanations of pemphigus pathophysiology.

This viewpoint highlights major, partly controversial concepts about the pathogenesis of pemphigus. The monopathogenic theory explains intra-epidermal blistering through the "desmoglein (Dsg) compensation" hypothesis, according to which an antibody-dependent disabling of Dsg 1- and/or Dsg 3-mediated cell-cell attachments of keratinocytes (KCs) is sufficient to disrupt epidermal integrity and cause blistering. The multipathogenic theory explains intra-epidermal blistering through the "multiple hit" hypothesis stating that a simultaneous and synchronized inactivation of the physiological mechanisms regulating and/or mediating intercellular adhesion of KCs is necessary to disrupt epidermal integrity. The major premise for a multipathogenic theory is that a single type of autoantibody induces only reversible changes, so that affected KCs can recover due to a self-repair. The damage, however, becomes irreversible when the salvage pathway and/or other cell functions are altered by a partnering autoantibody and/or other pathogenic factors. Future studies are needed to (i) corroborate these findings, (ii) characterize in detail patient populations with non-Dsg-specific autoantibodies, and (iii) determine the extent of the contribution of non-Dsg antibodies in disease pathophysiology.

Rituximab Use in Pediatric Dermatology.

Rituximab, an anti CD20 monoclonal antibody leading to transitory B cell depletion, is used to treat a wide variety of immune system tumors and immune mediated diseases. While most of data supporting the efficacy and safety of rituximab in treating autoimmune patients is focused on the adult population, the utilization of rituximab (RTX) for a wide range of pediatric conditions is also increasing. While there are a number of published case reports, a comprehensive review of the various uses for rituximab in pediatric dermatology is lacking. To better assess the therapeutic role of rituximab in the management of skin disease in children, here we comprehensively document reported cases of use including details regarding specific treatment regimens, efficacy and safety profile. Evaluation of the data supports consideration for the initiation of rituximab at early time points in the treatment ladder, before certain diseases become refractory to conventional treatment.

J Drugs Dermatol. 2016;15(7):821-829.

Development of a disease registry for autoimmune bullous diseases: initial analysis of the pemphigus vulgaris subset.

Pemphigus vulgaris (PV) is a rare, potentially life threatening, autoimmune blistering skin disease. The International Pemphigus and Pemphigoid Foundation (IPPF) has recently developed a disease registry with the aim to enhance our understanding of autoimmune bullous diseases with the long-term goal of acquiring information to improve patient care. Patients were recruited to the IPPF disease registry through direct mail, e-mail, advertisements, and articles in the IPPF-quarterly, -website, -Facebook webpage, and IPPF Peer Health Coaches to complete a 38-question survey. We present here the initial analysis of detailed clinical information collected on 393 PV patients. We report previously unrecognized gender differences in terms of lesion location, autoimmune comorbidity, and delay in diagnosis. The IPPF disease registry serves as a useful resource and guide for future clinical investigation.

Evaluation of a Newly Available ELISA for Envoplakin Autoantibodies for the Diagnosis of Paraneoplastic Pemphigus.

IMPORTANCE: Paraneoplastic pemphigus (PNP) is routinely diagnosed by the presence of autoantibodies for desmoplakin by indirect immunofluorescence (IIF) on rat bladder epithelium (RBE). IIF on RBE has recently been found to be positive in select cases of other blistering disorders. A new ELISA that detects envoplakin autoantibodies has recently been developed for the diagnosis of PNP. In this study, we measure the specificity of IIF on RBE and compare it to the new ELISA. OBSERVATIONS: We measured the specificity of IIF on RBE to be 86% which is on the lower end of the previously reported specificity of 83% to 98.9%. The ELISA for envoplakin autoantibodies has a technical sensitivity of 100%, diagnostic sensitivity of 83%, and specificity of 91%. CONCLUSIONS AND RELEVANCE: This ELISA for envoplakin autoantibodies is now commercially available and technically easier to perform then the immunoblot. We recommend that this new ELISA serves as a confirmatory test in cases of a positive IIF on RBE given its higher specificity.

Reproducible Novel Transcriptional Differences Between Psoriatic Lesional and Non-Lesional Skin Show Increased Inflammation and Metabolism.

BACKGROUND: Psoriasis is a common but complex chronic inflammatory skin Disease. Array-based studies can help identify therapeutic targets. OBJECTIVE: To reproducibly assess single-gene transcriptional changes in psoriatic skin. METHODS: We evaluated 210 top candidate genes from a first psoriasis study group (population 1), and then confirmed differential expression in a second independent psoriasis study group (population 2). RESULTS: One hundred and thirty-eight differentially expressed genes were replicated in the 2 studies, of which 57 have not previously been reported as associated with psoriasis. This is significantly greater than the 10 expected false positives. Lesional skin vs uninvolved areas showed inflammatory and cell regulation changes. CONCLUSION: Previously undescribed psoriasis-associated genes revealed in this study may provide potential future targets for development and assessment of novel therapeutic agents for psoriasis.

Cellular level robotic surgery: Nanodissection of intermediate filaments in live keratinocytes.

We present the nanosurgery on the cytoskeleton of live cells using AFM based nanorobotics to achieve adhesiolysis and mimic the effect of pathophysiological modulation of intercellular adhesion. Nanosurgery successfully severs the intermediate filament bundles and disrupts cell-cell adhesion similar to the desmosomal protein disassembly in autoimmune disease, or the cationic modulation of desmosome formation. Our nanomechanical analysis revealed that adhesion loss results in a decrease in cellular stiffness in both cases of biochemical modulation of the desmosome junctions and mechanical disruption of intercellular adhesion, supporting the notion that intercellular adhesion through intermediate filaments anchors the cell structure as focal adhesion does and that intermediate filaments are integral components in cell mechanical integrity. The surgical process could potentially help reveal the mechanism of autoimmune pathology-induced cell-cell adhesion loss as well as its related pathways that lead to cell apoptosis.

Non-melanoma skin cancer and NSAID use in women with a history of skin cancer in the Women's Health Initiative.

OBJECTIVE: Evidence for the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on non-melanoma skin cancer (NMSC) risk is inconsistent. We prospectively examined whether regular, inconsistent, or no/low-use of NSAIDs is associated with lower NMSC risk among 54,728 postmenopausal Caucasian women in the Women's Health Initiative Observational Study enrolled between 1993 and 1998. METHODS: Logistic regression models were used to assess odds of NMSC after adjusting for skin type, sun exposure history and indication for NSAID use. RESULTS: There were 7652 incident cases of NMSC (median follow-up: 6.9years). There was no association between regular NSAID-use and NMSC risk relative to no/low-users. However, in a subgroup analysis of 5325 women with a history of skin cancer (incident NMSC: 1897), odds of NMSC were lower among regular NSAID users whether <5years (OR 0.82, 95% CI: 0.70-0.95) or ≥5years (OR 0.82, 95% CI: 0.69-0.98) of use compared to no/low-users. Inconsistent NSAID use and acetaminophen use were not associated with NMSC risk. CONCLUSION: Overall, NSAID use was not associated with NMSC risk. However, in women with a history of skin cancer, regular NSAID use was associated with 18% lower odds of NMSC. Future studies on potential chemopreventative effects of NSAIDs should focus on subjects with prior history of NMSC.

Gender-based variability in disease presentation in pemphigus vulgaris.

Pemphigus vulgaris is a chronic autoimmune blistering disorder of the skin. As with many autoimmune diseases, a female predominance in pemphigus vulgaris is well established. The genetic and physiological basis for this gender bias is not well understood. Moreover, it is unclear whether the affect of gender extends beyond disease susceptibility to influence disease presentation. To address this issue, we performed a comprehensive analysis of 72 male and 125 female pemphigus vulgaris patients across a set of defined demographic (HLA type, ethnicity) and clinical (age at disease onset, anti-desmoglein antibody levels, site of lesions, and history of autoimmune disease) factors. We find that male patients are more likely to present with disease onset before age 40 than females. Additionally, we find that males have increased cutaneous involvement and display greater co-expression of anti-Dsg1 and anti-Dsg3 antibodies, while females tend to have mucosal predominance and stronger personal and family histories of autoimmunity. We do not find any differences in the distribution of HLA type or ethnicity between male and female pemphigus vulgaris patients. Our findings establish that gender does influence disease presentation in pemphigus vulgaris, supporting a role for genetic and hormonal factors in immune dysregulation and perpetuation of the autoimmune phenotype.

Gender differences in alopecia areata.

Alopecia areata (AA) is a common, non-scarring, autoimmune hair-loss disorder with a complex genetic and environmental etiology. A higher incidence rate of AA in the female population is well described. It is unclear why females are more likely to be diagnosed with AA and what, if any, differences in disease phenotype exist between males and females. The identification of gender specific characteristics of disease may help clinical management and patient education in cases of AA. Accordingly, we recruited 481 North-American Caucasian AA patients (336 female, 145 male) to assess age of onset, autoimmune and atopic co-morbidity, nail involvement, family history of AA and autoimmune disease, and disease subtype. There was a female predominance (female to male ratio 2.3:1) in this AA study population. We found that male AA patients are more likely to be diagnosed in childhood (age <10 years, P= 0.067) and have a family history of AA (P= 0.004). On the other hand, female AA patients are more likely to be diagnosed in adolescence (age 10-20 years, P= 0.083), have co-morbid nail involvement (P= 0.0257), and have concomitant autoimmune disease (P= 0.014), particularly thyroid disease (P= 0.058). The clinical implications of disease heterogeneity between males and females remains to be determined.

Desmosomal Cadherin Tension Loss in Pemphigus Vulgaris Mediated by the Inhibition of Active RhoA at Cell-Cell Adhesions.

Binding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in the blistering disorder pemphigus vulgaris (PV). After the initial disassembly of desmosomes, cell-cell adhesions actively remodel in association with the cytoskeleton and focal adhesions. Growing evidence highlights the role of adhesion mechanics and mechanotransduction at cell-cell adhesions in this remodeling process, as their active participation may direct autoimmune pathogenicity. However, a large part of the biophysical transformations after antibody binding remains underexplored. Specifically, it is unclear how tension in desmosomes and cell-cell adhesions changes in response to antibodies, and how the altered tensional states translate to cellular responses. Here, we showed a tension loss at Dsg3 using fluorescence resonance energy transfer (FRET)-based tension sensors, a tension loss at the entire cell-cell adhesion, and a potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions after PV antibody binding. Further, our data indicate that this tension loss is mediated by the inhibition of RhoA at cell-cell contacts, and the extent of RhoA inhibition may be crucial in determining the severity of pathogenicity among different PV antibodies. More importantly, this tension loss can be partially restored by altering actomyosin based cell contractility. Collectively, these findings provide previously unattainable details in our understanding of the mechanisms that govern cell-cell interactions under physiological and autoimmune conditions, which may open the window to entirely new therapeutics aimed at restoring physiological balance to tension dynamics that regulates the maintenance of cell-cell adhesion.

Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the Women's Health Initiative.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with decreased risk of gastric, colorectal, and breast cancer. However, the impact of NSAIDs on the risk of melanoma has been inconsistent. The authors evaluated the association between NSAID use and cutaneous melanoma risk in the Women's Health Initiative (WHI) Observational Study (OS). METHODS: At study entry, use of aspirin (acetylsalicylic acid [ASA]) and nonaspirin NSAIDs was assessed among 59,806 postmenopausal Caucasian women ages 50 to 79 years. Cox proportional hazards models were constructed after adjusting for participant skin type, sun exposure history, and medical indications for NSAID use among other confounders. RESULTS: During a median follow-up of 12 years, 548 incident melanomas were confirmed by medical review. Women who used ASA had a 21% lower risk of melanoma (hazard ratio, 0.79; 95% confidence interval, 0.63-0.98) relative to nonusers. Increased duration of ASA use (<1 year, 1-4 years, and ≥ 5 years) was associated with an 11% lower risk of melanoma for each categorical increase (Ptrend = .01), and women with ≥ 5 years of use had a 30% lower melanoma risk (hazard ratio, 0.70; 95% confidence interval, 0.55-0.94). In contrast, use of non-ASA NSAIDs and acetaminophen were not associated with melanoma risk. CONCLUSIONS: Postmenopausal women who used ASA had a significantly lower risk of melanoma, and longer duration of ASA use was associated with greater protection. Although this study was limited by the observational design and self-report of NSAID use, the findings suggest that ASA may have a chemopreventive effect against the development of melanoma and warrant further clinical investigation.