Perineal carcinoma of unknown origin is a rare and aggressive disease, so an early diagnosis and adequate treatment are essential to prevent its progression. We report the first series of cases of perineal carcinoma of unknown origin: (I) a 62-year-old male patient being followed up for a urethral stricture treated with periodic dilations with subsequent development of perineal abscesses and perineal carcinoma; (II) a 67-year-old male patient who consults for urinary discomfort associated with a perineal abscess. Recurrence of the abscess in the first month revealed the presence of an underlying perineal carcinoma; (III) a 78-year-old male patient that underwent urethroplasty with graft with subsequent regimen of periodical dilations. Recurrent formation of perianal abscesses revealed the presence of an underlying perineal carcinoma; and (IV) a 78-year-old male patient with history of in situ penile carcinoma treated by glans resurfacing. He consulted for penile pain, and imaging tests revealed a perineal abscess adjacent to the left corpus cavernosum. The core needle biopsy revealed a squamous cell carcinoma. Penile exploration and negative glans biopsy ruled out possible recurrence of penile carcinoma. The form of presentation of the disease has been very similar in all patients, demonstrating the presence of perineal abscess in all cases. Two patients had inguinal lymph node disease at diagnosis. All patients were treated by surgery, and three of them required adjuvant systemic treatment. Surgery combined with systemic treatment is probably the best option if the patient's conditions allow it. Carcinomas of unknown primary (CUP) origin represent 3-5% of all malignant tumors. Squamous cell CUP accounts for 5-10% of CUP, and the involvement of the male pelvis is extremely rare . InitialA 62-year-old male patient with a history of bulbar urethral stricture was treated with periodic dilations for three years. In this context, the patient develops a urethro-cutaneous fistula that was treated conservatively with a suprapubic and a bladder catheter.A combined cystography is performed through the suprapubic catheter and the bladder catheter, which reveals an extravasation of urine is observed at the level of the bulbar urethra compatible with urethral fistula. The endoscopic examination revealed a devitalized penile and bulbar urethra without finding a fistulous orifice. Conservative treatment fails, and the patient presents perineal abscesses that require treatment up to four times, two of them with percutaneous drainage and the other two by open surgery. The microbiological examination revealed the presence of gram +, gram -, and anaerobic bacteria. The patient was treated with piepracillin/tazobactan associated with IV metronidazole. During the follow-up, three months later, the patient underwent several CT scans in which anfractuous collection located in the root of the penis was observed, with approximate measurements of 66 × 25 mm, unchanged from previous studies. There are no images to suggest the presence of tumor tissue. Three months later and after the failure of conservative management, the case is discussed in the clinical session together with the other members of the urology department, and it is decided to perform a Wallace-type urinary diversion and a Friedrich of the perineal wound. The patient presented a good evolution after the intervention, and the pathological result of the debridement of the perineal wound was a well-differentiated perineal carcinoma that widely affects the margins of the analyzed tissue. An extension study was carried out with PET-CT after administration of 18-FDG in which a voluminous heterogeneous perineal mass was observed, with a significant increase in metabolism, affecting both the corpora cavernosa and spongiosum body, and involves the left ischiopubic branch as well as the anal canal. The prostatic apex is affected by contiguity.Bilateral inguinal lymphadenopathies of up to 11 mm are observed with increased metabolic activity. The case was presented in the multidisciplinary oncology committee, and it was decided to perform a complete pelvic exenteration with inguinal lymph node dissection and total penectomy.Phase I: A complete pelvic exenteration with iliac-obturator lymph node dissection was donePhase II: Incision was made with a cold scalpel over the limits of the mass in the cutaneous plane. The bulbar urethra and the corpora cavernosa were removed from their roots. Penile degloving was performed, and the penis was extracted through the perineal incision, thus achieving an en bloc removal of all tumor tissue. Osteotomy and resection of both ischiopubic branches were performed for on block removal of surgical piece . BilaterThe surgery consisted of two phases:A vacuum-assisted closure system (VAC) was placed to perform a delayed closure.Perineal closure was performed with the help of the plastic surgery department with a latissimus dorsi flap and a PTFE-polypropylene mesh. The patient remained hospitalized for 3 months. The functional recovery was excellent, allowing the patient the autonomy necessary to continue home rehabilitation.The pathological result of specimen resulted in a well-differentiated squamous cell carcinoma of the perineal region of 11 cm in diameter that massively infiltrates the soft tissues of the perineum, spreading and infiltrating the penile root, prostatic capsule, and perianal and peri-bladder adipose tissue, affecting the bone fragments of the pubis and ischium without infiltrating the cortex. Two lymph node metastases were observed in the left inguinal lymph node dissection piece containing 7 lymph nodes in total. The patient subsequently received adjuvant treatment with four cycles of carboplatin and gemcitabine. After 3 year of follow-up, he continues with periodic reviews with PET-CT without recurrence of his disease with excellent functional recovery.A 67-year old male patient with a medical history of diabetes mellitus, chronic kidney disease, and dyslipidemia who consults for urinary discomfort, dysuria, and frequency for three months was associated with a perineal abscess. The cystography shows a contrast extravasation at the level of the bulbar urethra compatible with urethral fistula, and the endoscopic examination shows a devitalized bulbar urethra with a stenotic area that prevents the endoscope from passing. During the exploration, abundant saline solution was observed through the perineum. Surgical drainage of the collection was performed as well as placement of a bladder and suprapubic catheter. Microbiological examination did not show growth of bacteria or fungi, despite which he was treated with piperacillin/tazobactan. In the first month of follow-up, the patient returned to the emergency room due to pain at the scrotal level and at the root of the penis associated with the recurrence of the collection, so it was decided to perform a new drainage of the abscess and a Friedrich of the perineal wound.The anatomopathological outcomes of the latter revealed the existence of a well-differentiated squamous cell carcinoma in areas of abundant keratinization that widely infiltrate the skin and soft tissue. On physical examination, the patient presents a perineal wound with drainage of purulent material, indurated on palpation, and adhered to deep planes.CT scan and MRI reveal a mass with irregular borders with a maximum diameter of 84 mm that invades both corpora cavernosa and the corpus spongiosum, reaching the urethral bulb. The existence of metastases was excluded. After discussing the case in the multidisciplinary tumor committee, the surgical treatment was decided.The surgical procedure consisted of different phases. Phase I: Total penectomy was performed, and en bloc removal of tumor tissue was done Figures . Phase IThe procedure lasted 9 hours and the estimated blood loss was 500 cc. During the postoperative period, the patient remained with the urinary catheter through the neourethra, a suprapubic catheter, and a rectal catheter to keep the receiving area of the flap as dry as possible. The patient was discharged on the twelfth day after surgery. During admission, he presented with a superficial dehiscence of the skin of the flap that was successfully treated with local paraffin dressings.The patient presented a satisfactory postoperative period, being able to remove the urinary catheter and suprapubic catheter at 3 weeks prior urethrography, achieving spontaneous urination without involuntary leakage of urine.The histological study reveals a moderately differentiated squamous cell carcinoma with keratinization and pleomorphic areas. The tumor shows neurotropism and frequent mitotic figures. The surgical edges were not compromised.The patient received three cycles of adjuvant treatment with immunotherapy (cemiplimab 350 mg every 21 days), because was not subsidiary to treatment with platinum for renal failure. At 7 months postoperatively, he was diagnosed with pulmonary metastases associating massive pleural effusion that required thoracentesis in addition to pelvic and local lymph node disease. He passed out 9 months after surgery.A 78-year-old male patient with history of high blood pressure, dyslipidemia, and bulbar urethral stricture was treated by urethroplasty with dura graft in 1989. Subsequently, he underwent periodical dilations due to a recurrence of the stricture. The patient has perineal abscesses on multiple occasions that required surgical drainage. In the last drainage, a mamelon lesion suspected of carcinoma was observed adjacent to the perineal collection. The pathological result of the lesion reveals the existence of a well-differentiated squamous cell carcinoma. The extension study confirms the existence of a perineal collection that extends through both corpora cavernosa measuring 79 × 15 mm with solid and necrotic areas. In the first instance, the patient underwent a resection of the perineal tumor and a radical cystoprostatectomy. Subsequently, the perineal defect was covered with a fasciocutaneous flap. The pathological examination revealed the existence of a squamous cell carcinoma that affected both corpora cavernosa and corpus spongiosum, the perineal soft tissues, and the prostatic apex, leaving the surgical margins free of tumor. After one year of follow-up, the patient presented on imaging tests a recurrence in the pelvic bed that seemed to infiltrate the right ischiopubic branch and the right lateral wall of the rectum. The case is discussed in the multidisciplinary tumor committee, and the surgical treatment is decided. The patient underwent an abdominoperineal amputation, resection of the previous fasciocutaneous flap, and partial resection of the right ischiopubic branch. The perineal defect is covered with an anterolateral flap of the thigh.The patient was discharged at 3 weeks without complications in the immediate postoperative period. After 2 years and 6 months of follow-up, the patient remains free of disease and with a complete functional recovery.A 78-year-old male patient with history of high blood pressure, a renal tumor that underwent partial nephrectomy, and a carcinoma in situ in the glans was treated by resurfacing. During the follow-up, the patient reported perineal and penile pain of months of evolution. The imaging tests performed revealed an abscess with a solid pole in the infrapubic region that affects the left corpus cavernosum. A core needle biopsy of the solid area was performed, diagnosing squamous cell carcinoma.In the extension study, multiple indeterminate pulmonary nodules were identified. In the preoperative study, a significant growth of the perineal mass was observed, reaching 75 mm in its maximum diameter and affecting the left ischiopubic branch, adductor muscles, and ipsilateral gracilis. Pathological left inguinal lymph nodes were also observed.Penile exploration and negative glans biopsy ruled out possible recurrence of penile carcinoma. The case was discussed in the multidisciplinary tumor committee, and the surgical treatment was decided.The patient underwent total penectomy, resection of left isquiopubic branch, and partial resection of adductor muscles of the thigh and left inguinal lymph node dissection.The perineal defect was covered with a contralateral gracilis flap.The patient required postoperative wound debridement due to partial necrosis of the wound. The patient was discharged 3 weeks after the intervention with good functional recovery. The histological study revealed the existence of a moderately differentiated squamous cell carcinoma with a maximum diameter of 7.5 that affects the root of the penis and both corpora cavernosa. Inguinal lymph node dissection showed one metastatic node of the six resected. The patient received adjuvant chemotherapy treatment with cisplatin and 5-FU. At 6 months of follow-up, the patient presented a single left inguinal lymph node, subjected to excision with pathological results of metastasis of squamous cell carcinoma. After 17 months of follow-up, the patient presented pulmonary progression of the disease under treatment with the fourth line of chemotherapy treatment.We present a series of cases of 4 patients diagnosed with perineal squamous cell carcinoma undergoing surgical treatment. The uniqueness of this series of cases is supported by the lack of published case reports describing men patients with this malignancy treated surgically . The twoCarcinomas of unknown primary origin represent 3-5% of all malignancies and are defined as a heterogeneous group of tumors for which the primary origin cannot be established at the time of diagnosis. Within them, squamous carcinoma of unknown primary origin represents between 5 and 10% and is more frequent in the head and neck region, although they are also described at the uterine level and in iliac lymph nodes .β that stimulates the NF-κB pathway, highly involved in angiogenic and protumorigenic processes [Regarding the pathophysiology of these tumors, several articles have been written relating the inflammatory status with an increase in IL-1rocesses .Patients with chronic infections of the perineal region, suppurative hydrosadenitis , urethraTransperineal biopsy proved to be a valid option for histological diagnosis. In experienced hands, the transperineal route allows to access to the small pelvis in complex situations . Based oTreatment regimens remain controversial, with limited cases to allow for consensus. Surgical intervention remains the leading form of therapy; however, approaches are case specific, depending on the location of the tumor and the degree of invasiveness .In general, CUP has a poor prognosis, with a median survival time of less than six months and only about 15% of patients surviving after 1 year [Squamous cell CUP located in the male pelvis represent a rare entity, so the ideal diagnostic work-up, the optimal treatment strategies, and prognosis are not well determined. Radical surgical treatment, followed by adjuvant chemotherapy in patients with a localized tumor and with good baseline status, appears to be the best treatment regimen, achieving higher survival rates than those published to date.


The rostral epidural rete mirabile is built of considerable small arterial vessels that anastomose with each other at the base of the cranial cavity. This structure is formed as a result of the division of a large arterial vessel into many small arteries. Furthermore, on the other side of the rete mirabile, these small arteries are joined together to form one large artery, through which blood flows out of the rete mirabile. This system participates in decreasing the temperature of the brain and thus protects the body from thermal stress. Moreover, it influences body–water balance and has a crucial role in the retrograde transfer of neuropeptides. According to old systematics, pigs and hippopotamuses are in one suborder. Hence it was decided to compare their structures and blood supplies. It was found that the shape of the analyzed structure and the inflows differed in these groups.rete mirabile epidurale rostrale) is built of considerable small arterial vessels that anastomose with each other. This structure is formed as a result of the division of a large arterial vessel into many small arteries. Furthermore, on the other side of the rete mirabile, these small arteries are joined together to form one large artery, through which blood flows out of the rete mirabile. This system participates in decreasing the temperature of the brain and thus protects the body from thermal stress. Moreover, it influences body–water balance and has a crucial role in the retrograde transfer of neuropeptides. The goal of this study was to describe the rostral epidural rete mirabile and pathways that provide blood to this structure as well as compare it in selected Suiformes and hippopotamuses. The study was performed on desert warthogs (Phacochoerus aethiopicus), Eurasian wild boars (Sus scrofa), collared peccaries (Pecari tajacu), pygmy hippopotamuses (Choeropsis liberiensis), and common hippopotamuses (Hippopotamus amphibius). Preparations were made using the latex method and corrosion cast. An elongated shape characterizes its anatomy with a much wider rostral part than caudal part in the Eurasian wild boars, desert warthogs, and collared peccaries. The main source of blood was the branch to the rostral epidural rete mirabile branched off from the internal carotid artery. Moreover, blood enters the rete by the caudal branch and rostral branch to the rostral epidural rete mirabile. In hippopotamuses, the major source of blood was the rostral branches to the rostral epidural rete mirabile.The rostral epidural rete mirabile ( It is situated at the base of the cranial cavity [Tamandua mexicana), the rete mirabile was found. The superficial brachial , cubital transverse (arteria transversa cubiti), and cranial and caudal interosseous arteries  have a structure of rete mirabile sending vessels to the muscles at the craniolateral part of the forearm. The medial and lateral branches of the superficial antebrachial artery , which arise as an extension of the superficial brachial artery, also form the rete mirabile. This structure is flat and wide. The major vessels of the forearm in the southern tamandua (T. tetradactyla), Cyclopes, and sloths also form the rete mirabile [sinus cavernosus). Arterial vessels contain blood at a higher temperature. The blood returning from the nasal cavity with lower temperature contributes to cooling arterial blood located in the rostral epidural rete mirabile. Due to the close proximity of the vessels of the rete mirabile and the cavernous sinus, there is a transfer of heat from the arterial blood to the cooler venous blood. Cooled arterial blood follows to the vessels supplying the brain [The rostral epidural rete mirabile , ten Eurasian wild boars (Sus scrofa) from the Suidae family, six collared peccaries (Pecari tajacu) from the Tayassuidae family from the Suiformes, two pygmy hippopotamuses (Choeropsis liberiensis), and three common hippopotamuses (Hippopotamus amphibius). The analyzed cadavers were obtained as post-mortem material from private breeders and zoos in Poland or obtained through hunting. The animals had not been euthanized or hunted for an experimental purpose. Of the cadavers obtained from hunting, only animals without damage to the head and neck were included in the study. Both genders were used in the study. Approval from research ethics committees was not needed to accomplish the aims of this study because the experimental work was conducted only on dead specimens. All procedures involving cadavers in accordance with the law on 15 January 2015 for the protection of animals used for scientific or educational purposes did not require the approval of the local ethics committee .The study was performed on five desert warthogs  was performed. In addition, in four specimens  was injected into the bilateral external jugular vein (vena jugularis externa). When the injected solution hardened, the specimens were moved to a special container with a washing powder  solution for enzymatic maceration. The temperature used in this process was 40 °C. The maceration lasted 45 days, during which the specimens were controlled every seven days. An arterial casting of the head and cranial cavity on a skeletal scaffold were obtained as a final step in the described process. The second method used for five specimens . This vessel is divided into the external carotid artery (arteria carotis externa) and the internal carotid artery (arteria carotis interna). The internal carotid artery exists only as an initial segment. It branches off from the common carotid artery together with the condylar artery (arteria condylaris) and occipital artery . The rest of the extracranial segment of the internal carotid artery is obliterated. The initial part of this artery becomes the ramus to the rostral epidural rete mirabile . This is the primary blood source to the rostral epidural rete mirabile. In the representatives of this family, the diameter of this vessel is 84.5% of the total diameter of the arteries supplying blood to the rostral epidural rete mirabile  is located caudally to the ramus to the rostral epidural rete mirabile. The condylar artery and occipital artery merge with the caudal epidural rete mirabile. This is a paired structure formed from a few vessels resembling a fishing net.The rostral epidural rete mirabile is supplied through several ways. They all originate from the common carotid artery (mirabile . In the arteria maxillaris). The maxillary artery is a continuation of the external carotid artery. From the maxillary artery, the middle meningeal artery branches off (arteria meningea media). From this vessel, the caudal branch to the rostral epidural rete mirabile   branches off from the maxillary artery. From this, the vessel branches off the rostral branch to the rostral epidural rete mirabile . It is a single vessel in the analyzed representatives of the Suiformes suborder. In one Eurasian wild boar, it was double bilaterally. The diameter of this vessel is 8.5% of the total diameter of the arteries supplying the rostral epidural rete mirabile.Another source of blood for the rostral epidural rete mirabile is branches of the maxillary artery   branchescirculus arteriosus cerebri), whose branches supply the encephalon.The rostral epidural rete mirabile is located at the base of the cranial cavity on the basisphenoid bone laterally surrounding the hypophyseal fossa. This is a well-developed, paired structure composed of numerous tiny anastomosing arteries . An elonsinus intercavernosus), situated rostrally from the sella turcica.Veins at the base of the brain are expressed in the form of venous sinuses. The most important for functional reasons is the cavernous sinus . This siIn this family, all ways that provide blood to the rostral epidural rete mirabile also take their origin from the common carotid artery. The internal carotid artery branches off from the common carotid artery together with the condylar artery and occipital artery . The maiNext, the caudal branch to the rostral epidural rete mirabile branches off from the middle meningeal artery. The diameter of this vessel is 17% of the total diameter of the arteries supplying blood to the rostral epidural rete mirabile. More rostrally, the rostral branch to the rostral epidural rete mirabile arises . It is aThe position of the rete mirabile is analogous to that in the representatives of the Suidae family . In thisThe internal carotid artery arises from the common carotid artery. From the initial part of this vessel, the ramus to the rostral epidural rete mirabile arises . This isFrom the maxillary artery, the middle meningeal artery arises, from which the caudal branch to the rostral epidural rete mirabile branches off . The diaThe rostral epidural rete mirabile is a well-developed, paired structure composed of numerous tiny anastomosing arteries. No widening is observed in the rostral part, but it has a similar diameter over its entire length. Bilateral structures are connected by several vessels in the caudal part.Camelus dromedarius) and Bactrian camel (Camelus bactrianus) as well as the llama (Lama glama) and guanaco (Lama guanicoe) [Giraffa camelopardalis), sitatunga (Tragelaphus spekei), nyala (Tragelaphus angasi), greater kudu (Tragelaphus strepsiceros), common eland (Taurotragus oryx), nilgai (Boselaphus tragocamelus), springbuck , blackbuck (Antilope cervicapra), dik-dik (Madoqua kirkii), saiga (Saiga tatarica), oribi (Ourebia ourebi), domestic cattle (Bos taurus taurus), goat (Capra hircus), domestic sheep (Ovis aries), banteng (Bos javanicus), yak (Bos mutus f. grunniens), European bison (Bison bonasus), American bison (Bison bison), common wildebeest (Connochaetes taurinus), mouflon (Ovis aries musimon), chital (Axis axis), European red deer (Cervus elaphus), wapiti (Cervus elaphus Canadensis), milu (Elaphurus davidianus), Eld’s deer (Rucervus eldii), sika deer (Cervus nippon), fallow deer (Dama dama), moose , roe deer (Capreolus capreolus), reindeer (Rangifer tarandus), and Chinese muntjac (Muntiacus reevesi) [Sus scrofa f. domestica) [The presence of the rostral epidural rete mirabile is a feature of almost all animals from the Artiodactyla order. Its occurrence has been found in the Tylopoda suborder, which includes the camels of the Old and New Worlds, specifically the dromedary (uanicoe) ,24,25,26reevesi) ,36,37,38reevesi) ,40. In Smestica) ,42.During the analysis of the anatomy of the rostral epidural rete mirabile in the cross-section, it can be seen that two types of rete mirabiles can be identified. A rete mirabile formed from vessels of similar diameter has been identified as a bipolar type . The samIn all the analyzed representatives of Suiformes, the rostral branch to the rostral epidural rete mirabile is a single, weak vessel. In the hippopotamuses, the vessels are more numerous (from three to five). They are also the primary source of blood for the rete mirabile . In the described Artiodactyla, those branches are developed in various ways. In the Tylopoda, these branches are very well developed. They occur in several numbers, and, close to the point of origin, they divide secondarily into a more significant number of small vessels, thus contributing to the expansion of the volume of the rete mirabile on the rostral side . The rosThe caudal epidural rete mirabile as the paired structure is found in desert warthogs, Eurasian wild boars, and hippopotamuses. This structure is also described in domestic pigs ,27. UnpaPhysiologically, the encephalon exhibits a relatively large temperature fluctuation of 2–4 °C, which is associated with the naturally varied activities of life. In addition to the observed physiological hyperthermia, some situations cause the temperature of the encephalon to rise above acceptable norms. This can cause numerous abnormalities leading to negative effects affecting neural activity and function . For thiThe function of the rete mirabile mentioned above indicates how multi-dimensional the physiological importance of the anatomical structure is for Artiodactyla species’ biology. This study provides information about the anatomy of the rostral epidural rete mirabile and the patterns of its blood supply in desert warthogs, Eurasian wild boars, collared peccaries, pygmy hippopotamuses, and common hippopotamuses. It is an elongated shape with a much wider rostral part in Suiformes. In hippopotamuses, no such widening was found. The caudal epidural rete mirabile is absent only in the collared peccaries. In all examined species, the rete mirabile is a bipolar type. The main blood vessel supporting the rete mirabile is the branch to the rostral epidural rete mirabile from the internal carotid artery. Other sources of blood contributed negligibly to its supply in Suiformes. In hippopotamuses, the main source of blood is the rostral branches to the rostral epidural rete mirabile. The rostral epidural rete mirabile as an evolutionary achievement has provided Artiodactyla with a better opportunity to adapt in terms of physiology to changing environmental conditions throughout history. The above research adds to the state of knowledge on the occurrence of this structure in hippopotamuses, in which it was not clear until now whether this structure exists. This could be useful information in the discussion of the evolution of this structure in Artiodactyla.


Higher mammals are able to simultaneously learn and perform a wide array of complex behaviors, which raises questions about how the neural representations of multiple tasks coexist within the same neural network. Do neurons play invariant roles across different tasks? Alternatively, do the same neurons play different roles in different tasks? To address these questions, we examined neuronal activity in the posterior medial prefrontal cortex of primates while they were performing two versions of arm-reaching tasks that required the selection of multiple behavioral tactics , a critical requirement for the activation of this area. During the performance of these tasks, neurons in the pmPFC exhibited selective activity for the tactics, visuospatial information, action, or their combination. Surprisingly, in 82% of the tactics-selective neurons, the selective activity appeared in a particular task but not in both. Such task-specific neuronal representation appeared in 72% of the action-selective neurons. In addition, 95% of the neurons representing visuospatial information showed such activity exclusively in one task but not in both. Our findings indicate that the same neurons can play different roles across different tasks even though the tasks require common information, supporting the latter hypothesis. Little is known about how the neural network enables flexible use of the same information for diverse purposes . In other words, how the finite number of neurons in the brain gives rise to an infinite number of behaviors in a dynamic environment is unclear. Does a neuron subserving a particular role  in one task also play the same role in different tasks? Alternatively, do neurons change their functions under different behavioral requirements? To address this issue, we examined neuronal activity from the dorsomedial prefrontal cortex of primates, especially its posterior part (pmPFC) while monkeys were switching between two variants of arm reaching tasks. The dorsomedial prefrontal cortex has been implicated in a wide array of functions, including mindfulness , the neuronal representation of relevant sensory stimuli varies across multiple tasks referred to by their usage for different purposes, e.g., a picture serving as a sample stimulus of a delayed matching to sample (DMS) task vs. a cue to call for a conditional motor response  participates in the selection of behavioral tactics  or resultant actions in one task paradigm, but changed their representation in the other task. Our findings indicated that the same function can be subserved by different groups of neurons even though the tasks require common sets of information relevant to the task performance.Macaca fuscata, male, weighing 10 kg), cared for in accordance with the guidelines of the National Bioresource Project of Japan and our institutional guidelines. The monkey sat in a primate chair and faced a switch panel  and response tactics  to determine the action (reach to either the left or the right target). A trial began when the monkey pressed the hold button attached to the armrest of the primate chair for 1 s. In the uedtask , the cenlocation-precued task . After the recovery period, we recorded neuronal activity with elgiloy electrodes (0.9–1.2 MΩ at 1 kHz). The electrodes were advanced by hydraulic manipulators . We identified unitary action potentials by the RASPUTIN software  as distinct clusters in its feature space during the experiments as well as in offline spike-sorting after each experiment. Further, we visually inspected the waveforms in the identified clusters. If they were indistinguishable from baseline noise, such data were discarded. While advancing the electrodes, if we found any task-related neurons, to ensure the same neuron was recorded across different conditions, we presented the same behavioral condition twice separated by other behavioral conditions. The selection criteria for neurons were at least five correct trials in all possible combinations for tactics pre-cued and location pre-cued trials.To define borders between the medial areas, in each electrode penetration, we examined neuronal responses to visual and somatosensory stimuli by illuminating the monkey’s eye with a flashlight, tapping on the monkey’s body surface, and manipulating the joints. We also examined evoked movements by applying intracortical microstimulation  through the recording electrode.t. These windows included pre-cue, post-cue, delay, and response periods, and were shifted in step sizes of 20 ms to calculate the IFR(t) at each new position. We repeated this procedure to obtain the temporal change in IFR(t) for all epochs.We wrote a software in C++ for offline display and quantitative analysis of neuronal activity. Statistical analysis was done using R. As behavioral response determinants, we defined tactics (pro- or anti-reach), cue position (left or right), and cue color . Additionally, we defined action as reaching either to the left or the right target. Moving time window analysis was performed to examine the temporal variance of neuronal representations of response determinants and action. In this analysis, we counted action potentials within the small time window (width 200 ms) to calculate the instantaneous firing rate (IFR) at time t) for response determinants and action, we computed the coefficient of partial determination (CPD). CPD was the percentage of the variance of IFR(t) ascribable to the variance of the particular factor X  defined as::To examine the effects of the response determinants and the action on the neuronal activity, we performed a multivariate analysis of variance (ANOVA) using tactics, cue position, action, and cue color as factors and firing rate as the dependent variable. To quantify the selectivity of IFR(t) was the sum of squared errors when factor X was omitted from the ANOVA and SSEfull(t) was the sum of squared errors when all the factors were included.where SSEpartial, action (left or right reach), and cue location (left or right) as factors.We identified the pmPFC, SMA, and pre-SMA using previously reported criteria  of neurons that encoded tactics during the response period of the location-precued task had reduced selectivity for the tactics during the post-cue period of the tactics-precued task . SimilarFinally, we examined the effect of task-type, action, cue position, and tactics during the response period in the three medial frontal areas . In the The present study showed that a single neuron can play different roles across different tasks even though the tasks require the same information for execution. In one task, the tactics was cued prior to the visuospatial cue while in the other task, the order of their presentation was reversed. Yet both tasks required the common response determinants (the cue location and the tactics) to decide the monkey’s action. Our results indicate that neurons in this region encode different aspects of task performance even if common information is given in various tasks , and 4.Neurons in the dorsolateral prefrontal cortex have been known to alter the representation of the same sensory stimuli depending on what task they were used for. Such task-dependent encoding could underly the mechanism by which a limited number of neurons can generate an almost infinite number of rule-based behaviors  of the cue location-selective neurons in the pmPFC exhibited a significant effect of the task . SimilarThe prefrontal cortex is involved in logical information processing, leading to flexible behavior (Blackman et al., The task-dependent encoding of response-determinants and actions in the pmPFC can be explained by the strong coupling between the mPFC and lPFC and the rostral-caudal hierarchical difference. Both regions are densely connected (Barbas and Pandya, At the single-neuron level, mPFC neurons show mixed selectivity for task-relevant aspects (Rigotti et al., Taken together, our results show that the same functions could be subserved by different neuronal populations in different tasks. The pmPFC neurons flexibly switch their functions across various tasks, which could enable the performance of diverse rule-guided behaviors.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study involving animals was reviewed and approved by the Institutional Animal Care and Ethics Committee of the Center for Laboratory Animal Research of Tohoku University.YM and MA conceived the study, designed the experiment, and collected the data. MA and YM conducted data analysis and wrote the manuscript. HM contributed to the revision of the manuscript. All the authors approved the submitted version.


Background: Cerebrospinal fluid (CSF) leaks are a well-known complication of posterior fossa neurosurgery. The use of dural repair adjuncts has been associated with fewer CSF leaks and subsequently, lower medical costs.Objectives: To determine if the use of polyethylene glycol hydrogel sealant , resulted in cost savings in the United States compared to use of fibrin glue in posterior fossa neurosurgery based on a published study of these two products.Methods: Primary analysis was based on a published cohort study (100 patients per cohort). Adjustments were made to account for the longer follow-up time of the fibrin glue cohort to better capture the incidence of CSF leaks, pseudomeningocele, wound infection, and meningitis using additional data from the literature. Resource utilization was calculated from literature studies and confirmed with consultations from two practicing neurosurgeons. The effective time horizon was 19 months. Undiscounted Medicare payments were used to calculate unit costs from a payer’s perspective based on hospital stay, cost of sealant application, and cost of complications. One-way sensitivity analysis was used to examine changes in costs as a result of model input changes.Results: In the base case, the cost of the hospital stay for the original surgery, which excludes the cost of complications, dominated costs for both cohorts. On a per patient basis, the use of fibrin glue cost $1666 more than the use of DuraSeal. Sensitivity analysis showed that using lumbar drainage instead of operative repair for a CSF leak reduced cost savings to $680. Holding the incidence of CSF leaks constant for the fibrin glue cohort while increasing the incidence for the DuraSeal cohort by 50% or 300% resulted in cost savings of $1438 and $755, respectively.Conclusions: The results of this study demonstrate a positive, consistent cost-benefit of DuraSeal compared to fibrin glue based on a cohort study of real world patients who underwent posterior fossa neurosurgery.


Patients undergoing elective colorectal surgery are at a higher risk of surgical site infections (SSIs), which delay their recovery, lead to increased morbidity, and result in significant financial burden to the healthcare services. The World Health Organisation (WHO) recommends the use of mechanical bowel preparation (MBP) and oral antibiotic prophylaxis (OAP) to reduce the rates of SSIs. However, there remains international contention on this topic, and the National Institute of Clinical Excellence (NICE) currently recommends against the routine use of MBP and does not address the issue of OAP. We reviewed the current guidelines and most up-to-date evidence from randomised control trials (RCTs) and meta-analyses since the latest NICE guideline update. Recent evidence continues to favour the effectiveness of the combination of MBP and OAP in reducing SSI rates in elective colorectal surgery.Elective colorectal surgery is associated with one of the highest rates of surgical site infections (SSIs), which result in prolonged length of stay, morbidity, and mortality for these patients and have a significant financial burden to healthcare systems. In an effort to reduce the frequency of SSI rates associated with colorectal surgery, the 2018 World Health Organisation (WHO) guidelines recommend the routine use of mechanical bowel preparation (MBP) and oral antibiotic prophylaxis (OAP) in adult patients undergoing elective colorectal surgery. However, this recommendation remains a topic of debate internationally. The National Institute of Clinical Excellence (NICE) guidelines, last revised in 2019, recommend against the routine use of MBP and do not address the issue of OAP. In this communication, we reviewed the current guidelines and examined the most recent evidence from randomised-control trials (RCTs) and meta-analyses on the effect of MBP and OAP on SSI rates since the 2019 NICE guideline review. This recent evidence clearly demonstrated an SSI-risk-reduction benefit with the additional use of OAP and the combination of MBP and OAP in this group of patients, and we therefore highlight the need for change of the current NICE guidelines. Surgical site infections (SSIs) pose a substantial clinical and financial burden to healthcare systems worldwide. The impact of these healthcare-associated infections on patient length of stay, morbidity, and mortality is significant . ElectivAs SSIs are largely preventable, it becomes essential to reach a consensus on interventions that can be made to reduce their frequency and clinical impact. The World Health Organisation (WHO) guidelines published in 2016 and updated in 2018 recommend the routine use of oral antibiotic prophylaxis (OAP) combined with mechanical bowel preparation (MBP) in adult patients undergoing elective colorectal surgery . HoweverIn this review, we aim to examine the recent evidence on the combination use of preoperative MBP and OAP and compare the current recommendations among international societies. The guidelines of the National Institute of Clinical Excellence (NICE) , World HData of interest included year of publication, comments, clinical practice recommendations on the use of preoperative oral antibiotic prophylaxis alone, comments on the use of mechanical bowel preparation alone, and comments on the use of their combination. The guidelines and recommendations were reviewed by the two authors (N.P. and C.K.), who independently identified discrepancies and areas of further research. The authors subsequently made recommendations in areas where the current NICE guidelines could be adjusted to account for the most recent evidence. The 2018 WHO global guidelines for the prevention of SSI recommend the routine combination use of MBP and OAP in adult patients undergoing elective colorectal surgery to reduce the risk of SSIs . The guiThe 2019 American Society of Colon and Rectal Surgeons (ASCRS) Clinical Practice Guidelines recommend the use of combined MBP and OAP for elective colorectal resections . They doIn contrast, the U.K. and Australia recommend against the use of MBP. In particular, the 2017 guideline of the Association of Coloproctology of Great Britain & Ireland (ACPGBI) recommends that routine use of MBP is to be avoided in elective colorectal surgery . They reThere is no official consensus statement or guidelines produced by the European Society of Coloproctology (ESCP). However, a 2017 survey that was conducted among 462 European Surgeons noted that 29.6% routinely used MBP prior to colonic surgery and 77% prior to rectal surgery. Oral antibiotics were only routinely used by less than 10% of respondents, whereas perioperative intravenous antibiotics were used by 96%. [The 2008 CG74 NICE guideline on the prevention and treatment of SSIs recommended against the use of MBP routinely to reduce the risk of SSIs [At the time of preparing the 2019 guideline update, NICE also completed an exceptional review on the use of OAP and MBP combination on SSI impact in elective colorectal surgery, assessing the evidence available at the time . Taking The current international recommendations on the use of MBP and OAP in elective colorectal surgery are summarised in The use of MBP and OAP either alone or in combination prior to elective colorectal surgery has been a longstanding topic of debate. As noted from the comparison of the international guidelines, universal consensus is yet to be reached. MBP alone has not been shown to reduce the risk of SSIs in elective colorectal surgery. Rising evidence from RCTs and meta-analyses, however, supports the routine use of a combination of MBP and OAP. A 2018 meta-analysis by McSorley et al. reviewing 14 RCTs and 8 observational studies, with a total number of 57,207 patients, concluded that OAP in combination with MBP and IV antibiotics was superior to MBP and IV antibiotics alone in reducing SSI in elective colorectal surgery and was associated with reduced frequency of anastomotic leak, ileus, reoperation, readmission, and mortality . A further 2018 meta-analysis by Toh et al. that included 8458 patients from RCTs only concluded that MBP combined with OAP was associated with the lowest risk of SSI, compared to MBP alone . SimilarRCTs published since the last NICE guideline review of 2019 all favour the use of OAP in elective colorectal surgery. A 2019 multi-centre RCT from the Netherlands by Abis et al. compared administration or absence of OAP in addition to the standard IV perioperative prophylaxis in patients that underwent elective colorectal surgery. MBP was given in all patients who had left-sided surgery . The findings of the trial showed superiority of the OAP addition in reducing infectious complications after colorectal resection . Moreover, a RCT by Uchino et al. (2019) investigating 335 patients with Crohn’s disease who underwent elective bowel resection and received preoperative MBP noted significantly lower incidence of incisional SSI in patients who also received OAP, and their multivariate analysis concluded that absence of OAP was an independent risk factor for incisional SSI . The comIn addition to the preoperative combination of MBP and OAP, the use of OAP alone in elective colorectal surgery has also been extensively evaluated. In a 2020 meta-analysis by Nelson et al. comparing the addition of OAP to IV antibiotics to IV antibiotics alone, they noted that the combined route was superior in reducing SSI rates compared to OAP or IV antibiotics alone . In a laRecent RCTs also favour the additional use of routine OAP in elective colorectal surgery. A multi-centre RCT by Espin Basany et al. (2020) of 565 patients not receiving preoperative MBP noted that patients who received OAP for 1 day before their elective colorectal surgery, in addition to the IV antibiotics given at induction, had significantly reduced incidence of SSIs compared to patients who received IV antibiotics on induction alone . They thIn practice, there remains no consensus for the optimal regimen of OAP, and a high degree of variation of antibiotic protocols is observed in keeping with the local and regional hospital policies. A 2014 Cochrane review of 43,451 participants within 260 RCTs using prophylactic antibiotics in elective and emergency colorectal surgery by Nelson et al.  determinTaking into consideration the evidence examined, we propose that the current NG125 NICE guideline is revised to recommend in favour of the combination MBP and OAP approach in patients who are undergoing elective colorectal surgery. The NG125 NICE guideline should also expand its antibiotic recommendations (currently limited to IV antibiotic prophylaxis only) to account for the SSI-risk-reduction benefit with the additional administration of OAP in this group of patients, as has been demonstrated via the multiple published RCTs.The combination use of MBP and OAP in elective colorectal surgery raises multiple considerations that need to be addressed, including the issue of antimicrobial resistance, the appropriate choice of antibiotic and optimal duration of OAP course, and the cost effectiveness of the MBP and OAP combination. Overall, however, current evidence supports the routine use of a MBP and OAP combination prior to elective colorectal surgery. The most recent evidence continues to align with the 2018 recommendations of the World Health Organisation (WHO) in contrast to the NICE guidelines that remain in need of revision.


Editorial on the Research TopicHernia related anatomy in abdominal wall surgery: Applied research in hernia repair by Konschake M, Mayer F, Fortelny RH. (2022) Front. Surg. 9: 1031593. doi: 10.3389/fsurg.2022.1031593Frontiers in surgery concerning the research topic “Hernia Related Anatomy in Abdominal Wall Surgery” addresses research in the field of Applied Anatomy, Human Embryology and Hernia Surgery. All the original articles and reviews presented are dealing with important facts with the goal of placing its findings to an interested broader surgical community.This special issue of Frontiers of Surgery, Andreas Lorenz, a surgeon at the university of Innsbruck (Austria), has imparted detailed anatomical knowledge of the preperitoneal space, the transversalis fascia and the urogenital fascia - which are of highest relevance for many different techniques in incisional hernia repair and minimally invasive techniques in groin hernia surgery - into the surgical community. Another issue of prevention is knowledge of neuroanatomy especially in the groin as recently published by our Austrian Hernia Group . New insights to the operation field  require new ways for access to anatomical layers needing special anatomic training for example by cadaver workshops. In order to avoid complications, such as injuries to nerves and vessels, but also unphysiological separations of musculoaponeurotic structures, anatomical knowledge is required to a special degree. The contributions of this publication are therefore essential to expand this knowledge.This issue comprises highly qualified papers, which provide interesting findings in human embryology of the anterior abdominal wall and associated malformations. These articles will lead to a better understanding of the development of the abdominal wall, possible herniations and therefore of surgical repair of abdominal and diaphragmatic pathologies.


Determining the aggressiveness of gliomas, termed grading, is a critical step toward treatment optimization to increase the survival rate and decrease treatment toxicity for patients. Streamlined grading using molecular information has the potential to facilitate decision making in the clinic and aid in treatment planning. In recent years, molecular markers have increasingly gained importance in the classification of tumors. In this study, we propose a novel hierarchical voting-based methodology for improving the performance results of the feature selection stage and machine learning models for glioma grading with clinical and molecular predictors. To identify the best scheme for the given soft-voting-based ensemble learning model selections, we utilized publicly available TCGA and CGGA datasets and employed four dimensionality reduction methods to carry out a voting-based ensemble feature selection and five supervised models, with a total of sixteen combination sets. We also compared our proposed feature selection method with the LASSO feature selection method in isolation. The computational results indicate that the proposed method achieves 87.606% and 79.668% accuracy rates on TCGA and CGGA datasets, respectively, outperforming the LASSO feature selection method. Tumor grading, i.e., the ability to determine the biological aggressiveness of glioma, is very important for adequate management, including treatment planning and monitoring and the rate of survival in patients ,2. GliomIn recent years, as molecular alterations have gained importance for the classification of CNS tumors ,8,9, a pFeature selection is concerned with the selection of the best feature subset from all features or patterns according to strategies that remove unrelated, insignificant, and redundant features . SpecifiTo this end, we aim to select the best subset of molecular and clinical features by reducing the number of features with various feature selection methods and ensemble-learning-based models in this study. We introduce a novel hierarchical voting-based methodology for the selection of the relevant features and improving the performance results of the machine learning models for the classification tasks. To reach the best performance result, we carried out experiments employing the possible combinations of supervised models in the soft-voting-based process employing two glioma datasets, TCGA and CGGA, that are currently in widespread use.To the best of our knowledge, our study illustrates the first method that employs the hierarchical voting-based approach in the processes of both feature selection methods and ensemble learning models together to improve glioma grading results, which is an innovative approach to large-scale molecular glioma data.To the best of our knowledge, our study also constructs the first organized and structural dataset from TCGA LGG and GBM data that aggregates molecular and clinical information to allow for validation and data sharing and to speed up research progress for researchers working in this field.We focus on fusing the advantages of various feature selection methods and machine learning models via a voting-based procedure for glioma grading on two commonly used glioma datasets (TCGA and CGGA).We carry out comprehensive computational results for the comparison of our novel voting-based feature selection method with the LASSO feature selection method in isolation, given that these are two commonly employed glioma datasets that share similarities but also exhibit differences.We aim to identify the best-performing combination of a voting-based ensemble learning model for the feature selection stage to obtain the most accurate results given dataset variability in large-scale datasets with transferable use.The performances of voting-based ensemble models are evaluated with six measures for glioma grading.The extensive effects of the combinations of sixteen ensemble learning models are presented.The main contributions of this study are summarized as follows:The remaining sections of this study are structured as follows: First, we briefly give an overview of the proposed methodology and explain the related feature selection methods and supervised learning models for glioma grading in This section defines the experimental processes, the dataset used and its characteristics, and evaluation metrics. Then, we present the comprehensive experimental results of the performance metrics of tumor grading in the following subsections.In this study, the proposed methods were implemented in Python programming language with the scikit-learn  package As a preliminary study, we focused on decreasing the number of combinations of preprocessing stage by selecting appropriate normalization techniques from  min-max normalization,  min-max normalization, or z-score normalization/standardization for age feature values. We experimented with these techniques on the various classifiers employed and decided to use the z-score normalization technique, given that it resulted in the best performance metric  value obtained from the models.For the minimum number of votes based feature selection, the weight of evidence, recursive feature elimination, Random Forest, and LASSO methods were applied. The minimum number of votes was set to 1 to eliminate features not chosen unanimously. For LASSO-based linear model operation, 10-fold cross-validation was carried out to find the best alpha parameter value through the iterations. A 10-fold cross-validation technique was also applied on the TCGA and CGGA datasets to construct and test the mean performance results of the learning models employed. In this study, the GBM class was considered positive and the LGG class was used as negative for the evaluation of learning models. The default values were assigned as the corresponding parameter values for the utilized classifiers . We set the random state number to 0 for all employed learning models in order to obtain the same computational results with the same random state number on the datasets used.To evaluate our proposed methodology for the hierarchical voting-based processes, we utilized the two most widely employed genome atlas databases, namely The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) , for anaTCGA’s original dataset consists of 3 clinical features, the most frequently mutated 20 molecular/mutation features, and class labels for glioma grading, resulting in 23 total features . The molAccording to TCGA, the distribution of the most frequently mutated 20 genes according to percentage of cases affected for glioma data are given in To measure the tumor grading performance of the proposed hierarchical voting-based feature selection and ensemble learning methodology, we employed 6 evaluation metrics, classification accuracy rate (ACC), Area Under the ROC Curve (AUC), F-Measure (F1), precision (PRE), recall (REC), and specificity (SPEC) .The classification accuracy rate was computed by dividing the total number of true positives and true negatives by the total number of true positives, false negatives, false positives, and true negatives. The equation is defined in Equation (1).AUC, the Area Under the Receiver Operating Characteristic (ROC) curve, was constructed by plotting the true-positive rate against the false-positive rate for the performance of the binary learning model. The area of the maximum AUC value  indicates a perfect test, and the AUC value of 0 specifies that the predictor classifies all instances incorrectly. A value of 0.5 for AUC indicates that the ROC curve will be diagonal , and hence suggests that the diagnostic test has no discriminatory ability and prediction problem .F-Measure is calculated by the harmonic mean of precision and recall. It is represented in Equation (2).Precision means the positive predictive value. It is computed by dividing the number of true positives by the total number of true positives and false positives. The equation is illustrated in Equation (3).Recall is the true-positive rate/hit rate or sensitivity. It is calculated by dividing the number of true positives by the total number of true positives and false negatives. The equation is shown in Equation (4).Specificity is expressed as the true negative rate. It is calculated by dividing the number of true negatives by the total number of false positives and true negatives. The equation of specificity is defined in Equation (5).In this study, we present the computational results to evaluate the effects of the features selection and ensemble learning model scheme stages for the TCGA and CGGA datasets . Bold vaWe initially performed voting-based feature selection results using four methods  for the ensemble combination sets in terms of ACC, AUC, F1, PRE, REC, and SPEC. Computational results revealed the best performance to originate from the ensemble of SVM, RF, and AdaBoost learning models with the values of 0.876, 0.858, and 0.815 for accuracy rate, F1, and precision values, respectively, for the TCGA dataset  reflectiThe mean numbers of selected features after applying voting-based feature selection through 10-fold cross-validation on the TCGA and CGGA datasets are 14.9 and 17.6 for TCGA and CGGA, respectively . The feaWe also investigated the effects of only using the LASSO feature selection method through individual supervised models on TCGA and CGGA datasets in comparison to the novel method, given the widespread use of LASSO in isolation . The LogFurthermore, we carried out experiments to observe the effects of only using the LASSO feature selection method through ensemble learning models on TCGA and CGGA datasets with the related combination sets . The higWhen comparing the LASSO-only-based results with the voting-based feature selection results, we noted that the hierarchical voting-based feature selection and ensemble learning process provided more accurate results as compared to employing the LASSO feature selection method. The number of selected features when employing only the LASSO operation on TCGA and CGGA datasets  resultedBased on the empirical results of our novel hierarchical voting-based feature selection and ensemble learning methodology including sixteen ensemble model combinations on two datasets with molecular and clinical characteristics, several insights follow.The empirical results indicate that our novel hierarchical voting-based feature selection and ensemble learning methodology can provide promising results for the glioma grading tasks. We employed four different feature selection methods and the combinations of five different individual learning models using the voting-based strategies to reach optimal results for this study. In this regard, to validate our ensemble feature selection method, we compared our methodology on two datasets with different ensemble model combinations and we outperformed the results of using the LASSO-only feature selection method.Our primary goal in this study was to reduce the cost and number of features of the proposed feature selection method and increase the prediction performance. In addition, although the selection of the best ensemble learning models and features varied in both datasets, we can conclude that our proposed novel ensemble-based feature selection method results in more accurate results as compared to only using the LASSO method. In this context, when datasets with a high sample number are obtained, factors such as the number of selected features, performance, and cost increase will become more stable.Our novel hierarchical voting-based methodology can be extended with a various number of feature selection methods and machine learning models as a framework to improve the many classifications, or pattern recognition tasks if desired.Voting-based ensemble schemes can give more flexibility as well as trustworthy and efficient results than those using individual schemes for related problems.Our feature selection methodology can also be combined with deep-learning-based feature reduction approaches.Considering the predictive performance of the ensemble learning models utilized for the voting-based feature selection process in this study, our proposed feature selection method outperforms the results of the using only LASSO feature selection method. The following results were obtained:The shortcomings of the dataset constructed are that we have a small size of data or features in this study since we accessed a limited number of important features; however, we need to explore higher-dimensional biomedical datasets to try these methods.In this section, we present an overview of the proposed methodology for glioma grading and explain the feature selection and classification methods applied for this study. We also describe the ensemble learning process in the following subsections.The overview of the proposed methodology for glioma grading is illustrated in As an initial step, the glioma datasets (TCGA and CGGA) are split into training–test datasets via a ten-fold cross-validation technique. Then, all clinical and molecular features and grade class label information are constructed for the subsequent machine-learning-related tasks. Next, data type conversion and removal of missing or insignificant values and columns are performed in the data preprocessing stage, followed by the hierarchical voting-stages-based ensemble learning scheme that is applied as a novel methodology for the glioma grading process. The substages of this methodology are briefly explained as follows.The minimum number of votes based feature selection stage uses four different feature selection methods, weight of evidence, recursive feature elimination, Random Forest, and least absolute shrinkage and selection operator (LASSO), to rank features individually by employing the five supervised learning models according to their importance levels . If the minimum number of votes is equal to 1, this means the feature to be selected must have at least a total of 1 vote from the four feature selection methods. Then, the selected features that meet the minimum number of votes following the administration of the four feature selection methods are transferred to the next level to experiment with all the possible combination sets for the voting-based ensemble learning process.The soft-voting-based ensemble model selection stage consists of five supervised learning models . To merge the advantages of the individual learning models, we explored all three, four, and five combinations of all employed learning models to improve the classification performance results of the soft-voting-based ensemble learning models. Each method is explained in the following subsections in detail.Feature selection methods are one of the types of dimensionality reduction approaches. They aim to find optimal feature subset n from all feature set m where n ≤ m . These mWe explain the four feature selection methods  employed in this study in the following subsections.The weight of evidence is a quantitative method that estimates the predictive power of an independent variable in relation to the dependent variable in an easy way. The WOE method is a probabilistic approach based on a log-linear form of Bayesian rule . WOE is −: Y = 0.Given a hypothesis and some evidence, the WOE seeks to respond to the following question : “How mu− = “the patient doesn’t have the flu.” The doctor might know that for a patient, the odds of having the flu roughly double once the patient’s fever is taken into account , which corresponds to WOE(h: e) ≈ log 2  be the predictor matrix. Assume the data are standardized. The LASSO estimates for the coefficients of a linear model are obtained by Equation (7) [λ is called the lasso regularization parameter and In statistics and machine learning, the least absolute shrinkage and selection operator is a linear model that estimates sparse coefficients of parameters. It is used for attribute selection, regularization, and regression analysis . Mathemation (7) .(7)β^=aASSO fit . The LASASSO fit . Thanks In machine learning, the classification stage is a supervised learning approach that predicts corresponding class labels from the given set of examples/instances. Supervised learning algorithms use labeled datasets and outputs to train machine learning algorithms on how to predict a class label or outcome .In this study, five supervised learning algorithms, namely Logistic Regression, Support Vector Machine, K Nearest Neighbors, Random Forest, and AdaBoost are employed for the machine learning tasks. We also applied a voting-based ensemble learning process to improve the classification results of these models. In the following subsections, we briefly describe these models.Logistic Regression is one of the simplest and most utilized statistical models for binary classification. It is a type of regression and predictive analysis technique that is used to explain the relationship between one dependent binary variable and one or more independent variables. The Logistic Regression model gives each variable a coefficient that measures its independent contribution to variation in the dependent variable .Support Vector Machine is a supervised learning algorithm proposed by Vapnik et al. ,54. It oK nearest neighbors is one of the most popular, simple, effective, robust, and fundamental classification models and lazy learning algorithms . It cateRandom Forest, proposed by Leo Breiman , is one AdaBoost, short for Adaptive Boosting, is a type of statistical ensemble learning method. The output of the base learners is combined into a weighted sum that represents the final output of the boosted learning model. AdaBoost focuses on instances that were previously misclassified and, in each iteration, the weights of misclassified samples are increased while the weights of correctly classified samples are decreased .Ensemble learning methods are meta-approaches that combine the results of the multiple learning algorithms to achieve better prediction final performance results by using various schemes such as bagging, boosting, voting ,32,60, oThis study introduces a novel hierarchical voting-based feature selection and ensemble learning methodology for glioma grading. Our study uniquely explores ensemble feature selection methods and leverages ensemble learning models. Sixteen ensemble model combinations were employed to identify the best tumor grading performance on novel constructed datasets originating in the most widely employed molecular glioma databases, TCGA and CGGA, with captured molecular and clinical characteristics. Voting-based feature selection surpassed the results of using either the LASSO method or its combination with ensemble learning models on the TCGA and CGGA datasets. Considering the widespread use of LASSO and TCGA/CGGA, an optimized limit-free approach that confidently and consistently achieves superior performance is key. Our study illustrates that optimal feature selection and learning model selection are subject to both the number of instances and number of features in large-scale datasets, and that, given existing heterogeneity, ensemble approaches are beneficial for transferability and for obtaining superior results in healthcare datasets such as TCGA and CGGA, in spite of their trade-off strategy between computational workload and performance metrics . We hope that our findings will serve as a basis for the development of efficient methods for value-added care pertaining to molecular markers while improving the predictive performance of models. The proposed methodology can also be utilized as a template framework to advance optimization considering the growing and already wide array of feature selection methods and machine learning models currently available for classification, pattern recognition, and data mining tasks.As a future direction of this study, we plan to use additional biomedical datasets  with higher-dimensional features to both leverage and compare the performance of this method with other approaches. Additional or novel machine learning predictors, instead of the models in our study, can also be employed to analyze our methodology and potentially further improve the performance results for specific large-scale medical data scenarios.


Our previous work using 3T functional Magnetic Resonance Imaging (fMRI) parcellated the human dentate nuclei (DN), the primary output of the cerebellum, to three distinct functional zones each contributing uniquely to default-mode, salience-motor, and visual brain networks. In this perspective piece, we highlight the possibility to target specific functional territories within the cerebellum using non-invasive brain stimulation, potentially leading to the refinement of cerebellar-based therapeutics for precision psychiatry. Significant knowledge gap exists in our functional understanding of cerebellar systems. Intervening early, gauging severity of illness, developing intervention strategies and assessing treatment response, are all dependent on our understanding of the cerebello-cerebral networks underlying the pathology of psychotic disorders. A promising yet under-examined avenue for biomarker discovery is disruptions in cerebellar output circuitry. This is primarily because most 3T MRI studies in the past had to exclude cerebellum from the field of view due to limitations in spatiotemporal resolutions. Using recent technological advances in 7T MRI  to identify functional territories of the DN, with a focus on dentato-cerebello-thalamo-cortical (CTC) circuitry can lead to better characterization of brain-behavioral correlations and assessments of co-morbidities. Such an improved mechanistic understanding of psychiatric illnesses can reveal aspects of CTC circuitry that can aid in neuroprognosis, identification of subtypes, and generate testable hypothesis for future studies. Cerebellum's role in schizophrenia, led by Andreasen's work on the role of cerebello-thalamo-cortical (CTC) circuitry , folgaining a refined mechanistic understanding of CTC circuity and improving our causal understanding of symptom amelioration in treatment strategies such as transcranial magnetic stimulation (TMS).A recent study , acknowlHeterogeneous FC arrangement of the cerebellar cortex with extracerebellar structures emerges from the backdrop of a homogenous cerebellar cortical cytoarchitecture. Anatomical connections between cerebellar cortex and extracerebellar territories engaged in cognition and affect form the basis of the neuroscience of cerebellar behavioral neurology and psychiatry . Improvedentate-cerebello-cerebral FC is imperative. DN, the largest and most lateral structure of the cerebellar nuclei system, receive projections from all aspects of the cerebellar cortex lateral to the paravermis  for psychosis develop psychotic symptoms later on. For the reliable implementation of cerebellar-based therapeutics, a thorough understanding of ravermis . DN projravermis . These aravermis . The funravermis ] is the ravermis .The functional parcellation of DN can add p  is another key component of this. Specific examples of how functional changes in brain network organization can be used for prediction has been reported previously in the context of conversion to psychosis  can modulate cerebral cortical dynamics as demonstrated by suppression/triggering of movement initiation  MRI contrast to noise (CNR) ratio, which is directly proportional to temporal signal-to-noise ratio (tSNR), is remarkably better at ultra-high field strengths. When used in combination with parallel transmit head coils  and optiThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Institutional Review Boards at Beth Israel Deaconess Medical Center and also by the Shanghai Mental Health Center. Written informed consent to participate in this study was not obtained since no human studies are present.SA conceived the presented idea. SA and XG performed the data analysis and verified the analytical methods for the two publications that are highlighted in this perspective piece. SW-G contributed the data needed for the work and fueled the critical thinking needed to accomplish the work. All authors discussed the results and contributed to the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


This cross-sectional study evaluates the association between the COVID-19 pandemic and reported new medical debt from 2018 to 2021 across the US. To better understand these factors, we analyzed trends in medical debt from January 2018 to September 2021 and their associations with local measures of pandemic severity.In the US, with millions of COVID-19 hospitalizations, considerable job losses, and corresponding losses in employer-sponsored health insurance, the COVID-19 pandemic has raised concerns about a substantial increase in medical debt.STROBE reporting guideline.In this cross-sectional study, we measured medical debt in collections using a nationally representative, randomly selected 10% panel of persons with credit reports maintained by TransUnion, a nationwide credit reporting agency. The University of Chicago Institutional Review Board deemed this analysis of deidentified credit bureau data not to be human participant research. We followed the 6 with newly available data through September 2021. Medical debt is typically reported at least 180 days after the bill was incurred; thus, these data largely reflect medical care provided through March 2021. The 10% panel yielded a sample of 1.457 billion person-month observations and 37 million unique persons.We supplemented data from January 2018 to June 2020, which were identical to those used in a previous medical debt study,The main outcome was the mean quarterly flow of medical debt, defined as the amount of new debt listed on credit reports during the preceding 3 months, averaged over persons with credit reports. For comparison, we constructed an analogous measure of the flow of nonmedical debt in collections. The data included zip codes. To analyze trends by income, we assigned each zip code to its population-weighted income quintile using estimates from the 5-year American Community Survey (2015-2019) and then plotted statistics on the quarter 3 flow of medical debt by year.New York Times; the change in unemployment rate from September 2019 to the peak of the pandemic (April 2020 for most counties) using data from the US Census Bureau; and the change in consumer spending between January 2020 and September 2021 using data from Opportunity Insights. Details on sample and variable construction appear in the eMethods in the We examined the sample-weighted association between county-level percentage changes in medical debt from September 2019 to September 2021 and the cumulative COVID-19 infection and vaccination rates through September 2021 using data from the Medical and nonmedical debt during the pandemic followed the prepandemic downward trends , with prWe found no evidence of a net association between the COVID-19 pandemic and medical debt, overall or across areas with different incomes and pandemic severity. These results are consistent with any increase in medical debt being offset by decreases in elective medical procedures and new health care–related governmental policies.Quantifying the importance of these factors is challenging because of the lack of data linkages at the individual level and the lack of variation in the timing and geographic coverage of many governmental policies. A limitation of this study is it analyzed only debts reported to TransUnion. It did not include debts not reported to credit bureaus, and our data may not be identical to debts reported to other credit bureaus.


Establishing a scientific and sustainable grading nursing care evaluation system is the key to realizing the rational distribution of medical and nursing resources in the combined medical and nursing care services. This study establishes a grading nursing care index system for medical and nursing institutions from both medical and nursing aspects, and proposes a grading nursing care evaluation model based on a combination of interval-valued intuitionistic fuzzy entropy and a two- stage gray synthetic clustering model for interval gray number under a social network context. Through case analysis, the proposed method can directly classify the elderly into corresponding grading nursing care grades and realize the precise allocation of medical and nursing resources, which proves the feasibility of the method. Population aging has become an irreversible worldwide trend, which is often accompanied by the characteristics of chronic disease and disability. At the same time, with the accelerating pace of life, the phenomenon of empty nesting is increasing, the traditional family pension is weakening, and the problem of “bed pressure” for the elderly in hospitals is prominent. At present, the mode of separation of medical and nursing care can no longer meet the needs of the elderly . “IntegrThe integrated medical and nursing care service mode is different from the traditional home-based care, community-based care, and institutional care services. It is not a separate service mode, but introduces medical services into traditional nursing care services, thus realizing the system integration and supply of life care, disease prevention, and rehabilitation care . At presHowever, there is no uniform standard for grading nursing care in numerous medical and nursing institutions in China. Most institutions are set up according to the elderly’s personal health status, economic level, and the requirements of family members. They are faced with the problems such as imperfect evaluation indices or inconsistent evaluation standards. The actual care content does not match well with the reality of the elderly. Differences between integrated medical and nursing care institutions and ordinary nursing care institutions lie in that the health condition of most elderly people is relatively poor; hence, it is significant to pay attention to rational allocation of medical resources. The grading nursing care system plays an important role in ensuring the quality of services, as well as in the rational allocation of human resources for care and the setting of fees for care services.Grading evaluation has been applied in many fields. Xian and Guo established that the interval probability hesitant fuzzy linguistic TOPSIS model can effectively and objectively help businesses classify the strategic cooperation supplier . Metin  classifiFor the nursing care institutions, there are also many studies that deeply discussed the grading evaluation. Li et al.  establisThe gray clustering model can effectively solve the problem of a small sample size and poor information. Karakoç  used graTo solve the above problems, Liu et al.  construcIn summary, this study proposes a grading nursing care evaluation model based on a combination of interval-valued intuitionistic fuzzy entropy and interval gray number type two-stage gray synthetic clustering model under a social network context. It provides a reference for medical and nursing care institutions to improve their service efficiency and rationalize the allocation of medical and nursing care resources.The are several contributions of this paper. Firstly, in order to realize the rational allocation of medical resources and elderly resources, a grading nursing care indicator system for the elderly is constructed from two aspects of medical treatment and nursing. Secondly, considering the social relations among decision-making experts, a large-scale group decision-making method for grading nursing care indicators of medical and nursing care institutions based on interval-valued intuitionistic fuzzy entropy under a social network context is constructed. Thirdly, in the two-stage gray synthetic clustering model, interval gray numbers are introduced to describe the complexity and uncertainty of the elderly’s physical condition.The determination of weight will have a significant influence on grading nursing care evaluation; therefore, many experts in various fields need to judge the importance of indicators in accordance with their own knowledge. To deal with the complex social relations among decision makers, the concept of social network has been gradually applied to group decision making ,23.Community detection algorithms are a powerful tool for partitioning social networks. The Fast-Unfolding algorithm, a cohesive clustering algorithm based on modularity optimality proposed by Blondel , can be Given a network with multiple nodes, the Fast-Unfolding algorithm proceeds as follows: (1) every node is regarded as an independent community; (2) for each node The weight determination of social nodes is mainly measured by the structural location attribute of nodes in the whole network . Degree Step 1: Compute the degree centrality of nodes.The degree centrality Step 2: Compute the closeness centrality of nodes.The closeness centrality Step 3: Calculate the PageRank value of nodes.Step 4: Calculate the importance of nodes Step 5: Calculate the weight of nodes.Using the Fast-Unfolding algorithm, the The weight of a partition is measured by the distance between the mixed center of the partition and the mixed center of the whole network , which is calculated using the method described in .Step 6: Calculate the normalized weight Step 7: Normalize the weight Given that most of the grading nursing care indicators of medical and nursing care institutions are qualitative indicators, it is difficult to express decision information with precise numbers due to the complexity of environment and uncertainty of decision makers’ cognition. Therefore, this study introduces interval-valued intuitionistic fuzzy number into the determination of grading nursing care indicator weights, and then describes the fuzziness and uncertainty of information from four aspects: membership, non-membership, ambiguity, and hesitation, thus reducing the loss of decision information.Let Step 8: Set the decision matrix as follows:Step 9: The ambiguity of IVIFE is defined by the distance relationship between interval numbers; thus, the ambiguity  numbers   of appraisers who have the experience in medical and nursing care service . The interval gray number matrix According to the interval gray values and weights for each indicator, using the constructed whitening weight function and Equation (17), the whitening weight function values and gray clustering coefficients of each indicator in different gray classes could be calculated, as shown in Analyzing the results in According to Equation (19), the synthetic weighted decision-making vector of each gray class can be obtained as follows:Through Equation (20), we can get the weighted decision-making coefficient vector of kernel clustering of medicine and nursing care as follows:After calculating the synthetic decision-making coefficient vector and reclassifying, the medical care level of the elderly As above, the weighted decision-making coefficient vectors of kernel clustering of the remaining elderly are shown in From the maximum weighted decision-making coefficient vector in As shown in Ordering the above results, the gray class of the object was judged according to weighted decision-making coefficient vector, and the grading nursing care level was determined. For example, both Through the above analysis, the final ranking results were as follows:Determine the ideal solution Calculate the distance Calculate the distance Calculate the relative closeness TOPSIS, as an evaluation method of multi-objective comprehensive decision making, has also been applied to various classification evaluation fields. For example, Wu  construcThe relative closeness values for the above five residents are as follows:Compared with  results .On the basis of the analysis of the characteristics of integrated medical and nursing care institutions, this study constructed a grading nursing care evaluation indicator system from two aspects: medical and nursing care. According to the social relations of decision-making members, a group decision-making method based on interval-valued intuitionistic fuzzy entropy under a social network environment was proposed to ensure the reliability of weight distribution. Finally, using a two-stage gray synthetic clustering model for interval gray number, the classification of nursing grading care of the elderly in integrated medical and nursing care institutions was realized. This study not only is conducive to the rational and accurate allocation of medical and nursing care resources, but also provides reference for the standardized development of integrated medical and nursing care services.Through case analysis, the proposed method has the following advantages: (1) aiming at the gray quality of the elderly in the assessment process of grading nursing care, the proposed method can help institutions allocate medical and nursing care resources more accurately; (2) traditional methods tend to only rank the results, which makes it difficult to obtain more classification information. The proposed method can directly divide the elderly into different grades while providing the ranking results, which is helpful for quick classification; (3) the proposed method does not need a control group to reflect the advantages or disadvantages of the scheme; hence, it is more suitable for the reality that residents have great mobility in grading nursing assessment.(1)Customer needs. When obtaining customer needs, we can adopt the questionnaire method, which is subjective and difficult to obtain samples. Therefore, it is necessary to combine big data technology, regional differences, gender differences, economic differences, etc. to establish a multidimensional customer needs analysis method that conforms to the characteristics of medical and nursing services.(2)Service resource planning. At present, with the limited resources, this study assessed the elderly with different abilities, which can allow studying the planning of medical care and pension resources according to their needs.This study provides a new way of thinking for the ability evaluation of the elderly in medical and nursing institutions, which has certain practical significance and theoretical value. At present, medical and nursing integration is in a high-speed development stage, and more mature contents will emerge in the future. Therefore, further research in the future will focus on the following aspects: