N-acetylaspartate from neuronal loss and low glutamine (a neuroexcitatory marker) but glutathione may be elevated, particularly in non-treatment responders. The literature in schizophrenia is difficult to evaluate because age, gender, symptomatology, comorbidities, therapy use, disease duration, substance abuse, and coexisting other psychiatric disorders have not been adequately controlled for, even in large studies and meta-analyses.In this review article we have consolidated the imaging literature of patients with schizophrenia across the full spectrum of modalities in radiology including computed tomography (CT), morphologic magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and magnetoencephalography (MEG). We look at the impact of various subtypes of schizophrenia on imaging findings and the changes that occur with medical and transcranial magnetic stimulation (TMS) therapy. Our goal was a comprehensive multimodality summary of the findings of state-of-the-art imaging in untreated and treated patients with schizophrenia. Clinical imaging in schizophrenia is used to exclude structural lesions which may produce symptoms that may mimic those of patients with schizophrenia. Nonetheless one finds global volume loss in the brains of patients with schizophrenia with associated increased cerebrospinal fluid (CSF) volume and decreased gray matter volume. These features may be influenced by the duration of disease and or medication use. For functional studies, be they fluorodeoxyglucose positron emission tomography (FDG PET), rs-fMRI, task-based fMRI, diffusion tensor imaging (DTI) or MEG there generally is hypoactivation and disconnection between brain regions. However, these findings may vary depending upon the negative or positive symptomatology manifested in the patients. MR spectroscopy generally shows low  In this review article we have consolidated the imaging literature of patients with schizophrenia across the full spectrum of modalities in radiology including computed tomography (CT), morphologic magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and magnetoencephalography (MEG). We look at the impact of various subtypes of schizophrenia on imaging findings and the changes that occur with medical and transcranial magnetic stimulation (TMS) therapy. Our goal was a consolidation of the state-of-the-art imaging results in untreated and treated patients with schizophrenia.Our review of the literature was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines with a priority placed on studies with large sample sizes, well-defined patient populations, homogeneous cohorts, and recent publication dates. Original and review articles that reported imaging findings of patients with schizophrenia were identified via searching PubMed-MEDLINE, Google Scholar, and EMBASE. Search items included schizophrenia, psychosis, MRI, CT, MRS, MEG, volumetry, diffusion tensor imaging (DTI), fMRI, treatment and TMS. We identified additional articles from the reference lists of the primary articles reviewed. We excluded (1) editorials and letters; (2) case reports or case series < 3 patients; (3) partially overlapping patient cohorts; (4) articles not written in English, and (5) non-human studies.Schizophrenia is a severe psychotic disorder. There are approximately 24 million patients carrying a diagnosis of schizophrenia worldwide . The disSchizophrenia can affect the physical and mental health of the patient and can disturb the person’s every-day life. This disorder includes a great range of symptoms . DelusioThe DSM-4 edition described five different subtypes  of schizophrenia. Although they have been subsequently eliminated in the 2013 DSM-V edition because of overlap, it is useful to describe them below. These subtypes vary widely in their symptomatology, and therefore describing specific imaging patterns on the whole for schizophrenia becomes perilous. The brain function in patients with paranoid schizophrenia manifested by frequent hallucinations, delusions, psychotic behavior, and disorganized speech and thinking is unlikely to be the same as in patients in catatonia where the symptoms may be mutism, echolalia, and abulia, coupled with absent (or excessive) voluntary movements. Disorganized schizophrenia occurs in the absence of hallucinations and delusions but is largely manifested by incomprehensible expressive speech. The patient may have a flat affect and disorganized thinking. Residual schizophrenia refers to the symptom complex when the patient has recovered from a psychotic break or delusions but still may be emotionless and disorganized in speech and thought. If a patient has a combination of the behaviors described above and does not fit neatly into one subtype, the patient’s condition is termed undifferentiated.The following disorders should be considered when making a clinical diagnosis of schizophrenia. One of the biggest challenges is to discern between schizophrenia and bipolar disorder (manic-depressive disease) since 50% of manic episodes in patients with manic-depressive disorder may mimic the positive symptoms of schizophrenia  The negative signs of schizophrenia can resemble depressive episodes of bipolar disorders or major depressive disorder  .2.5, PMC, PM10, SO2, and NO2 exposure)  twin gestation, (5) delivery by cesarean section, (6) history of asphyxia  is considered one of the important predisposing factors. Environmental factors such as being born in winter, living in an urban environment, air pollution (PMxposure) , immigraxposure) , constitxposure) . Certainxposure)  and autoasphyxia , and (7)asphyxia .There is no certain cure for schizophrenia, however, the symptoms of schizophrenia can be treatable. A small percentage of patients can recover entirely. Nearly one-third of people with schizophrenia will positively respond to pharmaceutical and behavior modification treatment and they can have a normal or mostly normal life. The disorder is not fatal itself but it can lead to behaviors that can be harmful to the patients and people around them. Nearly 10% of patients with schizophrenia die from suicide. They also may develop chronic conditions such as heart disease. Worse outcomes are associated with a family history of psychosis, substance use, earlier onset of disease, and longer duration of untreated psychosis .Therefore, due to myriads of risks that people with schizophrenia are dealing with, it is crucial to detect and treat schizophrenia in a timely manner .The main role of imaging, as with most psychiatric disorders, is to exclude structural lesions in the brain that may lead to symptoms that simulate schizophrenia. For example, anterior cranial fossa meningiomas that encroach on the frontal lobes are known to cause such symptoms as abulia, personality changes, and olfactory hallucinations which may lead to a misdiagnosis of schizophrenia. Standard CT and MR imaging are unable to “diagnose” schizophrenia, but the exclusion of other lesions is an important component of the work-up of patients with psychotic symptoms.Conventional imaging of the patient with an acute psychotic episode who is seen in the Emergency Department often starts with a head CT. Although there are no signature features of schizophrenia on CT scanning, this initial evaluation is used to identify other brain lesions that may lead to symptoms mimicking schizophrenia.Computed tomography scans may show “volume loss greater than expected for age” in the frontal lobes, temporal lobes, caudate heads, and thalami of patients with schizophrenia . This voAlthough CT is often the first study performed in new onset psychosis, MRI and functional imaging have proved the mainstay for schizophrenia assessment in both the clinical and research realms.Due to the high resolution of MRI, various brain abnormalities in schizophrenia such as increased volume of cerebrospinal fluid (CSF) and decreased volume of white and gray matter have been detected . Quantitp = 0.027) than healthy controls. Concomitant volume loss in the planum temporalis, insula, and cingulum was implied, a characteristic feature of the brains in patients with psychosis  levels in the anterior cingulate cortex in treatment resistent patients compared to responsive patients . InteresN-acetyl aspartate levels may occur in chronic schizophrenia in the temporal lobe, parietal lobe, and hippocampus, they are localized to the frontal lobe in early psychotic illness. In this case N-acetyl aspartate levels corroborated FDG PET results as a marker of neuronal metabolic function and therefore the hypofrontality theorem. Another theory is that hypometabolism results from aberrant synaptic function, which leads to decreased demand. A significant body of data links synaptic dysfunction to the pathophysiology of schizophrenia, including in vivo and post-mortem findings of reduced frontal synaptic protein levels  versus negative/deficit symptoms . The negative symptom form of schizophrenia is linked to lower metabolism in all regions of interest in cortical and subcortical structures on PET. Patients with the deficit type of schizophrenia had lower glucose absorption than patients with the non-deficit type in all neocortical regions of the brain , as well as the thalamus and the limbic system . In posiAs far as other variables that may affect the FDG PET results, A meta-analysis of non-FDG tracers used to evaluate patients with schizophrenia has recently concluded that a functional excess of brain dopamine in schizophrenia has been supported by many studies. Many different agents  show higher than normal uptake of the dopaminergic agonists in the striatal basal ganglia  of unmedicated patients. The early finding of increased dopamine synthesis capacity, however, is not pathognomonic of schizophrenia, since nearly half of patients have normal dopamine synthesis capacity and other patients with psychiatric manifestations may have elevated FDOPA accumulation as well. Once patients with schizophrenia are on antipsychotic medications, there may be normalization of these dopamine uptake studies .18F]MK-9470 agent in the nucleus accumbens, insula, cingulate cortex, inferior frontal gyrus, parietal and mesotemporal lobe regions of the brain  MRI measures cerebral blood flow directly by inverting the magnetization of arterial blood water using radiofrequency pulses to create an endogenous diffusible tracer , in contBlood oxygenation level-dependent (BOLD) fMRI is a method that relies on deoxyhemoglobin’s T2 shortening magnetic susceptibility effects, which result in regional signal intensity alterations on susceptibility-sensitive imaging sequences . Signal intensity is seen to rise overall in areas of the brain that are stimulated by task demands. This is due to an increase in regional oxygenated blood flow that is greater than the region’s oxygen consumption resulting in a decrease in the level of deoxyhemoglobin and thus a higher signal intensity on T2* scans. Event/Task-related fMRI uses the BOLD phenomenon to contrast the signal during stimulus presentation or performance of a task with that of a control stimulus or non-task.When different task-based paradigms have been tested across the domains of working memory, cognitive problem solving, and interpersonal communications, patients with schizophrenia have consistently shown decreased activation in the prefrontal cortex. One working memory task study showed that, with practice , medication naïve patients with schizophrenia showed a smaller reduction in activation versus controls in the dorsolateral prefrontal cortex which correlated with the severity of negative symptoms in patients . When thA recent meta-analysis by Pico-Perez et al. looked at 4,789 patients’ structural and functional studies across the domains of processing speed, attention/vigilance, working memory, verbal learning and memory, visual learning and memory, executive function/reasoning, problem solving, verbal fluency, and verbal comprehension, emotional perception, social perception and knowledge, theory of mind, and attributional bias. The authors noted dorsomedial prefrontal cortex, supplementary motor area, and right inferior frontal gyrus decreases in activation when presented with cognitive tasks . These authors noted that, through their meta-analysis, they were able to isolate the attention/vigilance tasks as the ones that most uniformly showed deficits in patients with schizophrenia across multiple studies. This comports with some of the DTI and resting state fMRI studies that highlight the salience network (see below). However, when the tasks were more social interaction/skills based, the reduction in brain activation was more focused in the right angular gyrus  . No areaOne study looked at 142 patients with schizophrenia having auditory verbal hallucinations who underwent task-based fMRI. The authors discovered that fMRI activation appeared to localize to the left insula and inferior parietal lobule during the auditory verbal hallucinations and to be associated with significantly reduced gray matter volume.When the Stroop task (saying a color of a word when it is printed in the correct or non-matching color) was compared between 42 patients with schizophrenia and 61 control subjects, the authors found deactivations in the medial frontal cortex, the middle and posterior cingulate gyrus and cuneus, the parahippocampal gyrus and the hippocampus in healthy controls. However, the patients with schizophrenia showed failure of deactivation in the medial frontal cortex suggesting default mode network (see below) dysfunction in schizophrenia . When neResting-state fMRI (rs-fMRI) has been extensively employed in evaluating patients with schizophrenia but, in addition to the patient factors described above which are not controlled for, the studies are plagued by multiple methodological differences, variable analysis techniques used, and small sample sizes . rs-fMRIThe frontal-dorsal medial prefrontal cortex, ventral medial prefrontal cortex, posterior medial cortex, and posterior lateral cortex make up the majority of the default mode network . There hOverall symptom burden was greater in patients with smaller default mode network and salience network activation surface areas, according to The connections of the thalamocortical network have also been implicated in schizophrenia and psychosis with reduced connectivity between the mediodorsal thalamus and the insula and orbitofrontal regions . GreaterUsing the same ROI pairings in the same anatomical area, Hoptman et al. evaluated the connection between resting state functional connectivity and structural connectivity in the default mode network in patients with schizophrenia and healthy controls. Data from the DTI and resting state fMRI sequences did not generally correlate, however, connections between the prefrontal cortex, posterior cingulate, and lateral temporal lobes with frontal and parietal regions did correlate . This isIn a study that conducted by Lottman et al., patients with schizophrenia showed an increased connectivity between auditory and subcortical networks. Also, a decrease connectivity between interhemispheric homotopic sensorimotor networks in rs-fMRI were seen in these patients .A typical metric in rs-fMRI called regional homogeneity defines the local synchronization of blood oxygenation level-dependent signals by comparing the time series of a particular voxel to the closest voxel . The regFurthermore, patients with schizophrenia showed elevated regional homogeneity values in the prefrontal cortex , inferioin vivo in health and disease. A large-scale study from the ENIGMA group identified widespread white matter microstructural abnormalities in chronic schizophrenia (Diffusion tensor imaging (DTI) has paved the way for investigating the white matter tracts in the brain ophrenia . These wophrenia . In anotophrenia . Fractioophrenia . When paophrenia .There may be a difference between treatment responsive and non-responsive patients as far as their DTI findings. This ties in to the relationship between the effectiveness of antipsychotic drugs and their affinity for dopamine receptors, particularly in the striatum where dopamine synthesis is elevated in schizophrenia (see “Positron emission tomography” section above). The associative striatum which receives afferent connections from the dorsolateral prefrontal cortex may play a role in psychosis by striatal dopaminergic dysregulation. To that end, one group has found an inverse correlation on DTI studies between the connectivity of the dorsolateral prefrontal cortex-associative striatum and dopamine synthesis in treatment responsive patients with schizophrenia, which is not present in treatment resistant patients . The disA recent review of 401 studies looking at the white matter in schizophrenia reported that the vast majority of authoritative papers showed decreased fractional anisotropy, predominantly in the corpus callosum . HoweverIn patients with first episode psychosis, white matter anisotropy DTI studies showed whole brain decreases in fractional anisotropy compared to controls , 2021; t1H, 31P, and 13C. Among them, 1H is the most sensitive and by far the most commonly used since no additional hardware is required to perform it on clinical MRI scanners (unlike the other nuclei). When performed at high magnetic field strengths (such as 7T) nearly 20 neurochemicals can be measured in the human. These include neurotransmitters/modulators such as glutamate, glutamine, gamma aminobutyric acid, aspartate and N-acetylaspartyl asparate glutamate  “markers,” compounds related to glycolysis (lactate), as well as antioxidants (glutathione and ascorbate)  is a non-invasive technique that has been used extensively for the evaluation of brain metabolism in neurological and psychiatric disorders, such as schizophrenia. MRS can be performed using several different MR-active nuclei, including lutamate . Other ccorbate) . Glutamaal level .N-acetylaspartate, myo-inositol, and total choline in the anterior cingulate cortex in patients with first episode psychosis patients  from those who may not benefit  is an electrophysiological measurement instrument which measures the magnetic fields emitted by postsynaptic neuronal activity of the brain in real time. MEG directly measures brain function with millisecond temporal resolution, unlike functional MRI which only measures the much slower delayed cerebral blood flow occurring in response to the neuronal activity, or MRI which shows brain structure. Because the skull and head soft-tissues are transparent to magnetic (but not electric) fields, the neuronal current sources can be localized with a few-millimeters of spatial resolution with MEG, significantly better than with electroencephalography. When fused with the patient’s brain anatomic structure shown on MRI, MEG can even show movies of the 3D location of brain activity (spontaneous or evoked) as it occurs in real-time, with millisecond temporal resolution .Using MEG to evaluate patients with schizophrenia compared to normal controls provides useful information (a) in the resting state (measuring spontaneous brain rhythms); (b) in evaluating auditory evoked responses; and (c) in evaluating functional connectivity networks .The most robust finding of resting-state MEG in patients with schizophrenia is increased slow wave activity in delta (1–4 Hz) and theta (4–8 Hz) bands, which localize to frontotemporal and parietal regions in adults with schizophrenia ; but mosOther resting-state frequency bands in patients with schizophrenia studied with MEG include the alpha (9–12 Hz) and beta (13–30 Hz) bands. For example, Gamma-band (30–71 Hz) activity in subjects with schizophrenia has also been studied with MEG. As one example, Lottman et al. conducted a study on 19 patients with schizophrenia and 24 healthy subjects using resting-state 7 Tesla fMRI and MEG. They found a decreased connectivity between task positive networks and sensorimotor in the delta frequency band in MEG .Because auditory hallucinations are a prominent manifestation of schizophrenia, many electroencephalography and MEG studies of auditory encoding have been performed, examining activity in the superior temporal gyri, including time-frequency plots of total power, and inter-trial coherence or phase-locking plots. Some but not all MEG studies show abnormal auditory gating in patients with schizophrenia: presented with two clicks 500 ms apart, normal subjects show decreased auditory activation response to the second click compared to the first, indicating habituation to the stimulus. Patients with schizophrenia do not show such decreased response to the second click .Because of MEG’s ability to sensitively measure neural oscillatory processes, and its good spatial localization using advanced source-reconstruction algorithms, MEG is a useful technique to evaluate whole-brain functional activity in normal subjects and patients with schizophrenia, superimposing the MEG neural activity on the brain MRI images. Both increased and decreased functional connectivity has been observed in patients with schizophrenia vs. controls, in resting state and during various tasks .For example, As described above in multiple sections, the pattern of imaging findings may vary depending upon whether the patients’ symptoms are negative (decreased motivation and diminished expressiveness) or positive . Thus, of the five types of schizophrenia described in DSM-4, three  are more negative in expression. Paranoid and undifferentiated schizophrenia types are more positive in symptomatology. Negative symptom schizophrenia is associated with lower FDG PET uptake, lower perfusion and lower activation on fMRI, particularly in cortical and subcortical regions  whereas Two voxel-based morphometry correlation studies  found a As stated previously, positive and negative symptoms may affect MEG results [patients high in positive symptoms have widespread low alpha power while patients high in negative symptoms showed greater beta power in the left hemisphere ], PET reMany studies reported a significant decrease in left and right asymmetry in the white matter tracts which are responsible for language processing (arcuate fasciculus) in patients with schizophrenia . BilaterXie et al. presented brain changes in deficit schizophrenia patients using MRI. They compared cortical thickness and surface area in 33 deficit schizophrenia, 41 non-deficit schizophrenia, and 41 healthy subjects. They discovered convergent cortical thinning in the bilateral inferior frontal gyri and left superior temporal gyrus. In addition, impaired cognition and visuospatial memory deficit was positively related to right inferior frontal cortex in deficit schizophrenia and non-deficit schizophrenia patients. However, deficit schizophrenia patients showed more cortical thinning especially in left temporo-parietal junction area compared to non-deficit schizophrenia group. Surface area in all three groups showed no specific differences . In anotThere are many types of therapies, either psychological or pharmacological, available for schizophrenia. Cognitive remediation therapy is considered one of the psychological treatments in schizophrenia. Cognitive remediation therapy uses drill and practice, compensatory, and adaptive strategies to improve deficits in memory, attention, and problem solving . TherapyCognitive behavioral therapy for neuropsychiatric diseases includes psychosocial education about the illness, goal setting, symptom monitoring, cognitive restructuring, skills training, safety monitoring, coping techniques, and graded homework assignments. While cognitive remediation therapy helps improve the underlying neuropsychological functions of cognition, concentration and learning, cognitive behavioral therapy teaches the patient how to think through emotionally challenging problems. B receptors.Repetitive transcranial magnetic stimulation is a non-invasive procedure which is used to treat mental disorders. Transcranial direct current stimulation is a non-invasive, painless brain stimulation treatment variant of transcranial magnetic stimulation. According to There are many diseases and factors that should be considered in assessing and imaging schizophrenia. Addiction is very prevalent among patients with schizophrenia. Although there are numerous imaging studies in patients with schizophrenia, most of the cohorts lack appropriate balancing for age, sex, comorbidities, and therapeutic pharmacologic interventions. Controlling for cigarette smoking, marijuana use, illicit drug habits, and educational level are important to a clearer understanding of this patient population. It has been shown in schizophrenia and other disorders that the patterns of brain activation on resting state and task-based fMRI in patients with neuropsychological disorders change with medication use. Additionally, the duration of disease appears to affect the neurophysiology of schizophrenia as evidenced by response to therapy studies that show such impact. The symptom complexes of patients with schizophrenia are also variable and affect imaging findings (see above). It stands to reason that DTI or fMRI or PET patterns of brain function and structure may vary depending upon whether the patient is experiencing hallucinations (positive symptoms) versus abulia (negative symptoms). Our review of the literature is limited by a great heterogeneity in neuroimaging data, depending on the diagnoses, sample sizes, tasks or paradigms used. Additionally, patients with schizophrenia are not immune to other psychiatric disorders such as autism, bipolar disorder, attention deficit hyperactivity disorder, and depression. Even general medical disorders such as diabetes, hypertension, and hyperlipidemia, which may affect vascular reactivity and perfusion in the brain, are rarely controlled for in neuroimaging studies of patients with schizophrenia.Because of the limitations described above, the neuroradiology medical literature would benefit from larger scale studies of individuals with new onset psychosis meeting DSM-5 criteria for schizophrenia. Sharing data from multiple groups (as in ENIGMA) to acquire more homogeneous study groups would be a useful effort. These patients should be screened for other medical and psychological comorbidities to ensure a homogeneous patient population. Ideally the patients will not be receiving medications at the initial evaluation of their brain. To maximize the benefit, a tailored structural and functional MRI protocol that examines diffusion tensor imaging, resting state and standardized task-based fMRI, MR spectroscopy, perfusion imaging, as well as high resolution volumetric MRI sequences that include quantitative susceptibility weighted imaging  would be most useful. After a baseline scan, treatment could be initiated in a standardized fashion so as to determine how anti-psychotic medications, TMS, and/or behavioral therapy impacts the brain functionally and structurally. Serial scanning to assess the role of the duration of disease would also be valuable to the literature.N-acetylaspartate and glutamate on MRS have been demonstrated most consistently in the anterior cingulate cortex in patients with schizophrenia. Other MRS investigators have focused on glutathione, usually reduced in patients with schizophrenia, to predict whether the patients will respond to treatment. These treatments, be they cognitive therapies, anti-psychotic medications, or direct stimulation magnetic techniques, may affect the structure and function of the brains of patients with schizophrenia. Finally, we note that the multitude of variables around patient demographics, disease types and manifestations, duration of disease, therapeutic state, comorbidities, and coexistent psychiatric and/or substance abuse issues in patients with schizophrenia has prevented a definitive picture of the morphologic and functional pathophysiology of this complex disorder.The neuroimaging studies to date on schizophrenia have yielded many observations about the brain in patients. Structurally there is consensus that there is gray matter volume loss and ventricular enlargement in patients with schizophrenia. Both structural studies (showing decreased volume) and functional MR studies (showing hypoactivation and/or reduced connectivity) have focused on (1) thalamocortical connections, (2) amygdalostriate pathways, (3) cortico-striatal-limbic hubs, (4) default mode network, and (5) salience networks. Diffusion weighted images and DTI derived indices showed widespread abnormalities in the white matter of patients with schizophrenia. FDG PET has consistently shown hypofrontality in brain uptake. However, this may be mitigated in part by the dominance of positive or negative symptoms. Dopamine PET studies have shown increased dopamine synthesis capacity in the basal ganglia while cannabinoid receptor studies have mainly focused on increased receptor concentration in the nucleus accumbens. Lower levels of MD and DY: conception or design of the work. MD, FD, KY, PB, RL, and DY: acquisition, analysis, or interpretation of data for the work, drafting the work, or revising it critically for important intellectual content, final approval of the version to be published, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved, they had full access to all of the data in this study, and take complete responsibility for the integrity of the data, and the accuracy of the data analysis.


The polycystic ovarian syndrome affects many women today. Previous research has demonstrated a direct link between it and serious ailments such as type 2 diabetes, heart disease, and infertility. Originally thought to be a reproductive disorder, polycystic ovarian syndrome (PCOS) is now understood to be a metabolic and psychological disorder. Women of reproductive age suffering from PCOS undergo hormonal imbalances in which progesterone, insulin, and testosterone are produced in excess. PCOS exhibits a variety of characteristics as well as a heterogeneity of symptoms, including acne, hirsutism, androgenic alopecia, irregular menstruation, infertility, obesity, and mood disorders like despair and anxiety. Chronic anovulation, hyperandrogenism, type 2 diabetes, dyslipidemia, and an elevated threat of coronary artery disease are some of its defining characteristics. PCOS develops due to interacting genetic and environmental factors. From a gynaecological curiosity, it grew into a multisystem endocrinopathy. It is fascinating to learn how hormonal issues result in gynaecological problems. Insulin resistance, compensatory hyperinsulinism, and an increase in ovarian androgenic hyperresponsiveness to circulating insulin are all directly related to hyperandrogenism and anovulation. Independent of weight, insulin resistance is more common with PCOS and plays a crucial role in the syndrome's metabolic and reproductive complications. Anovulation, polycystic ovaries, and elevated luteinizing hormones, which increase circulating androgen, are all caused by a reduction in follicle-stimulating hormone. High androgen levels cause hyperinsulinemia, which leads cells to become insulin resistant and makes PCOS patients more likely to develop diabetes mellitus. Later research established that women with polycystic ovarian shape and persistent anovulation are the only ones susceptible to insulin resistance. Insulin resistance is thus a distinct characteristic of the condition. The purpose of this review paper is to investigate how PCOS ultimately results in type 2 diabetes mellitus. The effects of polycystic ovary syndrome (PCOS) on the body and its correlation with type 2 diabetes mellitus are described here. A prevalent endocrine condition that influences women of fertile age is polycystic ovary syndrome, type 2 diabetes, and hyperlipidemia . PCOS caPatients with hyperinsulinemic PCOS may develop early follicular luteinization because insulin might increase the reactivity of granulosa cells to luteinizing hormone (LH) . GranuloAnti-Mullerian hormone (AMH) is found in low concentrations in primordial and primary follicles. It reaches its greatest concentration in the large preantral and small antral stages and subsequently decreases in granulosa cells but not cumulus cells throughout the last stages of follicular maturation. The anti-Mullerian hormone is typically produced by these granulosa cells . In ordiRecent research revealed that IR and hyperinsulinemia impact most women with PCOS . Given tIdentifying insulin receptor substrate (IRS) proteins and their role in linking cell surface receptors to intracellular signalling cascades is crucial to understanding the action of insulin and insulin-like growth factor (IGF). Additionally, IRS-proteins integrate signals from the insulin and IGF receptor tyrosine kinases with those produced by proinflammatory cytokines and nutrients. The IRS2 branch of the insulin and IGF signalling cascade has a substantial impact on both the peripheral insulin response as well as the proliferation and function of pancreatic beta-cells. Dysregulation of IRS2 signalling causes peripheral IR in mice, which results in the failure of compensatory hyperinsulinemia. Serine phosphorylation, proteasome-mediated degradation, or chronic stress associated with ageing all inhibit IRS protein signalling and may be essential mediators of IR following acute damage and infection . Figure MethodologyWe undertook a systematic search through PubMed and PubMed Central in August 2022, using keywords such as "polycystic ovary syndrome", "type 2 diabetes", (polycystic ovary syndrome (title/abstract)) OR (PCOS title/abstract) OR (insulin resistant *(title/abstract)) OR ("polycystic ovary syndrome" (MeSH Terms)) AND (("hyperandrogenism" (title/abstract)) OR (type 2 diabetes (title/abstract)) OR (insulin resistant" (MeSH Terms)). We additionally searched for key references in the bibliographies of the relevant studies. The search was updated in November 2022. Reviewers independently monitored the retrieved studies against the inclusion criteria, first based on the title and abstract and then on full texts. The flowchart reports the number of records identified from each database or registered search; it also indicates how many records were excluded, as shown in Figure Polycystic ovary syndromePolycystic ovary syndrome (PCOS) causes a hormonal imbalance with an increased amount of androgen, luteinizing hormone, and insulin. It shows various symptoms like acne, hirsutism, irregular menstruation, and obesity. Besides these, it is accompanied by hyperinsulinemia, hyperandrogenism, hyperlipidemia, anovulation, and insulin resistance . An exceAdditionally, PCOS encourages psychological morbidity, including sadness, a negative view of one's body and self, and a decline in a healthy lifestyle. Therefore, PCOS is linked to both short- and long-period manifestations that may negatively impact females at different times of their lives. To lessen the syndrome's financial and health costs, it is crucial to find effective medicines for its prevention and treatment . HyperanInsulin resistanceInsulin resistance occurs when the increased amount of insulin produced and put into circulation cannot meet the metabolic needs of peripheral tissue. According to research, the first women with PCOS were diagnosed with hyperinsulinemia around 1980 . SubsequNumerous phenotypic and clinical characteristics of women with polycystic ovary syndrome (PCOS) may serve as a reference for therapeutic alternatives for metabolic protection and ovulation induction. Metformin use may be beneficial for some PCOS-affected female patients. Women with PCOS should take precautions for the development of type 2 diabetes mellitus since this condition is indicated by raised insulin levels on a two-hour 75-g glucose tolerance test (DM). Metformin medication may potentially reduce cardiovascular risk factors, such as dyslipidemia and signs of subclinical inflammation. For ovulation induction in PCOS women, metformin is less effective than clomiphene citrate . In PCOSInsulin resistance is a distinctive feature of polycystic ovary syndrome. It is caused by a post-binding error in signalling that persists in cultured skin fibroblasts and is linked with constitutive serine phosphorylation on the insulin receptor. One reason for the post-binding impairment in insulin action diagnostic of PCOS is increased serine phosphorylation, which lowers the activity of tyrosine kinase. Therefore, it is interesting that insulin receptor autophosphorylation is a crucial factor in this resistance, based on several studies . After iStudies on hyperandrogenic teenage and adult PCOS women have found a clear link between insulin resistance, or hyperinsulinemia, and anovulation and biochemical hyperandrogenaemia. A proper investigation revealed that a patient's testosterone level was reduced concurrently with increased insulin sensitivity. Androgen may directly affect the signalling cascade, causing insulin action to be impaired. The signalling flaw specifically affected the insulin metabolic pathway and resulted in reduced protein kinase phosphorylation .Long-term PCOS treatment requires modifying additional lifestyle factors, including smoking, alcohol use, and psychosocial stressors . LifestyMore noteworthy than the percentage of PCOS patients who have insulin resistance is that these women have a higher risk of developing metabolic syndrome (syndrome X). The traits of this disorder include dyslipidemia, abdominal obesity, coagulopathy, poor fibrinolysis, a greater risk of developing high blood pressure, type II diabetes, and heart disease. Hyperglycemia has been linked to a profile of heightened cardiovascular risk factors in PCOS, according to research . It was Insulin resistance (IR) is an insulin resistance syndrome in which the peptide hormone insulin has a physiologic effect on peripheral target tissues that is less than predicted, resulting in hyperinsulinemia, the characteristic feature of IR . IR is fThe connection between hyperinsulinemia and insulin resistance in PCOS has to be further investigated. Researchers are currently looking for information to understand the origin of this mysterious illness.We infer that type 2 diabetes is more likely in women with PCOS. It is brought on by hormonal imbalance, which interferes with the insulin receptor and follicle formation. Even though the body produces a lot of insulin, cells resist it, making them more vulnerable to diabetes. Recent research has proven that women with polycystic ovary syndrome and persistent anovulation are the only ones who are insulin resistant. Thus, chronic anovulation syndrome has insulin resistance as a distinctive hallmark. Drugs such as insulin sensitizers are discussed as an optimistic and peculiar curative option for the chronic treatment of PCOS. It is important to note that polycystic ovaries are not a requirement for PCOS, and many women with them do not have the condition. If incidental polycystic ovaries are discovered on an ultrasound for another reason, PCOS should not be assumed to be present unless there is corroborating clinical evidence.


The role of B cells in antitumor immunity has been reported to be either promotive or suppressive, but the specific mechanism remains to be comprehensively understood. However, this complicated situation likely depends on the temporal and spatial relationship between the developing tumor and B cells that recognize tumor antigens. Unlike responses against microbial or pathogenic infections, tumor cells are derived from autologous cells that have mutated and become aberrant; thus, elimination by the adaptive immune system is essentially inefficient. If tumor cells can evade immune attack at an early stage, non-destructive responses, such as tolerance and immunosuppression, are established over time. In tumor-draining lymph nodes (TDLNs), tumor antigen-reactive B cells potentially acquire immunoregulatory phenotypes and contribute to an immunosuppressive microenvironment. Therefore, triggering and enhancing antitumor responses by immunotherapies require selective control of these regulatory B cell subsets in TDLNs. In contrast, B cell infiltration and formation of tertiary lymphoid structures in tumors are positively correlated with therapeutic prognosis, suggesting that tumor antigen-specific activation of B cells and antibody production are advantageous for antitumor immunity in mid- to late-stage tumors. Given that the presence of B cells in tumor tissues may reflect the ongoing antitumor response in TDLNs, therapeutic induction and enhancement of these lymphocytes are expected to increase the overall effectiveness of immunotherapy. Therefore, B cells are promising targets, but the spatiotemporal balance of the subsets that exhibit opposite characteristics, that is, the protumor or antitumor state in TDLNs, should be understood, and strategies to separately control their functions should be developed to maximize the clinical outcome. Tumorigenesis and immunity are closely linked by nature –4. If thVarious immunotherapies to treat tumor by activating the immune system were attempted in the past without remarkable progress for a long time , 6. Howevia cytokine production  In transplantable mouse cancer models, the loss/removal of B cells or their functional inhibition suppresses the tumor growth (r growth –33. Thus(B) In human clinical specimens, B cell infiltration and formation of lymphoid aggregates containing B cells in tumor tissues are positively correlated with the prognosis and therapeutic efficacy , where tumor antigens are delivered to induce adaptive immunity –54, is tvia afferent lymphatics , a secondary lymphoid organ incorporated into the lymphatic system that collects body fluid (lymph fluid) from peripheral tissues mphatics –57. LNs mphatics . LNs are venules . Lymphocodstream . Lymphocvia the T-cell receptor (TCR), they are activated to proliferate and differentiate into effector cells  in peripheral tissues which move into the neighboring lymphatic vessels –62. Durior cells . In contpathways . Antigenpathways , 14. If pathways . GC-B ce antigen .via the induction of anergy or active suppression by regulatory lymphocytes in secondary lymphoid organs  or damage-associated molecular patterns (DAMPs), respectively –76. Thisin human , 81, 82.+CD5+CD1dhi in mouse and CD19+CD24hiCD38hi in human , is significantly correlated with prognosis and therapeutic efficacy , 34–48. esponses , 123. B esponses , 124–127via tumor-antigen presentation is formed  or lymphocyte clusters within or adjacent to tumor tissues is correlated with prognosis and therapeutic efficacy , 129. TLs formed , 129.In addition to TIBs, active infiltration of other effector lymphocytes into the primary tumor should reflect an already present antitumor response in TDLNs , 92; theTaken together, the infiltration of B cells into tumors is a good indicator of ongoing antitumor immunity. If the balance between tolerance/immunosuppression and antitumor response in TDLNs is skewed toward the antitumor side, the degree of B cell tolerance/regulatory axis is weakened, resulting in more activated B cells entering the tumor lesion. If B cell activation or antibody production is linked to tumor suppression, it may directly correlate with prognosis after ICB therapy.Considering the dynamic behavior of B cells in TDLNs and tumor sites, the seemingly conflicting roles of B cells in various tumors can be regarded as reflections of the different phases of tumor progression as follows:(A) Protumor/immunoregulatory B cell functions are linked to the induction of tolerance and an immunosuppressive environment in early stage TDLNs.(B) Antitumor/tumor-suppressive B cell functions are linked to the degree of antitumor immune response in mid- and late-stage TDLNs.(A), the findings from genetically engineered animal models, in which the genetic background and environmental factors are homogeneous, represent the specific function of B cells in certain tumors. At present, it is difficult and risky to simply apply this knowledge to diverse human population for diagnostic and therapeutic purposes, such as for systemic B cell depletion. However, since B cells seem to contribute to the establishment of an immunosuppressive environment, it may be useful to combine ICB therapy with specifically targeting immunoregulatory B cells in the future.In the protumor functions of B cells as (B) is extremely useful for diagnosis, therapeutic decisions, and prognosis prediction based on biopsies from patients, especially as promising information for the choice of immunotherapy, such as ICB. However, patients with low infiltration of B cells and other lymphocytes into the tumor have not yet overcome their insensitivity to immunotherapy. Various novel strategies currently underway to activate the antitumor immunity will provide more insights (The antitumor role of B cells insights .In any case, it should be noted that TDLNs play critical roles. TDLNs act as a reservoir of activatable lymphocytes that can potentially become effectors of antitumor response, making them a critical target for ICB therapy , 131–138The author confirms being the sole contributor of this work and has approved it for publication.


Tumours develop within complex tissue environments consisting of aberrant oncogenic cancer cells, diverse innate and adaptive immune cells, along with structural stromal cells, extracellular matrix and vascular networks, and many other cellular and non-cellular soluble constituents. Understanding the heterogeneity and the complex interplay between these cells remains a key barrier in treating tumours and cancers. The immune status of the pre-tumour and tumour milieu can dictate if the tumour microenvironment (TME) supports either a pro-malignancy or an anti-malignancy phenotype. Identification of the factors and cell types that regulate the dysfunction of the TME is crucial in order to understand and modulate the immune status of tumours. Among these cell types, tumour-associated fibroblasts are emerging as a major component of the TME that is often correlated with poor prognosis and therapy resistance, including immunotherapies. Thus, a deeper understanding of the complex roles of tumour-associated fibroblasts in regulating tumour immunity and cancer therapy could provide new insight into targeting the TME in various human cancers. In this review, we summarize recent studies investigating the role of immune and key stromal cells in regulating the immune status of the TME and discuss the therapeutic potential of targeting stromal cells, especially tumour-associated fibroblasts, within the TME as an adjuvant therapy to sensitize immunosuppressive tumours and prevent cancer progression, chemo-resistance and metastasis. The tumour and its microenvironment (TME) not just consists of aberrant oncogenic cancer cells but are additionally composed of recruited and resident host cells such as various immune cells and other structural stromal cells . The tumApart from malignant tumour cells, various types of resident sentinel and infiltrated innate and adaptive immune cells, and stromal cells such as vascular endothelial cells, tumour-associated fibroblasts (TAFs), together with extracellular matrix (ECM) as well as multiple extracellular soluble factors such as cytokines, proteases, chemotactic factor, growth factors and others, are now recognized as part of the TME . The recTAFs are defined as fibroblast cells that surround both primary and metastatic cancers and represent one of the most abundant heterogeneous cell population in the tumour stroma. In general, fibroblasts as a cell type are difficult to identify since they lack specific and unique markers. Hence, identification of fibroblasts relies primarily on morphology and tissue location . Under rUnder the influence of the TME or in response to tissue injury caused by the growing tumour, fibroblasts can become activated to a distinct phenotype, and are termed tumour associated fibroblasts (TAFs)  , 11, 12.The heterogeneity observed even in normal fibroblast populations gives us a fair idea of the complex fibroblast subtypes involved in cancer. Recent advances in single cell technologies have led to greater understanding of the heterogeneity in fibroblast subpopulations in the dermis , 15 and However, a common theme emerges from the wealth of information brought forward by single cell technologies, and based on these studies, TAFs can be broadly classified into two key subpopulations: a matrix-producing and contractile phenotype termed myTAFs and an inflammatory phenotype termed iTAFs. For a long time, myTAFs with an α-SMA positive signature were considered to be the only TAF population and these played a predominant role in the expression of ECM components, myofibroblast markers and cell contraction. With the advancement in single cell RNA sequencing technologies, inflammatory TAFs or iTAFs were identified as another distinct population characterized by an inflammatory secretome . TAFs ha+ myofibroblasts (myTAFs) which have a pro-invasive phenotype  signalling  instead of oxidative phosphorylation. In the nutrient starved TME, cells need to adapt their metabolic pathways to survive and function efficiently. Some cells have the capacity to proliferate faster by having access to energy at a much higher rate through glycolysis. Cancer cells have long been thought to utilize glycolysis for energy supply, particularly in the (hypoxic) interior of tumours where oxygen cannot be supplied due to interrupted blood flow . More reAt a cellular level, an immune response requires substantial energy, necessitating metabolic changes to rapidly meet an urgent need for greater ATP production . BesidesApart from supporting cancer growth, angiogenesis, tumour metabolism and metastasis, recent evidence suggests that TAFs can also cripple the immune response to cancer and promote tumour immune escape by creating an immunosuppressive TME. For example, two TAF derived cytokines that have been implicated in multiple pathways of immune suppression are TGF-β and SDF-1/CXCL12. TAFs can therefore modulate the function of various immune cells in the TME, which have been discussed in the following sections.Among other antigen presenting cells, conventional dendritic cells (cDCs) are vital in initiating a T-cell response in cancer and represent the start of the cancer immunity cycle. DCs can endocytose dead cells and debris within the TME. Specifically, a small subset of cDC1s are required to cross-present antigens to CD8+ T cells . TAFs arTGF-β functions as a key inhibitor of DC migration and their ability to prime T cells. As discussed earlier, TAFs are major producers of TGF-β in many tumour types and also contribute significantly to the release of latent ECM bound TGF-β . TGF-β wT-cell infiltration into the tumour is an essential step that precludes T cell mediated killing of tumour cells, and thus, also represents a mode of resistance or lack of response to immunotherapies that aim to enhance T-cell activity. A subset of TAFs expressing fibroblast associated protein (FAP) have been documented to cause T-cell exclusion from cancer cell nests in multiple cancer models . Studiesvia interaction with immune checkpoints FAS and PD-1 in an antigen specific manner. On the contrary, normal fibroblasts did not exhibit this protection to tumours. Furthermore, non-deleted T-cells also showed increased expression of LAG3, a marker for exhaustion  and its interaction with its receptor CXCR4. This effect was also seen in lung cancer models (Another population of adaptive immune cells that TAFs influence is that of the Foxp3+ regulatory T cell (Treg). Treg cells guard against autoimmunity and are well known to suppress anti-tumour responses. Infiltration of Treg cells into the TME is correlated with a worse prognosis in most cancers . In varir models , howeverr models .Stemming from the diverse roles that TAFs play in cancer survival and growth as well as immunosuppression, targeting TAFs for slowing disease progression in cancer could be potentially beneficial and enhance the effect immuno/chemo-therapy. In the following section, we describe current efforts and approaches targeting TAFs to sensitise the immunosuppressive TME and prevent tumour progression, chemoresistance and metastasis.TAFs regulate an array of functions in the TME. TAFs secrete various cytokines, chemokines, and growth factors and play an essential role in promoting tumourigenesis, angiogenesis and chemo resistance, etc. Due to their phenotypic and functional heterogeneity, they have essential and sometimes contradictory roles in both eradication and progression of tumours . AlthougGiven the diverse role of TAFs in cancer progression, one probable way to target TAF function is to simply deplete their population, which can potentially alleviate TAF-mediated immunosuppression in the TME . Various(GluBoroPro dipeptide), demonstrated retardation of tumour growth in preclinical animal models  that has garnered a lot of attention lately. FAP is a type-II membrane bound serine protease which has dipeptidyl peptidase (DPP) and collagenase-like activity and is important in remodelling the ECM. Various small molecules targeting the enzymatic activity of FAP have been explored in the past decade. Talabostat , a boronic acid-based peptide inhibitor (from amino boronic dipeptide class) of FAP DPP activity, is the only FAP inhibitor to be tested in clinical studies. A combination of PT100 with Oxaliplatin reduced tumour growth and decreased recruitment of tumour associated macrophages in pre-clinical models of cancers . Howeverl models . Clinical models . A FAP tl models . Similarl models . A few ol models . It is wl models   and Lo et al. (2015), the use of FAP targeted CAR T cells produced inhibition of cancer growth both by improving CD8+ T-cell function , and by l models . Aside fl models . On simil models .+GPR77+ -TAFs, NF-κB signalling via p65 phosphorylation leads to IL-6 and IL-8 secretion, that aids in the development of chemoresistance. However, this effect could be reversed by blocking GPR77 with a neutralizing antibody x nanoparticle, have been studied (+ (28%) and FAP-α+ (56%) TAF populations  signaling inhibitor and SN38 (active metabolite of an anticancer drug Irinotecan) encapsulated in a polymeric PEG studied . Other Sulations . Chen anulations . In addiulations .+ myofibroblasts unexpectedly resulted in reduced animal survival. The resulting highly invasive tumours were characterized with higher levels of hypoxia, epithelial to mesenchymal transition (EMT) and cancer stem cell-like phenotype, along with increased recruitment of immunosuppressive Foxp3+ Tregs  to inhibit TAF activation related signaling. The authors used engineered lipid-protamine-DNA (LPD) nanoparticles carrying trap genes for IL-10 and CXCL12 to alleviate T cell inhibition. In pre-clinical studies, this approach led to changes in ECM remodeling with decreased levels of collagen and α-SMA as well as fewer immunosuppressive cells in a murine PDAC model , 141. InTargeting intracellular signaling in TAFs to modulate their phenotype is another potential therapeutic approach to modulate the TME. Suvarna et al. (2018) have targeted fibroblast migration using RKN5755, a ligand for beta-arrestin1 to interfere with downstream cofilin signaling pathways and restrict the migratory phenotype of activated fibroblasts . In anotIn summary, Targeting TAF derived cytokines and other upstream signaling modulators remains challenging in spite of the promise it holds as a potential therapeutic approach. Given the various different mechanisms by which TAFs can promote tumour progression— multiple cytokines, metabolites, exosomes, force-mediated contraction, and even direct contact with cancer cells and transcytosis — the scoAnother approach to deter TAF function in the TME is to target fibroblasts which have already differentiated into a tumour promoting phenotype and to reprogram them to their native quiescent state. This reprogramming of TAFs has been attempted at the transcriptional level by several researchers. For example, Kim et al. identified the small molecule Scriptaid, an HDAC 1/3/8 inhibitor, as a factor that can reduce TGF-β-induced TAF differentiation. This in turn led to lower ECM secretion, cell invasiveness and stiffness in preclinical animal models . Use of Aside from these, kinases involved in the complex signalling network in TAFs can also be potential targets for inhibition of TAF function. A multi-kinase receptor inhibitor Nintedanib was shown to downregulate the induction of collagens and α-SMA in TGF-β1 stimulated fibroblasts . BorrielOverall, fibroblasts are a dominant stromal cell type present in many tumours, which can be activated within the TME and ‘educated’ by cancer cells into overall tumour-promoting TAFs. Usually, quiescent fibroblasts become activated in tissue repair where they manipulate the ECM, regulate new vessel formation, and generate a skew towards an immunosuppressive, wound healing immune phenotype. Once the repair is complete, activated fibroblasts revert back to a normal phenotype. The continued activation of fibroblasts is thus characteristic of pathological responses such as organ remodelling and fibrosis, as well as tumours and cancers. Within the TME, cancer cells can program fibroblasts to pro-tumourigenic TAFs, which take on unique, heterogenous phenotypes, and are activated by different factors, including TGF-β. Further research is warranted to completely understand TAF differentiation and distinctions need to be made between the various subsets of TAFs that may influence tumour progression and metastasis in unique ways. The major hurdle for specifically targeting pro-tumourigenic TAF subsets is identifying reliable and specific markers that have largely remained elusive to date.TAFs are capable of promoting tumour progression in many ways, which include ECM modulation, promoting angiogenesis, modulating the metabolic environment and creating an immunosuppressive TME. However, some mechanisms involved in these processes remain yet to be elucidated. For example, a more concrete understanding of how TAFs affect metabolism of tumour cells and other stromal cells, such as immune cells, is vital. Similarly, their impact on different stages of the cancer immunity cycle should be carefully examined to uncover opportunities for combination treatments. Despite the bulk of evidence that suggests that key TAF subsets support tumour progression, it is interesting that non-specific TAF depletion leads to pro-tumour responses, while re-educating TAFs and reversal to a normalized phenotype is protective. This warrants closer study of phenotypes and signalling mechanisms involved in the anti-tumour functions of certain TAF subsets. Various preclinical studies indicate that TAF content in common syngeneic murine models is lower than in human tumours. Examining TAF content and developing TAF rich preclinical tumour models that mimic human tumours may make them more accurate and reveal further details of TAF influence on tumour progression, metastasis and chemo-resistance. It is likely that characterizing and targeting the tumour stromal component may become essential in future cancer treatment, and reprogramming TAFs could unlock the potential of many existing therapies. Additionally, positive outcomes from the various ongoing clinical trials compiled in KS initiated and wrote the manuscript and was the major content provider. KS, SB, PG and AI contributed to determining the content of each section. KS, SB, PG and AI collected data and contributed to writing each section of the manuscript. All authors contributed to editing and have read and approved the final manuscript.This research was supported by Alembic Pharmaceuticals, India including salary support to SB, PG and AI. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.Authors KS, SB, PG and AI were employed by the company Alembic Pharmaceuticals Ltd., India.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


It is well documented that knowledge improvement alone is not sufficient to sustain systems level changes. Through supporting dementia care workforce training and the embedding of Aliviado program tools  into hospices’ clinical workflow across the U.S., we learned that both technologies and human support strategies are essential for lasting changes. In this presentation, we first discuss our experience leveraging a powerful customer relationship management software  to assign, manage, and encourage completion of the interprofessional Aliviado Dementia Care training for thousands of active users across the nation. We then share how we provide additional human support and implementation tools in the face of COVID-19, which can inform implementation of similar trials, including office hours, training reports, Plan-Do-Study-Act worksheets, symptom management cheat sheets, champion calls, and electronic health records integration meetings with each agency to locally tailor and embed Aliviado tools.


Personalized medicine requires an understanding of treatment effect heterogeneity. Evolving toward causal evidence for scenarios not studied in randomized trials necessitates a methodology using real-world evidence. Herein, we demonstrate a methodology that generates causal effects, assesses the heterogeneity of the effects and adjusts for the clustered nature of the data. This study uses a state-of-the-art machine learning survival model, riAFT-BART, to draw causal inferences about individual survival treatment effects, while accounting for the variability in institutional effects; further, it proposes a data-driven approach to agnostically (as opposed to a priori hypotheses) ascertain which subgroups exhibit an enhanced treatment effect from which intervention, relative to global evidence—average treatment effects measured at the population level. Comprehensive simulations show the advantages of the proposed method in terms of bias, efficiency and precision in estimating heterogeneous causal effects. The empirically validated method was then used to analyze the National Cancer Database. Knowing which subgroup of individuals could best benefit from a treatment is crucial to evidence-based medicine. It is critical to understand the treatment effect heterogeneity (TEH), which reflects the variability in patient response to treatment . The popIn health research, patient survival is of most clinical relevance. There is a pressing need for robust causal inference methods to evaluate heterogeneous treatment effects on clustered patient survival. Existing methods for assessing heterogeneous treatment effects on patient survival are largely focused on subgroup analysis with a priori hypotheses about either subpopulations who might depart from the population average or interactions between treatment and pre-selected covariates. These methods are prone to multiple testing concerns and estimation bias . More imWe developed a random-intercept accelerated failure time model leveraging a probabilistic machine learning technique, Bayesian additive regression trees (BART) ,4,5, forPutting riAFT-BART in the causal framework  ,10, we cechnique . The treechnique . We first used simulated data to evaluate the proposed method. An expansive and representative simulation was conducted following the state-of-the-art guidance ,10,15 onIn both scenarios of proportional hazards (PH) and nonproportional hazards (nPH), our method, riAFT-BART, yielded the smallest biases  and rootNext, we applied our method on 64,569 high-risk localized prostate cancer patients diagnosed between 2004 and 2015, drawn from the NCDB. We evaluated the TEH among three treatments: (i) radical prostatectomy (RP); (ii) external beam radiotherapy (EBRT) combined with androgen deprivation (AD) (EBRT + AD); and (iii) EBRT plus brachytherapy with or without AD (EBRT + brachy ± AD) . PatientWe developed a machine learning-based method to evaluate the heterogenous causal effects on patient survival using real-world evidence data with clustered patient observations. This method provides a much-needed causal analysis tool for researchers to conduct in-depth analyses of multilevel data with a survival endpoint . Our method can be used to gain insights into personalized treatment and institutional variation in treatment effects. Expansive and representative simulations provide strong empirical evidence that our method has better performance than existing methods in a wide range of data settings. Application to the NCDB data elucidates the importance of estimating heterogenous institutional and treatment effects. The developed methods provide an analysis apparatus for researchers working with large health datasets with clustered observations, and can aid in treatment effect discovery in subpopulations and inform the planning of future confirmatory trials.For evidence-based medicine, it is difficult to apply evidence of population average effects to individual patients who might deviate from the population average. To reveal a potentially complex mixture of causal treatment effects , robust analyses of TEH are needed. Large-scale clinical datasets collected from multiple institutions become common for generating real-world TEH evidence but introduce clustered observations. We developed a robust method to overcome these challenges and to provide accurate and efficient estimation of heterogenous causal treatment effects on patient survival. The TEH analysis of the NCDB prostate cancer data suggests that there may exist heterogeneous treatment effects between the EBRT-based treatments, which can inform individualized treatment strategies. The examination of variation due to clusters may stimulate further investigation into reasons why patient outcomes are different across clusters, which may lead to new insight into the quality of treatment delivery. Results from applying our methods to the NCDB prostate cancer data suggest a substantial variability in institutional effects, with hospitals in the New England area having much better patient outcomes than hospitals in the East Central region. Importantly, the results based on our methods are relevant to all stakeholders, including researchers, patients, clinicians and policymakers. For future research, an immediate extension of the proposed methods is to include the random slopes in the model so that the variability of the covariate effects across different clusters can be incorporated. Developing a sensitivity analysis to potentially have no unmeasured confounding factors could also be a worthwhile contribution.


One of the central debates in the psychiatric community is the difficulty in distinguishing Dissociative Identity Disorder (DID) from Borderline Personality Disorder (BPD). The fact that core symptoms of these pathologies such as emotional dysregulation, alterations in sense of Self, amnesia, depersonalization, self harm, hearing voices, difficulties in maintaining relationships, are symptoms that feature in both disorders can lead physicians to a misdiagnosis, thus depriving patients with DID of adequate treatment.To report a complex clinical case of a DID patient initially misdiagnosed as BPD.Clinical case report.A 45-year-old Caucasian woman with a history of childhood intrafamilial sexual abuse and domestic violence, substance use disorder, autolesionistic and suicidal behaviour with an active diagnosis of BPD presented to our ambulatory mental health care service. A more thorough examination revealed a history of emotional and affect dysregulation, depersonalization, amnesia, intrusive traumatic memories and nightmares with affective, cognitive, and sensorimotor aspects, persistent negative Self-perception. Auditory verbal hallucinations were also present described as inner space with commentary and derogatory nature with one of them being a child voice. The diagnosis of tertiary structural dissociation and DID was finally made when three Apparently Normal Personalities emerged with several Emotional Personalities, authorising for cautious partial pharmacological washout and initiation of three phase-orientated treatment approach.DID is more common than is assumed and the overlap of core symptoms with other disorders can lead to a misdiagnosis. A careful clinical interview and evaluation of symptoms is mandatory to a correct DID diagnosis with a consequent appropriate therapy.No significant relationships.


Raman spectroscopy is a popular non-invasive spectroscopic technique for molecular characterization and imaging with a high spatial resolution. In biology, it is particularly appropriate for the identification of biomolecules and the specific spectral signatures of cells . In thisConfocal Raman microscopy and surface-enhanced Raman spectroscopy (SERS) present fascinating applications in cancer nanomedicine . These tThanks to its high spatial resolution of a few hundreds of nanometers, Raman spectroscopy is an ideal label-free tool to characterize single cells ,7. ConfoAs a whole, this Special Issue covers various practical, technical and applicative aspects of Raman spectroscopy for analytical  purposes. It provides significant contributions for which I sincerely congratulate the authors.


The abandonment of irrigated paddy land has increased in Japan, which can cause a decline in food security and biodiversity. Despite the importance of individual decisions, most studies have only examined regional or community-based determinants of paddy land abandonment. This study aimed to uncover the socio-economic determinants affecting individual landowners’ decisions to abandon paddy land, using Japanese agricultural census data  composed of over one million unique paddy landowners. Results showed that low agricultural benefits are a key driver of abandonment, similar to European countries. Conversely, there is a positive correlation between the population of full-time cultivators in a household and paddy land abandonment, which contradicts previous evidence. Although some mosaics of socio-ecological landscapes with high biodiversity formed through long-term human influence  are less-favored agricultural areas, the paddy land in some of these landscapes tends not to be abandoned. These findings support effective policymaking that balances biodiversity conservation and the provision of agroecosystem services in semi-natural landscapes. Irrigated paddy land is a key component of private land in the Asian monsoon climate region, accounting for over 60% of the world’s irrigated farmland ,2; sustaIn contrast, paddy land has been abandoned as well as other types of farmlands around the world, especially in developed countries . This trHowever, there is limited knowledge regarding the landowners’ determinants of irrigated paddy land abandonment in the Asian monsoon climate region. First, most studies were conducted in China, which mainly cultivated corn and wheat in drylands and grasslands –26. Secohttps://www.gsi.go.jp). Irrigated paddy land provides habitat for more than five thousand species; however, many species using paddy lands have been threatened )Regarding the finding that plays a key role in preventing abandonment, it makes sense that recent Japanese agro-environmental policies are based on economic incentives for paddy land conservation . In othePaddy land tends to be abandoned, particularly in less-favored areas apart from the Forestry Areas. Thus, our findings also imply that economic incentives can still be insufficient to maintain irrigated paddy land cultivation in less-favored regions, although the prevention of paddy land abandonment is also affected by factors other than subsidies. In particular, there is still an increasing trend towards paddy land abandonment in Mountainous Areas. Considering the rich biodiversity and ecosystem services provided by features such as terraced paddy land, the government should enhance paddy land cultivation in these areas. Given our finding that higher income from agricultural products can prevent the abandonment of paddy lands, introducing a market-based approach can also enhance the conservation of multiple benefits from paddy lands. Previous studies have revealed that the market-based approach using wildlife labels is supported by consumers and generates higher revenue ,41,81. MUsing an enormous set of individual panel data from the Japanese Census of Agriculture and Forestry, this study investigated the socio-economic determinants that influence irrigated paddy land cultivation sustainability in Japan, which is abandoned more than other types of farmlands such as drylands . In thisThe findings of this research also provide several practical implications, such as the enhancement of a market-based approach to conserve the numerous benefits of paddy lands. This study also indicates the importance of socio-economic dimensions in developing biodiversity and agroecosystem conservation strategies. Considering that irrigated paddy land cultivation contributes to biodiversity –5,16,18,S1 TableNote: Models 1 and 2 correspond to those in (DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Immunotherapy has revolutionized colon cancer treatment. Immune checkpoint inhibitors (ICIs) have shown clinical benefits for colon cancer patients, especially those with high microsatellite instability (MSI-H). In 2020, the US Food and Drug Administration (FDA)-approved ICI pembrolizumab as the first-line treatment for metastatic MSI-H colon cancer patients. Additionally, neoadjuvant immunotherapy has presented efficacy in treating early-stage colon cancer patients. Although MSI has been thought of as an effective predictive biomarker for colon cancer immunotherapy, only a small proportion of colon cancer patients were MSI-H, and certain colon cancer patients with MSI-H presented intrinsic or acquired resistance to immunotherapy. Thus, further search for predictive biomarkers to stratify patients is meaningful in colon cancer immunotherapy. Except for MSI, other biomarkers, such as PD-L1 expression level, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), certain gut microbiota, ctDNA, and circulating immune cells were also proposed to be correlated with patient survival and ICI efficacy in some colon cancer clinical studies. Moreover, developing new diagnostic techniques helps identify accurate predictive biomarkers for colon cancer immunotherapy. In this review, we outline the reported predictive biomarkers in colon cancer immunotherapy and further discuss the prospects of technological changes for biomarker development in colon cancer immunotherapy. Colon cancer is currently one of the malignant tumors with a high incidence and death rate worldwide . TraditiCurrently, MSI-H/dMMR is the only well-recognized biomarker that can be used to guide the immunotherapy of colon cancer. However, the mechanism of why MSI-H/dMMR can be used as a biomarker for colon cancer immunotherapy is still not clarified . The posOther potential predictive biomarkers which are proposed in colon cancer immunotherapy include PD-L1 expression level, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), gut microbiota, ctDNA, and circulating immune cells –24. In aMicrosatellites (MS) are short tandem repeats (STRs) in the human genome that are composed of several short and repetitive DNA sequences. Microsatellite instability (MSI) refers to the failure of the DNA mismatch repair mechanism during the DNA replication process, which results in length changes in MS . MSI wasApproximately 20% of colon cancer patients are MSI-H/dMMR . Except However, although MSI-H/dMMR has a promising prospect as the biomarker for colon cancer immunotherapy, the reported ORRs in MSI-H mCRC patients vary from 30%-70% , 11–14; Furthermore, reasonable direct evidence for MSI-H/dMMR as a biomarker for immunotherapy is still lacking. Existing studies suggest that the main reason for the response of MSI-H patients to immunotherapy is that MSI may cause the production of new antigens, leading to the recruitment of immune cells and the release of proinflammatory factors. A higher TMB and infiltration of TILs were found in patients with MSI-H/dMMR . HoweverTMB is another potential effective biomarker in the field of tumor immunotherapy. TMB is usually defined as the total number of somatic mutations detected per million bases (muts/Mb). It was thought that a high TMB (TMB-H) status was related to more tumor neoantigens, and more tumor neoantigens presented on the surface of tumor cells may be recognized by immune cells and activate the body immune system to kill the tumor . In KEYNIn colon cancer, TMB was found to be potentially correlated with patient survival. It was reported that colon cancer patients with high TMB (TMB≥8 muts/Mb) presented longer OS than those with low TMB . AdditioOne of the greatest obstacles causing this controversy is the difficulty in defining the TMB cutoff value. Nonetheless, the cutoff of 10 muts/Mb presented a relatively good sensitivity in the prediction of immunotherapy in NSCLC and melanoma, but this cutoff value cannot be generalized for different tumor types . CurrentIn summary, although several pieces of evidence indicate that TMB cannot be used as an independent predictive biomarker in colon cancer immunotherapy, it is still valuable in immunotherapy efficacy prediction, especially when sufficient evidence is obtained for a valid TMB cutoff value in colon cancer. TMB can be used as an important complementary biomarker, such as when combined with MSI, and for identifying other significant gene mutations; it was found, that some MSS colon cancer patients with high TMB had polymerase epsilon (POLE) mutation, and they responded well to immunotherapy .Colon cancer is a heterogeneous disease. Colon cancer patients usually present different molecular subtypes. Some molecular subtypes, such as RAS and BRAF mutations, have already been used to guide the treatment and prognostic assessment of colon cancer . Among tThe CRC Subtyping Consortium, based on the gene expression of the tumor, proposed four CMSs for CRC using transcriptomics in 2015. The CMS classification included CMS1, CMS2, CMS3, and CMS4. CMS1 is categorized as MSI immune and presents with strong immune activation; CMS2 is categorized as canonical and is characterized by chromosomal instability as well as WNT and MYC signaling activation; CMS3 is categorized as metabolic and is associated with metabolic dysregulation; CMS4 is categorized as mesenchymal and is associated with prominent transforming growth factor β (TGF-β) activation, stromal invasion, and angiogenesis . CMS claHowever, existing CMS classification still has certain limits. CMS classification relies on transcriptome analysis of the entire tumor, which has inherent limitations such as stromal confounding and the presence of varied cell-type mixtures. Moreover, the differences in cancer cells and other stromal cells  are masked and indistinguishable , 78. TheIn conclusion, existing molecular subtypes and CMS may not be suitable for stratifying colon cancer patients for immunotherapy. The molecular subtypes and CMS help define the molecular and immunological characteristics of colon cancer, which contribute to the precise therapy of colon cancer. As research progresses, the understanding of the molecules subtype of colon cancer patients continues to improve and a more precise molecular subtype of colon cancer may be recognized, and a more precise CMS classification may be refined, which will further contribute to colon cancer immunotherapy.TME plays an essential role in tumorigenesis, development, and immune escape . IncludiIn several clinical trials of colon cancer immunotherapy, TILs showed potential in being used as predictive biomarkers for immune response. In an analysis study of the KEYNOTE 177 trial, colon cancer patients’ response to immunotherapy was found to be not associated with TMB, but rather with TILs. Immunotherapy-responsive CRC patients were found rich in CD-8+PD-1+ T cells . In LoupCD3+ T cells and CD8+ T cells are two important types of TILs that represent the total T cells and cytotoxic T cell subsets, respectively. In 2018, the Society for Immunotherapy of Cancer proposed using Immunoscore (IS) to estimate the risk of recurrence in colon cancer patients, and their findings proved the powerful role of IS in CRC recurrence risk assessment . IS is bPD-L1 is another important indicator for TME. Tumor cells induce tumor immune escape by upregulating PD-L1 expression, which binds to PD-1 on the surface of T cells, causing T-cell deactivation. ICIs can reactivate the body’s antitumor immunity by blocking the binding of PD-1 and PD-L1 . Thus, iNonetheless, PD-L1 expression still has value in immunotherapy for colon cancer patients. The PD-L1 expression level is an important indicator of the immune status of cancer patients –140, andTherefore, TME immune landscape is significantly related to tumor immunotherapy response. It is not sufficient to evaluate tumor response to immunotherapy by a single index only, such as PD-L1 expression or the number of TILs. A more comprehensively quantified TME immune landscape is necessary for the prediction of colon cancer immunotherapy response.via the secretion of various cytokines and chemokines, shaping an immunosuppressive TME and helping tumor cell immune evasion. In addition, CAFs play a significant role in constituting the inflammatory TME of colon cancer  were identified and used to construct a risk-scoring model. The results of this study show that the inflammatory response has a direct impact on CRC patient prognosis and immune infiltration. Thus, further classifying inflammatory response-related genes may help find predictive biomarkers for immunotherapy in colon cancer .Through analysis by transgenomic techniques, some TME-related gene signatures were proposed for use as biomarkers for colon cancer immunotherapy. However, most of these studies were derived from bioinformatic analyses of databases; further validation of these genes in large prospective clinical studies is necessary.The gut microbiota is another hot topic in the current field of immunotherapy. Several studies have proposed that gut microbiota are involved in tumor formation and progression and correlate with patient therapy response in solid cancers –164. It Colon cancer presents with an altered state of gut microbiota, which is known as dysbiosis . The gutThe testing method of gut microbiome detection also needs to be optimized and unified. Current methods for testing the gut microbiome are mainly stool-based genetic tests. The two commonly used methods are PCR-based 16S amplicon sequencing and macrogenome sequencing. PCR-based sequencing of 16S amplicons is relatively less costly, however this method is limited to the genus level and can easily miss microbiomes with low expression levels. In contrast, macrogenomic sequencing has several potential advantages over 16S amplicon sequencing. Macrogenomic sequencing can extend gut microbiome taxonomic resolution to the species level and can also provide information on metabolic pathways of the microbiome. However, the cost of macrogenomic sequencing is relatively high, and the interpretation of analysis results is complex . MeasureCtDNA is the most used peripheral blood biomarker. Previously, ctDNA already presented high sensitivity in colon cancer early diagnosis, recurrence detection, and treatment outcome prediction , 177. CtIn addition to ctDNA, various immune cells can also be tested in the peripheral blood, including T cells, B cells, NK cells, and myeloid cells . These cInflammation also plays an essential role in colon cancer tumorigenesis and influences patients’ immunotherapy response . LymphocIn summary, tissue-based predictive biomarkers are more accurate and closely related to TME. However, there are still some challenges in some clinical situations. Tissue biopsies are invasive, and may be difficult to obtain in advanced and metastatic patients. In addition, intratumoral heterogeneity is prevalent among tumor tissues. Multipoint sampling is necessary to obtain more accurate results, but it is difficult to achieve in clinical settings, as it requires invasive procedures for the patient . Under sIn recent years, ICI-based immunotherapy has brought revolutionary breakthroughs in the treatment of colon cancer. While immunotherapeutic agents continue to be researched and developed, it is also worth focusing on precisely screening beneficial patients through predictive biomarkers. Currently, MSI is the only approved biomarker for screening colon cancer immunotherapy-benefiting patients. However, the results of existing clinical studies indicated the low efficacy of MSI as a predictive biomarker for colon cancer immunotherapy. Several new predictive biomarkers have been proposed in colon cancer immunotherapy. Developments have also been made in the detection method of predictive biomarkers for immunotherapy of colon cancer. In this review, we summarized the currently reported predictive biomarkers in existing studies of colon cancer immunotherapy.We concluded that immunotherapeutic biomarkers reported in the clinical studies for colon cancer can be divided into four main categories Figure 1In summary, there is no optimal predictive biomarker for immunotherapy of colon cancer till now, and each biomarker has its limitations. Although the combined application of multi-methods for recognizing multi-indicators could improve the accuracy of biomarkers for colon cancer immunotherapy, large numbers of clinical trials are needed to verify that. With the optimization and improvement of the technology, more accurate biomarkers for predicting immunotherapy of colon cancer will help to stratify patients, which will also greatly improve the prognosis and the overall survival rate of patients(I) Conception and design: WH, CY, HZ; (II) Administrative support: CY; (III) Provision of study materials or patients: CY, HZ; (IV) Collection and assembly of data: WH, CY, HZ; (V) Manuscript writing: WH, CY, HZ. All authors contributed to the article and approved the submitted version.This study was supported by grants from the Key research projects of Science & Technology of Sichuan Province (2022YFS0189) and the Fundamental Research Funds for the Central Universities (2022SCU12058).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


SAPHO  syndrome is a rare autoinflammatory condition describing the constellation of inflammatory skin, bone, and joint manifestations which result in diagnostic difficulty and therapeutic challenge.  Here, we present a case of a young male diagnosed with SAPHO syndrome with osteoarticular and cutaneous involvement from an early age in his life. He suffered diagnostic challenges for a long time and was hence inadequately treated. He had minimal response to conventional DMARDs but showed excellent response to TNF inhibitor . Later, he defaulted treatment and presented with acute anterior uveitis which was also dramatically improved with adalimumab and tofacitinib although financial constraint was always an issue for the patient.  The uniqueness of this case was that the patient had a multiorgan involvement including osteoarticular system, skin, and eye. Both TNFi  and JAKinib (tofacitinib) had a good response to all organs with a net improvement in the quality of life of this patient. SAPHO  syndrome is a rare form of autoinflammatory condition involving cutaneous and musculoskeletal (bone and joint) systems. Owing to varied manifestations, it often poses diagnostic and therapeutic challenges . First rAn eighteen-year-old male, symptomatic for six years, had developed pain and swelling in bilateral forearms and had been diagnosed with chronic osteomyelitis following a bone biopsy. He subsequently noticed acneiform and pustular lesions over the face, which spread to the neck, trunk, and limbs that crusted and healed with residual hyperpigmentation. Initial skin biopsy showed inflammation with giant cells in the epidermis and lymphoplasmacytic infiltrate in the dermis with a probable diagnosis of tubercular verrucosa cutis. He was treated with antitubercular therapy (ATT) for six months without any improvement. Repeat skin biopsy showed nonspecific inflammation with dense neutrophilic infiltrate. Meanwhile, the patient developed inflammatory polyarthritis of both knees, ankles, and sternoclavicular joints when he visited our outpatient clinic. On examination, he had active synovitis in both knees, wrist, elbow and sternoclavicular joints, multiple acneiform and pustular lesions over the chest, back, face, and upper and lower limbs . ImagingFour months later, he developed acute onset right eye painful redness with the blurring of vision and was diagnosed as acute anterior granulomatous uveitis with posterior synechiae formation . He was SAPHO syndrome should be suspected when a young patient presents with predominant large joint arthritis, axial arthritis, and osteomyelitis with certain cutaneous changes. Its diagnosis is based on clinic-radiological findings and after the exclusion of infective or malignant aetiology. There are a few criteria proposed for this entity, among them modified Kahn and Benhamou's criteria are commonly used. As per modified Kahn criteria , inclusiLPIN2 gene), or deficiency of Il-1 receptor antagonist (DIRA) (caused by recessive inherited mutation in IL1-RN gene) [Other differential diagnoses should be ruled out before making a diagnosis of SAPHO . The twoRN gene) .α in bone specimens of SAPHO patients have been described recently [α blocking agents (infliximab and etanercept) has been reported with significant improvement.Although the pathogenesis remains elusive, elevated levels of TNF-recently , and theDaoussise et al.  identifiLiterature showed variable cutaneous response with TNF inhibitors mainly with infliximab. Several authors  reportedAssociation of SAPHO syndrome and uveitis was first reported by Villaverde et al.  in a 40-The use of JAK inhibitor in SAPHO syndrome is relatively new and limited to very few case reports. A 44-year-old woman with SAPHO was treated with tofacitinib 5 mg BD dose with marked improvement in arthralgia by 4 weeks . AnotherThe combination of adalimumab with background conventional DMARD therapy proved to be safe and efficacious for the treatment of cutaneous, osteoarticular, and ocular involvement in SAPHO syndrome, determining the rapid onset and sustained clinical remission. Tofacitinib is another promising therapy although data are limited. Most of the published reports of SAPHO syndrome are individual case-based, so large, multicentre observational studies are needed in order to assess the long-term outcomes of patients affected by SAPHO syndrome.