Staphylococcus aureus (MSSA) with identical antibiotic sensitivities. Further imaging failed to reveal an underlying greater pathology. Intranasal swab revealed identical culture and sensitivity results as previous blood, CSF, and urine cultures and was thus hypothesized to be the source of infection. This case aims to elucidate the harmful effects of nose-picking as well as the importance of prevention, diagnosis, and management.Rhinotillexomania, more commonly known as nose-picking, is a body-focused repetitive behavior that involves compulsive picking of the nares. While nose-picking in general is a common and largely unharmful practice worldwide, severe complications from chronic nose-picking do exist. This case highlights a 66-year-old female with a longstanding history of nose-picking and nose blowing who presented to the emergency department with acute delirium and various bodily complaints. She was subsequently admitted multiple times for recurrent sepsis, meningitis, endocarditis, cystitis, and discitis with each culture positive for methicillin-sensitive  Nose-picking is an almost universal practice in adults with 91% of adult respondents to the Rhinotillexomania Questionnaire acknowledging digitalization of the nares as an active and regular behavior . In addiRhinotillexomania can result in minor disruptions of midline structures with the potential for routine healing if the inciting picking stimulus is aborted. Extreme cases of continued digital trauma can cause clinically significant epistaxis from the exposure of the underlying Kiesselbach’s vascular plexus which serves as the terminus of the sphenopalatine artery branch of the maxillary artery from the external carotid artery, the greater palatine branch of the maxillary artery from the external carotid artery, the superior labial branch of the facial artery from the external carotid artery, and the anterior ethmoidal branch from the internal carotid artery .Staphylococcus aureus in the nares [ Staphylococcus aureus are also commonly attributed to nose-picking. Furthermore, sinus and nasal skin infections can lead to septic cavernous sinus thrombosis, a rare and life-threatening condition caused by the formation of a blood clot in the cavernous sinus of the brain. With many possible avenues for distant spread of infection, we discuss a novel case of a 66-year-old female with a history of chronic nose-picking who presented to the emergency department with recurrent sepsis, meningitis, endocarditis, discitis, and cystitis refractory to IV antibiotics.There are few deleterious effects of nose-picking, most of which are confined to the nares. However, the more severe cases are exceedingly rare and largely unreported in the literature. Some cases of nasal septal perforations are due to the digital trauma from chronic nose-picking, causing erosion through the nasal septal cartilage . The lithe nares . Mild epThe patient is a 66-year-old Caucasian female with a history of well-controlled non-insulin dependent Type 2 diabetes mellitus, right total knee arthroplasty in 2012, and left total knee arthroplasty in 2014 who was initially referred to otolaryngology for evaluation of chronic rhinorrhea. She reported a greater than 30-month history of daily and repetitive intranasal tissue manipulation coupled with alternating daily use of over-the-counter oxymetazoline and phenylephrine nasal spray preparations. The physical examination revealed dry nasal mucosa with a left inferior bone spur along with intranasal scarring bilaterally over the anterior nasal septum likely secondary to excessive tissue use. For rhinitis medicamentosa, she was treated with a tapering dose pack of prednisone, intranasal flunisolide spray, and the directive to discontinue all over-the-counter medicated nose sprays. The patient did not return for follow-up evaluation.The patient required hospitalization 26 months later for evaluation of a three-week history of progressive posterior neck pain and headache associated with nausea, and asymptomatic palpitations without febrility, vomiting, or mental aberrations. Blood, urine, and cardiac workup revealed no significant abnormalities. Chest and brain imaging was inconclusive. Neurologic consultation confirmed cervicalgia secondary to osteoarthritis with the degenerative joint disease of the cervical spine with cervical paraspinous muscle spasm. The head and neck discomfort resolved with physical therapy and acetaminophen. Lumbar puncture was declined by the patient who was discharged within 48 hours of admission.The patient required another hospitalization six weeks later for evaluation of an acute onset and rapidly progressing dyspepsia with nausea and vomiting, febrility, confusion, disorientation, slurred incoherent speech, and atrial fibrillation with rapid ventricular response requiring cardiology and neurology consultation and medical intensive care unit (MICU) admission.Lumbar puncture on the second day of hospitalization revealed RBC count of 5,220/mm3, WBC of count 5850/mm3, segmented neutrophils 93%, lymphocytes 7%, no cells observed for cytology, glucose 169 mg/dl, and total protein 127 mg/dl.Staphylococcus aureus (MSSA) with identical sensitivities. The patient developed right lateral elbow erythema, swelling, calor, and dolor with cellulitis and olecranon bursitis. The elbow and forearm had fullness noted in the region of the olecranon bursa with no underlying lytic or blastic bone lesions and no joint effusion. Ceftriaxone, vancomycin, and doxycycline were discontinued and nafcillin was initiated to better target MSSA. The specific sensitivities are detailed in Table Two blood cultures, urine cultures, and cerebrospinal fluid cultures revealed methicillin-sensitive The patient presented to the ED from the acute rehabilitation hospital four weeks later for symptomatic palpitations and hypokalemia without leukocytosis or febrility which promptly responded to treatment with intravenous and oral potassium replacement therapy and the initiation of beta-blockade therapy with no findings indicative of acute coronary syndrome. The patient was discharged to return to the ARH.C. difficile toxin A and B. Gastroenterology consultation confirmed acute viral gastroenteritis with the patient promptly responding to intravenous fluid (IVF) hydration, oral and intravenous potassium and magnesium replacement therapy, probiotic therapy, and cholestyramine therapy. The patient was discharged home with home health where she manifested persistent anorexia, dyspepsia, and weight loss. She would later admit that she continued to excessively digitally manipulate her nares with a finger covered with tissue paper multiple times daily exhausting the supply of a medium-sized paper tissue box containing 65 tissues approximately every three days.The patient required another hospitalization two weeks later after being admitted from the ARH for diarrhea, profound hypokalemia, generalized weakness, dehydration, and hypomagnesemia without leukocytosis or febrility with two serial stool sample specimens both negative for The patient required another hospitalization four weeks later for progressive intractable nausea, vomiting, increasing weight loss with a BMI of 17.8 kg/m2, and increasing generalized weakness with infrequent loose stools without febrility, chest pain, or palpitations. Her evaluation revealed dehydration and profound hypokalemia with a serum potassium of 1.9 millimoles/liter requiring IVF hydration and oral and intravenous potassium replacement for treatment. Two repeat blood cultures revealed MSSA with identical sensitivities to the blood cultures obtained 10 weeks earlier. The patient was discharged to a long term care facility for subacute care to receive six weeks of intravenous nafcillin therapy. During the subacute long term care facility admission for the administration of six weeks of intravenous nafcillin therapy, nasal swab bacterial culture of the right nares revealed MSSA with identical sensitivities to the two blood cultures, urine cultures, and cerebrospinal fluid cultures obtained 12 weeks earlier and the two blood cultures obtained two weeks earlier. Referral to otolaryngology revealed right anterior septum superficial excoriations and abrasions with no erythema or purulence. They initiated treatment with mupirocin ointment to the right anterior septum three times a day for seven days followed by the application of saline nasal gel to the anterior septum with the specific directive to discontinue all applications of paper tissue into the nares.The patient required another hospitalization eight weeks later for evaluation of progressive weakness, right knee swelling and pain, left hip and proximal femur pain, and right neck pain and stiffness with chest x-ray (CXR) revealing no acute cardiopulmonary disease. Nuclear medicine leukocyte scan revealed no abnormal tracer accumulations in the head, chest, abdomen, or pelvis with no sites of acute infection or inflammation identified. Laboratory testing revealed a leukocytosis of 21.06 K/mm3 and at admission the patient was provided with empiric vancomycin and Levaquin therapy. The two blood and cerebrospinal fluid (CSF) cultures showed similar sensitivities as the previous hospitalizations. The patient was discharged home with home health to complete a 10-day course of oral Levaquin therapyThe patient required another hospitalization 10 days later for recurrent generalized weakness, anorexia, cachexia, and debility with dehydration. She also had relative hypotension with mild leukocytosis and two negative blood cultures. She promptly responded to treatment with IVF hydration. The patient was discharged home with home health on oral levaquin therapy. The patient required another hospitalization one week later for recurrent and progressive neck pain with generalized weakness, anorexia, cachexia, and debility without febrility, hypotension, or leukocytosis. MRI of the cervical and thoracic spine with and without contrast revealed discitis and osteomyelitis at T4-T5 with elevation of the posterior longitudinal ligament and mild central canal stenosis with surrounding soft tissue inflammation lateral and anterior to the spine without epidural abscess formation Figure . The patStaphylococcus aureus (MRSA). Three days later, the patient received a left total knee resection with revision of both arthroplasty prosthesis components and antibiotic articulating spacer insertion. The left knee intraoperative tissue culture revealed MRSA as well. The patient was discharged to a long-term care facility for subacute care to receive six weeks of intravenous vancomycin therapy.The patient required another hospitalization 13 months later for revision of a right total knee arthroplasty with the insertion of an antibiotic spacer for an infected right total knee prosthesis subsequent to the acute onset of bilateral knee pain with erythema, calor, dolor, and swelling two weeks previously. The right knee synovial fluid culture and intraoperative tissue culture revealed methicillin-resistant Subsequent to the successful modification of the aberrant behavior of rhinotillexomania and the cessation of the use of over-the-counter intranasal spray products, the patient has not required any further antibiotic therapy or inpatient hospital care.Over the course of several months, the 66-year-old white female detailed in this case report experienced a potentially life-threatening sequelae of sepsis with acute metabolic encephalopathy and delirium, respiratory failure requiring non-invasive ventilatory support, cystitis, meningitis, endocarditis, pneumonia, discitis, cellulitis, bursitis, and septic arthritis secondary to MSSA. After successful treatment during the two hospital admissions in which blood, urine and CSF cultures were positive for MSSA, the patient was referred to otolaryngology for treatment of her nasal lesions which were found to carry MSSA with identical sensitivities as those from the prior blood, urine and CSF cultures. After adequate counseling and treatment of the nasal lesions, the patient remained culture-negative throughout the remainder of her hospital admissions. The identical culture and sensitivities suggest a common etiology for her widespread systemic infection. In addition, MSSA, being an unusual cause of infection in the organs affected in this patient, suggests spread from a distant site and possibly a more rare and ill-defined etiology for infection. Corynebacterium, Propionibacterium, and Staphylococcus genera are the most abundant bacteria [S. aureus nasal carriers were three times more likely to develop nosocomial S. aureus bacteremia compared to non-carriers [S. aureus was associated with three times greater risk of bacteremia, it did not accompany a greater risk of mortality. In fact, S. aureus bacteremia-related death was significantly higher in non-carriers than in carriers [S. aureus with identical culture and sensitivity results as those obtained from the nares and did not suffer from bacteremia associated death. It is theorized that exposure of the nasal septal vasculature to the nasal microbiota provided a route for systemic hematogenous spread. Chronic nose-picking has been widely associated with increased bacterial colonization of the anterior nares. The adult nasal microbiota differs between individuals, but species belonging to bacteria ,8. Althobacteria . In our carriers . Furthercarriers . SimilarThe complications associated with chronic rhinotillexomania can range from minor to severe and, potentially, life-threatening. Treatment relies on the prevention of extension and progression to greater complications which are often limited by patient access to treatment, patient compliance, and physician accuracy of diagnosis. The condition may initially present as a nosebleed or localized intranasal lesion, but a thorough history and physical examination are essential for early diagnosis and treatment. Once a history of chronic nose-picking has been identified as a potential cause of the patients symptoms, early management should involve counseling the patient on the importance of cessation. While most cases of nose-picking represent a benign habit, when the practice is extreme, as in our patient, it can be a manifestation of an underlying condition. Potential causes may include anxiety, dementia, obsessive-compulsive disorder, empty nose syndrome, allergic or non-allergic rhinitis, and/or anatomical defects ,10,11. TS. aureus infection affecting multiple organs as detailed in this case, a thorough history and physical examination revealed a longstanding history of rhinological complaints and nose-picking evidenced by extensive nasal excoriations requiring prompt medical attention. After evaluation and management with otolaryngology, the patient remained culture-negative and was able to experience a full recovery. Thus, we concluded that the patient’s history of nose-picking was a largely preventable risk factor and cause for her illness presentation. Since the identification and diagnosis, in this case, progressed to the point of multidisciplinary involvement, there is a need for otolaryngologists and primary care specialists to educate and counsel patients on the importance of nose-picking cessation in an effort to avoid another case of near-fatal nose-picking.Although the vast majority of nose-picking is unharmful, the progression to chronic nose-picking has gained some attention in the literature and has been termed rhinotillexomania. After an unusual recurrence of widespread


Bartonella henselae. The most common ophthalmological involvement due to infection by Bartonella is Parinaud oculoglandular syndrome, whereas the most common posterior segment findings are neuroretinitis and subsequent late macular star. Moreover, other findings, such as retinal or subretinal lesions, intermediate uveitis and angiomatous lesions, may be present.Cat scratch disease is a systemic infectious illness caused by the bacterium Bartonella infection was evaluated via multimodal retinal exams. The patient received treatment with doxycycline 100 mg twice daily for 2 weeks. One month after treatment, complete improvement of her visual scotoma symptoms was confirmed. A swept-source optical coherence tomography exam also showed decreases in the size and intraretinal extension of the lesion. Improvement of light perception at the affected area was confirmed by microperimetry.A 37-year-old female patient with retinal findings and serological confirmation of Bartonella henselae infection, particularly retinitis, can present a variable spectrum of clinical and ophthalmological findings. Multimodal retinal exams can clearly identify lesion characteristics, thus providing important information for diagnosis and the evaluation of lesion improvement after antibiotic treatment. Bartonella henselae, a gram-negative bacillus responsible for a disease with a variable clinical spectrum [Cat scratch disease is a systemic infectious illness caused by the bacterium spectrum –3.Bartonella is Parinaud oculoglandular syndrome, first described in 1889, which presents as ulcerative chronic conjunctivitis and lymphadenopathy [The most common ophthalmological manifestation of enopathy . The mosenopathy , but othenopathy .Bartonella infection who was evaluated with multimodal retinal exams, including retinography, swept-source optical coherence tomography (SS-OCT), fundus autofluorescence (FAF), fluorescein angiography (FA), angio-OCT, and microperimetry, before and after antimicrobial treatment.This case report describes a female patient with retinal findings and serologically confirmed A 37-year-old female presented at the emergency sector with a chief complaint of paracentral visual scotoma in her left eye for 3 weeks. She referred that the scotoma occurred suddenly and that this symptom was steady and painless. A couple days prior to the onset of the visual complaint, she had a mild headache and unverified fever.Upon ophthalmological examination, she presented with best corrected visual acuity of 20/20 in both eyes and intraocular pressure of 14 mmHg (OD) and 15 mmHg (OS). Anterior biomicroscopy revealed a clear cornea, clear conjunctiva, deep anterior chamber, no anterior chamber reaction and no vitreous cells in both eyes. The retinal fundoscopic exam indicated one small (0.1 optic disc diameter) white round lesion in the superior nasal vessels area of the right eye and two small parafoveal round nasal yellowish lesions and one small white lesion at the inferior temporal vessels area of the left eye , FAF (fundus autofluorescence), FA (fluorescein angiography), angio-OCT and microperimetry were performed. General ancillary exams included general tests such as systemic serum laboratory workup, thorax radiography and infectious serologies.SS-OCT showed preserved retinal layers in macular topography and well-limited intraretinal lesions extending from superficial to deep retinal layers Fig. . EpidemiThe first diagnostic hypothesis considered was chorioretinopathy of both non-infectious causes, such as punctate inner choroidopathy (PIC), multiple evanescent white dot syndrome (MEWDS), and sarcoidosis, and infectious causes, such as tuberculosis, syphilis, toxoplasmosis or bartonellosis.Bartonella henselae serology was positive, with an IgG of 1/128, and treatment with 100 mg doxycycline every 12 h for 2 weeks was administered.Her laboratory workup included non-reactive serologies for syphilis, HIV and toxoplasmosis, tuberculin skin-test of zero, non-reactive anti-nuclear factor, reactive c-protein of 7  and erythrocyte sedimentation rate of 44 . Her complete blood count exam reported normal red blood cell and platelet values and mild leukocytosis due to mild neutrophilia  but without a left shift. Thorax radiography did not show significant findings. One month after treatment, she reported an improvement of visual scotoma symptoms. At her retinal fundus examination, it was possible to locate only one of the previous lesions , and the presentation of this lesion was more subtle than at the first evaluation. SS-OCT also showed decreases in lesion size and intraretinal extension. Microperimetry showed an improvement in light perception in the affected area Fig. .Fig. 2CoEighteen months after the initial presentation, the patient underwent another evaluation. She had no visual complaints and her ophthalmologic exam was normal. There were no more signs of retinal lesions at the fundoscopy. Microperimetry showed a greater improvement in light perception at the previous affected area and SS-OCT showed only a mild disorganization in intermediate retinal layers at the site of the previous lesion surrounded by a halo Fig. .Bartonella henselae neuroretinitis is a swollen optic disc and macular edema as described by Sweeney and Drance in 1970, but this disease may present a variable spectrum of clinical and ophthalmological findings [Bartonella henselae.The classic presentation of findings . This caMultimodal retinal exams helped to clearly identify the lesions’ characteristics as well as their improvement after antibiotic treatment. SS-OCT, angio-OCT and en-face evaluation facilitated the determination of the exact lesion topography and the exclusion of other macular involvement. FAF and FA enabled the evaluation of the lesions’ characteristics and the exclusion of other conditions, such as neuritis and vasculitis. Microperimetry examination objectively detected visual scotoma and subsequent improvement in both eyes. All exams showed improvement at one month follow-up after antimicrobial therapy, with a decrease in lesion size and improvement of visual scotoma based on microperimetry. Eighteen months after the initial presentation, multimodal retinal evaluation showed an even greater improvement of the retinal involvement and light perception at the affected area of the previous lesions.Bartonella henselae infection, particularly retinitis, can present as a variable spectrum of clinical and ophthalmological findings. It is important, as soon as this etiology is suspected, to actively investigate and question the epidemiologic exposure, since it is an information that is usually neglected by patients during interrogation and that helps on the formulation and corroboration of the diagnostic hypothesis, especially if it is a positive finding [ finding . MultimoBartonella henselae retinitis with multimodal retinal exams before and after treatment, which led to an objective improvement in symptoms.To the best of our knowledge, this is the first report of the evaluation of In summary, we report the utility of multimodal retinal exams in the diagnosis, follow-up, and improved characterization of a retinal infectious disease, particularly for an atypical case in which other possible diagnoses have to be considered.


Me & My Wishes are person-centered videos of long term care residents (ages 65-95) living with dementia discussing their preferences for care including end-of-life (EOL) medical intervention. We evaluated the congruence of six EOL treatment preferences between the residents’ personal videos, medical records (e.g. advance directive), and surveys of family (n= 49) and staff  knowledge of their preferences. Results were highly discordant. Treatments with the most discordance when comparing videos to comparison groups were IV fluids  and life support . Residents reported EOL treatments were considered acceptable if they were temporary, would relieve suffering, or enabled a return to baseline health. These caveats may lead to discordance if they are not conveyed to family or staff. Our findings highlight the need for conversations among residents living with dementia and their caregivers to improve understanding, congruence and adherence of resident EOL preferences.


As for many other adult stem cells, the behavior of hematopoietic stem and progenitor cells (HSPCs) is subjected to circadian regulatory patterns. Multiple HSPC functions, such as proliferation, differentiation or trafficking exhibit time-dependent patterns that require a tight coordination to ensure daily blood cell production. The autonomic nervous system, together with circulating hormones, relay circadian signals from the central clock—the suprachiasmatic nucleus in the brain—to synchronize HSC niche physiology according to light/darkness cycles. Research over the last 20 years has revealed how specific neural signals modulate certain aspects of circadian HSC biology. However, only recently some studies have started to decipher the cellular and molecular mechanisms that orchestrate this complex regulation in a time-dependent fashion. Here we firstly review some of the recent key findings illustrating how different neural signals (catecholaminergic or cholinergic) regulate circadian HSC egress, homing, maintenance, proliferation, and differentiation. In particular, we highlight the critical role of different neurotransmitter receptors in the bone marrow microenvironment to channel these neural signals and regulate antagonistic processes according to circadian cues and organismal demands. Then, we discuss the potential biological meaning of HSC circadian regulation and its possible utility for clinical purposes. Finally, we offer our perspective on emerging concepts in HSC chronobiology. Throughout evolution, most species have developed the capacity to adapt their behavior and physiology to the day-night oscillations derived from earth's 24 h rotation. In mammals, these so-called circadian functions are synchronized by light-darkness shifts, and influenced by other factors, such as alimentary habits. The circadian system has at least two different levels of complexity. Centrally, the suprachiasmatic nucleus, located in the hypothalamus, is the anatomical structure that orchestrates the organism's circadian activities. This master clock receives photic input from photosensitive neurons in the retina through the retino-hypothalamic tract and processes this information to synchronize the circadian rhythms in peripheral tissues. However, most cells display at least one intrinsic or internal clock that influences their proliferation, differentiation and migration properties. This cellular clock is periodically reset by neuroendocrine signals emanating from the suprachiasmatic nucleus, which resets or synchronizes the peripheral oscillators throughout the body .Already in the late 70s it was suspected that circadian rhythms might decisively influence stem cell functions and thus control both homeostasis and regeneration of peripheral tissues . HematopThe sympathetic branch of the autonomic nervous system connects the master clock in the central nervous system with peripheral organs to relay circadian information. For instance, adrenergic signals regulate clock gene expression in mouse liver , mouse hSympathetic nerves enter the BM associated with arteries and arterioles, and once inside the BM these nerves sprout throughout the BM space. BM sympathetic fibers mainly release noradrenaline in the BM, although both circulating noradrenaline and adrenaline can also reach the BM cavity via the vascular network . In sharIn this article, we discuss recent findings clarifying the roles of (nor)adrenergic and cholinergic signals to regulate different circadian HSC functions in BM niches. The future directions and perceived challenges for the future development of this multisystemic research are outlined below.The HSC is a unique type of adult stem cell since it preserves a remarkable migratory capacity at adulthood . HSCs ci−/− mice  and modulate CXCL12 production. This regulation leads to daily fluctuations in BM CXCL12 levels that inversely correlate with HSC numbers in the bloodstream. At daytime (the resting period in mice), light-induced noradrenergic signals downregulate CXCL12 expression via Sp1 transcription factor and promote HSC egress to the bloodstream. At night, BM CXCL12 levels are restored and HSCs preferentially return to the BM . Remarkably, although circadian signals reach the BM through sympathetic terminals, their origin is set in the clock genes of the suprachiasmatic nucleus since normal circadian fluctuations are entrained by light and disappear in Bmal1−/− mice . Importa−/− mice . Interes−/− mice , suggestDifferent types of adrenergic receptors cooperate in the regulation of HSC traffic. Besides the described role for β3-adrenergic receptor, β2-adrenergic receptor appears to regulate clock gene expression in BM stromal cells and cooperates with β3-adrenergic receptor in HSPC mobilization induced by granulocyte colony-stimulating factor (G-CSF), the agent most commonly used in the clinics . InteresDespite these important findings, some critical aspects of circadian hematopoietic stem and progenitor cell (HSPC) traffic have long remained unanswered. For instance, A) how do BM stromal cells integrate similar noradrenergic signals at different circadian times and yet trigger distinct migratory processes (egress vs. homing)? In contrast to BM stroma-restricted expression of β3-adrenergic receptor, β2-adrenergic receptor is ubiquitously expressed , 29. As An additional candidate neurotransmitter regulating HSPC traffic was hypothesized to be acetylcholine. Although modest, cholinergic innervation arising from the cholinergic forebrain and brain stem nuclei has been found in the suprachiasmatic nucleus. These cholinergic neurons have been proposed to play a role in the formation of time memory (memory of a specific time of the day associated with a certain event) . RecentlIn the context of physiological human hematopoietic cell trafficking between the BM and peripheral blood, one group of leukocytes  peak in the bloodstream at daytime, whilst another group (CD4+ T cells and B cells) exhibit an increase at night. Interestingly, those leukocytes with peak numbers in circulation at daytime express a higher density of adrenergic receptors, whereas those peaking at night carry a higher proportion of cholinergic receptors . TogetheIndeed, we recently showed that the autonomic cholinergic nervous system  cooperates with (nor)adrenergic sympathetic signals to orchestrate day/night oscillations of circulating HSPCs and leukocytes . Our finAt night, inhibitory central cholinergic signals (parasympathetic) dampen sympathetic noradrenergic tone to reduce nocturnal egress of HSPCs and leukocytes from the BM into bloodstream. Whether central parasympathetic circadian activity is regulated by core clock genes in the suprachiasmatic nucleus or elsewhere remains unknown. Collectively, the results suggest that this cholinergic regulation cooperates with adrenergic signaling to drive HSPC and leukocytes recruitment to the BM during the active phase . We propose that plasma adrenaline, which follows circadian fluctuations peaking at night , 37, preIn mice, light cues trigger sympathetic noradrenergic activity, which signals through β3-adrenergic receptor leading to predominant BM egress of HSPCs and leukocytes in the morning . HoweverSelective predominance of different β-adrenergic signaling at daytime and night, together with differential affinities of catecholamines for β-adrenergic receptors, may explain how sympathetic noradrenergic signals trigger BM egress or homing at different time points. Furthermore, we propose that a robust circadian rhythmicity in β-adrenergic receptor expression in BM stromal cells allows for these fine-tuned oscillations. Whereas, β3-adrenergic receptor expression is higher after light exposure (when BM egress becomes overriding), β2-adrenergic receptor expression predominates at night (when BM homing is maximum) . An addiWhilst it has been long appreciated that mouse and human HSPC proliferation (indirectly measured as DNA synthesis in the BM) follows a cyclic pattern, whether it is subjected to a bona-fide circadian rhythmicity has remained controversial for a long time –45. A poThe Lapidot group confirmed these initial findings in humans using immature CD34+ cells . It is iThe Lapidot laboratory has recently revealed the role of circadian BM noradrenergic signals in regulating the maintenance, proliferation and differentiation of mouse HSCs . InteresCxcl12  might actually represent a paradigmatic example of integrated physiology , since rCxcl12 . These dCxcl12 , suggestCxcl12 . TherefoMore broadly, many cytokines regulating bone accrual and bone formation work in a circadian fashion (with higher bone formation rate during the day in rodents) , 58. Theper se from the physiological processes undergoing oscillations. For instance, sleep deprivation in mice reduces by 50% the capacity of HSCs to engraft into recipient mice undergoing normal day/night sleep cycles  might contribute to regenerate BM stem cell niches , 59. Cirp cycles , but it Another possible function of circadian HSPC traffic would be to maintain a pool of circulating progenitor cells to anticipate potential requirements derived from stress situations. In this sense, inflammatory monocytes have been found to follow circadian oscillations. However, this was shown to be mediated by intrinsic Bmal1 expression in myeloid cells, rather than light or environmental cues . In the As indicated above, clock genes in HSCs do not seem to play a crucial role in the homeostatic regulation of healthy HSCs but, as gatekeeper regulators of cell cycle, they can acquire a prominent role during stress  . In contSince both circadian HSC proliferation and migration can impact HSC numbers in circulation, on a practical note it is recommended that clinicians consider harvesting blood (apheresis) later during the day to increase the stem cell yield in cases where HSC numbers might be limiting for the success of HSC transplantation procedures. Based on experimental evidence, a 2-3-fold higher HSPC number can be harvested by apheresis in the evening, compared with the morning apheresis, even after G-CSF-enforced HSC mobilization , 71. In In this article, we have summarized our current knowledge of the circadian regulation of HSPCs with a particular focus on the important yet intriguing role of sympathetic noradrenergic signals promoting HSPC proliferation, differentiation and egress during the resting phase (daytime for rodents), and HSPC maintenance, self-renewal and BM homing during the active phase (night for rodents) . The conThe pathophysiological implications of the internal HSC clock remain largely unknown. In other systems, like the epidermis, the molecular clock machinery underlies the heterogeneity in the epidermal stem cell pool and could directly impact cell fate decisions, such as proliferation vs. dormancy. Particularly, differential clock gene expression leads to distinct responses of epidermal stem cells to transforming growth factor (TGF)-β and Wnt, which are signals that normally sustain their quiescence or proliferation, respectively . Furtherin vitro pluripotent potential inversely correlates with the establishment of a circadian clock machinery, suggesting a function of the clock genes during embryonic stem cell differentiation (Whilst the influence of the neural system on HSPC differentiation has already been noted , the molntiation , 75. Comntiation . The potFinally, cumulative evidence points toward the interplay among circadian clock system disruption, stress situations and multiple systemic diseases . In the AG-G prepared the figure. AG-G and SM-F authors wrote the manuscript.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.


Blue light cystoscopy (BLC) is the most recent clinical approach in the detection and diagnosis of bladder cancer, a common type of cancer with a high rate of recurrence. Representing a significant advance over previous approaches, this photodynamic diagnostic technique uses a photosensitiser prodrug as an adjunct to white light cystoscopy to enhance the in vivo detection of malignant tissues in the bladder based on their distinctive fluorescence. Whilst it does improve detection rates, BLC remains an invasive and costly procedure. Meanwhile, a variety of noninvasive urine detection methods and related microdevices have been developed, none of which have yet entered routine clinical use due to unsatisfactory sensitivity. Following a brief description of the current approaches and their limitations, we provide here a systematic review of a newer niche research aiming to develop a noninvasive adaptation of photodynamic diagnosis. The research to date surrounding the ex situ use of photosensitiser prodrugs for urinary diagnosis of bladder cancer is also discussed. Urothelial bladder cancer (UBC) is the sixth most common cancer in the world. According to the World Health Organization (WHO), there were 549,000 new cases and 200,000 deaths from bladder cancer worldwide in 2018 . If the There is currently no screening test for bladder cancer in asymptomatic people. Diagnostic procedures are performed in response to symptoms, with urine cytology and cystoscopy being the standard procedures. Urine cytology is a noninvasive method, based on the visual identification of abnormal cells from urine sediment following an extensive multistep sample preparation process. It has reasonable sensitivity for advanced tumours but for early or low-grade cancer, the sensitivity of cytology is only 33% . FurtherWhile the advantages of BLC over WLC are no longer contested ,14, it rNew noninvasive tests based on the detection of cancer-specific biomarkers in urine have been in development over the last decades. The different types of target biomarkers found in urine are summarised in In the quest for an accurate urinary biomarker for bladder cancer, many new—omics biomarkers have been reported ,22, as rIn attempts to reduce the operating complexity of urinary tests without compromising their efficiency, existing  and novel  detection approaches have been integrated into microdevices . Most ofFor instance, a negative pressure-driven microchip integrating magnetic microbead-assisted immunocapture of bladder cancer biomarker apolipoprotein A1 (APOA1), report a measurement time of 40 min which is six times faster than a conventional ELISA test . The detOverall, no urinary test based on urinary biomarker detection has yet replaced cystoscopy in screening and primary detection for NMIBC bladder cancer, according to current oncological guidelines /Society of Urologic Oncology (SUO) , NationaDespite these efforts, the greatest advance in bladder cancer diagnosis over the last decade remains blue light cystoscopy. A new body of work in the field has been identified where photodynamic diagnostic is used ex vivo in combination with microdevices. We will now review research which capitalises on the fundamental principle underpinning the cancer specificity of blue light cystoscopy to develop photobiology-enabled tests for noninvasive bladder cancer diagnostics.Blue light fluorescent cystoscopy using 5-aminolevulinic acid (5-ALA) as a photosensitiser prodrug has been introduced into practice in several countries, following its FDA approval for intraoperative PDD of bladder cancers in 1999 . 5-ALA iThe preferential accumulation of the photosensitiser PpIX in tumour tissue means that bladder cancer tissues show brighter and sharper red fluorescence than normal tissues when excited with blue-violet light . This is5-ALA, however, has limited bioavailability because it is a polar charged zwitterion. Esterification of 5-ALA has been used to improves its lipophilicity, thus overcoming the challenge of low bioavailability. Hexyl ester (hexyl aminolevulinate or hexaminolevulinate (HAL)) is the most successful 5-ALA derivative, and has been approved by the FDA and the European Association of Urology for the photodetection of bladder cancer via fluorescently assisted cystoscopy in 2010. HAL induces higher PpIX fluorescence at lower concentrations and with shorter time-spans. HAL-induced fluorescence cystoscopy improves the effectiveness of PDD in bladder cancer diagnosis [Hypericum perforatum also called St. John’s Wort. It is a polycyclic fluorescent red pigment present in different parts of the plant. Hypericin has absorbance maxima at 540 and 590 nm and emits an orange-red fluorescence at 590 nm and 640 nm as shown in Another important shortcoming of 5-ALA and its hexyl derivative is their fast photobleaching. For example, Sharwani et al.  reportedThe light emission of hypericin is strongly oxygen-dependent, hypericin generally shows minimal or no toxicity in the dark but generates singlet oxygen and reactive oxygen species (ROS) with a light wavelength around 590 nm . These rThe drawbacks of HY, however, are low solubility, costly production and hydrophobicity in solution. For these reasons, 5-ALA remains the most popular photosensitiser prodrug in clinical settings, however, the high resistance to photobleaching displayed by hypericin means that this alternative photosensitiser could be promising for ex situ applications, where light exposure is more of an issue.A systematic search of the literature published between 1950 and 2020 was conducted using PubMed and Web of Science. The search strategy used the following keywords:  and (hexaminolevulinate or aminolevulinic acid or protoporphyrin IX or 5-aminolevulinic acid or hypericin) and (detection or diagnosis) and (Urinary cytology or urine or noninvasive) and (fluorescence or photodynamic). Based on these initial selection criteria, a total of 275 original articles were identified. 46 duplicates, 28 articles not written in English and 19 articles not belonging to journal articles were excluded. Papers were eligible for inclusion where they focus on an ex vivo or in vitro use of 5-ALA, its derivative or hypericin for diagnostic purpose. Reports on invasive diagnostic methods, specifically blue light cystoscopy, photodynamic therapy (PDT) or the use of different photosensitising agents were, for instance, excluded. Following screening for eligibility, 23 studies met the criteria  59,60,6,80,81,82From the mid-1990s, several studies have investigated the response of cell lines to the exogenous administration of 5-ALA ,60,61,62The combination of 5-ALA intravesical instillation followed by urinary cytology later emerged as fluorescence cytology ,64,65, a5-ALA administration was investigated by Inoue’s group. 5-ALA was orally administered to 66 bladder cancer patients and 20 healthy volunteers, urinary porphyrin concentrations were measured by high-performance liquid chromatography (HPLC). They indicated that the fluorescence porphyrins can act as tumour biomarkers in urine samples [Since then, the ex vivo administration of 5-ALA ,69 and HThey conducted several experimental studies to refine the use of 5-ALA for ex vivo PDD where the photosensitiser prodrug is added directly to voided urine samples. In a comparative study , urine fAttempts to improve the performance of this method have included the use of HAL as the fluorescence inducing agent. HAL may be a better candidate than 5-ALA for ex vivo use in urine samples because it induces the intracellular PpIX accumulation at lower concentration and shorter incubation time than 5-ALA in vitro . FurtherAlthough hypericin has a strong tumour selectivity in vivo, an in vitro study investigating the hypericin-induced photosensitivities of different cultured cell monolayers (human bladder cancer and nonbladder cancer) revealed that normal cells displayed the same photosensitivity as cancer cells . While lNonetheless, following Pytel and Schmeller initial work with hypericin instillation , Olivo a5-ALA guided cystoscopy improves bladder cancer detection sensitivity compared with WLC but remains a costly invasive procedure. In contrast, cytology is noninvasive and selective but it has limited sensitivity. The application of cancer-specific photosensitiser prodrugs in urine cytology has the potential to combine the strength of both BLC and conventional cytology. This approach would also be a cost-effective alternative to next-generation omics-based tests, which could, therefore, be used for routine surveillance testing. However, in bringing bladder cancer detection techniques towards routine clinical use a number of challenges remain. Using fluorescence detection techniques in isolation is still associated with a significant number of false-positive tests and the low number of cancer cells shed in urine in many patients is a clear limitation. The use of immune-assisted microfluidic devices designed to enrich the cancer cells population compared to the background benign cells might overcome these issues and combined with HAL and/or hypericin may have the potential for improving bladder cancer diagnosis from urine samples.


Eosinophilic gastroenteritis (EGE) is characterized by dense infiltration of eosinophils in gastrointestinal tissues, resulting in morphological and functional abnormalities of the gastrointestinal tract. EGE susceptibility is most common among individuals aged 40-50 years old, and hence it is likely that affected patients will be encountered at the time of a medical checkup. In this report, we present two rare cases of EGE that presented interesting manifestations in findings obtained in a fluoroscopic examination performed at an annual medical checkup. Accumulation of case reports is important to provide information to pathologists to enable them to make correct early diagnosis and begin effective treatment at the earliest. Eosinophilic gastroenteritis (EGE), a type of eosinophilic gastrointestinal disorder (EGID), is a rare chronic inflammatory disease characterized by patchy or diffuse infiltration of eosinophils into different layers of the gastrointestinal tract -3. AffecCase 1Helicobacter pylori (HP) antibodies, and parasite egg tests were all negative. Concentrated folds were observed on the anterior and posterior walls of the stomach in fluoroscopic imaging  revealed convergency of folds on the anterior and posterior walls in the middle-body area of the stomach, though there were no obvious fold disruption or fusion findings Figure .We obtained biopsy samples from sites close to the center, both yellow and orange ulcer scars. Greater than 100 eosinophil infiltrates per high-power field (HPF) were observed in specimens from the stomach, and also from the mucosa of the duodenum and esophagus Figure .Since this case was accompanied by eosinophil infiltration through the esophagus, we initially administered a proton pump inhibitor (PPI). Following that administration, the patient immediately showed improved clinical symptoms, and eosinophil infiltration was also dramatically decreased in endoscopic re-examination findings.Case 2A 78-year-old male came to us complaining of postprandial discomfort from food impaction around the epigastric region. Narrowing of the gastric antrum had also been shown on X-ray imaging performed at a regular medical checkup. A local doctor had performed HP eradication treatment two years prior and it had been successful. There was no history of allergy or notable prior drug use. A blood test revealed mild anemia, while immunoglobulin G (IgG) and IgE levels were slightly elevated. White blood cell count was within the normal range and no increase in eosinophil count was observed. Furthermore, antinuclear antibody and parasite egg test results were negative. The antral portion demonstrated a tunnel-like narrowing over approximately 2 cm in X-ray imaging  per HPF were observed in the mucosal layer Figure . AdditioThe patient demonstrated a temporary improvement in symptoms without therapy, though we plan to administer steroids should symptoms recur in the future.EGID is characterized by dense infiltration of eosinophils in gastrointestinal tissues, resulting in morphological and functional abnormalities of the gastrointestinal tract -3. AlthoThe most frequently reported symptoms associated with the disease are abdominal pain, diarrhea, and vomiting, though they can vary depending on the site of involvement . PotentiEGE is classified into three types based on the extent and layer of the bowel with eosinophil infiltration: mucosal disease, muscular layer disease, and subserosal disease . AccordiOver the past six years, 27 patients have been diagnosed with EGE at our hospital, of whom 13 had large numbers of eosinophilic infiltrates within the stomach confirmed by endoscopic biopsy results. In addition, these 13 patients showed non-specific abnormalities, such as an ulcerative pattern  or elevated pattern , or no significant findings (n=1). Therefore, we consider that a histopathological examination of biopsy specimens provides a critical addition to endoscopic study findings, even when no apparent macroscopic endoscopic abnormality is found.EGE is an uncommon condition, though affected patients often present with signs and symptoms similar to many other diseases. It is important to share information such as the present case findings to assist pathologists, practitioners, as well as surgeons in making a correct early diagnosis and providing effective treatment to avoid a futile surgical procedure.


Cochlear implants are increasingly used to treat sensorineural hearing disorders in both children and adults. Pre-operative computed tomography and magnetic resonance imaging play a pivotal role in patient selection, to rule out findings that preclude surgery or identify conditions which may have an impact on the surgical procedure. The post-operative position of the electrode array within the cochlea can be reliably identified using cone-beam computed tomography. Recognition of scalar dislocation, cochlear dislocation, electrode fold, and malposition of the electrode array may have important consequences for the patient such as revision surgery or adapted fitting. Pre-operative imaging plays a pivotal role in patient selection for cochlear implant surgery.Key imaging findings on pre-operative scans that may have an impact on the surgical procedure need to be reported.Post-operative scans are indispensable to recognize dislocation, fold, and malposition of the electrode array, thereby allowing the best possible management of such a postsurgical complication.A cochlear implant (CI) is a surgically implanted device consisting of external and internal components . An exteOver the past few decades, CI surgery has increased and revolutionized the treatment of severe to profound sensorineural hearing loss (SNHL) in both children and adults. In brief, current indications are (a) children (12–24 months) with profound SNHL (> 90 dB) and limited benefit from binaural amplification trial based on the meaningful auditory integration scale; (b) children (2–17 years) with severe to profound SNHL (> 70 dB) with limited benefit from binaural amplification defined by ≤ 20–20% word recognition scores; and (c) adults with moderate to profound SNHL in both ears (> 40 dB) with limited benefit from binaural amplification defined by ≤ 50% sentence recognition in the ear to be implanted (or ≤ 40% by centers for medicare and medicaid services criteria) and ≤ 60% in the contralateral ear or binaurally [Absolute contraindications are complete labyrinthine aplasia, cochlear aplasia, and complete cochlear ossification. CI in cochlear nerve aplasia or hypoplasia is controversial. Patients are less likely to benefit, but meaningful hearing can be achieved in selected cases , 4. In cRadiologists play an essential role in the pre- and post-operative evaluation and selection of CI candidates. Pre-operative imaging is essential to diagnose any type of inner ear malformations and to identify other abnormalities in the temporal bone that may be encountered , 11. It This pictorial review aims to provide a comprehensive overview of the most relevant pre-operative and post-operative imaging aspects in CI candidates intending to help radiologists and surgeons in routine practice.Pre-operative imaging in CI candidates is based on high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) . PracticThe strength of HRCT is the detailed visualization of the bony structures of the middle and inner ear. The cochlea is composed of the central modiolus with bony septa that separate the basal, middle, and apical turns (2.5–2.75 turns) Fig. . Each tuEight different types of cochlear malformations can be differentiated by HRCT: (1) complete labyrinthine aplasia—Michel deformity , (2) cochlear aplasia (absence of the cochlea), (3) rudimentary otocyst (incomplete millimetric otic capsule remnant), (4) common cavity (cochlea and vestibule are represented by a single chamber), (5) incomplete partition of the cochlea , (6) cochlear hypoplasia , (7) large vestibular aqueduct syndrome , and (8) cochlear aperture abnormalities  .The strength of the MRI is the visualization of the fluid content of the membraneous labyrinth Fig. . VisualiComplete labyrinthine or isolated cochlear aplasia Fig. Cochlear sclerosis Fig. Cochlear nerve deficiency Fig. The most commonly accepted imaging findings precluding cochlea implantation are :CompletThe common cavity is a malformation in which the cochlea and vestibule are represented by a single chamber . It can Cochlear hypoplasia may appear as bud-like cochlea (type I), cystic hypoplastic cochlea (type II), cochlea with less than 2 turns (type III), and with normal basal turn, but severely hypoplastic middle and apical turns (type IV) . Due to Incomplete partition type I Fig.  shows noIncomplete partition type II Fig.  shows a Incomplete partition type III Fig.  is reporModiolar base defects in incomplete partitions have increased risk of intraoperative cerebrospinal fluid leakage into the middle ear, named gusher , 29. An This syndrome shows an enlarged vestibular aqueduct with the otherwise regular cochlea, vestibule, and semicircular canals , 32. CinMalformations of the inner ear are frequently accompanied by abnormal positions of the facial nerve, which increases the risk of facial nerve palsy during surgery . The labIf the cochlear windows cannot be identified, it is very difficult to localize the cochlea for the correct cochleostomy site . A CT-guCochlear nerve canal hypoplasia is defined by stenosis of the bony cochlear nerve canal diameter at the mid-modiolus of 1.5 mm or less . In abouChronic otitis media, temporal bone fractures, meningitis, and Cogan’s syndrome may lead to cochlear fibrosis . In someFar advanced otosclerosis may show irregular ossifications affecting the cochlea, which prevent regular entry and insertion of the CI. Split electrode arrays and inverse approaches can be successful .Fig. 16Identification of a chronic otitis media with or without cholesteatoma is important to prevent infection of the labyrinth during surgery . Either Post-operative imaging is required when a malfunction of the device is suspected . HoweverThe post-operative position of the electrode array is evaluated using HRCT (similar protocol as for pre-operative imaging) or cone-beam computed tomography (CBCT) Fig. . CBCT haThe visibility of the electrode array depends on the size and spacing of electrode contacts. An extensive overview of the cochlear implant electrode array designs from different manufacturers can be found in the article by Dhanasingh et al. . For optDepending on the anatomical situation, the electrode array is inserted into the cochlea via three routes: (a) round window (preferred), (b) extended round window—enlarging and then opening the round window by drilling the anterior-inferior margin, and (c) cochleostomy—surgical opening of the cochlea . The eleSplit electrodes are two electrodes which are independently implanted in the basal and the second cochlear turns. Such an approach may be needed in patients with a cochlea ossification/fibrosis and in far-advanced otosclerosis , 54.FigPostmeningitic basal turn ossification and fibrosis may block successful antegrade cochlear implantation despite the availability of sophisticated implants and advanced drill-out procedures. In such a case, a retrograde electrode insertion through a cochleostomy near the apex can be performed .Fig. 22Complications from cochlear electrode insertion are related to the degree of damage to the organ of Corti located at the basilar membrane and damage of neuronal structures at the spiral lamina . HistoloAn electrode array located in an intermediate position close to the midline of the cochlear lumen elevates the basilar membrane and bends or deforms the spiral ligament (grade 1 trauma) , 59. It An electrode array placed in the scala vestibuli is more frequently seen after a cochleostomy approach . This coElectrode array translocation from scala tympani into scala vestibuli may be seen in > 20% and is more frequently observed when pre-curved electrodes are used , 62, 63.An overinserted electrode array can be recognized when the most proximal contact of the electrode is located more than 3–4 mm from the round window/cochleostomy. This may occur when the opening of the round window or cochleostomy is too large and the electrode is pushed too far into the cochlea. Clinical consequences can be reduced stimulation of the high frequencies, which may result in a poorer speech understanding .Fig. 26An underinserted electrode array exposes several contacts of the electrode array outside of the cochlea. The electrode array has been chosen too long or extruded contacts were a clinical compromise. Risk factors are otosclerosis, meningitis, chronic otitis media, temporal bone fractures, and neurofibromatosis-2 . UnderinWhen the electrode array is inserted with too much force or cannot pass further into the cochlea duct, a bending or a more severe accordion-like pinching of the electrode array may be observed , 65. TheTip fold-over may have an occurrence rate of 1.5% and usually occurs with flexible and slim perimodiolar electrodes , 66, 67.When the electrode array cannot be fully inserted, excessive pushing may result in a fold-over of the basal part of the electrode array. Extensive fold-over may present as a second electrode array in the basal turn , 63. TheIt the condition of an angulated entry to the basal turn, e.g., in case of CHARGE syndrome, the electrode array may not enter the basal turn and remains in the tympanic cavity near the round window niche . RevisioThe electrode array enters into the internal auditory canal or may form a more basal slope within the internal auditory canal. The condition of an incomplete partition type III is a risk factor, since there is no bony separation between cochlea and internal auditory canal , 70.FigThe electrode array may enter the vestibulum or semi-circular canals in small round windows in children, or, in the condition of an anteriorized facial nerve, because there is an awkward insertion angle for the electrode array via the retro-facial route .Fig. 33Extracochlear electrode array placements like placement in the canal of the internal carotid artery or the Eustachian tube have been very rarely reported in the literature , 72.Late complications occur after the acute post-operative period.An electrode array may migrate because of loss of support of the electrode lead, micro-movements in the soft tissue cover of the radical cavity, or a tension that pushes the electrode back . PerimodSubcutaneous ulcer, infection, and wound dehiscence may occur at the implanted area of the magnet , 76. FlaBacterial labyrinthitis may be secondary to the spread of middle ear flora into the cochlea. Otitis media and mastoiditis are more frequently observed in children. Cholesteatoma may occur after the inclusion of epithelial cells into the tympanic cavity , 78.Surgical trauma, foreign body tissue response, or disruption of any soft tissue or venous structure of scala tympani during insertion may induce intracochlear fibrosis . The buiCI candidates need a thorough pre-operative imaging for diagnosis and classification of inner ear malformations and to identify any other abnormality in the temporal bone. HRCT and MRI are complementary and both image modalities are useful in patients with a history of meningitis, severe middle ear disease, and dysmorphic syndromes. Important contraindications such as aplasia and labyrinth sclerosis need to be ruled out. Implant surgeons need to be informed about any anatomical findings that may have an influence on the surgical procedure. After surgery, the position of the electrode can be evaluated using CBCT or HRCT. Scalar dislocation, cochlear dislocation, electrode fold, and malposition should be reported and may have important consequences for the patient, such as refined tuning or revision surgery.


Semiarid regions are apparently low biodiversity environments; however, these environments may host a phylogenetically diverse microbial community associated with plants. Their microbial inhabitants are often recruited to withstand stressful settings and improve plant growth under harsh conditions. Thus, plant-associated microorganisms isolated from semiarid and seasonally dry environments will be detailed in the present review, focusing on plant growth promotion potential and the microbial ability to alleviate plant abiotic stress. Initially, we explored the role of microbes from dry environments around the world, and then, we focused on seasonally dry Brazilian biomes, the Caatinga and the Cerrado. Cultivable bacteria from semiarid and seasonally dry environments have demonstrated great plant growth promotion traits such as plant hormone production, mobilization of insoluble nutrients, and mechanisms related to plant abiotic stress alleviation. Several of these isolates were able to improve plant growth under stressful conditions commonly present in typical semiarid regions, such as high salinity and drought. Additionally, we highlight the potential of plants highly adapted to seasonal climates from the Caatinga and Cerrado biomes as a suitable pool of microbial inoculants to maintain plant growth under abiotic stress conditions. In general, we point out the potential for the exploitation of new microbial inoculants from plants growing in dry environments to ensure a sustainable increase in agricultural productivity in a future climate change scenario. Plants can host many microbes in the rhizosphere, endosphere, leaf surfaces, and other tissue compartments, collectively known as the plant microbiome. Many of these plant-associated microbes are known to be able to benefit plant health by positively influencing plant physiology, development, and environmental adaptation . The plaArid lands cover approximately 30% of the world’s land area. Particularly in semiarid and seasonally dry regions, drought, high temperature, and high salinity are commonly reported abiotic stresses that have a significant impact on the plant-associated microbiota . Plants The best-known mechanisms involved in plant growth promotion are the production of plant phytohormones [such as indoleacetic acid (IAA) and gibberellins] , mobilizThus, this review will initially focus on assessing the potential and features of bacteria from semiarid environments worldwide exhibiting plant growth-promoting (PGP) traits to alleviate abiotic stresses. Additionally, we explored the biological diversity of two seasonally dry environments as a prospective microbial inoculant source to promote important crop growth under stress conditions. The Caatinga, an exclusively Brazilian biome, comprises a highly diverse tropical dry forest that faces a seasonal water regime . The CerPlants from semiarid regions are exciting sources of promising PGPB, as they may harbor associated microbes with the potential to alleviate abiotic stress related to dry environments . For thiUsually, investigation of PGPB from semiarid regions searches for common traits related to direct plant growth promotion such as ACC deaminase activity, nitrogen fixation, phosphate solubilization, IAA production, and siderophore production . HoweverSetaria italica L.), a drought-tolerant crop growing in a semiarid agroecosystem in northeastern China, and they were able to find four isolates with the potential to alleviate drought stress. Similarly, in vitro growth and that were salt-tolerant.Because semiarid areas impose drought and high salinity stresses on plants and the associated bacterial community , strategPsoralea corylifolia L. grown in a salt-affected semiarid region of India. They found that bacteria isolated from the rhizosphere and rhizoplane showed the highest salt-tolerance ability, probably due to their previous exposure to high salt concentrations in the soil. Such information could guide future studies interested in isolating halotolerant bacteria.The prospect of PGPB to alleviate semiarid stresses could benefit from a more targeted approach. Moreover, in another report, In summary, when investigating PGPB from semiarid regions, one should consider: (1) the host choice, evaluating its habitat conditions; (2) prospecting bacterial common PGP traits; (3) prospecting bacterial PGP traits related to dry environment stress alleviation; and (4) using more targeted approaches, focusing either on a particular abiotic stress alleviation or on a specific plant to enhance growth.Bacteria that exhibit several PGP traits—such as nitrogen fixation, phosphate solubilization, phytohormone production, and salt and drought tolerance—become interesting candidates to be evaluated under greenhouse and field conditions aiming for the selection of new plant growth promoters under the harsh environmental conditions of a semiarid climate . BacteriBacteria able to promote plant growth under drought stress significantly affect root architecture and/or growth, improving water and nutrient acquisition . The rooOxidative stress, characterized by the enhanced production of various reactive oxygen species (ROS), is one of the main causes of plant injury under drought stress . Plants Previous reports have shown an increase in antioxidant enzymes in plants inoculated with PGPB under drought conditions . HoweverLavandula dentata depend on the single or co-inoculation of different arbuscular mycorrhizal fungi with endophytic Bacillus thuringiensis. In particular, the interaction of the arbuscular mycorrhizal fungal mixture and B. thuringiensis induced the highest activity of some antioxidant plant enzymes and increased mycorrhizal development  under drought stress. The reduced drought stress effect on the antioxidant activity in inoculated seedlings may be explained by the protective effect granted by other bacterial traits that avoid dehydration , showing several PGP traits   . Its genrritory) . The setrritory) . During rritory) .Although plants inhabiting the Caatinga semiarid lands possess inherent traits for survival in a harsh climate, the plant-associated microbiome has also been suggested to play an essential role in plant fitness under seasonal water availability and extended drought periods. This point is a neglected topic in plant microbiology, but some recent research has revealed the potential of bacteria associated with Caatinga native plants as inoculants for plant growth promotion under drought conditions.Cereus jamacaru (Bacillus genus) were significantly enriched during the dry season, whereas the phyla Proteobacteria and Bacteroidetes were more abundant in the rainy season. However, although shifts in the rhizosphere microbial community driven by seasonality are also evidenced in other rhizosphere systems  under water stress. Most cactus isolates showed in vitro PGP traits, exopolysaccharide production, and the ability to grow in a medium with reduced water availability (0.919 Aw) (Bacillus spp. (LMA52 and LMA3) and Pantoea sp. in maize seedlings protected against the negative effects of drought and increased the leaf area, stalk length, and shoot dry biomass under water stress. These results indicate that selecting osmotolerant microorganisms with common PGP traits is a promising approach to prospecting potential PGPB to mitigate plant drought stress. More recently, other Bacillus spp. from the cactus rhizosphere of Brazilian Caatinga showed the potential to promote maize growth under drought conditions (One of the hypotheses is that root-associated microorganisms have developed cellular mechanisms for water stress tolerance that lead to plant protection against the negative effects of desiccation . To test.919 Aw) , 2. The nditions . These rTripogonella spicata (Nees) P.M. Peterson and Romasch  plants or “resurrection plants” can desiccate and survive during severe and long drought periods . Tripogo Romasch , a DT wi Romasch , possess Romasch . Howeverse Ab-V5 , a commenditions , 2. Althnditions , their aL–1 NaCl , which sT. spicata, several other DT plants, such as the pteridophyte Selaginella spp. (Selaginellaceae), Vellozia cenerascens (Velloziaceae), and Nanuza plicata (Velloziaceae), are found in the Caatinga biome. These data show that plants from Caatinga semiarid areas display a promising niche for isolating novel beneficial microbes with remarkable plant growth-promoting rhizobacteria traits. Research efforts to study the indigenous microbes associated with these species open possibilities for prospecting for new chemical and biological agents to improve the growth of different crop species in dry agricultural lands.The biological process related to vegetative desiccation tolerance is exhibited by less than 0.2% of vascular plant species. In addition to Legume plants are the unique family with the ability to establish mutualistic associations with “rhizobia,” a collective term given to root/stem-associated bacteria that form nodule structures to the BNF. All rhizobia are members of the phylum Proteobacteria within the classes α- and β-proteobacteria, also known as α- and β-rhizobia . A recenMimosa spp. through amplified ribosomal DNA restriction techniques reveal high diversity and low similarities with several known reference isolates  were closely related to the Paraburkholderia sabiae and Rhizobium genera. Furthermore, rhizobial isolates from Caatinga drylands were more efficient in increasing plant biomass in gnotobiotic inoculation assays. These results corroborate Mimosa spp. by Paraburkholderia (Syn. Burkholderia) in Caatinga and Cerrado Brazilian biomes. A large diversity of Paraburkholderia also nodulate other Mimosoid legumes. In the case of Calliandra, although the majority of the β-rhizobia were related to Paraburkholderia nodosa, some isolates were not related to known rhizobia from Mimosa hosts  rather than β-rhizobia (Paraburkholderia spp.), but both classes are found in mulungu nodules (Rhizobium and Bradyrhizobium encompass promising bacteria with superior symbiotic efficiency compared with the other native isolates and non-inoculated treatments (both with sterile and non-sterile substrates).The diversity and ecology of rhizobial papilionoid native legumes in Caatinga are poorly understood. In recent years, bacterial isolation efforts have shown the high biodiversity and biotechnological potential of some rhizobial species.  nodules . ConsideChamaecrista spp. collected in several areas of Bahia state in the heart of Brazilian drylands. The molecular evaluation based on 16S ribosomal RNA, housekeeping, and symbiosis gene sequencing indicated that they belonged to the Bradyrhizobium genus. The taxonomic positioning based on the multilocus sequence analysis approach showed that most isolates (12 of 16 bacteria) were clustered in a separated clade that was not related to classical Bradyrhizobium elkanii and Bradyrhizobium japonicum taxonomic superclades. Overall, these results indicate that diverse rhizobia can nodulate different legumes, even those of closely related species.Compared with the Papilionoideae and Mimosoideae clades, the Caesalpinoideae clade has fewer nodulating members, comprising approximately 25% of the members within this group . For thiGiven that the Caatinga biome has (until now) more than 600 legume species, its expected rhizobial diversity is still not revealed. Efforts to isolate and identify these bacteria will probably lead to the description of several new taxa and exploration of potential PGPB traits.Vigna unguiculata) is one of the most used, being an important crop in the economy, culinariness, and culture of the people living in the Brazilian semiarid region. For cowpea, there are four Bradyrhizobium spp. strains used for commercial inoculant production in Brazil. Among these strains, Bradyrhizobium yuanmingense BR 3267 was officially recommended in 2004 and is currently the most commonly used in Brazil , mainly in low-income family based production systems. Among these legumes, cowpea  in target species. Then, together with the plant biomass and total N accumulation, the N incorporated in the system  is estimated  ranged from 6 to 11 kg N ha–1 year–1 in pristine Caatinga areas. These low amounts were associated with a low density of N2-fixing species. In contrast, the authors verified a more significant contribution of N2-fixing legumes in Caatinga areas under natural recovery (amount of 130 kg fixed N ha–1 year–1) due to the high density of fixing legumes, mainly M. tenuiflora. These results indicate the contribution of rhizobia–legume associations to nitrogen incorporation in natural systems in semiarid Brazilian areas, even with low successional stages.Furthermore, soil parameters and atmospheric temperature also influence the total amount of N fixed in Caatinga drylands. The total amount of phosphorus in soils is significantly correlated with the N derived from the atmosphere  in pristine and recovering areas . This inSuch studies are essential because Caatinga biome degradation is an ongoing problem, and the use of environmentally friendly solutions is needed. Further research should focus on soil management approaches that consider both microbiota and plant diversity to increase fundamental nutrient availability.2  (The climate of the Cerrado biome is characterized by high-temperature averages (22–27°C), rainfall , and solar radiation  . Despite2 day–1) .Cerrado soils are highly weathered, acidic, deficient in nutrients, and rich in iron and aluminum oxides, supporting only adapted vegetation . ConsequBradyrhizobium in the agricultural soils, in contrast to the higher abundance of Rhizobium in the undisturbed Cerrado. The presence of Rhizobium species that are tolerant of acidity and other stressful environmental conditions indicates adaptation to the particular edaphoclimatic characteristics of this biome  play a key role in nitrogen fixation in association with leguminous plants (Paraburkholderia (formerly Burkholderia) are the primary symbionts of Mimosa species in the Cerrado (s plants . Previou Cerrado . Pires eP. nodosa was the main N2-fixing species trapped by promiscuous common bean (Phaseolus vulgaris L.) in the Brazilian “Cerradão.” “Cerradão” is a type of Cerrado phytophysiognomy that is a forest formation with xeromorphic aspects, and despite the forest-like vegetation, the floristic composition is similar to the Cerrado sensu stricto  and common bean (Phaseolus vulgaris L.) to trap nodules for further rhizobial isolation using Cerrado soils from different locations. This work resulted in the identification of several highly symbiotically efficient Rhizobium spp. strains with competitive ability and genetic stability. Common bean inoculation with these strains showed economic viability and high potential to obtain a more effective and suitable inoculant for commercial purposes. stricto . The pre content . MercantBradyrhizobium strains have been selected and isolated from areas previously inoculated, showing greater N2 fixation capacity, higher competitiveness, and tolerance to frequently stressful tropical conditions (Bradyrhizobium diazoefficiens) and CPAC 15 (B. japonicum), included in the list of strains authorized for use as soybean commercial inoculants in 1992. These strains are currently used successfully by farmers in the Cerrado region. It is important to note that the annual economic return of BNF with soybeans in Brazil is estimated to be approximately US$ 15 billion  and B. megaterium (isolated from maize rhizosphere), with the capacity to induce higher maize yield and grain P content under field conditions  and screened for some enzymes of biotechnological interest. The isolates of Bacillus spp., Pseudomonas spp., Corynebacterium spp., Actinomyces spp., and Staphylococcus spp. presented differential proteolytic, amylolytic, lipolytic, and esteratic activities. These studies show the vast potential of microorganisms associated with Cerrado plants for agricultural improvement and highlight the increasing expectations about the future use of these biological assets.The high microbial diversity from Cerrado soils is expected to present a diverse number of features that could be explored biotechnologically. For example, These results collectively show that assessing the plant-associated microbial diversity from semiarid regions could be an essential strategy to find PGPB that can successfully alleviate plant abiotic stress commonly present in such climates. Additionally, their plant growth promotion potential has become an interesting alternative to enhance crop yield using more sustainable agricultural practices. With society’s eyes focusing on sustainable exploitation of natural resources and life quality improvement with environmentally friendly technologies, efforts to discover new PGPBs from harsh environments may sustain agricultural productivity in a future scenario of climate change and increased arid lands.MB, GL-J, IM, and MQ contributed to the conception of this review. MB and MQ analyzed the plant-associated microbial diversity in semi-arid regions around the world. GL-J, FRJ, PF-J, and IM focused on the diversity of plant-assocated microbes from Brazilian semiarid and seasonally dry environments. MB and GL-J contributed equally to this work and have combined the first authorship. All authors contributed to manuscript revision and read and approved the submitted version.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.