question:You will be shown a question, followed by excerpts from biomedical research papers. Please answer the question based on the provided context. Do not include any text in your response other than the answer.Question: What is the use of Brain Metastasis Velocity (BMV) Model?Context: PURPOSE/OBJECTIVE(S): Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery (SRS).Background: Brain metastasis velocity (BMV) predicts outcomes after initial distant brain failure (DBF) following upfront stereotactic radiosurgery (SRS).lso tells the history of the derivation and validation of BMV, a recently identified biomarker for survival and neurologic death in the brain metastasis population treated with SRS.CONCOBJECTIVE: To provide a review of the current status of predictive nomograms and brain metastasis velocity (BMV) in the prognostication of brain metastasis outcomes.INTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS).Background: Brain metastasis velocity (BMV) predicts outcomes after initial distant brain failure (DBF) following upfront stereotactic radiosurgery (SRS).We introduce a novel clinical metric, brain metastasis velocity (BMV), for predicting clinical outcomes after initial DBF following upfront SRS alone.PURPOSE/OBJECTIVE(S): Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery (SRS).e. We introduce a novel clinical metric, brain metastasis velocity (BMV), for predicting clinical outcomes after initial DBF following upfront SRS aloneINTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosOBJECTIVE: To provide a review of the current status of predictive nomograms and brain metastasis velocity (BMV) in the prognostication of brain metastasisPURPOSE/OBJECTIVE(S): Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotacticSRS). We developed an integrated model of clinical predictors and pre-SRS MRI-derived radiomic scores (R-scores) to identify high-BMV (BMV-H) patients upon initial identification of brain metastases (BMPURPOSE/OBJECTIVE(S): Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactINTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radioBackground: Brain metastasis velocity (BMV) predicts outcomes after initial distant brain failure (DBF) following upfront stereotactic radiosuBesides clinical and treatment related factors, brain metastasis velocity (BMV) as a newly described clinical prognostic metric was included and calculated between first and second treatment.stasis velocity (vBMV) was defined as the volume of new intracranial disease at the time of distant brain failure (DBF) for the first DBF (DBF1) and s

question:You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: ["Outcome", "Participant", "Intervention"].Please return the output as a JSON object of the format: {"Participant" : ["patients with COPD", ...], "Intervention" : ["Atenolol", ...], "Outcome" : ["blood pressure", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].Only output the JSON object and do not include any additional text.Abstract:Potential effect of the risk of ovarian cancer algorithm ( ROCA ) on the mortality outcome of the Prostate , Lung , Colorectal and Ovarian ( PLCO ) trial . Recently , the Prostate , Lung , Colorectal and Ovarian ( PLCO ) Trial reported no mortality benefit for annual screening with CA-125 and transvaginal ultrasound ( TVU ) . Currently ongoing is the UK Collaborative Trial of Ovarian Cancer Screening ( UKCTOCS ) , which utilizes the risk of ovarian cancer algorithm ( ROCA ) , a statistical tool that considers current and past CA125 values to determine ovarian cancer risk . In contrast , PLCO used a single cutoff for CA125 , based on current levels alone . We investigated whether having had used ROCA in PLCO could have , under optimal assumptions , resulted in a significant mortality benefit by applying ROCA to PLCO CA125 screening values . A best-case scenario assumed that all cancers showing a positive screen result earlier with ROCA than under the PLCO protocol would have avoided mortality ; under a stage-shift scenario , such women were assigned survival equivalent to Stage I/II screen-detected cases . Updated PLCO data show 132 intervention arm ovarian cancer deaths versus 119 in usual care ( relative risk , RR = 1.11 ) . Forty-three ovarian cancer cases , 25 fatal , would have been detected earlier with ROCA , with a median ( minimum ) advance time for fatal cases of 344 ( 147 ) days . Best-case and stage-shift scenarios gave 25 and 19 deaths prevented with ROCA , for RRs of 0.90 ( 95 % CI : 0.69-1.17 ) and 0.95 ( 95 % CI : 0.74-1.23 ) , respectively . Having utilized ROCA in PLCO would not have led to a significant mortality benefit of screening . However , ROCA could still show a significant effect in other screening trials , including UKCTOCS .

question:You will be shown a paragraph from a biomedical research paper, followed by a question about the paper. Please extract text from the paragraph to answer the question. Do not include any text in your repsonse other than the answer.Paragraph: Eighteen months after disease onset, 40% of patients are found to still have anti-CHIKV IgM [6, 18, 23, 24] . The chronic stage of CHIKF is characterized by polyarthralgia that can last from weeks to years beyond the acute stage [6] . CHIKV has been shown to attack fibroblasts, explaining the involvement of muscles, joints, and skin connective tissues. The high number of nociceptive nerve endings found within the joints and muscle connective tissues can explain pain associated with CHIKF [25, 26] . More than 50% of patients who suffer from severe CHIKF are over 65 y old, and more than 33% of them die. Most adults who suffer from severe CHIKF have underlying medical conditions [6, 24, 27] . The other group that is disproportionately affected by severe CHIKV is children. Other complications associated with CHIKV, from most common to least common, include respiratory failure, cardiovascular decompensation, meningoencephalitis, severe acute hepatitis, severe cutaneous effects, other central nervous system problems, and kidney failure [6, 18, 20, 23, 24, 26, 27] . CHIKV undertakes a complex replication cycle upon host infection (Figure 2 ), which makes its genome susceptible to mutations [28, 29] . For instance, Ae. aegypti, responsible for epidemics in Kenya, Comoros, and Seychelles, carried CHIKV with an alanine in the 226 position of the E1 gene (E1-A226) [4, 18] . However, when the virus struck La Reunion Islands, a decline in population of Ae. aegypti, due to massive dichlorodiphenyltrichloroethane usage and dearth of Ae. albopictus species' www.plosntds.org population, resulted in an ecological pressure, favoring replacement of alanine at position 226 with valine (E1-A226V) [5] . This mutation allowed CHIKV's secondary vector species, Ae. albopictus, to supplement Ae. aegypti as its primary vector [5] . Within a year, the E1-A226V mutation was present in La Reunion Island, and Ae. albopictus apparently vectored the large epidemic infecting 34% of La Reunion Island's population [5] . All of the CHIKV strains isolated from Mayotte carried the E1-A226V mutation, and the mutation was also found in Madagascar in 2007 [5] . The E1-A226V mutation was not present at the beginning of the Indian Ocean Islands outbreak (before September 2005). However, more than 90% of later viral strains found there had incorporated the mutation (December-March 2006), indicating a genotype switch during the winter season [5, 18, 20] . The E1-A226V mutation also enabled an increase in infectivity of Ae. albopictus when compared to its infectivity of Ae. aegypti [4, 11, 18, 30] , and with several factors taken together, Ae. albopictus has become the new preferred and more lethal vector for CHIKV [4, 5, 11] . In fact, Tsetsarkin et al. found that a Green Fluorescent Protein tagged E1-A226V virus was 100 times more infective to Ae. albopictus than it was to Ae. aegypti [4] . In all the Indian Ocean Islands, Ae. albopictus became the main vector for CHIKV within 1-2 y after CHIKV was introduced to the region [31] . Of note is that Ae. aegypti has most likely been established in North America for over 300 y, while Ae. albopictus has been in many areas of the US, since 1985, primarily in Florida [32] and since then has expanded its range in the country. Reiskind et al. set out to determine if Ae. aegypti and Ae. albopictus mosquitoes captured in Florida were susceptible to CHIKV infection by a La Reunion isolate [32] . Each mosquito tested was highly susceptible to infection by a full-length infectious clone of the La Réunion Island isolate, CHIKV LR2006 OPY1 strain. Even though the Ae. albopictus strains were more susceptible to infection, overall ecology and differences in human biting patterns need to be studied further Characteristically, there are two rounds of translation: (+) sense genomic RNA (49S9 = 11.7 kb) acts directly as mRNA and is partially translated (59 end) to produce non-structural proteins (nsp's). These proteins are responsible for replication and formation of a complementary (2) strand, the template for further (+) strand synthesis. Subgenomic mRNA (26 S = 4.1 kb) replication occurs through the synthesis of full-length (2) intermediate RNA, which is regulated by nsp4 and p123 precursor in early infection and later by mature nsp's. Translation of the newly synthesized sub-genomic RNA results in production of structural proteins such as Capsid and protein E2-6k-E1 (from 39 end of genome). Assembly occurs at the cell surface, and the envelope is acquired as the virus buds from the cell and release and maturation almost simultaneous occurred. Replication occurs in the cytoplasm and is very rapid (,4 h) [28, 29] . doi:10.1371/journal.pntd.0000623.g002 www.plosntds.org to gain a more accurate understanding of a potential CHIKV epidemic in the US [32] . During the 7 d preceding birth, no human mother has been reported to transmit the disease vertically. However, about 50% of newborns delivered while the mother was infected with CHIKV contracted the disease from their mother, despite the method of delivery. Furthermore, there have been instances of CHIKV transmission from mother to fetus causing congenital illness and fetal death [33] . During the 2005-2006 La Reunion Island outbreaks, Ramful et al. discovered that mothers could transmit CHIKV to their progeny during the perinatal period (Day 24 to Day +1) [33, 34] , and it is associated with a high degree of morbidity. By mean Day 4 of life, all of the neonates were symptomatic for CHIKV, exhibiting common CHIKF symptoms. Six neonates were confirmed to have contracted CHIKV and developed mengoencephalitis. Of those mothers who, during the La Reunion Island epidemic, were infected long before delivery, only three fetal deaths were reported [12, 33] . Ramful et al. theorized that motherto-child transmission most likely happens transplacentally shortly before delivery [33] . A similar study by Gerardin et al. reported nineteen cases of neonatal infection associated with intrapartum maternal viremia that progressed to develop encephalitis owing to vertical transmission from infected mothers [34] . Clinical and epidemiological similarities with dengue fever make CHIKV diagnosis difficult, which may lead physicians to misdiagnose CHIKV as dengue fever; therefore, the incidence of CHIKV may actually be higher than currently believed (Table 1 ) [6, 12, 35] . The amount of time elapsed since disease onset is the most critical parameter when choosing a diagnostic test. CHIKV can be detected and isolated by culturing with mosquito cells (C6/36), Vero cells (mammalian), or in mice [26] . However, this method can take at least a week and only achieves a high sensitivity during the viremic phase, which usually only lasts up to 48 h after the bite. Five days post-infection, the viral isolation approach has a low sensitivity but is still the preferred method for detecting the CHIKV strain [12, 26, 31, 35] . RT-PCR on the other hand is a faster and more sensitive method that can be used within the first week of disease onset [26] , and it is currently the most sensitive method for detecting and quantifying viral mRNA [4, 36] . Classic serological detection, by assays such as ELISA [37] , immunofluorescence [5, 38] , complement binding, and haemagglutination inhibition [39] , constitutes the second diagnostic tool used for biological diagnosis of CHIKV infection. These proven techniques are useful for detection of Antigen in mosquitoes during epidemiological studies. These assays detect virus-specific IgM and IgG, however the sensitivity and specificity of these assays has been poorly characterized. Viral competence, or the potential of viral infection and transmission, is an important parameter that can be quantified by ELISA, viral culture, and PCR. A study by Ng et al. showed biomarkers indicative of severe CHIKV infection [40] . They found decreased levels of RANTES and increased levels of Interleukin-6 (IL-6) and Interleukin-1b (IL-1b) that could be sued for CHIKV detection in patients as indicators of CHIKV-driven cytokine storm. Couderc et al. demonstrate another cytokine, type-I IFN, as a key player in the progression to CHIKV infection [26] . Using an IFN-a/b null mouse model, they demonstrated evidence of muscles, joints, and skin as privileged CHIKV targets, which is consistent with human pathology. Although Ng et al. concluded that RANTES levels were significantly suppressed in severe CHIKF patients [40] , interestingly, an increase in levels of RANTES has been observed in dengue infection [41] . Since the symptoms of CHIKF mimic those of dengue fever, results obtained from this study strongly suggest that RANTES could be a potential distinctive biomarker that differentiates between these two clinically similar diseases. There are no approved antiviral treatments currently available for CHIKV [1, 3, 12, 42] . Currently, CHIKF is treated symptomatically, usually with non-steroidal anti-inflammatory drugs or steroids, bed rest, and fluids. Movement and mild exercise are thought to decrease stiffness and morning arthralgia, but heavy exercise may exacerbate rheumatic symptoms. Corticosteroids may be used in cases of debilitating chronic CHIKV infection. There is a debate about the appropriateness of chloroquine as treatment for unresolved, non-steroidal anti-inflammatory drugresistant arthritis [43] . A study showed that viral production was www.plosntds.org drastically reduced at 16 h post-infection after treatment with 100 mM dec-RVKR-cmk (Decanoyl-Arg-Val-Lys-Arg-chloromethylketone), a furine inhibitor [42, 44] . Chloroquine acted by raising the pH, blocking low pH-dependent entry of virus into the cell. It is important to note that dec-RVKR-cmk or chloroquine only inhibited viral spreading from cell to cell, not CHIKV replication once it had entered the cell [43] . However, most would agree that the best weapon against CHIKV is prevention. A live CHIKV vaccine developed by the United States reached phase II clinical trial encompassing 59 healthy volunteers [45] . Eight percent of the volunteers experienced transient arthralgia, while 98% of the volunteers had seroconversion [45] . However, live CHIKV vaccines are still questionable. One cannot discount the risk of a live vaccine possibly inducing chronic rheumatism. Also, there is the question as to whether widespread use among the public could trigger mosquito transmission or lead to chronic infection or viral reversion [1] . An alternative approach would be to produce a chimeric vaccine against CHIKV. Wang et al. developed a chimeric alphavirus vaccine that is uniformly attenuated and does not cause reactogenicity in mice [3] . Three different versions of this vaccine were made using three different backbone vectors: Venezuelan equine encephalitis virus (VEEV) attenuated vaccine strain T-83, naturally attenuated eastern equine encephalitis virus (EEEV), and attenuated Sindbis virus (SINV). In short, CHIKV structural proteins were engineered into the backbones of the aforementioned vaccines to produce the chimeras [3] . These chimeras were found to stimulate a strong humoral immunity, and even at doses of 5.3-5.8 log 10 PFU, they did not trigger reactogenicity. When vaccinated mice were challenged with CHIKV, neither adult nor neonatal mice gained weight, had fever, or displayed signs of neurological illness. Upon comparison of the chimeras with the Army181/25 vaccine, the Army vaccine resulted in higher levels of viremia and replication in the joints of neonatal mice. Because the joints are known targets of CHIKV, Wang et al. noted their vaccine might avoid the negative reactogenic side effects of the Army vaccine. After being subcutaneously vaccinated with 5.3-5.8 log 10 PFU of the chimeric vaccines, mice produced strong neutralizing antibody titers. The VEEV and EEEV chimeras yielded higher neutralizing antibody titers than the SINV chimera without being more virulent. On top of this, the VEEV and EEEV CHIKV chimeras seemed to be more immunogenic than the Army vaccine despite the chimeras' lower viremia and replication in the joints of neonatal mice [3] . Tiwari et al. [46] adopted a different strategy using formalin inactivated CHIKV in combination with alhydrogel (Aluminum Hydroxide) as an adjuvant. This study clearly suggests that this vaccine elicits both humoral and cell-mediated immune responses in mice, providing its immunogenic potential. A recent study by Couderc et al. [47] showed passive immunization as a potential treatment for CHIKV infection. Using purified immunoglobulin extracted from convalescent CHIKV patients, they demonstrated effective neutralizing activity against CHIKV infection both in vitro and in vivo. This thereby establishes a potential preventive and therapeutic approach to combat CHIKV infection. Pathogenesis studies conducted with related alpha virus, like RRV, have shown the role of macrophages in persistence on infection [48] . They also demonstrated the role of RRV-specific CD8 T cells in clearing viral load in infected patients, thereby warranting similar investigations with CHIKV and the importance of investigating a cell-mediated immune response-based vaccine against CHIKV [49] . There are always certain risks associated with live attenuated or inactivated viral vaccines [50] . One way to avoid these potential problems is to construct a consensus-based DNA vaccine.Question: What percentage of the patients still have the CHIKV IgM after eighteen months?

question:You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.Title: Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma}Article:Abstract:Neurotrophin-3( Ntf3) and brain derived neurotrophic factor( Bdnf) are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreERT line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury.Introduction:The trophic factors, neurotrophin-3( Ntf3) and brain-derived neurotrophic factor( Bbnf) play critical roles in the embryonic inner ear, contributing to the survival of cochlear and vestibular sensory neurons and to the establishment of their projections into the respective sensory epithelia( Fritzsch et al., 2004; Ramekers et al., 2012). Both Bdnf and Ntf3 continue to be expressed in inner ear sensory epithelia after birth. In the postnatal vestibular epithelia, Bdnf is expressed only by supporting cells( Schecterson and Bothwell, 1994; Montcouquiol et al., 1998), whereas Ntf3 is expressed by both supporting cells and hair cells( Farinas et al., 1994). In the postnatal organ of Corti, Bdnf is expressed by both inner( IHCs) and outer hair cells( OHCs) and supporting cells at early postnatal ages( P1–P6), but is only detected in supporting cells from P10 onwards( Wiechers et al., 1999). All cells in the early postnatal organ of Corti appear to express Ntf3, but in the adult, expression is restricted to the IHCs and their surrounding supporting cells, with higher levels in the apical( low-frequency) region than at the base of the cochlear spiral( Sugawara et al., 2007). Thus Bdnf and Ntf3 could have significant functions in the postnatal inner ear, and alterations in expression of these neurotrophins may modulate structure and function in the adult inner ear. In this study, we investigated the roles of postnatal Ntf3 and Bdnf in both normal and damaged inner ears. Using cell-specific and inducible knockout or overexpression technology, we eliminated or increased neurotrophin expression from supporting cells or hair cells in the postnatal inner ear. We show that these neurotrophins, when expressed by the glia-like supporting cells in these sensory epithelia, are required for the formation and/or maintenance of ribbon synapses, a role distinct from the one they play in embryogenesis. Ntf3 has major effects only in the cochlea, while postnatal Bdnf appears to act only in the vestibular organs. Furthermore, we show that Ntf3 overexpression can elicit regeneration of the synaptic contacts between cochlear nerve terminals and inner hair cells after noise-induced synaptopathy, a type of neural damage which appears to be widespread even in ears exposed at sound levels well below those which cause hair cell damage and permanent threshold shifts( Kujawa and Liberman, 2009).Discussion:Neurotrophins are key molecular mediators for synaptic development and function in the central nervous system( Gomez-Palacio-Schjetnan and Escobar, 2013). In this study, we show that Ntf3 and Bdnf, which are necessary for sensory neuron survival in the developing inner ear( Fritzsch et al., 2004; Ramekers et al., 2012), continue to play important and complementary roles in the postnatal inner ear, specifically by modulating the number of synapses between hair cells and sensory neurons. Our results indicate that supporting cells of the sensory epithelia are the key source of these neurotrophins in the postnatal inner ear. Importantly, we show that increasing the availability of Ntf3, but not Bdnf, promotes the recovery of both cochlear responses and IHC synapses after acoustic trauma, even when Ntf3 expression is induced after noise exposure. The specificity of the effects of each neurotrophin on each organ cannot be explained simply by the spatio-temporal expression pattern of the components for these signaling pathways, as both Bdnf and Ntf3, as well as their respective receptors Ntrk2( TrkB) and Ntrk3( TrkC), are expressed in the postnatal and adult cochlea and vestibular organs( Pirvola et al., 1992; Fritzsch et al., 1999; Gestwa et al., 1999; Wiechers et al., 1999; Farinas et al., 2001; Stankovic and Corfas, 2003; Sugawara et al., 2007). A similar specificity in the biological roles of these neurotrophins has been shown in embryonic development, that is, constitutive knockout of Bdnf or Ntf3 reveals predominant pro-survival roles on vestibular or cochlear neurons, respectively( Farinas et al., 1994; Jones et al., 1994; Ernfors et al., 1995; Schimmang et al., 1995; Bianchi et al., 1996). However, while genetic replacement of one neurotrophin with the other can almost completely rescue neuronal survival deficits caused by constitutive deletion of either Bdnf or Ntf3( Coppola et al., 2001; Agerman et al., 2003), we observed that Ntf3 and Bdnf have distinct and non-overlapping roles in postnatal synapse formation. Thus, it appears that vestibular and auditory primary sensory neurons can respond equally to endogenous levels of either Bdnf or Ntf3 during development, but this ability is lost after birth. In the vestibular system, supporting cell-derived Bdnf is the sole neurotrophin necessary for postnatal formation and maintenance of hair cell synapses( Gomez-Casati et al., 2010b), and the levels of Bdnf expressed by these non-neuronal cells is not limiting, as Bdnf overexpression does not alter vestibular function. While previous studies of constitutive knockouts showed that Ntf3 is necessary for the survival of a subpopulation of vestibular neurons during embryogenesis( Ernfors et al., 1995), our data indicate that Ntf3, which like Bdnf is expressed primarily by supporting cells in the postnatal vestibular sensory epithelia( Sugawara et al., 2007), is dispensable in the vestibular system after birth. In contrast to the vestibular organs, supporting cell-derived Ntf3, but not Bdnf, is necessary for the establishment of normal synapses and auditory function in the cochlear base. The correlation of Ntf3 expression levels with synapse numbers and cochlear sensitivity in both knockout and overexpression models indicates that supporting cell-derived Ntf3 is not only a critical but also a limiting factor in the postnatal cochlea. Interestingly, postnatal knockout of supporting cell-derived Ntf3 and Bdnf did not affect the survival of the sensory neurons themselves, in either the vestibular( Gomez-Casati et al., 2010b) or the cochlear( spiral) ganglion, indicating that endogenous Ntf3 and Bdnf become dispensable for neuronal survival after birth. These sensory neurons may become independent of trophic support in the adult, or alternatively, other trophic factors, such as insulin-like growth factor-1( Igf1) and macrophage migration inhibitory factor( Mif), may promote survival after birth. Both Igf1 and Mif are expressed in the postnatal cochlea, and, for both, loss results in ganglion cell death or altered innervation after birth( Camarero et al., 2001; Bank et al., 2012). In addition, glial cell line-derived neurotrophic factor( Gdnf) is also expressed in postnatal inner ear( Stankovic and Corfas, 2003), and it has been suggested that vestibular neurons switch trophic sensitivity from Bdnf to Gdnf after target innervation( Hashino et al., 1999). Although adult inner hair cells also express Ntf3( Wheeler et al., 1994; Sugawara et al., 2007), we found no cochlear dysfunction in mice lacking Ntf3 expression in these cells. The lack of phenotype in the hair cell-specific Ntf3 knockout is unlikely due to the partial recombination in hair cells because( a) recombination in supporting cells and IHCs had similar efficiency( ∼60%);( b) cochlear Ntf3 expression was reduced to a similar extent by deletion from either supporting cells or hair cells; and( c) Ntf3 overexpression by hair cells had similar effects on cochlear function and synapse density as that seen in Ntf3 overexpression by supporting cells, indicating that modulation of Ntf3 expression in a subset of hair cells is sufficient to produce phenotypic outcomes. These observations support the conclusion that endogenous Ntf3 expressed by postnatal supporting cells, but not inner hair cells, is necessary for normal cochlear function. The mosaic recombination pattern in the Pou4f3/CreERT Ntf3 overexpression revealed that the effects of Ntf3 on hair cell synaptogenesis are precisely localized, that is, synapse density was increased only on hair cells in which the transgene was activated. Thus, it appears that supporting cells create a physical barrier, allowing for local signaling events without cross talk between adjacent hair cells. The lack of effect of postnatal Ntf3 knockout or overexpression on the total number of myelinated sensory axons in the osseous spiral lamina indicates that the changes in synapses is not due to alterations in the number of sensory neurons, and thus it is consistent with the notion that the effects of Ntf3 are local. Present results suggest that Ntf3 levels may regulate the number of synapses by influencing branching of the unmyelinated terminals of cochlear sensory neurons. Regardless of the cellular origin, the effects of Ntf3 knockout or overexpression on synaptic density and cochlear function are restricted to the high-frequency( basal) half of the cochlea. The pro-survival effects of embryonic Ntf3 have the same tonotopy, that is, the loss of spiral ganglion cells in mice with Ntf3 or Ntrk3 knockout are primarily seen at the cochlear base( Fritzsch et al., 1997; Tessarollo et al., 1997; Coppola et al., 2001; Farinas et al., 2001). Thus, it appears that Ntf3 is the key endogenous trophic factor for both embryonic development and postnatal function of high-frequency cochlear neurons. A previous study showed that Ntf3 promotes axonal growth and synaptogenesis in organ of Corti explants after excitotoxicity( Wang and Green, 2011). Our results indicate that in vivo, Ntf3 regulates ribbon synapse numbers without altering cochlear nerve axonal numbers, suggesting a direct effect of Ntf3 on IHC synaptogenesis. Most importantly, overexpression of Ntf3, but not Bdnf, promotes recovery from noise-induced synaptic degeneration and the associated decrements in auditory evoked potentials. Since the Ntf3 receptor Ntrk3 is expressed by cochlear neurons, not IHCs( Gestwa et al., 1999), our results suggest that Ntf3 overexpression acts first by promoting the recovery of post-synaptic terminals, which prevents the progressive loss of pre-synaptic ribbons, and enhances the regeneration of IHC synapses after noise exposure. There has been extensive exploration of the use of Bdnf and Ntf3 as therapeutics for sensorineural hearing loss, based on their pro-survival effects on spiral ganglion neurons after hair cell degeneration due to ototoxic drugs( Ramekers et al., 2012). It has been suggested that these neurotrophins might promote long-term neuronal survival in cochlear implant users, who typically have few, if any, remaining hair cells( Budenz et al., 2012). Recent studies in mice have shown that significant synaptic loss precedes hair cell death and spiral ganglion cell degeneration in both noise-induced and age-related hearing loss( Kujawa and Liberman, 2009; Sergeyenko et al., 2013), and it has been suggested that this primary neuropathy is a major cause of problems hearing in a noisy environment, the most common complaint of those with sensorineural hearing loss. Therefore, treatment of cochlear synaptopathy presents a novel therapeutic approach for age-related and noise-induced hearing loss. While a number of trophic factors, including Bdnf and Ntf3, can mediate the survival of injured sensory neurons( Roehm and Hansen, 2005; Ramekers et al., 2012), our findings indicate that specific neurotrophins are required to promote regeneration and to regain function of the synaptic connections in damaged inner ear epithelia.

question:You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.Title 1:Twenty Months of Evolution Following Sympathectomy on Patients with Palmar Hyperhidrosis: Sympathectomy at the T3 Level is Better than at the T2 LevelAbstract 1:OBJECTIVE To compare two surgical techniques ( denervation levels ) for sympathectomy using video-assisted thoracoscopy to treat palmar hyperhidrosis in the long-term . METHODS From May 2003 to June 2006 , 60 patients with palmar hyperhidrosis were prospect ively r and omized for video-assisted thoracoscopic sympathectomy at the T2 or T3 ganglion level . They were followed for a mean of 20 months and were evaluated regarding their degree of improvement of palmar hyperhidrosis , incidence and severity of compensatory hyperhidrosis and its evolution over time , and quality of life . RESULTS Fifty-nine cases presented resolution of the palmar hyperhidrosis . One case of therapeutic failure occurred in the T3 group . Most of the patients presented an improvement in palmar hyperhidrosis , without any difference between the groups . Twenty months later , all patients in both groups presented some degree of compensatory hyperhidrosis but with less severity in the T3 group ( p = 0.007 ) . Compensatory hyperhidrosis developed in most patients during the first month after the operation , with incidence and severity that remained stable over time . An improvement in quality of life was seen starting from the first postoperative evaluation but without any difference between the groups . This improvement was maintained until the end of the follow-up . CONCLUSION Both techniques were effective for treating palmar hyperhidrosis . The most frequent complication was compensatory hyperhidrosis , which presented stable incidence and severity over the study period . Sympathectomy at the T3 level presented compensatory hyperhidrosis with less severity . Nevertheless , the improvement in quality of life was similar between the groupsTitle 2:T3/T4 thoracic sympathictomy and compensatory sweating in treatment of palmar hyperhidrosis.Abstract 2:BACKGROUND Compensatory sweating ( CS ) is one of the most common postoperative complications after thoracic sympathectomy , sympathicotomy or endoscopic sympathetic block ( ESB ) for palmar hyperhidrosis . This study was conducted to examine the relevance between CS and the sympathetic segment being transected in the surgical treatment of palmar hyperhidrosis , and thus to detect the potential mechanism of the occurrence of CS . METHODS Between October 2004 and June 2006 , 163 patients with primary hyperhidrosis were r and omly divided into two groups , T(3 ) sympathicotomy ( 78 patients ) and T(4 ) sympathicotomy ( 85 ) , who were operated upon under general anesthesia via single lumen intubation and intercostal video-mediastinoscopy ( VM ) . RESULTS No morbidity or mortality occurred . Palmar hyperhidrosis was cured in all patients . Follow-up ( mean ( 13.8 + /- 6.2 ) months ) showed no recurrence of palmar hyperhidrosis . The difference of rates of mild CS in groups T(3 ) and T(4 ) was of no statistical significance . The rate of moderate CS was significantly lower in group T(4 ) than in group T(3 ) . No severe CS occurred . CONCLUSION The rates of occurrence and severity of CS are lowered with the lower sympathetic chain being transectedTitle 3:Endoscopic thoracic sympathectomy for palmar hyperhidrosis: a randomized control trial comparing T3 and T2-4 ablation.Abstract 3:BACKGROUND Compensatory sweating is a major and troublesome complication noted frequently after sympathectomy in patients with primary palmar hyperhidrosis . This r and omized clinical trial was projected to measure the impact of limited denervation on compensatory sweating while performing endoscopic thoracic sympthectomy . METHODS Two hundred thirty-two patients with primary palmar hyperhidrosis were r and omly allocated to either a T3 sympathectomy treatment , called group T3 , or a T2 - 4 sympathetic treatment , called group T2 - 4 . The patients underwent bilateral sympathetic ablation at corresponding levels . All patients were followed up and evaluated for comparison of symptom resolution , postoperative complication , levels of satisfaction , and severity of compensatory sweating between the two groups . RESULTS Sex , age , family history , and distribution of sweating were similar in both groups . The postoperative complications were minor , and Horner 's syndrome was not detected in either group . The frequency of mild and moderate compensatory sweating was not significantly different between the two groups , but the incidence of severe compensatory sweating was significantly lower after T3 sympathectomy ( 3 % versus 10 % ) . As for satisfaction rate , group T3 was superior to group T2 - 4 ( 96.6 % versus 89.6 % ) . The rate of symptom resolution was 100 % , and no recurrence was found in either group . CONCLUSIONS The single-level sympathetic denervation under thoracoscopy is a safe and effective procedure to treat primary palmar hyperhidrosis . This method reduces the incidence of severe compensatory sweating postoperatively without compromising the patient 's satisfactionTitle 4:Quantification of eccrine sweat glands with acetylcholine sweat-spot test and anatomical redistribution of sweating after T2–T3 thoracoscopic sympathicolysisAbstract 4:Background In this study , patients treated by thoracoscopic sympathicolysis for palmar hyperhidrosis were evaluated to determine the number and response of sweat gl and s to intradermal acetylcholine stimulus . Methods A total of 30 patients were included in the study . Group A consisted of 10 patients with palmar hyperhidrosis who underwent thoracoscopic sympathicolysis in October 2005 , and group B consisted of 20 patients who underwent surgery during the years 1999 , 2000 , and 2001 . The study procedure involved applying iodine alcohol to the palm and then intradermally injecting 0.1 ml 1 % acetylcholine . This activated the sweat gl and s , which were then photographed and counted . The study procedure was performed prospect ively over different periods in group A and retrospectively in group B. Results In group A , the mean number of gl and s activated 1 , 3 , 6 , and 12 months after surgery were 41 , 174.20 , 522.8 , and 747.2 , respectively ; this gradual increase was statistically significant over the first 6 months ( p = 0.004 ) but not between months 6 and 12 ( p = 0.255 ) . The trend towards an increasing number of active gl and s occurred in both groups , with a mean of 1369.8 active gl and s in group B compared to 747.2 ( p = 0.095 ) in group A after 12 months . Conclusion It is well-known that Cannon ’s law of denervation ( 1939 ) is not applicable to the sweat gl and s , that is , there is no hyperactivation following intradermal acetylcholine stimulation . However , some response , which increased over the first 6 months following surgery , was observed in our study . Nevertheless , this activation is subsequently self-limiting , result ing in no gl and atrophy , and reinnervation occurs without patient awarenessTitle 5:Objective evaluation of patients with palmar hyperhidrosis submitted to two levels of sympathectomy: T3 and T4.Abstract 5:This study compares the results obtained of video-assisted sympathectomy performed on two distinct ganglion levels ( third vs. fourth thoracic ganglion ) in the treatment of palmar hyperhidrosis ( PH ) , through a blind r and omized clinical trial . All participants were r and omized into two groups of 20 patients ( G3 and G4 ) and underwent the operation , and were followed for 12 months . We used an objective method for measuring sweat , checking the transepidermal water loss ( TEWL ) , and evaluated the quality -of-life ( QoL ) before and after the operation . All patients ( n=40 ) ceased suffering from PH after surgery , with statistical difference when we compared the values of TEWL palmar preoperatively with their respective values at one week , one month , six months and 12 months . The main side effect observed was compensatory hyperhidrosis ( CH ) , which was most frequent in G3 after 12 months of follow-up . There was an improvement in QoL since the first evaluation of the postoperative period with no difference between groups . Both techniques were effective in the treatment of PH , generating objective reduction of TEWL regardless of the ganglion operated . Sympathectomy G3 had a higher incidence of CH , yet the improvement in QoL was similar in both groupsTitle 6:Thoracoscopic sympathicotomy for disabling palmar hyperhidrosis: a prospective randomized comparison between two levels.Abstract 6:BACKGROUND Thoracoscopic sympathicotomy is highly effective in treating disabling palmar hyperhidrosis . The ideal level to maximize efficacy and minimize the side effect of compensatory hyperhidrosis ( CH ) is controversial . This study compared sympathicotomy over the second ( R2 ) vs third ( R3 ) costal head relative to these variables in patients with massive palmar hyperhidrosis . METHODS This prospect i ve , r and omized study enrolled 121 patients with disabling palmoplantar hyperhidrosis assigned to bilateral sympathicotomy ( sympathetic transection ) , which was done over R2 in 61 ( n = 122 extremities ) or R3 in 60 ( n = 120 extremities ) . Patients were question ed at 6 months and at 1 year or more to assess efficacy , side effects , and satisfaction with the procedure . RESULTS Sympathicotomy at R2 failed to cure palmar hyperhidrosis in 5 of 122 ( 4.1 % ) extremities , but only 2 ( 1.6 % ) were to a truly profound dripping level of recurrence . Sympathicotomy at R3 failed to cure palmar hyperhidrosis in 5 of 120 extremities ( 4.2 % ) , and all were dramatic failures with dripping recurrent sweating . The patients whose palmar hyperhidrosis was not completely cured were aged 19.7 ± 2.5 vs 26.4 ± 8.0 years ( p = 0.04 ) . Two R3 patients with failure underwent three redo R2 sympathicotomies , with curative results . R2 patients showed a trend toward a higher level of CH vs R3 patients at 6 months and after 1 year . The CH severity scale was 4.7 ± 2.7 ( n = 38 ) for R2 vs 3.8 ± 2.8 ( n = 36 ) for R3 ( p = NS ) at 6 months and 4.7 ± 2.5 ( n = 43 ) for R2 vs 3.7 ± 2.8 ( n = 37 ) for R3 ( p = NS ) after 1 year . Younger age , male sex , and higher levels of preoperative and postoperative plantar sweating were predictors of failed sympathicotomy . Increased age was associated with increased CH . CONCLUSIONS R2 and R3 sympathicotomy for massive palmoplantar hyperhidrosis are highly effective , with low recurrence and incidences of severe CH . R2 tends to have a higher level of CH vs R3 , and a higher incidence of dramatic failures is suggested in R3 patients , for which reoperation at the R2 level will likely be curativeTitle 7:Surgical treatment of primary palmar hyperhidrosis: a prospective randomized study comparing T3 and T4 sympathicotomy.Abstract 7:OBJECTIVE Endoscopic thoracic sympathetic surgery was effective for palmar hyperhidrosis ( PH ) , but side effects such as compensatory sweating and over dry h and s were common . A multiple centers prospect i ve r and omized study was design ed to compare the efficiency and side effects of T3 and T4 sympathicotomy in the treatment of PH . METHODS From September 2004 to February 2006 , 141 consecutive patients with PH were r and omized into two therapeutic groups : group T3 underwent T3 sympathicotomy ( n=68 ) and group T4 underwent T4 sympathicotomy ( n=73 ) . Improvement of h and sweating , side effects like compensatory sweating or over dry h and s , and satisfactory rate of the patients were recorded . RESULTS There were 78 males and 63 females . The median age was 26.9 years . The two groups were comparable in gender , age , severity of sweating and average period of follow-up . All operations were successful with no severe complications or perioperative mortality . A 17.8+/-7.9 month follow-up showed that palmar sweating improved in all patients and the effective rate was 100 % . Mild moist h and s occurred more frequent in group T4 than in group T3 ( 59.4 % vs 25.8 % , p<0.0001 ) . Most involved patients were ' very satisfied ' with this result except for four patients ( 5.8 % ) in group T4 ; incidences of compensatory sweating and over dry h and s were both lower in group T4 than in group T3 ( 56.5 % vs 77.4 % , p=0.011 and 1.4 % vs 12.9 % , p=0.013 , respectively ) . Moderate compensatory sweating ( CS ) occurred in 14.5 % in group T3 and 2.9 % in group T4 ( p=0.017 ) . ' Very satisfied ' rate was higher in group T4 than in group T3 ( p<0.0001 ) while ' partially satisfied ' rate was comparable between the two groups . CONCLUSION T3 and T4 sympathicotomies are both effective for the treatment of PH . T4 sympathicotomy , decreases the side effects but do not compromise the therapeutic effects , and should be the method of choice

question:You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: ["HealthCareActivity", "InjuryOrPoisoning", "BodySubstance", "IntellectualProduct", "AnatomicalStructure", "SpatialConcept", "Chemical", "Bacterium", "MedicalDevice", "Organization", "BiomedicalOccupationOrDiscipline", "Finding", "BiologicFunction", "Virus", "ResearchActivity", "ClinicalAttribute", "PopulationGroup", "Eukaryote", "BodySystem", "Food", "ProfessionalOrOccupationalGroup"].Please return the output as a JSON object of the format: {"Virus": ["HIV", ...], "Bacterium": ["MRSA", ...], "AnatomicalStructure": ["Lung", ...], "BodySystem": ["CNS", ...], "BodySubstance": ["Serum", ...], "Finding": ["Headache", ...], "InjuryOrPoisoning": ["Fracture", ...], "BiologicFunction": ["Death", ...], "HealthCareActivity": ["Biopsy", ...], "ResearchActivity": ["Clinical trial", ...], "MedicalDevice": ["Lenses", ...], "SpatialConcept": ["Camps", ...], "BiomedicalOccupationOrDiscipline": ["Forensic medicine", ...], "Organization": ["WHO", ...], "ProfessionalOrOccupationalGroup": ["Provider", ...], "PopulationGroup": ["Swimmers", ...], "Chemical": ["Gold", ...], "Food": ["Rice", ...], "IntellectualProduct": ["RPAM", ...], "ClinicalAttribute": ["Biomarker", ...], "Eukaryote": ["Dogs", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].Only output the JSON object and do not include any additional text.Abstract:Proline -rich antimicrobial peptides targeting protein synthesis Covering: up to 2017The innate immune system employs a broad array of antimicrobial peptides (AMPs) to attack invading microorganisms. While most AMPs act by permeabilizing the bacterial membrane, specific subclasses of AMPs have been identified that pass through membranes and inhibit bacterial growth by targeting fundamental intracellular processes. One such subclass is the proline -rich antimicrobial peptides (PrAMPs) that bind to the ribosome and interfere with the process of protein synthesis. A diverse range of PrAMPs have been identified in insects, such as bees, wasps and beetles, and crustaceans, such as crabs, as well as in mammals, such as cows, sheep, goats and pigs. Mechanistically, the best-characterized PrAMPs are the insect oncocins, such as Onc112, and bovine bactenecins, such as Bac7. Biochemical and structural studies have revealed that these PrAMPs bind within the ribosomal exit tunnel with a reverse orientation compared to a nascent polypeptide chain. The PrAMPs allow initiation but prevent the transition into the elongation phase of translation. Insight into the interactions of PrAMPs with their ribosomal target provides the opportunity to further develop these peptides as novel antimicrobial agents.