The complete removal of cancerous tissue is an important predictor of patient outcomes after surgery, in particular for head and neck cancer surgery. Normally, surgical tissues are examined by a pathologist to determine whether a full removal of the cancer was performed. However, these analyses are often imperfect due to time constraints, limitations in frozen sections, and tissue orientation challenges. Newer intraoperative imaging techniques have shown great promise for increasing both the accuracy and efficiency of this process while in the operating room. This review summarizes and analyzes the current state of the literature on intraoperative imaging in determining cancer margins in head and neck cancers.Surgical margin status is one of the strongest prognosticators in predicting patient outcomes in head and neck cancer, yet head and neck surgeons continue to face challenges in the accurate detection of these margins with the current standard of care. Novel intraoperative imaging modalities have demonstrated great promise for potentially increasing the accuracy and efficiency in surgical margin delineation. In this current study, we collated and analyzed various intraoperative imaging modalities utilized in head and neck cancer to evaluate their use in discriminating malignant from healthy tissues. The authors conducted a systematic database search through PubMed/Medline, Web of Science, and EBSCOhost (CINAHL). Study screening and data extraction were performed and verified by the authors, and more studies were added through handsearching. Here, intraoperative imaging modalities are described, including optical coherence tomography, narrow band imaging, autofluorescence, and fluorescent-tagged probe techniques. Available sensitivities and specificities in delineating cancerous from healthy tissues ranged from 83.0% to 100.0% and 79.2% to 100.0%, respectively, across the different imaging modalities. Many of these initial studies are in small sample sizes, with methodological differences that preclude more extensive quantitative comparison. Thus, there is impetus for future larger studies examining and comparing the efficacy of these intraoperative imaging technologies. A clear surgical margin is one of the strongest prognosticators in head and neck cancer (HNC) , and posThe current standard of care in HNC surgery often utilizes frozen section analysis for intraoperative margin assessment. However, histopathologic analysis of frozen sections for surgical margins is limited by time constraints, architecture distortion, and inability to assess certain tissues, with decreased accuracy pertaining to close and positive margins . FurtherAdvances in intraoperative imaging techniques have been developed to address these limitations in determining cancer margins in HNC. These modalities include optical coherence tomography, narrow band imaging, autofluorescence, and fluorescent-tagged probe techniques. Initial studies have demonstrated encouraging sensitivity and specificity in detecting HNC margins and cancer from normal tissue. However, these studies remain preliminary and in smaller cohorts. Additionally, the different techniques have not been compared with one another. For these reasons, firm guidelines have yet to be established in the use of intraoperative imaging technologies, despite these initial promising results. To date, there have been no attempts to collate and compare these investigations pertaining to HNC in the literature. The current study aims to address these gaps in the literature by providing a comprehensive review of current intraoperative imaging modalities, with the goal of providing future directions and guidance on this topic to head and neck cancer surgeons.Author K.Y. conducted a comprehensive literature search through PubMed/Medline, CINAHL (EBSCOhost), and Web of Science, with no restrictions in publication date. Search terms including “head and neck”, “oral”, “pharyngeal”, “laryngeal”, “malignancy”, and “intraoperative imaging” were combined in differing permutations, as detailed in There were 102 titles initially identified through the systematic database search, with 67 remaining after duplicate deletion. There were 13 studies that were subsequently identified through handsearching. Seven studies were excluded for not featuring an intraoperative and in vivo procedure. Four studies were excluded for focusing on lymph node status instead of tumor or margin tissue differentiation. There were three studies excluded for having insufficient data or not involving an intraoperative or in vivo setting each. There were two studies that did not investigate head and neck cancers. The last study to be excluded was performed on cadavers. After study screening, 23 studies were included in this review. The technologies from the 23 studies included optical coherence tomography (2 studies), narrow band imaging (NBI) (3 studies), Storz Professional Image Enhancement System (SPIES) (3 studies), autofluorescence imaging (NBI) (4 studies), hyperspectral imaging (HSI) (1 studies), fluorescence-tagged imaging (5 studies), and tag-free fluorescence imaging (4 studies). One included study investigated both SPIES and NBI. Descriptive technical information on the included imaging modalities is shown in Optical coherence tomography (OCT) measures the echo time delay and intensity of light, which is reflected and captured with low-coherence interferometry. OCT is a noninvasive and label-free diagnostic tool that can deliver high-fidelity imaging in real-time intraoperative settings, providing vital information on tumor margins. Since its inception in 1991, OCT was largely relegated to ophthalmological use . HoweverNearly a decade later, this technique has been expanded to oral malignancies as well in intraoperative ex vivo settings ,18. HereNBI utilizes an optical filter that only permits a narrow range of wavelengths to be emitted as light, with varying levels of tissue penetrance dependent on the selected spectra . This teThe Storz Professional Image Enhancement System (SPIES) utilizes a high-definition camera system with image-enhancing technology to improve the appearance of the mucosal surface and the vascular architecture across five spectral ranges ,29. ThisLi et al. conducted a pilot study involving SPIES technology in the assessment of sinonasal inverted papilloma (SIP) . The stuFluorescence lifetime imaging (FLIM) has been a burgeoning area of research since it was first discovered in decades prior . Here, eFollowing a similar fluorophore-dependent mechanism as FLIM, dynamic optical contrast imaging (DOCI) was developed to bypass the complex mathematical models required in FLIM . This meAlthough first developed in the context of improving space exploration , HSI hasNear-infrared (NIR) fluorescent probes have been developed with the goals of improving cancer detection and characterization, lymphatic imaging, and intraoperative surgical guidance . Near-inSeveral studies have investigated the use of label-free NIR fluorescent dyes in the delineation between cancerous and healthy tissues. Stubbs et al. explored how free indocyanine green (ICG) dye could be infused 24 h prior to surgery and still provide benefit to surgeons in 3/14 surgeries for squamous cell carcinoma and adenoid cystic carcinoma . HoweverNIR fluorescently labeled probes targeting EGFR, which is overexpressed in the majority of HNC, have been investigated as an intraoperative imaging technique for HNC . Van KeuAn important drawback of both free and tagged NIR fluorescence imaging is the requirement of fluorescent tracers and associated probes, which are associated with their own risks ,57. FurtThis current investigation has identified and collated the available literature on the use of intraoperative in vivo imaging modalities in head and neck surgery. While the reported sensitivities (83.0–100%) and specificities (79.2.0–100%) were promising across the included studies, these data were derived from preliminary investigations with small cohorts examining specific anatomical subsites. Subsequently, additional prospective trials with greater sample sizes must be performed to acquire an accurate assessment of sensitivities and specificities of the aforementioned modalities. These investigations should also attempt to compare and contrast cohorts with different HNC sites to determine the generalizability of these modalities across different subsites. Notably, the integration of such technologies may not be feasible outside of larger academic institutions. Several fluorescent materials may be more accessible than others, including more commonly used nontagged fluorescent molecules (ICG) when compared with antibody-tagged fluorescent probes (panitumumab-IRDye800). As these agents are investigational, they currently require clinical trial designs and appropriate personnel to run such trials, which carry significant cost and effort. Furthermore, tools with high overhead costs, including the pulsed diode lasers used in FLIM/DOCI or hyperspectral cameras required in HSI, currently are not available in rural areas or developing countries. Therefore, these imaging modalities may not be of immediate benefit to those with limited access to high-quality healthcare, regardless of any potential benefits that they may confer. Further considerations to expand access to potential care-altering technologies should be made in the additional expansion of intraoperative imaging devices. Furthermore, many of these technologies have been seamlessly integrated into existing clinically approved devices, including TORS, endoscopes, and various cameras. In these cases, added time to surgery is often minimal (a few minutes at most) in comparison with the overall surgical length, which can last many hours. However, the added costs of these technologies, at least in the early investigational stage, may be high and may not be amenable to those in developing or under-resourced regions. While several of the aforementioned modalities provide high-resolution imaging of tissue architecture, those relying on light penetrance for image acuity suffer from various drawbacks. In the case of OCT, the quality of the image is dependent on the degree of multiple scattering in a sample, preventing meaningful imaging at deeper tissue depths. While the conventional wavelength of light used with this modality is around 1.3 µm, there have been several studies that have utilized longer wavelengths (1.7 µm) of light with improved imaging acuity at deeper depths ,60. AddiDespite showing great promise, FLIM autofluorescence imaging has been limited by time-consuming, computationally intensive models, and this is particularly true with lower photon/pixel ratios . HoweverTag-free fluorescent dyes have shown some initial findings in surgical margin demarcation due to the increased vascular supply observed in malignant tissues. Unfortunately, due to the lack of specificity of these dyes, other sources of inflammation or tissue damage may limit their efficacy and accuracy as diagnostic agents. Indeed, nanoparticle distribution in the context of systemic shock was found to be heavily retained in various organs, including the spleen . IncreasFurther technological iterations of imaging modalities will be critical to improve the sensitivity and specificity of cancer imaging agents. For instance, recent advances in near infrared imaging have been made in NIR-II models (with wavelengths ranging from 1000 to 1700 nm), which have advantages over NIR-I, including deeper tissue penetration and an improved signal-to-noise ratio [Additionally, several of the aforementioned imaging modalities have already been combined as multimodal options. For instance, Vasquez et al. combined FLIM, OCT, and Raman spectroscopy in a clinically applicable and compact setup . Here, tAlthough the featured imaging modalities have varying benefits and drawbacks, the overarching important points are outlined as follows. The major strength of intraoperative in vivo imaging is providing real-time, high-fidelity delineation of the surgical margin, which is integral in improving patient outcomes. However, the major weaknesses are that many of these studies are still in their preliminary stages, and the required technologies may not be available in rural or developing areas. Further research will create opportunities to determine the optimal imaging modality for surgical margin detection, with improvements in efficiency and accuracy. However, major threats on the implementation of these technologies include the inherent difficulties of running surgical clinical trials, precluding meaningful comparisons between imaging modalities from being made. Encouragingly, the increasing number recently completed, active, and pending clinical trials that are using these technologies  highlights the burgeoning interest in this field. Nevertheless, larger multi-institutional studies with standardized data acquisition and analysis should be conducted for future investigation and meta-analysis.This study is the first attempt to gather and synthesize the current literature on using intraoperative imaging to define surgical margins in the context of HNC. Head and neck surgeons will likely have access to a broader array of imaging options as these techniques continue to develop and improve throughout the years to come. Although many of these imaging modalities are promising, all of the included investigations have been limited by smaller cohorts and differences in measures, control groups, and institutional heterogeneity. Additional iterative studies with improved sensitivities/specificities are necessary to build on the existing data and should explore the potential of multimodal processes. Future research should feature larger controlled trials and strive to systematically report findings for comparison in this burgeoning, critical, and exciting field.


Therapeutic interventions for disorders of fear and anxiety rely on behavioral approaches that reduce pathological fear memories. For example, learning that threat-predictive stimuli are no longer associated with aversive outcomes is central to the extinction of conditioned fear responses. Unfortunately, fear memories are durable, long-lasting, and resistant to extinction, particularly under high levels of stress. This is illustrated by the “immediate extinction deficit,” which is characterized by a poor long-term reduction of conditioned fear when extinction procedures are attempted within hours of fear conditioning. Here, I will review recent work that has provided new insight into the neural mechanisms underlying resistance to fear extinction. Emerging studies reveal that locus coeruleus norepinephrine modulates amygdala-prefrontal cortical circuits that are critical for extinction learning. These data suggest that stress-induced activation of brain neuromodulatory systems biases fear memory at the expense of extinction learning. Behavioral and pharmacological strategies to reduce stress in patients undergoing exposure therapy might improve therapeutic outcomes. Survival depends on detecting and defending against threats in the environment. These functions, shaped over millennia by natural selection, rely on specialized neural and behavioral adaptations. For example, when a rat detects a predator, it will draw from a repertoire of species-specific defense responses that include freezing, jumping, fleeing, and biting . The natOf course, animals must not only defend against present danger, but they must also learn to anticipate future threats should they survive. Decades of work have described brain circuits that rapidly encode and store memories of an aversive experience to ward off future threats . LearninSeveral forms of learning are recruited to encode memories for aversive events. For example, intense noxious stimuli rapidly potentiate and sensitize behavioral responses they elicit . SensitiThe durability of fear memory has been underscored by decades of work on another learning process: extinction. During experimental extinction procedures, CSs are repeatedly presented to the animal in the absence of the US . ConsequOver 15 years ago, we discovered more evidence for the durability of fear memory. We found that extinction procedures performed soon after fear conditioning failed to yield long-term suppression of conditioned fear . We termFrom an evolutionary perspective, resistance to extinction under stress serves to protect recently acquired fear memories from disruption and functions as a critical adaptation that permits animals to survive future threats. However, the resistance of fear memories to extinction poses challenges for therapeutic interventions for fear and anxiety disorders in humans. These interventions rely on extinction-based procedures such as prolonged exposure therapy and are susceptible to relapse . For thiIt has long been known that memories are labile soon after they are encoded . A wide Because of these vulnerabilities, we imagined that behavioral manipulations, such as extinction, might be particularly effective if delivered shortly after conditioning. To test this hypothesis, we submitted male rats to an auditory fear conditioning procedure and followed that by an extinction procedure  either 15 min or 24 h after conditioning . CriticaAdditional experiments suggested that the footshock stress associated with the conditioning procedure was responsible for the IED. For example, we found that delivering unsignaled footshock immediately prior to a delayed (24 h) extinction session impaired later extinction retrieval . Similarweaker relapse of conditioned fear. Relapse was indexed by the return of conditioned responding that is normally observed with the passage of time (spontaneous recovery), testing the CS outside the extinction context , or intervening exposure to the unconditioned stimulus (reinstatement). Based on these findings, the authors concluded that the immediate extinction procedure disrupted the consolidation of fear memory, produced long-term reductions in the expression of conditioned fear and eliminated fear relapse. However, close inspection of the data reveals that the lack of relapse observed after immediate extinction was not due to superior extinction, but just the opposite: conditioned fear was, in fact, resistant to immediate extinction. Because the animals did not acquire an extinction memory, they were unable to show relapse.Although several groups have observed the IED, there are some notable exceptions. Using auditory fear conditioning and extinction procedures similar to those of Interestingly, the IED has been observed after appetitive conditioning  and in hAlthough the precise behavioral mechanisms underlying the IED are still uncertain, the existing data are most compatible with the possibility that conditioning results in emotional arousal or stress (whether aversive or appetitive) that impedes extinction learning. This conclusion is perhaps most strongly supported by recent data showing that pharmacological treatments that limit stress-sensitive neuromodulatory circuits in the brain attenuate the IED.Extinction procedures engage multiple neural circuits that mediate not only the retrieval and expression of conditioned responses, but also the encoding of prediction errors and contextual stimuli associated with the extinction contingency . BrainstConsiderable work indicates that both acute and chronic stressors regulate extinction learning by modulating neural activity within hippocampal-prefrontal-amygdala networks . AversivThis paradox might be explained by the non-linear (inverted-U) function relating noradrenergic activity to learning and memory . Either Footshock stress results in sustained LC activation and NE release in forebrain regions critical for fear conditioning and extinction. Importantly, shock-induced activation of the LC-NE system may undermine extinction learning in the immediate aftermath of fear conditioning, resulting in the IED. Consistent with this idea, there is extensive evidence that β-adrenergic receptor antagonists, such as propranolol, reduce stress-induced fear responses in both rodents and humans . SystemiTo explore this possibility, we administered propranolol immediately after auditory fear conditioning in male rats undergoing an immediate extinction procedure in which CS-alone trials were presented 15 min after the last conditioning trial . ConsistDecades of work have revealed that the IL cortex, a mPFC region that is interconnected with both the HPC and amygdala, is a critical neural substrate underlying the extinction of conditioned fear . NeuronaBecause systemic propranolol administration rescues the IED, we hypothesized that it might promote extinction under stress by regulating post-shock spike firing in the mPFC. Consistent with this possibility, rats that received systemic propranolol injections prior to auditory fear conditioning exhibited much smaller perturbations of mPFC spike firing than vehicle-treated rats . SpecifiSystemic propranolol administration may regulate neuronal activity by direct effects on β-adrenergic receptors in IL or by affecting a brain region that regulates IL activity. For example, it is well-known that NE promotes aversive memory formation through its actions in the BLA, which, in turn, projects to and regulates IL function . Indeed,N-oxide (CNO) and coupled activation of LC with the delivery of weak footshock. Weak footshocks alone produced minimal increases in BLA spike firing that were dramatically potentiated when delivered concomitant with chemogenetic activation of LC-NE neurons  injections in rats expressing excitatory DREADDs in the LC . AnimalsIn addition to the strong efferent projections to the BLA, the LC-NE system also receives a potent descending projection from the CEA . ImportaThe excitatory effect of the CEA on tonic LC-NE firing suggests that CEA-CRF neurons may be involved in the IED. To explore this issue, per se insofar as the drug did not affect freezing during the immediate extinction session. Moreover, a no-extinction control group revealed that the drug did not exert its effect by disrupting the consolidation of fear memory. In contrast, local infusion of a CRF agonist into the BLA prior to a delayed extinction procedure results in an extinction impairment (The stress-induced activation of CEA has also been suggested to increase CRF levels in the BLA . Moreovepairment . Interespairment . This supairment  affect sFear conditioning is an adaptive form of learning that allows an animal to mobilize defensive behaviors in anticipation of threat. Aversive memories are rapidly encoded, long-lasting, and susceptible to relapse after conditioning. Critically, fear memories are highly resistant to extinction soon after they are encoded, resulting in an IED when extinction trials are delivered within hours of fear conditioning. A growing body of evidence reveals that the IED is mediated by the recruitment of a stress-sensitive network that prioritizes the encoding and consolidation of fear memory even when the prevailing threat has passed. Stress-induced impairments in extinction learning involve activation of the LC-NE system, which appears to regulate amygdalo-prefrontal circuits involved in extinction learning. Specifically, we propose that noradrenergic activation of the BLA recruits mPFC-projecting neurons that functionally inhibit IL principal cells involved in extinction learning. We imagine that this is supported by BLA afferents on mPFC interneurons, which provide potent feed-forward inhibition of mPFC principal cells. In addition to the LC-NE system, CRF-containing neurons in the CEA play a critical role in the IED. Descending CEA→LC projections may amplify shock-induced increases in LC excitability, potentiate NE effects on BLA principal cells, and drive feed-forward excitation of BLA neuronal activity that protects fear memory from extinction under stress.The role for the LC-NE system in mediating resistance to extinction under stress has important implications for understanding disorders of fear and anxiety . PatientSM wrote the manuscript.The author declares 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. 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Given the under-utilisation of cardiac rehabilitation despite its benefits, there has been a shift towards alternative delivery models. The recent coronavirus disease 2019 (COVID-19) pandemic has accelerated this shift, leading to a growing interest in home-based cardiac rehabilitation including telerehabilitation. There is increasing evidence to support cardiac telerehabilitation, with studies generally demonstrating comparable outcomes and potential cost-benefits. This review aims to provide a synopsis of the current evidence on home-based cardiac rehabilitation with a focus on telerehabilitation and practical considerations. Exercise-based cardiac rehabilitation programs should be considered an essential part of the contemporary management of heart failure (HF). Several systematic reviews have confirmed the benefits of these programs, including improved quality of life, reduced hospitalisations in people with HF , and theIn light of the suboptimal uptake of cardiac rehabilitation despite its benefits, there is a growing interest in home-based cardiac rehabilitation. In a Cochrane systematic review of 23 trials with a total of 2890 individuals, home-based cardiac rehabilitation programs demonstrate comparable effects on mortality, exercise capacity, modifiable risk factors and health-related quality of life compared with centre-based programs in people who have suffered a myocardial infarction, angina, HF or who have undergone revascularisation . HospitaWith advances in new technologies and the exponential growth of the Internet, there are emergent opportunities to deliver cardiac rehabilitation into the home via telerehabilitation. Telerehabilitation is defined as the delivery of rehabilitation services at a distance via telecommunication technology such as phone, videoconferencing and the Internet . CardiacThere has been a recent proliferation of literature investigating the effects of cardiac telerehabilitation. Chien et al. extend the evidence for remote cardiac rehabilitation in people with HF . In thisFrom our clinical and research experience, we suggest some practical tips for implementing cardiac telerehabilitation  towards home-based cardiac rehabilitation programs (16 to 76%), in the 12-month pre-pandemic to a comparable period during the pandemic . This shA critical factor in the sustainability of alternative cardiac rehabilitation programs beyond the pandemic is a better understanding of an individual’s preferences. A recent Belgian study has shed some light on an individual’s willingness to participate in these alternative programs . For exaWhilst healthcare professionals are optimistic about retaining hybrid cardiac rehabilitation programs beyond the pandemic, there are opportunities to refine rushed implementation approaches , 45. In Given the expansion of these alternative models of cardiac rehabilitation, a need exists to further build our understanding of the facilitators and barriers of cardiac rehabilitation. Specifically, future research should identify the most effective strategies for promoting program uptake, adherence and completion within different models of care. We also recognise that not all of the programs included in this review meet the full definition of cardiac rehabilitation as established by multiple international organisations. The impact of exercise-only cardiac telerehabilitation programs on morbidity, mortality and readmission is currently unknown and represents a direction for future research. Other identified priority research areas include under-represented populations, patient-centred outcomes, effects on long-term outcomes and cost and implementation in diverse settings . A betteThere has been a growing interest in home-based cardiac rehabilitation programs to widen access and improve program attendance. With rapidly evolving technology and the ubiquitous Internet, there are emergent opportunities to deliver cardiac rehabilitation services into the home via telerehabilitation. Telerehabilitation may be delivered as remote, virtual and hybrid cardiac rehabilitation programs. There is increasing evidence to support cardiac telerehabilitation, with studies generally demonstrating non-inferiority, safety and cost-effectiveness. However, further research should explore the effects of patient-centred and long-term outcomes in diverse populations and settings. With the experience gained during the COVID-19 pandemic, many health services today are in a better position to incorporate telerehabilitation into their usual care and enable greater participant choice.


Changes to the healthcare system due to COVID-19 have altered care delivery during birth and the postpartum period, a transitional time that requires intensive healthcare support and that is complicated by well-established health disparities. Our objective was to identify additional challenges to healthcare interactions that emerged for low-income postpartum individuals during the pandemic.This is a qualitative investigation of low-income postpartum individuals enrolled in a trial of postpartum care, who gave birth in the United States in the first three months of the COVID-19 pandemic. Participants completed in-depth semi-structured interviews that addressed healthcare experiences during and after birth, both for in-person and telemedicine encounters. Transcripts were analyzed using the constant comparative method.Of 46 eligible individuals, 87% (N = 40) completed an interview, with 50% identifying as non-Hispanic Black and 38% as Hispanic. Challenges were organized into three domains: unanticipated changes in the birth experience, delayed care, and perceived disadvantages of telemedicine. Changes in the birth experience addressed uncertainty about COVID-19 status, COVID-19 testing, separation from newborn, and visitor restrictions. Delayed care themes addressed logistical challenges, postpartum care, health maintenance, and pediatric care. Participants reported multiple telemedicine-related challenges, including difficulty establishing rapport with providers.Understanding the challenges experienced by low-income peripartum individuals as the COVID-19 pandemic evolves is critical to informing guidelines and diminishing inequities in healthcare delivery. Potential solutions that may mitigate limitations to care in the pandemic include emphasizing shared decision-making in care processes and developing communication strategies to improve telemedicine rapport. The postpartum period is a challenging phase during which individuals are recommended to receive intensive psychosocial and health care support as they transition from pregnancy to parenthood, while recovering from giving birth and caring for themselves and their newborns. Healthcare engagement during this period is an essential component of promoting short- and long-term health outcomes. Yet, postpartum care in the United States (US) remains highly fragmented, with as many as 40% of individuals not attending a postpartum care visit, and with well-established disparities that undermine the delivery of optimal care during this period . As a reAs the COVID-19 pandemic reshapes the delivery of healthcare, existing barriers have been exacerbated, further restricting how pregnant and postpartum individuals access care and interact with the healthcare system. Moreover, guidelines aiming to reduce the spread of COVID-19 may make it increasingly difficult for low-income individuals to transition to and obtain postpartum care, and thus may result in a disproportionate increase in adverse outcomes for already vulnerable populations. For example, recommendations by the American College of Obstetricians and Gynecologists (ACOG) to delay the in-person, comprehensive postpartum visit to 12 weeks acknowledge that this decision may negatively affect individuals with publicly funded insurance that expires within 60 days of giving birth ,4. FurthAlthough recent survey studies have helped to elucidate the experiences of pregnant people with prenatal care during the COVID-19 pandemic, little work has focused on the narrative of individuals’ peripartum experiences, especially those of low-income status, as it pertains to their delivery and subsequent engagement with healthcare –7. IdentThis qualitative study was designed to evaluate interactions with the healthcare system experienced by postpartum individuals in the US during the COVID-19 pandemic. This study was conducted among individuals participating within the Navigating New Motherhood 2 (NNM2) study, a randomized controlled trial to determine whether patient navigation can improve postpartum health outcomes for low-income individuals  . EligibiAs NNM2 began enrolling participants in the late third trimester in January 2020, early trial participants were newly postpartum at the onset of the COVID-19 pandemic in mid-March, a time when Chicago government and public health officials enacted shelter-at-home orders, subsequently followed by further limitations on non-emergent surgeries and visitor access to hospitals in an effort to limit the spread of the virus. During this first wave, common obstetric guidelines at the participants’ medical institution included a visitor limitation during labor and postpartum , neonatal separation for those who were COVID-19 positive, attempts at early postpartum discharge to limit hospital exposure, and exclusive telemedical care for postpartum visits. Furthermore, COVID-19 testing capacity was initially limited, with universal testing for labor and delivery admissions not beginning until April 2020. While guidelines and diagnostic protocols were updated with evolving information on the virus, the majority of participants were subjected to these aforementioned restrictions. Thus, interview questions were developed through team discussions incorporating these recent changes to healthcare delivery with preliminary reports from patient navigators regarding participants’ experiences of the pandemic. Participants were asked open-ended questions that encouraged them to share their experiences with healthcare, whether positive or negative.From March to June 2020, all NNM2 participants were approached to participate in a single in-depth interview regarding their late pregnancy and early postpartum experiences with healthcare amidst widespread COVID-19 restrictions and changes. Participants were approached after completion of a postpartum visit  in order to allow them to engage with their medical providers for postpartum care prior to the interview. Individual interviews were conducted over the telephone by three trained research assistants who were either medical students and/or had master’s level training; all team members had undergone training in the empathic nature of open-ended qualitative interviewing. Interviews used a semi-structured interview guide with open-ended, in-depth queries that allowed participants and interviewers to creatively explore their experiences with prenatal care, labor, telemedicine, postpartum care, and pediatric care. Example topics are noted in www.dedoose.com), a secure web-based qualitative data management and analysis software that facilitates collaborative data exploration and identification of themes. Transcripts were analyzed by a team of four investigators using a constant comparative method [Transcripts were uploaded on Dedoose  were interviewed, with the study team members agreeing upon saturation of themes at this point. Interviews took place on average 10 weeks after giving birth. Fifty percent of participants identified as non-Hispanic Black and 37.5% as Hispanic. Participant demographic characteristics are shown in Although the interview guide invited responses on either positive or negative experiences, participants’ responses overwhelmingly focused on barriers to care, emphasizing that COVID-related changes in health care delivery were not perceived by this population to facilitate their care. As such, interview responses were organized into three major domains regarding the challenges experienced by low-income postpartum individuals at this time: 1) unanticipated changes in the birth experience, 2) delayed care, and 3) perceived disadvantages of telemedicine. Multiple themes were further developed within each domain. Themes commonly highlighted specific barriers to patient satisfaction with the care received. Exemplary quotations of each theme are found on individual tables.uncertainty about COVID-19 status, COVID-19 testing, separation from newborn, and visitor restrictions , identifying impersonal care and internet connectivity problems as barriers to effective antenatal virtual consultations during the pandemic; their findings aligned with our themes of technical difficulties and difficulty establishing rapport with providers as perceived disadvantages of telemedicine. Participants in the same study were also torn between avoiding healthcare settings in the antenatal period to limit COVID-19 exposure and worrying over their health as a result of limited in-person appointments and ultrasounds, with this finding resembling our domain of delayed care [Few studies have explored the experiences of low-income individuals as they navigate healthcare in the postpartum period during the COVID-19 pandemic. In a recent study of patients’ experiences with obstetric care, participants reported being forced to alter their original plans of having family members and/or doulas present during their delivery ; our finyed care . Anotheryed care . DespiteWith the rapid expansion of telehealth services, optimization of telemedicine care remains an important need. The removal of reimbursement restrictions by the US DHHS and the Centers for Medicare & Medicaid Services has promoted the widespread adoption of this technology . Prior wdelayed care, we propose an emphasis on shared decision making for healthcare services, particularly for cases that providers or patients feel might not be effectively addressed over telemedicine. Essential to this process are transparent conversations on the medical rationale for in-person versus telemedicine appointments. For patients with chronic health conditions, we propose providing patients with clear and comprehensive instructions and/or necessary equipment, such as blood pressure cuffs or scales, to effectively monitor their health at home. Having consistent access to objective data that can be addressed with their medical providers via telemedicine may help patients feel in control of their health status during a time of uncertainty Click here for additional data file.


Susana Portillo works in the field of mother-infant immunity with an emphasis on vaccination and prevention of respiratory diseases. In this mSphere of Influence, she reflects here on how two pertussis vaccine articles made an impact on her research. She discusses how much more remains to be understood about the role of maternal antibodies in preventing or reducing infant illnesses, their capacity to engage other immune components to deliver an efficient antimicrobial response, and their influence on the infant’s own response to vaccination. She emphasizes the need for safe and effective interventions that strengthen maternal and infant immunity before and after birth. Vaccines are among the most successful public health interventions that have improved quality of life by reducing or eliminating serious infectious threats. The effectiveness of vaccine intervention stands on its capacity to prevent or reduce risk of illness. As the science developed, vaccine-induced immunity has been inferred on the evidence of specific antibodies. Considering the diversity of the antibody repertoire and impact on function, the magnitude of vaccine-specific antibodies portrays an incomplete picture. Probing into how antibodies protect us from disease and for how long and answering associated questions are important to understanding vaccine performance and population immunity and are vital to the overarching goal of controlling and preventing diseases. However, detailed inquiries about what the vaccine-specific antibodies are doing, exactly how they work, and how long they last are scarce in the literature. The articles by Healy et al., “Kinetics of maternal pertussis-specific antibodies in infants of mothers vaccinated with tetanus, diphtheria and acellular pertussis (Tdap) during pregnancy,”  and HaveMaternal vaccination augments the immunity naturally passed to the fetus and infant through the placenta and breast milk. The nursing infant receives ample immunity from the mother in this manner, which is critical to prevent infection in the first months of life until the child’s own immunity develops following routine immunization. Currently, influenza and Tdap vaccines are given during pregnancy, and the more recent coronavirus disease 2019 (COVID-19) vaccine is now also recommended. Through such vaccination efforts, infant morbidity and mortality have declined dramatically since the administration of the combined pertussis vaccine in 1948 . DespiteBoth papers mentioned above point out two important outcomes of mother-infant pertussis immunization that require particular attention to maximize the benefit to the vulnerable infant population. First, Healy determined the antibody content in both the mother and the infant and described a faster decline in infant circulating IgG antibodies from what was previously reported . Healy’sHaemophilus influenzae type B are also available for children. The Havers study examined prevalence of immunity based on type of vaccine received. The antibody level difference resulting from wP and aP priming was assessed in a cohort of 1,012 infants divided into the following three groups: those born to mothers who received aP in their primary childhood vaccine series (aP primed), those born to mothers who received whole-cell vaccine (wP primed), and infants from mothers primed with either vaccine (mixed wP/aP primed). The serological analysis in this study was focused on antibodies to PT. While there is no firm correlate of protection for pertussis, PT-specific IgG are necessary to prevent disease. Some have argued that PT IgG levels above 5 IU/mL could be considered to be protective  vaccine in their childhood vaccine series compared to those who received the acellular (aP) pertussis vaccine after the 1997 Advisory Committee on Immunization Practices (ACIP) recommendations. Different combination vaccines have been used to prevent whooping cough in various populations, including Tdap and DTaP, which contain acellular pertussis antigens , and DTwP, a whole-cell pertussis vaccine that contains PT, FHA, PRN, and also FIM; all such vaccines also contain diphtheria (DT) and tetanus (TT) toxoids. Combination vaccines that include DTaP plus hepatitis B, polio, or otective , and morotective . The anaThe difference in circulating PT IgG levels in aP-primed childbearing-age women and their offspring is a paramount finding, as lower availability of PT antibody might compromise protection in the mother-infant dyad, with the infant being more susceptible and at higher risk of infection. While the overall implications of these findings are unclear, they warrant corroboration and careful examination, as they could have a major impact on public health. Currently, in winter 2023, there is a surge in respiratory syncytial virus (RSV), influenza, and COVID-19 in young children that has overwhelmed US health care facilities , Luminex, or Meso Scale Discovery (MSD) assays and calibrated against the WHO First International Standard Pertussis Antiserum 06/140. Functional assays, such as B. pertussis opsonophagocytosis and PT neutralization, hold promising value to evaluate antibody functional activity; development and optimization efforts are under way. Furthermore, breast milk, a rich resource for infant immunity, has yet to be explored for its full protective potential, including the presence in breast milk of functionally active antibodies, an important focus of my own research. Recently, various groups have used the systems serology platform to characterize maternal antibody transfer, focusing on various pathogens such as HIV, Mycobacterium tuberculosis, and Ebola virus and more recently severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Shigella (–There is an opportunity to tackle pertussis and other immunization challenges through well-characterized human studies, including ongoing controlled infection models, and by making use of technological advances. For example, the Shigella –13. This


The mechanism of anesthesia-induced neurotoxicity still requires further elucidation in primates.Anesthesia is unavoidable in surgical procedures. However, whether the general anesthetics are neurotoxic to immature brains remains undefined. Neurodevelopmental impairment induced by anesthesia has been a critical health issue and topic of concern. This review summarizes recent progress made in clinical and preclinical studies to provide useful suggestions and potential therapeutic targets for the protection of the immature brain. On the one hand, clinical researchers continue the debate about the effect of single and multiple exposures to anesthesia on developing brains. On the other hand, preclinical researchers focus on exploring the mechanisms of neurotoxic effects of general anesthesia on immature brains and seeking novel solutions. Rodent models have always been used in preclinical studies, but it is still unclear whether the mechanisms observed in rodent models have clinical relevance. Compared with these models, non-human primates (NHPs) are more genetically similar to humans. However, few research institutions in this area can afford to use NHP models in their studies. One way to address both problems is by combining single-cell sequencing technologies to screen differential gene expression in NHPs and perform  Anesthesia is unavoidable in surgical procedures, which often causes concerns for the parents of children who are scheduled to undergo surgery .General Over the years, numerous clinical and preclinical studies have been conducted to improve the safety of general anesthesia exposure and find potential novel targets to protect the immature brain . TherefoThe warnings issued by the FDA have been the driving force behind numerous clinical and preclinical studies. Due to ethical and technical restrictions, it is hard to perform prospective, randomized studies on human fetuses and neonates without confounding factors. Although many animal studies have shown the neurotoxic effects of general anesthetics on the immature brain, there are few studies on what effect general anesthetics have on human fetuses and neonates . ConsequSeveral clinical studies have been conducted to further explore the side effects general anesthetics have on immature brains, including three well-known clinical studies, which are the General Anesthesia vs. Spinal Anesthesia (GAS) study, the Pediatric Anesthesia, and Neurodevelopment Assessment (PANDA) study, and the Mayo Anesthesia Safety in Kids (MASK) study . The GASAdditionally, these three clinical studies found that multiple exposures to anesthesia might lead to behavioral and executive function deficits. The results of the secondary analysis of this study published in 2021 proposed a new idea that multiple, but not single, exposures might cause adverse effects on specific neuropsychological domains, such as processing speed, fine motor abilities, motor skills, and visual-motor integration , 2021. CIn addition to the three well-known clinical studies above, other remarkable studies were recently published. A cohort study in Avon was recently published in 2020, in which 13,433 children grouped by none, single, and multiple exposures to anesthesia were recruited, and the results indicated that multiple exposures might cause adverse effects on motor ability and social, linguistic ability . RecentlRecently, an observational study has revealed that children under the age of 5 years with a single exposure to surgery and anesthesia were 37% more likely to need attention-deficit hyperactivity disorder (ADHD) medications than unexposed children, which means even single exposure to anesthesia might be associated with deficits in behavior and executive function . In contFinally, the results of the above studies have provided strong evidence that single or multiple exposures to general anesthesia may not lead to reduced IQ scores in later childhood, while receiving multiple exposures to anesthesia might increase the risk of neurodevelopmental impairment and long-term cognitive dysfunction . AnestheHowever, clinical research cannot address or resolve all the problems of anesthesia-induced neurotoxicity. Only preclinical studies could identify which mechanisms are implicated in neurotoxicity . TherefoPreclinical research will always be a major actor in research on the toxicity of general anesthesia. Tremendous attention has been paid to anesthesia-induced neurotoxicity in the immature brain. Parents’ anxiety is almost inevitable when referring to the unsure risk of anesthesia to children. Unnecessary parental anxiety is one of the controversies regarding anesthesia-related neurotoxicity . CommonlApoptosis is a kind of programmed cell death that occurs in many cell types due to various circumstances and aging . ExposurAccording to recent studies, intranasal use of insulin appears to be a feasible approach to protect the vulnerable immature brain from anesthesia-induced apoptosis. Intranasal use of insulin can bypass the blood–brain barrier to deliver insulin to the hippocampus and other cerebral regions and bind to their receptors . By perfIn addition, the extent of apoptosis is probably associated with age and gender differences. Exposing P7 rats to isoflurane 4 h leads to decreased recognition memory in male but not female rat . Accordivia other molecular mechanisms. In the above study, researchers observed that testosterone reduces KCC2 expression, leading to developmental retardation of brains  might lead to cognitive dysfunction poptosis . Howevervia nuclear factor-kappa B (NF-κB) signaling, which is associated with M1 activation , which is harmful to neurons, and the alternative activation (M2), which is helpful for tissue repair . A well-tivation .via the mechanism of ceRNA (As a part of the mitogen-activated protein kinase (MAPK) signaling pathway, the JNK signal transduction pathway is associated with the secretion of IL-6. A recent study demonstrated the functional role of lncRNA Riken in attenuating sevoflurane-induced neuroinflammation and also revealed the underlying miRNA-101a-associated molecular mechanisms . One funof ceRNA . By inhiof ceRNA .Pyroptosis is a novel inflammatory form of programmed cell death defined as gasdermin-mediated programmed necrosis , 2017. AA series of animal experiments have suggested that NF-κB is an essential regulator of many pathways of neuroinflammation Zhang, . By inhiA fine balance between the presence of ROS and antioxidants is crucial for the proper normal functioning of the cell . ExposurUsually, doctors tend to focus only on how hypoxia disrupts normal functions of immature brains, which may not always be correct. Normal brain functions are based on maintaining the partial pressure of brain tissue oxygen within a relatively narrow range. Damage to the immature brain has been related to hypoxia, while hyperoxia-induced neurotoxicity should not be underestimated. Administration of general anesthetics might increase the level of ROS by elevating partial pressure of brain tissue oxygen of neonates, then disrupt cognitive functions in immature brains . AdditioWell-balanced ROS and antioxidants is crucial to the proper development of the central nervous system. Hypoxia might lead to injured brain tissues, while the effects of hyperoxia should also be considered. To prevent aggravation of brain damage, anesthesiologists may choose general anesthetics after much deliberation. In addition, clinical use of near-infrared spectroscopy (NIRS)-based cerebral oximetry provides conditions for monitoring brain tissue oxygen .Synaptogenesis in the human neocortex occurs from the third trimester to the postnatal 2 or 3 years . A serieDendritic spines include different types of spines, such as thin spines, defined as “learning spines,” and mushroom spines, defined as “memory spines.” Dendritic spines receive excitatory input, and their morphology is strongly related to learning and memory abilities . Long-tePropofol is popular among intravenous general anesthetics . AccordiOther studies revealed that sex hormones might contribute to synaptic changes. As discussed above, testosterone reduces KCC2 expression, leading to neurodevelopmental retardation of brains . The undAdditionally, exposure to general anesthetics may disrupt normal mitochondrial function. Mitochondrial unfolded protein response (UPRmt) helps upregulate mitochondrial function and frequency of miniature excitatory postsynaptic currents when exposed to general anesthetics . Therefovia inhibition of phosphoinositide 3-kinase, thus blocking the formation of the autophagic vesicle  administration inhibited the activation of Cyclin-dependent kinase 5 (CD5), which can upregulate SIRT1-induced autophagy. SIRT1-induced autophagy might reverse sevoflurane-induced neurodevelopmental impairment and cognitive dysfunction . HoweverProper myelin formation is essential to neurocognitive function. In the central nervous system, oligodendrocytes (OLs) are a particularly specialized type of glial cell which provide fundamental support to neuronal activity by producing the myelin sheath . HoweverAdditionally, disrupted folate metabolism is associated with myelination deficits as well. A study performed by Zhang and colleagues showed that sevoflurane decreased TYMS  and ERMN (a myelination-related gene) levels in both rhesus macaques and mice. Additionally, the expression of TYMS and ERMN is strongly related to folate metabolism . ExposinMyelination deficit is one of the key mechanisms of anesthesia-induced cognitive dysfunction. Iron therapy, folic acid supplementation, and ERMN are well-established therapeutic regimens for patients. These studies provide more targets for protecting immature brains in clinical works by discovering the underlying mechanisms of myelination deficits.Dual specificity protein phosphatase 4 (Dusp4) plays a crucial role in neural differentiation, which can mediate the differentiation from human embryonic stem cells (hESCs) to neural progenitor cells (NPCs) . Accordiin vivo validations in rodents. The combination of NHP and rodent models may further elucidate our understanding in human subjects.According to the above study, we concluded that downregulated level of Dusp4 in the prefrontal cortex appeared in NHPs but not in rodents. This study provides us with a potential therapeutic target while reminding us that the mechanism of neurotoxicity may not be the same between NHPs and rodents. Although few research institutions in this area can afford to use NHP models, the article provides new ideas for future work, such as combining single-cell sequencing technologies to screen differential gene expression in NHPs and carry out Ferroptosis is another novel kind of programmed cell death characterized by iron-dependent lipid peroxides accumulation . GlutathMeanwhile, exposure to sevoflurane might also lead to iron-induced neurotoxicity in the hippocampus and cognitive dysfunction by upregulating NMDA receptors and enhancing divalent metal transporter 1 (DMT1)-mediated iron upregulation and iron release from lysosome . The damThe dysregulation of the gut microbiota might also influence the immature brain. A recent study has shown that the clinical concentration of sevoflurane did affect the gut microbiota. Exposing 6 to 8-week-old mice to 2.21% sevoflurane for 4 h might reduce the microbiome’s variety in neonatal mice . MicrobiOn the one hand, most clinical studies have paid attention to the dose, timing, and frequency of exposure. According to the above clinical studies, single or multiple exposure might not reduce IQ scores. In contrast, multiple exposures may adversely affect processing speed, fine motor abilities, social, linguistic ability, visual-motor integration, and motor skills. Therefore, parents do not need to worry excessively about single and short exposure. In addition, future clinical studies should give greater attention to prospective, multicenter, and long-term follow-up clinical studies.in vivo. Different anesthetic agents might induce neurotoxicity through various mechanisms. In addition, the translational value of preclinical studies is limited by multiple factors. First, although most preclinical studies are conducted under general anesthesia, they are not stimulated by surgeries. Clinically, this is virtually absent. Children and pregnant women receive general anesthesia for surgeries rather than only exposing to anesthesia. Second, due to a species difference, the results found in rodent models may not fully explain the mechanisms in humans. Therefore, we need to improve the quality of experiments and look for animal models that best suit clinical situations.On the other hand, preclinical studies resolve the problem of how general anesthetic agents induce neurotoxicity, a challenging area of clinical studies. There has been much discussion about the potential mechanisms of general anesthesia-induced neurotoxicity . Howeverin vivo validation in rodents. Notably, studies have suggested that this trend will continue in the future , the Natural Science Foundation of Shanghai (Grant No. 22ZR1437200), and the scientific research fund of Shanghai Ninth People’s Hospital (Grant No. JYHX2021012).The authors declare that the review 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.


Alcohol use disorder (AUD) and anxiety disorders (AnxD) are prevalent health concerns in clinical practice which frequently co-occur (AUD-AnxD) and compound one another. Concurrent AUD-AnxD poses a challenge for clinical management as approaches to treatment of one disorder may be ineffective or potentially counterproductive for the other disorder.We present the case of a middle-aged man with anxiety disorder, AUD, chronic pain, and gamma-hydroxybutyrate use in context of tapering prescribed benzodiazepines who experienced severe alcohol withdrawal episodes during a complicated course of repeated inpatient withdrawal management. After medical stabilization, the patient found significant improvement in symptoms and no return to alcohol use with a regimen of naltrexone targeting his AUD, gabapentin targeting both his AUD and AnxD, and engagement with integrated psychotherapy, Alcoholics Anonymous, and addictions medicine follow-up.Proper recognition and interventions for AUD and AnxD, ideally with overlapping efficacy, can benefit individuals with comorbid AUD-AnxD. Gabapentin, tobacco cessation, and integrated psychotherapy have preliminary evidence of synergistic effects in AUD-AnxD. Meta-analysis evidence does not support serotoninergic medications (e.g. selective serotonin reuptake inhibitors) which are commonly prescribed in AnxD and mood disorders as their use has not been associated with improved outcomes for AUD-AnxD. Additionally, several double-blind placebo-controlled randomized trials have suggested that serotonergic medications may worsen alcohol-related outcomes in some individuals with AUD. Areas for future investigation are highlighted. Alcohol use disorder (AUD) is a prevalent health concern with a recent epidemiologic survey of the United States indicating a lifetime AUD prevalence of 29.1% and previous 12 month prevalence of 13.9%  = 12) as well as relapse to any alcohol use (NNT = 20) , which mAcamprosate, which modulates glutamate and GABA signaling disrupted by chronic alcohol use, is another first-line AUD medication effective in preventing relapse to any alcohol use (NNT = 12) . In termGabapentinoids such as gabapentin and pregabalin also modulate glutamate and GABA signaling implicated in AnxD and AUD specifically by antagonism of voltage-gated calcium channels. For AUD, gabapentin can be used in the short-term to treat alcohol withdrawal symptoms and in the longer-term to reduce heavy drinking days although efficacy for other endpoints such as reduction in cravings is debated . ImportaThe available evidence more strongly supports efficacy of gabapentinoids in treatment of isolated primary AnxD. Gabapentin may be effective for several types of AnxD,  althoughIn sum, the current evidence indicates gabapentinoids have a role in the treatment of both AUD and AnxD and this class of medications may hold promise for treatment of comorbid AUD-AnxD. This emerging evidence supported the prescription of gabapentin in the above case which we believe ultimately contributed to the substantial benefit the individual found with the regimen described. In the interim while further evidence accumulates, a pertinent consideration in the application of gabapentinoids remains the risk of misuse. Gabapentin misuse occurs in the general population, particularly those with substance use disorders, for a variety of reasons including self-medication  as well as documented recreational use or self-harm . Even inOther medications which have received research attention for AUD include baclofen, topiramate, antipsychotics, and benzodiazepines . The eviRegarding selective serotonin reuptake inhibitors (SSRIs), the prevalent pharmacologic treatment for AnxD , a CochrWe note with interest the underappreciated phenomenon of enhanced serotoninergic neurotransmission exacerbating AUD for certain individuals. For example, a secondary analysis of a RCT studying naltrexone for individuals with AUD and comorbid mood and anxiety disorders found prescriptions for SSRI outside of study protocol during follow-up to be associated with worse drinking outcomes for participants randomized to placebo, an effect which was attenuated if participants received naltrexone . More coTrazodone, another psychotropic medication which modulates serotonin transmission, although used for mood disorders and insomnia rather than AnxD, should be addressed in context of AUD. Trazodone is occasionally prescribed with intent as an antidepressant and sleep aid for individuals with AUD but one RCT found a minimal short-term improvement in sleep quality, while also reporting reduced abstinent days, and increased severity of alcohol consumption following withdrawl of trazodone .In sum, despite the evidence for first-line treatment of isolated AnxD or mood disorders with serotoninergic agents such as SSRIs, clinicians should reconsider and exercise caution in prescribing these medications for patients with comorbid AUD given current observational, RCT, and meta-analysis evidence demonstrating lack of benefit and potential of harm to alcohol use outcomes. In the interim, further investigation is needed to clarify which selected subpopulations in clinical practice would benefit from step-wise approach later involving serotoninergic agents or conversely serotonin antagonists . CarefulAlthough not directly relevant to the individual described in our case report, tobacco use may impact clinical outcomes for individuals with AUD-AnxD. Research indicates that weekly smoking in youth is a risk factor for worsening of AUD , and tobFormal psychotherapy holds promise for addressing the propagating psychosocial factors of AUD and AnxD alone or in addition to pharmacotherapy. In the realm of AnxD, CBT can be equally or more effective than medication alone . For comAnxD and AUD are prevalent health concerns which frequently co-occur and can compound one another as demonstrated in our report. Their co-occurrence requires a thoughtful approach to treatment given the evidence that treatments of one disorder have been shown to be ineffective or counterproductive for the other disorder Fig. . Althoug


Symptoms of hoarding disorder, such as significant household clutter, difficulty discarding, and excessive acquisition tend to increase in later life. With many challenges involved in aging in place, older adults may be particularly vulnerable to adverse events occurring while living with excessive clutter . Therefore, understanding what factors predict hoarding symptom severity is an essential step towards increasing older adults’ ability to age in place while experiencing hoarding symptoms. Personality traits have been demonstrated to predict hoarding symptoms in a wide range of ages. However, a sample of older adults in this clinical population has not been evaluated. The IPIP-NEO-60 is a shortened version of a widely used open-source personality measure that utilizes the five-factor model of personality . We used this measure to evaluate the personality profiles of rural-dwelling older adults  enrolled in an ongoing treatment study for hoarding disorder (n = 14). Compared to normative data from 910 adults aged 50 and up and matched for gender, most participants scored in the average range for Neuroticism, Extraversion, and Openness, with a nearly even split between high, low, and average scores for Agreeableness. Half of participants scored in the low range for Conscientiousness. Given the considerable proportion of participants demonstrating low Conscientiousness in this sample, screening a larger sample for beyond-average facet scores within this factor  may assist clinicians in selecting impactful treatment targets for hoarding disorder in older adults.


Precision-cut tumor slices (PCTS) have recently emerged as important ex vivo human tumor models, offering the opportunity to study individual patient responses to targeted immunotherapies, including CAR-T cell therapies. In this review, an outline of different human tumor models available in laboratory settings is provided, with a focus on the unique characteristics of PCTS. Standard PCTS generation and maintenance procedures are outlined, followed by an in-depth overview of PCTS utilization in preclinical research aiming to better understand the unique functional characteristics of cytotoxic T cells within human tumors. Furthermore, recent studies using PCTS as an ex vivo model for predicting patient responses to immunotherapies and other targeted therapies against solid tumors are thoroughly presented. Finally, the advantages and limitations of the PCTS models are discussed. PCTS are expected to gain momentum and be fully utilized as a significant tool towards better patient stratification and personalized medicine. The recent advances in immunotherapies, such as immune checkpoint modulators and adoptive T-cell transfer, open new opportunities for the treatment of cancer. With this broad spectrum of new therapeutic agents available, however, the need for robust, predictive preclinical models to minimize translational failures in immuno-oncology is increasing.Several preclinical mouse models have been developed throughout the years to model human cancer and predict patient responses. These mouse models carry important limitations, as they are unable to fully recapitulate human tumor genetics and histology as well as the human tumor microenvironment (TME) ,2. For tThe ex vivo generation and culture of live precision-cut tumor slices (PCTS) deriving from various human solid tumor sites has lately emerged as a potential tool for successful personalized drug screening ,4. PCTS,This review delves into the important role of PCTS slices in modern cancer research with a focus in immunotherapy, as well as in the progress of patient stratification and personalized medicine.Within laboratory settings, several standardized human tumor models have been widely used throughout the years to study the biology of cancers . The mosThe culture of tumor cell lines in specialized collagen or other gel-like matrices allows for tumor cells to obtain a more 3D, spherical-like shape ,9. These. They are used in various applications, including the preclinical testing of clinically available therapies to determine optimal combinations for individual patients, predictive biomarker discovery, drug screening and the elucidation of mechanisms leading to drug resistance [PDX models are developed via subcutaneous or organ-specific implantation of fresh patient tumor tissue or cells in immune-deficient mice. The engraftment of primary tumor cells or fragments results in the development of nodules that retain the phenotypic characteristics of the original tumorsistance . Despitesistance ,15. Furtsistance ,15. Mostsistance .PCTS are an ex vivo platform able to recapitulate the high in vivo intratumoral complexity more accurately than other existing models ,16. PCTSPCTS are generated using vibrating microtomes, known as “vibratomes”. Microtomes, used extensively in diagnostic histopathology, are relatively simple instruments comprising of a blade and a blade holder, an object clamp used to hold and secure objects, an advancement mechanism, and a mechanism for section thickness adjustment that allows for precise control . The wayVibratomes incorporate vibration to the microtome blade, resulting in less pressure and stress to the tissue sample than a stationary blade, and are therefore ideal for fresh tissue slicing . In the The generation of PCTS involves the acquisition of adequate volume of fresh tissue, usually provided as a surplus to diagnostic procedures. The production of PCTS occurs within a few hours post-surgery to promote tissue survival and retain high levels of tissue viability ,18.Fresh tissue samples are placed in ice-cold tissue storage buffers  immediately following surgical excision. Once in the laboratory and using a biopsy punch, several cores can be obtained from the tissue sample ,25. AlteTissue slicing speed (mm/s) and vibration amplitude (mm) are selected according to tissue type, density, consistency and integrity . Once PCPCTS can usually retain their viability as well as the same histological, architectural, and phenotypical characteristics as the original tumor for an average of 6–7 days, depending on tumor type ,31,33,34PCTS offer the opportunity to study the localization and function of the several immune cell types within the TME, and how the latter behave following treatment. With CD8+ cytotoxic and CD4+ helper T cells playing a central role in anti-tumor immunity, several PCTS-based studies have focused on understanding the localization and function of tumor infiltrating lymphocytes (TILs) in solid tumors, including lung, breast and melanoma ,45,46,47CD103+ CD45RO+ CD8+ tissue resident memory T cells (Trms) have recently emerged as a highly cytotoxic CD8+ T-cell subset localized within mucosal tissues and playing a key role in anti-tumor immunity in several solid tumors ,44,45,46In a similar study by the same group, the motility and migration patterns of CD8+ TILs within lung and ovarian cancer PCTS were explored . ImmunosData from such studies can be helpful in identifying factors that block spatial distribution of TILs within tumor cell-rich areas, as well as factors with a role in TIL anergy, ultimately contributing to the discovery of biomarkers of response to immunotherapies.PCTS use in CAR-T cell research is still in its infancy. A 2021 study used EGFR-targeting CAR-T cells in co-cultures with either PCTS derived either from a BxPC3 EGFR-expressing pancreatic cancer PDX model or from PCTS derived from NSCLC and ccRC . ConfocaThe potential of PCTS in predicting patient response has been under evaluation for several years. Most studies to date have used PCTS to assess patient responses to chemotherapy and targeted therapy ,48,49. UMore recently, PCTS from nine hepatic metastatic colorectal cancer patients were treated with clinically relevant oxaliplatin (chemotherapy), cetuximab (EGF inhibitor) and pembrolizumab (PD-1 inhibitor) . It was Seo et al. generated PCTS from surgical resections of patient PDA tumors  and demoIn a 2020 study, researchers treated PCTS derived from clear cell renal carcinoma (ccRC) patient surgical resections with either emsirolimus (mTOR inhibitor blocking cancer cell proliferation), pazopanib (angiogenesis blockade), or sunitinib (blockade of angiogenesis and tumor cell proliferation) to explore differences in drug sensitivity of different patients’ PCTS . Indeed,A recent study by Horowitz et al. aimed at developing a more automated, digitally manufactured microfluidic platform, allowing for multiplexed drug testing using intact glioblastoma (GBM) PCTS derived from patients or PDX models . This miPCTS are highlighted as the ex vivo model that fully retains the real tumor 3D landscape, along with its TME, including stroma and immune cells. They are relatively easy to produce and, within their viability timeframe of up to a week, can offer a platform to test tumor responses of immunotherapies, such as checkpoint inhibitor antibodies and CAR-T cells. As CAR-T cells are a “living drug”, ex vivo PCTS models can be used to study CAR-T cell kinetics, spatial distribution, and migration patterns, additional to their function. Thus, within the next decade, more preclinical PCTS-based research studies on CAR-T cells are expected to emerge.PCTS present with several limitations, such as the inability to be cultured long-term and to be biobanked due to current limitations in the PCTS freezing processes . Another important limitation is that PCTS are low throughput systems. Tissue dissociation leading to tumor and immune cell isolation allows for high-throughput assays, such as transcriptomics, multi-omics, single-cell profiling, multi-color flow cytometry and multi-panel drug testing. In contrast, PCTS allow for limited drug testing each time , and for imaging and immunohistochemistry techniques that usually permit the testing of only a small number of fluorescent markers. The development of commercial microfluidic systems in the future could lead to platforms capable of supporting multiplexed drug testing in live tumor slices.Although PCTS cannot be used directly for multi-omics analyses, they can still be dissociated or PCTS lysates can be generated and can subsequently be used for transcriptomic, proteomic and metabolomic assays ,55,56. AThe biggest limitation of PCTS is the heterogeneity between slices of the same sample, which reflects tumor heterogeneity. To date, there is no standardized approach to cultivating tumor PCTS and studies are limited by their minimal biochemical characterization of the impact of slice preparation and cultivation conditions. It is difficult to systematically compare different slicing techniques and cultivation methods due to the inherent heterogeneity between tumor histology, patients and individual slices. A recent study of 108 resected primary or metastatic liver tumors revealed significant variability in growth and proliferative activity among different tumors, and significant metabolic heterogeneity at baseline between slices cut from the same tumor . AdjacenAside from inter- and intra-tumoral heterogeneity at baseline, studies show that the process of slicing and cultivating PCTS may induce changes in the tissue that render it biologically different from the original tumor. A study to comprehensively characterize the transcriptional changes in PCTS during cutting and culturing using RNA sequencing was recently published . By compA similar study looking at the effect of culture on gene transcription was performed in pancreatic ductal adenocarcinoma , where bThese two studies highlight the transcriptional changes that occur during the slicing and culturing of PCTS. The changes appear to be both disease and organ specific, with different organs demonstrating different susceptibility to changes over time. Interestingly, even PCTS generated from the same organ, but of different patients, show variability in genomic changes during culture. The greater the number of changes, the less comparable PCTS are to their tissue of origin. The supplementation of culture media and manipulation of culture conditions have been proposed as mechanisms to overcome some of these changes ,61,62, aBy retaining the landscape of the original tumor, PCTS are a physiologically relevant and important culture system for the study of solid tumor immunobiology. Data to date have also shown that this approach can be a relevant model across several tumor types for the individualized testing of drug susceptibility to improve clinical response rates. Having identified several limitations in the use of PCTS, recent and ongoing work from our team and others aims to better understand the potential of this platform as well as to optimize culture condition protocols to fully utilize it. Nevertheless, we anticipate that further work will eventually make PCTS useful for personalized clinical immunotherapy, especially in the case of adoptive cell therapy.


Accurate tissue differentiation during orthopedic and neurological surgeries is critical, given that such surgeries involve operations on or in the vicinity of vital neurovascular structures and erroneous surgical maneuvers can lead to surgical complications. By now, the number of emerging technologies tackling the problem of intraoperative tissue classification methods is increasing. Therefore, this systematic review paper intends to give a general overview of existing technologies. The review was done based on the PRISMA principle and two databases: PubMed and IEEE Xplore. The screening process resulted in 60 full-text papers. The general characteristics of the methodology from extracted papers included data processing pipeline, machine learning methods if applicable, types of tissues that can be identified with them, phantom used to conduct the experiment, and evaluation results. This paper can be useful in identifying the problems in the current status of the state-of-the-art intraoperative tissue classification methods and designing new enhanced techniques. Identifying and differentiating individual tissue types and anatomical structures is one of the most fundamental skills a surgeon must have to perform surgery in a safe and successful manner. Taking spinal surgery as an example, the combination of poor visualization, complex anatomy, and vital adjacent structures such as the spinal cord, peripheral nerves, and the aorta imposes a particular set of challenges for the surgeon . During Computer-assisted surgical navigation can be noted as the most common technique for providing surgical guidance during operation , 6 and rInspired by the enhanced ability of surgeons when combining visual and non-visual senses to determine a specific tissue type, a growing body of research strives to leverage intraoperative sensing technologies  for tissue classification and differentiation to improve the effectiveness of surgical navigation and autonomy of surgical robotics –12. PartThe increasing number of publications on this topic suggests the need for a systematic review of available intraoperative tissue classification methods in the fields of orthopaedics and neurosurgery and to understand the development status of available technologies. In this article, we have characterized the existing papers with respect to the underlying sensing technology, the clinical application, the data processing algorithms, the classification accuracy, and outlook from a clinical perspective.(tissue OR nerve OR cartilage OR bone OR artery OR ligament OR state) AND (classif* OR sens* OR detect*) AND (surgery OR intraoperative) AND (orthop* OR spine OR neurosurgery) AND where “OR” and “AND” terms denote the corresponding logical operations between the individual keywords. The first group includes the tissue types such as nerve, artery, cartilage, bone, or ligament. The term “state” was added to include relevant articles concerning state identification within the anatomy. The second group comprises synonymous words for classification including sensing and detection. To include both nouns and gerunds, only the word root was used together with wildcards, e.g., classif* instead of classification and classifying. Since we intended to cover sensor fusion, machine learning, and classical signal processing, a third group was added accordingly.In this study, we conducted a systematic review on intraoperative tissue classification methods in orthopedic and neurological surgeries based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The sea•The topic of the paper concerned real-time tissue classification during orthopedic and neurological surgeries.•The method for classifying different tissue structures was binary or multi-class. Since some studies involved shape detection , one versus rest classification approach-based reports were excluded.•in-vivo or ex-vivo conducted on either human or animal tissues or synthetic anatomical models.The study was either Preliminary individual search and screening were performed on November 23, 2021, by two independent reviewers in a blinded fashion . In caseWe only included studies that were published in English.•The surgical task for which the proposed method was developed.•The main sensor or sensing technology used for tissue classification.•The implemented data processing steps.•If the method involves machine learning: the name of the machine learning method or framework used.•The type of specimen used in the study •Classes or tissue types classified with the proposed method •Criteria used for performance evaluation such as accuracy, recognition rate, success rate, sensitivity, and specificity.•Further prospective on clinical applications.To facilitate the systematic extraction of data from the included articles, we created the following template based on which the key characteristics of each study were recorded:A total of 3,008 publications were retrieved through our initial database search. As no duplicates were found, two independent reviewers screened the titles and the abstracts of all retrieved publications. The screening process resulted in 2,944 papers that were further evaluated against the above-mentioned criteria. A total of 64 papers passed through the screening from which 60 full-text papers were included in this systematic review. Three papers were excluded due to missing online full text and one paper was excluded as it was not written in English.The identified papers were grouped into categories depending on the sensing technology used, namely hyperspectral imaging, spectroscopic sensing, ultrasound imaging, force, robotic and impedance sensing, vibro-acoustic sensing, optical coherence tomography, endoscopic and microscopic imaging, and x-ray imaging. The general overview of categories is tabulated in Hyperspectral imaging is a spectroscopy method that captures both spectral and spatial information. Each pixel represents hundreds of spectral bands, which correlate with the chemical composition of the underlying imaged material .Six publications , 14–18 wExtracted reports used different technologies of varying spectral wavelengths. The majority of studies used Visual and Near-Infrared (VNIR) push-broom cameras covering a 400–1,000 nm wavelength range , 17, 18.The data preprocessing steps for hyperspectral imaging conventionally start with image calibration, where the raw data is calibrated with respect to white and dark reference images. This is followed by image denoising and band averaging. Afterward, spectral signatures are normalized to prevent the differences in radiation intensities caused by surface irregularities , 15–17. The processed hyperspectral data is then generally used as an input for machine learning methods that are trained to perform tissue classification. Within the collected articles, different machine learning algorithms were used for this task, namely: Support Vector Machines (SVM) , 16, 17,The majority of studies were based on human brain tissue samples and aimed at differentiating between healthy tissue, tumor, blood vessels, and background using push-broom hyperspectral sensors. The method reported in Urbanos et al.  additionIn spine surgery, hyperspectral imaging might be useful in differentiating intervertebral disc or scar tissue from nerve structures to identify vital structures earlier, more accurately, and without missing sequestered disc fragments in close relation to other tissues. In this regard, till today there is no intraoperative technology providing that functionality.Spectroscopy provides a precise analytical method for identifying the chemical composition of the material based on its emission spectrum. The contactless nature of the spectroscopic technology makes it suitable for intraoperative tissue identification during surgical interventions. Spectroscopy provides a similar reflectance spectrum as hyperspectral imaging but it does not capture spatial information. Instead, light is dispersed with diffraction grating first and then projected onto charge-coupled devices (CCDs). Afterward, spectral information is extracted from this digital format.The majority of studies that we found in this category –28 used Spectroscopic sensing methods found in the reviewed articles can be categorized into the following technologies: optical scattering spectroscopy probe , high-reThe preprocessing pipeline of spectral data consisted of signal denoising , 24, 25,Multiple studies aimed at using RS in detecting different types of tumor tissues such as solid tumors , infiltrSpectroscopic sensing is a potentially powerful technology for spine surgical use cases as it might assist in breach detection during pedicle screw preparation, detection of low-grade infections, differentiation of seroma and cerebrospinal fluid, and tissue differentiation.Ultrasound imaging is an established clinical imaging method that provides real-time information about anatomy and physiology based on the emission and detection of sonar signals. This technology has been widely used in guiding interventional and diagnosis procedures owing to its portability, low price, and non-invasiveness (no radiation exposure). However, it is typically accompanied by low resolution, image artifacts, and operator dependency.Within the reviewed articles, three studies , 34, 35 Carson et al.  used an In the work by Carson et al. , the edgThe data collection for the U-net method was conducted on in-vivo porcine specimen with the objective to categorize it into three classes, namely nerve, bone, and psoas muscle . The groWith accurate real-time imaging of soft tissues even with plastic deformation, ultrasound offers a potential benefit for anterior approaches to the spine, which are challenging due to their proximity to vital soft-tissue structures, especially in the revision situation with scarring and altered anatomy. Furthermore, by visualizing posterior vertebral structures, ultrasound could be used as a data basis for non-ionizing spinal navigation.Through physical contact and tactile sensation, humans can perceive a variety of object properties including size, hardness, and stiffness. Tactile sensing is especially crucial when areas are inaccessible for visual perception. With the rapid development in robotics, research in robotic control and force sensing has gained interest in the development of robots having surgeon-like tactile sensations. Besides, impedance sensing is another promising technology allowing the evaluation of the physiological state of the tissue, given that biological structures of the tissue cause impedance differences.Bone drilling and milling are common surgical procedures in orthopedic surgeries. In manual bone-cutting procedures, surgeons use their tactile sensation to ensure a safe and accurate operation. Therefore, the majority of studies found in this category –43 propoRobotic bone drilling and milling-related articles used force sensors , 39, 40,The approaches reported in Al-Abdullah et al. , Deng etThe evaluation of the method in Torun et al.  classifiIn addition to yet investigated fields of use like breach detection and tissue differentiation, force and impedance sensing could help spine surgeons to intraoperatively assess bone mineral density and quality of screw purchase or the need for cementation, respectively. This would help avoid revision surgery for mechanical failure at the implant-bone interface.Auditory perception arises from sensing the vibrations in the physical world, whereas a vibration signal depicts information on the oscillations occurring during an equilibrium event. Therefore, vibration signals can characterize the differences between textures and detect the roughness of the surface.In a surgical setup, information about the relative position between the instrument and the bone can be extracted from the cutting vibration. Specifically, the direct contact between the surgical tools as drilling and milling machines and bone induces vibration signals that differ with respect to the in-contact bone layer type. Vibration signals can be measured with accelerometers , 48 to sAcceleration sensing methods performed by Dai et al. , 48 tackDai et al.  reportedMethods found in Ostler et al.  and SeibDai et al.  classifiWith its high specificity in classification of different bone tissue, vibro-acoustic sensing might be of particular promise in predicting pedicle breaches. Pedicle breaches can be predicted during the pedicle drilling step, when the drill or bone awl has close contact with cortical bone.in situ and in real-time. Image resolution varies between 1 µm and 15 µm. However, a maximum imaging depth ranges between 2 mm and 3 mm  is known as a non-invasive and radiation-free medical imaging technique capable of generating 2D or 3D images of biological tissues based on backscattered light measurement. It can be performed and 3 mm .All the extracted articles of this category –61 were Möller et al.  used a cThe processing steps in Möller et al.  and LenzLenz et al. , 62 usedAs a non-ionizing high-resolution real-time medical imaging, optical coherence tomography could potentially aid with the classification of nervous tissue in the surgical treatment of intradural pathologies such as tumors or tethered cords.via an endoscopic tube with a small camera that is inserted into the incision area.Microscopic and endoscopic approaches are common MIS methods. Microscopic surgery is performed with high-powered microscopes that allow magnifying the field of view, whereas endoscopic surgery allows visualizing the hidden interior structures Studies using surgical endoscopes focused on spinal endoscopic surgeries  and percA surgical endoscope was used in the studies by Cui et al. , 63, wheStudies reported in Cui et al. , 63 usedSurgical endoscope-based studies , 63 idenSpinal endoscopy and microsurgery already are indispensable pillars of spine surgery with continuous development. Currently, in addition to decompressions, lumbar fusion surgeries with interbody cages are also performed endoscopically. Here, a combination with other sensing technologies is of particular interest as haptic feedback is reduced.X-ray imaging uses electromagnetic energy beams to produce images of various media based on the interaction of x-rays with matter. Two main phenomena happen during x-ray – matter interaction, namely absorption and scattering effects. Compton scatter, coherent scatter and photoelectric effects are the major effects that are considered in medical applications. The detection of x-rays can be accomplished either indirectly or directly. The (older) indirect x-ray detection method uses scintillators first to convert received radiation to light and then photodetectors to detect the generated light. Whereas the direct method is based on semiconductor detectors that convert x-ray photons directly into electrical signals. Although x-ray imaging is a widely used imaging technology in medicine, it is invasive due to the radiation exposure to the patient.X-ray imaging is widely used in diagnosing tumors or bone fractures. Extracted papers , 68 are No technical details were provided.Furuo et al.  used deeThe studies of Furuo et al.  and Ho eX-ray imaging probably has limited applicability for tissue classification in spinal surgery, as superimpositions particularly complicate the delineation of individual tissues in the spine. Research efforts are aimed more at 3-dimensional registration of the anatomy as a basis for low-radiation navigation.The clinical applications of reviewed methods can be categorized into two main groups. The first group concerns intraoperative tissue classification methods for brain tumor resection in neurosurgery. This group entails hyperspectral imaging e.g., , spectroThe second group addresses intraoperative tissue classification in orthopedic surgery. Some of the surgical instruments used in orthopedic surgeries  create forces, vibrations or even damage to the manipulated anatomical structure and surrounding tissues. Thus, real-time feedback to classify the tissue during orthopedic surgery is addressed using spectroscopic sensing e.g., , force aAmong brain tumor detection-related studies, the technologies that were used to detect brain tumors  intraopeThe majority of the work related to orthopedic surgery based their tissue classification methods on the biomechanical properties of the bone during bone cutting, milling, and drilling processes. Such work formed on the accelerometer e.g., , microphOverall, based on current analysis, integration of sensors [e.g., a fiber laser and non-contact microphones , a free-Recent work on tissue classification using hyperspectral imaging used CNNs after image calibration, noise filtering, band reduction, and normalization steps e.g., , 18. SimOverall, the application of various deep learning approaches facilitates the possibility of interpreting the data in a more robust and precise fashion compared with conventional signal processing methods. However, the development of a deep-learning approach requires access to large amounts of annotated data. The reviewed methods providing tissue classification algorithms based on imaging methods  can provide much-needed redundancy and complement the overall information on tissue types, which in turn can help in making more comprehensive decisions. Thus, a sensor fusion deep-learning enabled approach is one of the most promising research directions that could substantially enhance existing technologies for intraoperative tissue classification.