Tears are easy to collect, repeatable, and reflect the state of the corneal surface—attributes that make them attractive for bedside monitoring after surgery or injury. We performed a cross-species meta-analysis of tear proteomes from patients undergoing photorefractive keratectomy (PRK) and from mice after mechanical epithelial abrasion to define molecular programs that are both conserved and clinically actionable. Roughly one-third of the injury response was shared between species, centering on innate immune activation (complement/acute phase), epithelial migration and cytoskeletal remodeling, and a calibrated suppression of proteolysis. From this overlap we distilled a small, secreted tear panel that stages injury and early resolution in both species: transferrin and hemopexin (iron/heme scavenging), albumin (vascular leak), apolipoprotein A-I (barrier lipid transport), and the coagulation modulators kininogen-1 and α2-antiplasmin (protease/fibrinolysis control). This panel rises at the first post-injury sampling (D0 in humans; 6–12 h in mice) and trends toward baseline during recovery (D3 in humans; ∼24 h in mice), providing a practical kinetic signature for clinical decision-making. Standardized sampling at D0/D3 can therefore quantify acute damage and early healing, enable pharmacodynamic readouts for anti-inflammatory or barrier-stabilizing therapies, and support risk stratification after epithelial procedures. Species-specific differences (human: secretory/immune surveillance; mouse: mitochondrial/metabolic reboot) clarify which preclinical signals are most likely to translate. Together, these findings establish a conserved tear blueprint of corneal repair and nominate a minimal, deployable biomarker set to accelerate clinical monitoring and therapeutic development in ocular surface disease.

Corneal stromal bioprinting requires bioinks that combine optical transparency, structural stability, printability, and a biologically instructive microenvironment capable of maintaining keratocyte quiescence. Here, we report the development of GAME, a composite bioink integrating gelatin methacryloyl (GelMA) with murine amniotic membrane extract (AME), and comprehensively characterize its biochemical composition, physicochemical properties, bioprintability, and ability to support human induced pluripotent stem cell-derived corneal stromal keratocyte-like cells (hiPSC-CSKs).Quantitative proteomic analysis demonstrated that AME possesses a conserved proteome enriched in collagens, small leucine-rich proteoglycans, fibronectin, nidogens, and growth factor-associated regulatory proteins, with compositional consistency across independently prepared batches. Incorporation of AME into GelMA generated a transparent hydrogel with an interconnected porous microarchitecture, sustained structural stability, and elastic-dominant viscoelastic behavior within the range reported to support corneal stromal cell function. The GAME bioink also tolerated surgical suturing and enabled reproducible extrusion bioprinting of corneal-scale constructs with high printability and geometric fidelity following photocrosslinking. Bioprinted hiPSC-CSKs embedded in GAME exhibited high viability throughout 21 days of culture while maintaining expression of the keratocyte-associated markers keratocan, ALDH3A1, and CD34, with minimal α-smooth muscle actin (α-SMA) expression, indicating preservation of a quiescent, non-fibrotic stromal phenotype after bioprinting.These findings establish GAME as a compositionally defined, mechanically robust, and cytocompatible bioink for corneal stromal tissue engineering. More broadly, this work demonstrates that proteomic characterization of biologically derived supplements provides a rational framework for the development of reproducible and biologically instructive bioinks for corneal tissue engineering.

PURPOSE. The purpose of this study was to determine how Pax6 haploinsufficiency alters epithelial maturation, immune balance, sensory innervation, and lacrimal function across the ocular surface, and how these defects affect corneal repair. METHODS. Pax6tm1Ued mice crossed with CMV-Cre were used to generate Pax6+/- animals. Ocular-surface maturation, epithelial organization, immune infiltration, and sensory innervation were assessed by whole-cornea immunostaining. Standardized corneal abrasion was used to evaluate epithelial and neural repair. Corneal RNA sequencing and tear-film proteomics were performed in both sexes to define genotype-and sex-dependent molecular programs. RESULTS. Pax6+/- mice showed heterogeneous ocular phenotypes, delayed eyelid opening, reduced KRT12, persistent central KRT14 expansion, and a sustained deficit in central proliferation. Immune infiltration was elevated from eyelid opening onward. Corneal nerves were markedly reduced and disorganized, with decreased sensitivity despite minimal trigeminal transcriptional changes. Transcriptomics revealed sex-specific gene-expression patterns converging on inflammation and extracellular-matrix remodeling. After abrasion, closure rates were preserved, but Pax6+/- corneas failed to fully restore normal epithelial identity, territorial patterning, or nerve density. Tear secretion was impaired in a sex-dependent manner, and proteomics showed depletion of structural and antioxidant proteins with exaggerated inflammatory and keratinization responses after injury. CONCLUSIONS. Our model showed that Pax6 haploinsufficiency is associated with epithelial dysmaturation, chronic inflammation, denervation, defective repair, and sex-modulated lacrimal dysfunction. These integrated abnormalities mirror key features of AAK and underline inflammation, neurotrophic support, and tear-film quality as therapeutic targets.

Congenital aniridia is a rare disorder presenting as a panocular malformation with variable severity, often complicated by progressive keratopathy. The purpose of this study was to characterise the tear-film proteome in adults with PAX6-related congenital aniridia and to identify dysregulated pathways linked to aniridia associated keratopathy (AAK). Tears were obtained with Schirmer strips from four genetically confirmed patients and four age- and sex-matched healthy volunteers. Peptides prepared with the single-pot, solid-phase–enhanced (SP3) protocol were analysed by data-independent nanoLC-MS/MS. Proteins were identified with a false discovery rate (FDR) <1

Abstract Purpose Pitx2-associated developmental glaucoma is characterized by anterior segment dysgenesis, ocular hypertension, and optic neuropathy. Its consequences for corneal sensory innervation remain poorly understood. We investigated whether this disease alters corneal nerve structure and sensory function in a sex-dependent manner. Methods Male and female Pitx2 egl1/egl1 and Pitx2 +/+ mice were examined at 1 and 3 months. Ocular phenotyping included intraocular pressure, fundus imaging, visual evoked potentials, and optic nerve ultrastructure. RNA sequencing of corneas and trigeminal ganglia was performed at 3 months. Corneal innervation was assessed by βIII-tubulin immunofluorescence and volumetric quantification of nerve fibers. Corneal sensitivity was measured using Von Frey filaments. Results Pitx2 egl1/egl1 mice developed progressive ocular hypertension, fundus abnormalities, reduced visual evoked potential amplitudes, and optic nerve degeneration, supporting the model as early-onset glaucoma. Baseline sex-related transcriptional differences were limited in both cornea and trigeminal ganglia. In contrast, Pitx2 mutation induced sex-dependent molecular responses. Female corneas showed broader transcriptional changes enriched in inflammatory, stress-response, and tissue-remodeling pathways, whereas male corneas showed a more restricted response involving metabolic and homeostatic processes. Similar sex divergence was observed in trigeminal ganglia. Corneal nerve fiber volume was reduced in both sexes at 3 months but not at 1 month, whereas reduced sensitivity was detected only in mutant males. Conclusions This study identifies sexual dimorphism as a component of Pitx2-associated developmental glaucoma. Furthermore, our findings suggest that glaucoma affects the corneal sensory system beyond optic nerve pathology, highlighting a potentially overlooked dimension of disease relevant to ocular surface monitoring and patient management. Highlights Disruption of the cornea–trigeminal ganglion axis with coordinated molecular and functional alterations in Pitx2-associated early-onset glaucoma Sex-dependent modifications in both cornea and trigeminal ganglion responses to early-onset glaucoma Progressive corneal neurodegeneration in early-onset glaucoma

The cornea, the transparent outermost layer of the eye, possesses exceptional wound healing capabilities essential for vision preservation. The complexity of the corneal microenvironment is central to its rapid healing; however, the molecular mechanisms orchestrating this process remain poorly defined, limiting therapeutic advancements. Here, we elucidate the extensive remodeling of the corneal molecular landscape following physical injury. Multi-omics analyses, including transcriptomic, epitranscriptomic, and proteomic profiling, uncover significant induction of epithelial cell plasticity driving wound closure. Moreover, lacrimal gland ablation further suppresses Pax6 expression, highlighting its regulatory role. Our multi-omic approach uniquely reveals bilateral remodeling of the molecular environment, a phenomenon constrained by an intact tear film. Collectively, our findings identify novel molecular factors critical to corneal healing, significantly advancing the understanding of epithelial plasticity. These insights will facilitate the translation of cell plasticity research into innovative strategies for tissue and organ regeneration. ### Competing Interest Statement The authors have declared no competing interest.

Purpose:To map time-resolved tear proteome changes during corneal epithelial wound healing after photorefractive keratectomy (PRK) and nominate tear-based biomarker panels with translational potential. Methods:Tears from 10 healthy adults were collected before PRK (Pre), ∼30-60 minutes after PRK (D0), and day 3 (D3) using Schirmer strips. Proteins were extracted (SP3), trypsin-digested, and analyzed by DIA on an Evosep One-timsTOF HT platform. DIA-NN (1% FDR) provided identification/quantification. Paired contrasts (Pre vs. D0; Pre vs. D3) defined differentially abundant proteins (adjusted P < 0.05; |fold change|≥2) for pathway enrichment. A stringent screen (adjusted P < 0.001; FC>2.5) and UniProt-based annotation distinguished secreted versus intracellular candidates. Results:Across 2025 identified proteins, 909 (∼45%) were significantly modulated. D0 tears showed an "injury/ECM" program (e.g., TGFBI, lumican, keratocan, fibrinogen chains, complement C8B, APOA1), whereas D3 shifted toward remodeling and epithelial polarity with regulated proteolysis (e.g., SERPINA3, MMP7, THBS1, MUC5B, CXCL17). A subset persisted across time points (e.g., A2M, haptoglobin, OLFML3). Intracellular signatures paralleled phase transitions: D0 was enriched for chromatin/DNA-repair and RNA-binding proteins (histones, XRCC5/Ku80, HNRNPs), whereas D3 highlighted transport/cytoskeletal factors linked to apical remodeling and fluid/ion handling (AQP5, NHERF1/EBP50, ANO1/TMEM16A, ACTN1, RDX). H6PD was elevated at both D0 and D3. Conclusions:Time-stamped, tear-accessible biomarker panels emerge from this analysis: early-injury (TGFBI, lumican/keratocan, fibrinogen/complement), sustained (A2M, haptoglobin, OLFML3), and late-remodeling/epithelial (SERPINA3, MMP7, THBS1, MUC5B, CXCL17), with complementary intracellular markers (AQP5/NHERF1/ANO1). These candidates may support perioperative monitoring, risk stratification (delayed closure, stromal haze), and phase-adapted therapy after PRK, warranting prospective clinical validation.

Neurotrophic keratitis (NK) is a rare, vision-threatening corneal disease characterized by impaired epithelial healing and frequent recurrence of defects. Amniotic membrane transplantation (AMT) is an established therapeutic option, but outcomes remain variable and predictors of failure are poorly defined. We aimed to identify clinical and systemic factors associated with recurrence following AMT using both classical statistics and machine learning approaches. We conducted a retrospective cohort study of 66 patients with NK who underwent AMT at a tertiary referral center between 2019 and 2025. The primary endpoint was post-AMT epithelial defect recurrence. The prespecified primary analysis was a multivariable logistic regression, complemented by exploratory machine learning approaches. Clinical, demographic, and ophthalmic variables were abstracted from medical records. All patients had complete outcome data; covariate-level missingness was minimal and handled with complete-case analyses. Associations with recurrence were examined using bivariate tests and multivariable regression; data structure was explored with principal component analysis (PCA) and hierarchical clustering; and predictive performance was additionally evaluated using random forest classifiers. Epithelial defect recurrence occurred in 46 patients (70

The tear film plays an essential role in corneal protection and regeneration following injury. Although the cornea is a structurally conserved organ across terrestrial vertebrates, the extent to which tear film mediated wound healing responses are evolutionarily conserved remains unclear. This study aimed to identify core and species-specific molecular pathways activated in the tear film during corneal wound healing in humans and mice. We conducted a meta analysis of tear proteomic datasets from human subjects undergoing photorefractive keratectomy (PRK) and mice subjected to mechanical corneal abrasion. Differentially expressed proteins were identified and subjected to Reactome and Gene Ontology (GO) enrichment analyses to determine conserved and divergent biological responses. Approximately one third of the tear film proteomic response to corneal injury was conserved across species. Shared upregulated pathways included complement activation, actin cytoskeletal remodeling, protein synthesis, and acute inflammatory responses. Simultaneously, pathways related to adaptive immunity, proteolysis, and general metabolism were consistently downregulated. Human specific responses were enriched in secretory pathways, vesicle trafficking, and immune surveillance, whereas murine specific responses highlighted mitochondrial activation, oxidative metabolism, and stress adaptation. These distinctions reflect species dependent physiological strategies in managing epithelial repair. Our findings reveal a conserved molecular framework that governs corneal wound healing across species, with notable species specific adaptations. This cross species comparison underscores the translational relevance of tear film analysis and supports the development of targeted therapies tailored to human specific wound healing mechanisms in ocular surface disease. ### Competing Interest Statement The authors have declared no competing interest.

The cornea, a transparent tissue critical for clear vision, is uniquely characterized by a dense network of peripheral sensory nerves. This innervation not only enables sensation but also provides vital trophic support, ensuring corneal health and integrity. Damage or loss of these peripheral nerves leads to neurotrophic keratitis (NK), a debilitating condition that disrupts corneal healing and function, ultimately threatening vision. Remarkably similar to other peripheral neuropathies, NK arises from various injuries, diseases, or surgical interventions, yet its underlying regenerative mechanisms remain poorly understood, limiting effective treatment options. In this study, we investigated how corneal nerves regenerate following two different types of clinically relevant injuries-axotomy (mimicking nerve damage during corneal transplantation) and epithelial abrasion (resembling superficial corneal surgery). We found that the type of injury distinctly influences both the structural and functional recovery of corneal nerves. Axotomy resulted in delayed nerve regeneration, significant disruption of epithelial cell homeostasis, and increased risk of severe corneal damage. Conversely, epithelial abrasion induced rapid but structurally abnormal nerve recovery. Furthermore, we identified specific molecular pathways activated differently depending on injury type. Our findings highlight the complexity of peripheral nerve regeneration, underscoring the necessity for targeted therapeutic strategies tailored to individual injury scenarios. By illuminating the variability in nerve recovery, our study provides valuable insights applicable not only to NK but potentially to a broader spectrum of peripheral neuropathies, paving the way for novel therapeutic interventions.

The cornea, a transparent tissue covering the eye, is essential for clear vision and represents the most densely innervated tissue in the body. Its extensive sensory innervation provides both sensory perception and crucial trophic support, maintaining corneal health and integrity. Disruption of corneal innervation leads to neurotrophic keratitis (NK), a pathological condition caused by ocular injury, surgical procedures, or underlying diseases. The limited understanding of NK pathophysiological mechanisms has hindered the development of innovative therapeutic approaches. In this study, we comparatively analyzed corneal innervation morphogenesis and regeneration across two clinically relevant injury models, highlighting both commonalities and differences among these contexts. Our results demonstrate that corneal nerve morphogenesis and maturation span approximately 13 weeks, from embryonic day 12 (E12) through three months of age. Additionally, we observed that the specification of distinct nerve fiber types coincided temporally with a significant enhancement in corneal sensitivity. Furthermore, we found that the type of innervation loss, either via axotomy or abrasion, differentially affected corneal sensitivity and epithelial cell homeostasis. Importantly, the regeneration mechanisms following injury were also distinctly dependent on the type of nerve damage sustained. Collectively, these findings underscore both the shared characteristics and unique aspects inherent in each NK model, highlighting the necessity for tailored therapeutic strategies specific to individual patterns of corneal innervation disruption. ### Competing Interest Statement The authors have declared no competing interest.

Rapid and efficient epithelial regeneration is fundamental for tissue homeostasis and proper function. As the outermost ocular structure, the cornea is transparent, multilayered, and vital for clear vision. Due to its exposed position, the cornea frequently undergoes various forms of injury affecting either the epithelium itself or its surrounding microenvironment, including corneal innervation and the tear film. Corneal abrasion, occurring commonly through trauma or as part of refractive surgical procedures, is typically viewed as a minor event since it usually resolves rapidly. Consequently, the cornea serves as an excellent model for studying epithelial wound healing. However, complications such as persistent epithelial defects or corneal opacity can develop, underscoring critical gaps in understanding the underlying molecular mechanisms. Utilizing a unilateral corneal abrasion mouse model, we conducted a comprehensive multi-omics analysis, integrating transcriptomics, proteomics, and epitranscriptomics, to dissect the dynamic molecular responses post-injury in both wounded and contralateral tissues. To elucidate the role of the tear film, we performed additional studies involving lacrimal gland ablation combined with corneal injury. We applied RNA sequencing to profile transcriptomic changes in corneal and lacrimal gland tissues, and mass spectrometry to study tear proteomics and epitranscriptomic modifications. We revealed a major modulation of the cornea transcriptome after abrasion, suggesting a regulation of pathways including JAK-STAT, Wnt and TGF-β, and a reduction of nucleoside modifications. The lacrimal gland transcriptome and tears proteome were also significantly affected. Plus, we highlighted a bilateralization, both in the cornea transcriptome and tears proteome. In the tear-deficient conditions, the wound closure rate and molecular responses were altered, and the bilateralization was impacted, with an increased matrix remodeling and a modulation of keratins expression. Our multi-omics analyses revealed extensive epithelial cellular plasticity as a key mechanism driving rapid wound closure, characterized by profound remodeling of transcriptional networks and RNA modifications. Importantly, we uncovered a previously underappreciated role of the lacrimal gland and tear film in mediating bilateral molecular responses following unilateral injury, emphasizing their pivotal roles in tissue regeneration. Additionally, we identified novel regulatory roles for RNA methylation events and critical signaling pathways implicated in epithelial healing.

Donor–recipient sex mismatch is an under-recognized risk factor for corneal graft rejection, yet the biological underpinnings at the ocular surface remain undefined. We hypothesized that sex hormones coordinately tune the tear–nerve–epithelium axis and that androgen exposure could normalize sex-linked differences relevant to alloimmune risk. We profiled 12-week-old mice in three hormonal contexts, i.e. male, female, and testosterone-treated female, combining tear biochemistry and label-free proteomics with epithelial lineage dynamics, in vivo sensory function, and corneal/trigeminal transcriptional readouts. Tear collection rate was comparable across groups, but total tear protein was reduced in females. Proteomics revealed extensive sex differences in extracellular composition, spanning lipid transport, protease–antiprotease balance, complement activity, and secretory/mucin pathways. Epithelial analyses showed sex-linked differences in progenitor output and spatial deployment, and sensory metrics indicated divergent innervation architecture and function. Across modalities, androgen supplementation in females shifted molecular and physiological profiles toward the male state, attenuating nearly all dimorphic signals, demonstrating that close to all sexual dimorphism observed here is reversible by testosterone and reflects an actively maintained endocrine state rather than a fixed developmental program. Complementary metabolite profiling provides a sex-stratified atlas of free modified nucleosides in tears, positioning extracellular epitranscriptomic markers as accessible indicators of hormonal context. Together, these results establish a multiscale, hormone-responsive sexual dimorphism at the ocular surface and offer a mechanistic framework linking sex and endocrine status to parameters that influence graft integration. They motivate sex-aware biomarkers, stratification by hormonal context in diagnostics and trials, and therapeutic strategies, including androgenic modulation, to mitigate the elevated rejection risk associated with sex mismatch in corneal transplantation. ### Competing Interest Statement The authors have declared no competing interest. ATIP-Avenir, 2018

Mitochondrial dysfunctions are detrimental to organ metabolism. The cornea, transparent outmost layer of the eye, is prone to environmental aggressions, such as UV light, and therefore dependent on adequate mitochondrial function. While several reports have linked corneal defects to mitochondrial dysfunction, the impact of OPA1 mutation, known to induce such dysfunction, has never been studied in this context. We used the mouse line carrying OPA1 delTTAG mutation to investigate its impact on corneal biology. To our surprise, neither the tear film composition nor the corneal epithelial transcriptomic signature were altered upon OPA1 mutation. However, when analyzing the corneal innervation, we discovered an undersensitivity of the cornea upon the mutation, but an increased innervation volume at 3 months. Furthermore, the fibre identity changed with a decrease of the SP+ axons. Finally, we demonstrated that the innervation regeneration was less efficient and less functional in OPA1 +/- corneas. Altogether, our study describes the resilience of the corneal epithelial biology, reflecting the mitohormesis induced by the OPA1 mutation, and the adaptation of the corneal innervation to maintain its functionality despite its morphogenesis defects. These findings will participate to a better understanding of the mitochondrial dysfunction on peripheral innervation.

In this issue of Neuron, Yokose et al. show that mice groom a mark on their forehead when exposed to a mirror. Comparing this behavior with hominids' helps carve self-awareness into its component parts and explore the neural mechanisms of its shared components.

The cornea acts as the eye foremost protective layer and is essential for its focusing power. Corneal blindness may arise from physical trauma or conditions like dystrophies, keratitis, keratoconus, or ulceration. While conventional treatments involve medical therapies and donor allografts—sometimes supplemented with keratoprostheses—these options are not suitable for all corneal defects. Consequently, the development of bioartificial corneal tissue has emerged as a critical research area, aiming to address the global shortage of human cornea donors. Bioengineered corneas hold considerable promise as substitutes, with the potential to replace either specific layers or the entire thickness of damaged corneas. This review first delves into the structural anatomy of the human cornea, identifying key attributes necessary for successful corneal tissue bioengineering. It then examines various corneal pathologies, current treatments, and their limitations. Finally, the review outlines the primary approaches in corneal tissue engineering, exploring cell-free, cell-based, and scaffold-based options as three emerging strategies to address corneal failure.

Receiving touch is of critical importance, as many studies have shown that touch promotes mental and physical well-being. We conducted a pre-registered (PROSPERO: CRD42022304281) systematic review and multilevel meta-analysis encompassing 137 studies in the meta-analysis and 75 additional studies in the systematic review (n = 12,966 individuals, search via Google Scholar, PubMed and Web of Science until 1 October 2022) to identify critical factors moderating touch intervention efficacy. Included studies always featured a touch versus no touch control intervention with diverse health outcomes as dependent variables. Risk of bias was assessed via small study, randomization, sequencing, performance and attrition bias. Touch interventions were especially effective in regulating cortisol levels (Hedges’ g = 0.78, 95% confidence interval (CI) 0.24 to 1.31) and increasing weight (0.65, 95% CI 0.37 to 0.94) in newborns as well as in reducing pain (0.69, 95% CI 0.48 to 0.89), feelings of depression (0.59, 95% CI 0.40 to 0.78) and state (0.64, 95% CI 0.44 to 0.84) or trait anxiety (0.59, 95% CI 0.40 to 0.77) for adults. Comparing touch interventions involving objects or robots resulted in similar physical (0.56, 95% CI 0.24 to 0.88 versus 0.51, 95% CI 0.38 to 0.64) but lower mental health benefits (0.34, 95% CI 0.19 to 0.49 versus 0.58, 95% CI 0.43 to 0.73). Adult clinical cohorts profited more strongly in mental health domains compared with healthy individuals (0.63, 95% CI 0.46 to 0.80 versus 0.37, 95% CI 0.20 to 0.55). We found no difference in health benefits in adults when comparing touch applied by a familiar person or a health care professional (0.51, 95% CI 0.29 to 0.73 versus 0.50, 95% CI 0.38 to 0.61), but parental touch was more beneficial in newborns (0.69, 95% CI 0.50 to 0.88 versus 0.39, 95% CI 0.18 to 0.61). Small but significant small study bias and the impossibility to blind experimental conditions need to be considered. Leveraging factors that influence touch intervention efficacy will help maximize the benefits of future interventions and focus research in this field. This pre-registered systematic review and multilevel meta-analysis examined the effects of receiving touch for promoting mental and physical well-being, quantifying the efficacy of touch interventions for different ways of administration.

AbstractIntroduction: Receiving touch is of critical importance for human well-being. A number of studies have shown that touch promotes mental and physical health. However, effect sizes differ considerably across studies and potential moderators of touch interventions remain unknown to this day.MethodsWe conducted a preregistered (CRD42022304281) systematic review and a large-scale multivariate multilevel meta-analysis encompassing 137 studies in healthy participants and patients (166 cohorts, 9617 participants and 643 effect sizes) in the meta-analysis and 75 additional studies as part of the systematic review to identify critical factors moderating touch intervention efficacy. Included studies always featured a touch vs. no touch control intervention with health outcomes as dependent variables.ResultsWe found comparable and medium-sized (Hedges’g∼ 0.5) effects of touch on both mental and physical health. Touch interventions were especially effective in regulating cortisol levels (0.78 [0.24;1.31]) and increasing weight (0.65 [0.37;0.94]) in newborns, as well as in reducing pain (0.69 [0.48;0.89]), feelings of depression (0.59 [0.40;0.78]) and state (0.64 [0.44;0.84]) or trait anxiety (0.59 [0.40;0.77]) for adults and children. Comparing touch interventions involving objects or robots with humans resulted in similar physical (0.56 [0.24;0.88] vs. 0.51 [0.38;0.64]) but lower mental health benefits (0.34 [0.19;0.49] vs. 0.58 [0.43;0.73]). Adult clinical cohorts profited stronger in mental health domains compared to healthy individuals (0.63 [0.46;0.80] vs. 0.37 [0.20;0.55]) but showed comparable physical health benefits (0.53 [0.38;0.69] vs. 0.47 [0.29;0.65]). We found no difference in children and adults comparing touch applied by a familiar person or a health professional (0.51 [0.29;0.73] vs. 0.50 [0.38;0.61]) but parental touch was more beneficial in newborns (0.69 [0.50;0.88] vs. 0.39 [0.18;0.61]). Intervention frequency positively correlated with increased health benefits in adults and children while session duration did not show significant effects.DiscussionLeveraging those factors that influence touch intervention efficacy will help maximize the benefits of future touch interventions and focus research in this field.

Group living is thought to benefit from the ability to empathize with others. Much attention has been paid to empathy for the pain of others as an inhibitor of aggression. Empathizing with the positive affect of others has received less attention although it could promote helping by making it vicariously rewarding. Here, we review this latter, nascent literature to show that three components of the ability to empathize with positive emotions are already present in rodents, namely, the ability to perceive, share, and prefer actions that promote positive emotional states of conspecifics. While it has often been argued that empathy evolved as a motivation to care for others, we argue that these tendencies may have selfish benefits that could have stabilized their evolution: approaching others in a positive state can provide information about the source of valuable resources; becoming calmer and optimistic around animals in a calm or positive mood can help adapt to the socially sensed safety level in the environment; and preferring actions also benefiting others can optimize foraging, reduce aggression, and trigger reciprocity. Together, these findings illustrate an emerging field shedding light on the emotional world of rodents and on the biology and evolution of our ability to cooperate in groups.