IntroductionNeurologic activity is mediated by electrochemical signaling pathways that generate an electric charge. These electrical signals generate electromagnetic fields (EMF) that have been found to be measurable through magnetoencephalography and induction sensors. These technologies typically rely on expensive shielding via shielded rooms to remove influence from the external environment. We aimed to investigate the effects of a lightweight shielded helmet constructed of Mu-metal and interlaced copper mesh and Mu-metal EMF “channels” on shielding externally mediated EMF when measuring cortically generated EMF during human activity.MethodsNon-contact, non-invasive, proprietary induction sensors were utilized with a combination of a dual-layer Mu-metal and interlaced copper mesh helmet with sensors placed within EMF channels connected to the helmet. Five human volunteers participated in motor activities, verbalization activities, and visual object naming to evaluate the effectiveness of shielding solely via the helmet and EMF channel construct on generated EMF without placement of individuals within a shielded room. Background data without a subject were obtained.ResultsDifferences in fast Fourier transformed data were noted in the background compared to rest and various activities throughout all trials. There were differences in rest phases and activity phases in each individual identifying active measurement of differences in cortically generated EMF during each activity.ConclusionIt appears that eliminating a Mu-metal shielded room is possible when shielding is isolated to the helmet and EMF channels with induction sensors. The external EMF was appropriately excluded with differences in background data in all trials. During the activity, differences were noted between rest phases and activity phases in all activities noting the discernibility of these induction sensors in measuring cortically generated EMF. Measured activity through motor tapping with changes between 4 and 6 Hz appeared to correlate with previously documented changes during motor activity using these sensors in conjunction with shielded rooms. Measuring the electromagnetic field (EMF) generated by the cortex of human individuals in vivo has become possible through advances in technology -4. EMF sWe have found that it was possible to measure these signals in previous studies using proprietary induction sensors  without the need for these SQUIDs -4. TheseIn our investigations, the usage of a shielded helmet with an EMF channel using proprietary induction sensors was discussed by Brazdzionis et al. . This heTherefore, as this shielding construct appeared to aid in measurements of the generated EMF from significant distances away from the subject, we wished to investigate the efficacy of the induction sensors with the shielded helmet and EMF channel technology on the external environment after removal from the shielded room. In doing so, we wished to evaluate whether the shielded helmet and EMF channel would provide sufficient shielding without a shielded room and outside of a building. External noise and generated signals from the Earth’s magnetic field are thought to provide interference to these sensors without appropriate shielding and would thus impair appropriate data analysis, which would be significantly greater outside a building and shielded room than within it. Therefore, if induction sensors combined with an EMF channel and shielded helmet demonstrate efficacy in shielding, it may be a viable technology to reduce limitations in research related to EMF and MEG technologies that have higher start-up costs due to the need for investments in SQUID-based devices or a shielded room, which can cost hundreds of thousands of US dollars. This may increase access to this technology and its subsequent utilization may increase. Although differing from the induction sensors that are under investigation in this trial, recent studies have begun to investigate non-shielded helmets with OPM-MEG technologies to reduce the need for SQUIDs and with the addition of dynamic field controls and computer suppression of interference to try to minimize associated costs with shielding . InitialTo improve on this novel technology using previously tested sensors, we investigated minimizing shielding by removing the shielded room component and instead relying solely on shielding through a helmet and EMF channel construct. Shielded rooms can cost upwards of hundreds of thousands of dollars, and therefore, the goal was to demonstrate the potential for reduced shielding costs and improved correlation to more expensive shielded rooms beyond that of computational analysis. This may stimulate increased research and evaluation of clinical applications of this EMF-based technology.Institutional review board approval was obtained from Arrowhead Regional Medical Center entitled “In-vivo non-contact remote measurement of neuronal activity” (protocol #: 21-05). A shielded helmet was constructed using dual layers of Mu-metal  separated by 2.5 cm with an inner and outer layer of interlaced copper mesh as demonstrated by Wiginton and Brazdzionis . Holes wIndividual testsFive volunteer adult male subjects all over the age of 18 years were asked to place the helmet on their head and participate in repeated activities to evaluate generated EMF from each subject’s cortical structures during designated activities. Subjects were placed within a fabric tent with the shielded helmet placed on their heads. The helmet was supported via a line and pulley system with suspension from above and support from stands and tripods below to eliminate motion, such as from the wind, during testing as small motions can induce magnetic noise in induction sensors due to sensor motion within the direct current (DC) Earth field. Mu-metal shielded room and Faraday cage were not utilized during testing and instead the shielding for analysis came strictly from the helmet and EMF channel construct. Subjects were asked to participate in several activities using a modification of the reproducible synchronizing stimulus protocol described by Brazdzionis et al. with substitutions of the designated motor activity for the action activity under investigation . This prSubjects were asked to participate in the following activities: right-hand tapping at 2 Hz with the metronome, language activities through verbalization of the English alphabet with one letter per metronome click (120 beats/min), and visual object naming using a deck of cards to name as many cards as possible within the 60-second investigated period. During visual object naming, subjects were asked to minimize motor movement when moving a playing card from the right hand to the left hand after naming a card; however, motor activity was required during the activity. During all trials, the generated frequency and waves were analyzed in real time to evaluate for motion artifact, and if motion artifact was present, the test was repeated from the beginning. Right-hand tapping occurred similarly to protocols described by Wiginton and Brazdzionis . During During verbalization of the English alphabet, subjects remained seated with the arms, sensors, and helmet supported and were asked to recite the alphabet in its standard order at a rate of one letter per 0.5 seconds during the 60-second activity phase of the experiment; the alphabet was repeated from beginning to end throughout the duration of the activity phase. The preceding 30-second rest period and the post-30-second rest period in relation to activity were maintained. Subjects were asked to keep their eyes closed during this trial to minimize visual stimulation.Finally, during visual object naming, subjects were again seated and supported in the same position. Participation was 30 seconds of rest followed by 60 seconds of visual object naming followed by 30 seconds of rest for a total of 120 seconds. The subject was asked to name the card and suit of a playing card in the right hand and pass it to the left hand with minimal movement. Subjects were asked to name as many cards as possible during the 60-second activity period. The metronome was again set at 2 Hz for consistency although the timing was not utilized during this trial.Data analysis and technical specificationsA 16-bit National Instruments Data Acquisition Card and LabVIEW software  were utilized as described by Wiginton et al. [Baseline testing without a subjectInitial baseline EMF data were evaluated without a subject and while outdoors within the tent and suspension construct. Initial baseline waveforms after FFT are seen below in Figure Measurement of generated EMF through motor activitiesEach of the five subjects was instructed to participate in a repeated motor activity through right-hand tapping at a rate of 2 Hz synchronized by a metronome with a preceding 30 seconds of rest period and with a subsequent 30 seconds of rest period after the activity. Baseline rest and tapping data are identified below for each subject in plots of FFT data in Figures When evaluating baseline EMF seen in Figure Measurement of generated EMF through verbalization activitiesEach subject was again instructed to don the shielded helmet and EMF channel construct while within the tent but without the usage of a shielded room. Subjects were each asked to recite the English alphabet (one letter per 0.5 seconds as synchronized with the metronome). Rest phase data and alphabet verbalization data are seen below in Figures Baseline resting data seen in each panel A of Figures Measurement of generated EMF through visual object naming activitiesFinal testing occurred to evaluate the effects of compound activity, particularly visual object naming. Subjects were instructed to visualize and subsequently name verbally as many playing cards as possible from a standard deck of playing cards while moving the cards with minimal movement from the right hand to the left hand. Rest phase data between five and 25 seconds and activity phase data between 50 and 70 seconds were analyzed using FFT and are plotted below in Figures In our final trials on visual object naming, changes between baseline EMF without a subject Figure  were agaThis project evaluated the feasibility of measuring an EMF using induction sensors with a Mu-metal shielded helmet and EMF channels while outside of a shielded room. Multiple subjects and differing cortical activities were utilized to evaluate for differences, if any, in morphologies comparing rest, motor activity, and visual object naming. The results indicate that each activity had demonstrably different morphologies compared to baseline rest activity immediately prior to each activity. Further, the measured EMF at rest and during each activity appeared to differ in each of the five subjects.Due to the effects of the FFT function, changes represent summative repeated measurements in activity. Therefore, increases or changes in activity represent a repeated subset of measured EMF activity during the evaluated period. As each period measured was a 20-second selected bin, the summative total temporal period of measurement did not differ. Further, these changes in summative repeated activity likely represent regions of the brain more actively generating excitatory and inhibitory postsynaptic potentials to create a temporal summation of activity and electrical charges generating an EMF. These changes in activity, therefore, represent areas of cortical activity and the above differences in the FFT curves identify the effectiveness of this prototype helmet with inductive sensors and EMF channels in measuring EMF within the conical region of sensing for each sensor without the need for a shielded room.Previous studies have investigated induction sensors on measured EMF in human subjects participating in motor activities, motor imagery, and emotional thought ,3. ThereEffects of micromotion on induction sensors were previously investigated and evaluated without significant effects on output and measured EMF . HoweverThe potential benefits from limiting shielding to the helmet and EMF channel include potential cost savings due to the usual high costs in the creation of a shielded room. Further opportunity costs for the space required to contain the shielded room are also considered, in that the shielded room takes up a fixed clinical or research space that traditionally is not utilized for other purposes. As this compact, lightweight helmet and EMF channel device appear to appropriately shield, the decreased opportunity costs could promote more easy clinical usage as well as increase research opportunities, as individuals would not have to retrofit their own spaces to conduct evaluations. Since the shielding is constrained to the helmet itself, there is increased portability allowing for transport between locations. In future studies, increased clinical usage through the use of a point of care type helmet or device could be feasible due to this portability. This reduces risks related to the transport of patients for imaging, and as shielding was appropriate in an external environment, it may potentially be beneficial in spaces with other technologies present, such as an inpatient room. Further, portability may also promote increased ease of access to allow for direct comparison with altering modalities such as OPM-MEGs or other MEG devices.Although OPM-MEG devices and other sensor modalities were not utilized in this trial, future studies may attempt to utilize this two-layer Mu-metal shielding with an interlaced copper mesh design and integrate it into alternate sensor modalities to evaluate efficacy in shielding external EMF with these different sensor types during EMF evaluation. It appears that the shielded helmet and EMF channel construct act in a summative fashion for appropriate shielding and measuring. Furthermore, it appears the helmet is a necessary component for shielding as seen in previous trials . The EMFDuring this trial, it was noted that despite nearby moving vehicles and flying aircraft within the proximity of the sensors, there was no interference or artifact seen in real time while the subjects were being evaluated. During other such experiments in this lab, notably by Carson et al., even though mouse hippocampal cells were appropriately evaluated within Mu-metal tubes with air gaps, there was intermittent real-time evidence of outside interference presumably from moving vehicles, lab equipment, large electronics, or aircraft overhead . It is hIn evaluating quantitative metrics, there are noted similarities within this trial compared to previous studies investigating these induction sensors -4. ChangLimitationsThis project was conducted with a small sample size and was conducted on healthy greater than 18-year-old males, which may not represent the overall population. Further, these induction sensors were not compared to MEG technologies to identify temporal relationships between peaks or evaluate signals with known data. Additional studies may be needed to utilize MEG technology and compare it with this novel induction sensor and helmet construct to assist in defining “normal” values for clinical applications. Further studies may also utilize known OPM-MEG technologies with integration into the shielded helmet to see if this shielding is sufficient with alternative sensor modalities.Through evaluation of repetitive motor activities, alphabet verbalization, and visual object naming, it appears that a dual-layer helmet constructed with two sheets of Mu-metal and interlaced copper mesh combined with an EMF channel made of Mu-metal are effective methods of shielding external EMF when measuring the brain's intrinsically generated EMF. It appears that this method is durable enough to promote adequate and appropriate shielding without the need for a Mu-metal shielded room or Faraday shield. This may lead to increased research into EMF and MEG technologies due to point of care ability and increased portability of such devices leading to clinical applications and correlation.


The circadian clock is a time keeping mechanism that drives daily rhythms in the body, including behavior and gastrointestinal digestion, inflammation, and metabolism. These daily rhythms are endogenous to cells, and they must adjust themselves to cyclic environmental cues like feeding schedules and light dark cycles. However, when the cyclical environment is chrono-disrupted (ex. shiftwork and jetlag), the temporal organization in the body is lost. Chrono-disruption is linked to an increase in the risk of Inflammatory Bowel Disease (IBD); studies in rodents shown that IBD is more severe in mice without a circadian clock and intestinal regeneration is compromisedRecent studies have shown that time-restricted feeding , that aligns with circadian behavior improves daily organization in the body and health. Therefore, we hypothesized that time-restricted feeding would be an effective strategy to ameliorate IBD and improve regeneration in chrono-disrupted animals.Bmal1-/-) and controls with an intact clock  and compared ad libitum feeding vs. TRF conditions (food available from 7pm to 7am).To test this, we used the DSS induction of colitis in mutant mice without clock function  and regeneration in the colon. (Hopx). Our results show that TRF increases the number of Ki67 positive cells and the expression of fetal-like regenerative precursor Hopx in both animals with and without a functional clock.Our results show that TRF ameliorates IBD symptoms and protects against epithelium colon damage in animals without clock function. Our preliminary results suggest that TRF may function by increasing the expression of the anti-inflammatory signal PPARg in the colon. Currently, we are testing if the circadian clock controls the daily expression of Together these data suggest that TRF enhances regeneration in the colon after colitis. Moving forward, we are testing transcriptional pathways that are activated during regeneration in animals under TRF. Our results show that time restricted feeding can ameliorate IBD and highlight the role of circadian rhythms in regeneration and intestinal stem cell biology.CIHR, OtherCrohn's and Colitis CanadaNone Declared


As governments impose restrictive policies to contain infectious disease outbreaks, pre-existing gender-based inequalities are often exacerbated, increasing the risk of gender-based violence (GBV). Despite international guidance on the need for continued provision of GBV services during emergencies, governments often de-prioritise GBV services and programmes. We conducted a rapid assessment in South Africa, Kenya, Uganda, and Nigeria to examine the impact of COVID-19 policies on the availability of GBV prevention and response services. The study team interviewed 80 stakeholders representing different GBV services in the four countries. The interviews revealed strikingly similar government mis-steps that disrupted the availability of comprehensive GBV services. In all four countries, the government’s failure to exempt the provision of multi-sectoral GBV services from initial lockdown restrictions led to confusion and disrupted the provision of critical GBV services such as clinical management of rape, legal and judicial services, psychosocial services, availability of shelters, and community-based prevention activities. The government’s imposition of curfews, stay-at-home orders, and transportation restrictions further diminished access to services. Governments must strengthen currently available GBV prevention and response services and be better prepared for future pandemics. Following international guidelines, governments should deem GBV services as essential from the beginning with clear implementation plans. Governments must invest in community-based solutions and the expansion of digital tools to ensure everyone, especially those likely to be structurally excluded, have access to critical services during an emergency. Survivors can face life-long health consequences such as unintended pregnancies, sexually transmitted infections, fistula, pelvic pain, urinary tract infections, poor mental health, and other chronic conditions due to lack of access to timely critical care.6 The Ebola outbreak in West Africa highlighted the negative impacts on women and girls of mobility restrictions, school closures, and de-prioritisation of GBV and sexual and reproductive health (SRH) services.5 GBV increased in the region during this prolonged emergency, while access to GBV services became harder. In the Democratic Republic of Congo, these policies and the environment of fear and isolation during the outbreak resulted in women and girls experiencing increased emotional violence in their homes, and delaying seeking post-rape care.7Pandemics present complex humanitarian crises with impacts that exacerbate pre-existing gender-based and other socio-economic vulnerabilities.8–10 Mirroring earlier pandemics, governments across the globe imposed restrictive policies to contain the pandemic that ignored gender-based vulnerabilities and did not initially deem GBV and SRH services as essential.11 Evidence suggests that in most regions of the world, GBV increased during the pandemic,12–14 while service providers in multiple countries struggled to provide care amidst insufficient resources, lockdowns and mobility restrictions, and de-prioritisation of GBV services in government emergency response plans.15Early reports suggest that the COVID-19 pandemic, like previous epidemics, has exacerbated gender-based inequalities with particularly severe impacts on harder to reach women and girls.16 In South Africa, President Cyril Ramaphosa declared on 13 April 2020 that GBV response services, including shelters, medico-legal services, and psychosocial support, were essential and would remain operational.17 In early April 2020, the Kenyan Ministry of Health released its guidelines for continuing care for sexual, reproductive, maternal, and newborn healthcare needs, which included clinical services needed by survivors of GBV, but other essential GBV services were not mentioned.18 In Uganda, the Minister of Gender, Labour and Social Development called upon all stakeholders in government, civil society, and the community to implement and enforce laws, policies, and programmes aimed at GBV prevention and response on 28 April 2020.19 In Nigeria, while health services were deemed essential, GBV services were not clearly designated as essential, and policies varied across states.20This rapid study investigated the impact of government policies to contain COVID-19 on the availability of comprehensive GBV prevention and response services in South Africa, Kenya, Uganda, and Nigeria during the first six months of the pandemic from March to September 2020. All four countries implemented their first pandemic-related lockdowns and movement restrictions in March 2020, without an explicit declaration that GBV prevention and/or response services would be considered essential and remain available. These countries only included GBV services in their essential services list after public outcry over increasing incidents of GBV surfaced, and their initial efforts were piecemeal and lacked sector-specific guidelines for implementation.21 resulting in an additional 3650 cases of GBV reported from March through July.22 In South Africa, a national counselling hotline called Lifeline SA documented a 500% increase in the number of GBV calls in the two months after the lockdown began.23 In Nigeria, government-collected data from two-thirds of the states demonstrated a 149% increase in reports of GBV from March to April, 2020.24 In Uganda, 3280 cases of GBV were reported to police in April 2020 as compared to a monthly average of 1137 cases in 2019.25As these restrictive policies were being implemented, available information from call centres and hotlines indicated a surge in GBV in these countries. In Kenya, calls to the national GBV hotline increased by 775% in March and April 2020,Clearly, government policies in the early phase of the pandemic narrowly focused on infection control and did not consider the potential impact of the policies on historically marginalised and vulnerable groups such as women and girls. We provide in-depth analysis of the impact of these policies on availability and access to GBV services and programmes at a time of heightened need. For the purposes of this paper, we use the term GBV to indicate violence against women and girls.27 In Uganda and Nigeria, 56% and 36% of ever partnered women respectively had experienced at least one form of IPV over their lifetime.29 Adolescent pregnancies and harmful practices such as child marriage and female genital mutilation also persist in these countries.26–29Even prior to COVID-19, GBV was highly prevalent in the four countries. Most recent pre-COVID estimates from the countries suggest that high levels of intimate partner violence (IPV) were prevalent. In South Africa, 26% of ever partnered women had experienced physical, sexual, or emotional IPV in their lifetime, while the corresponding figure for Kenya was 47%.30–33 In all four countries, plural legal systems create contradictions and inconsistencies through the simultaneous application of statutory, customary, and religious laws  in large urban centres, while in rural areas, survivors lack access due to distance and transportation costs.43 In South Africa, OSCs are more widely available, at least at the provincial level.44 In Uganda, in the absence of investments in OSCs, the government relies on referral mechanisms that are managed by both government departments as well as NGOs providers, but these referral systems tend to be weak in rural and remote areas.42 In Nigeria, only 17 of 36 states have OSCs  that provide free clinical, counselling, and support services to GBV survivors.45 Additionally, despite commitments to multi-sectoral and comprehensive approaches to tackle GBV, de-prioritisation and lack of financial investments have led to a prioritisation of sexual violence and a focus on providing services such as clinical management of rape, over other forms of GBV such as domestic violence, physical and emotional violence, and services such as shelters, other psychosocial services, and prevention programmes. Shelters are primarily run by NGOs and are scarce in Kenya and Uganda, while South Africa has a more robust network of shelters managed both by the government and NGOs but still fell short of the demand for services.44 Despite investments in legal reform and building capacity of police and judicial officials, accessing justice remains a challenge due to corruption, lack of implementation of GBV laws, and inefficiencies of the judicial system.46 Although civil society in Uganda and South Africa have been at the forefront of investing in creative GBV prevention programmes, overall, prevention work remains underfunded across the four countries and does not systematically reach a large majority of the affected population. Due to limited funding, these programmes are often layered over HIV programmes and do not comprehensively address the varied drivers and groups affected by GBV.47Despite policy commitments as described previously, GBV services and programmes were underfunded and de-prioritised even prior to the pandemic. Governments across the four countries largely relied on bilateral and multilateral donors to fund GBV services and programmes. In South Africa, after brutal attacks against women and protests in 2019, the government prepared a plan and allocated funding to address violence against women, which was to be implemented in 2020. The governments use a mix of providers from the government sector to local non-governmental organisations (NGO) and international NGOs to deliver services and programmes. Effectively coordinating between the different sectors and providers has always been challenging, leading to fragmented services, breakdown of referral mechanisms, and variation in service quality based on type of provider and geography. Comprehensive multi-sectoral services with well-functioning referral systems were primarily available in major urban areas, while rural and remote areas had sub-optimal coverage.We conducted a mixed-methods study which included in-depth interviews and online surveys with GBV and SRH stakeholders in the four countries. This manuscript focuses on data from the in-depth interviews conducted with 80 GBV stakeholders, including GBV programme managers, service providers, donors, and government officials . RespondInterviews were conducted remotely  in July–September 2020, using semi-structured interview guides. Interviewers took detailed notes during the interview. Interviews were also audio-recorded with the respondent’s consent. Interviews were not transcribed. The detailed notes were finalised after reviewing the audio recordings. We utilised both inductive and deductive analysis to identify emerging themes. A data matrix was created to examine similar impacts and differing impacts, as well as innovations and adaptations within each service area across the four countries.Verbal informed consent was obtained from all participants. Only study staff had access to the recordings and interviewer notes. The study was determined to be exempt by the Institutional Review Board of Columbia University.Respondents from all four countries perceived that government determination of what constituted essential services, coupled with lockdowns and mobility restrictions, greatly impeded the provision of and access to comprehensive GBV prevention and response services. Our findings outline the impacts of these governments’ policies on critical GBV services and programmes: (1) health services, (2) psychosocial services, (3) shelters, (4) judicial and police services, (4) community-based prevention services, and (5) coordination among these sectors.“There was always difficulty in filling Police Form 3 [forensic exam documentation] in cases of sexual violence because most of the health centers were busy attending to COVID-19 patients or the officers were not available, particularly those qualified to fill the Police Form 3 under law. In most cases it was time to attend to COVID-19.” Additionally, curfews and restrictions on public transportation limited the ability of survivors to visit clinics and receive appropriate medical treatment in a timely manner. Respondents from the four countries described how restrictions on public transportation constrained survivors’ access to medical clinics, especially for those living in rural areas.“We also have challenges in terms of physical visits because some survivors are not able to access the center because of restriction in movement.” All four countries deemed health services essential but GBV services appeared to be de-prioritised. Respondents cited factors that made it hard for service providers to deliver services and survivors to utilise services. Respondents in all four countries described how the government decision to shift health personnel to the COVID response led to fewer available providers to serve the specific medical needs of survivors, including medical forensic exams. In Kenya, health workers overburdened by COVID-19 cases de-prioritised clinical management of rape cases. Survivors who did reach health facilities were sometimes told to return later for care, which some respondents associated with an observed rise in unintended pregnancies. In South Africa, the Department of Health focused on keeping the large public community health centres open, while smaller community clinics closed entirely. As one respondent from a local NGO in South Africa summarised, “everything else that wasn’t COVID-related had to take a back seat.” Respondents in Uganda described how it became even more challenging to find appropriate medical personnel to complete forensic exams  that led to delays in survivors having access to care that would help them with their legal cases.“We never imagined having to respond in terms of this kind of work without being physically present especially in the beginning it was very, very tough … not only because we were not able to be on the ground, the regulations were really unclear around … .who, where, what, all of those things we deal on a day to day basis.” In Kenya and South Africa, respondents described providing counselling services remotely to survivors during the lockdowns. In Uganda, the police department established a new toll-free hotline after women’s rights organisations demanded remote psychological counselling services and general information about violence against women and children be made accessible to the community. Organisations in Nigeria maintained use of a 24-hour helpline, staffed by professional counsellors who worked and received calls from their respective homes.“What happened was that during the lockdown, we had a child Helpline … . So what we did was that we've got our professional counselors taking the phones home so that they will be available 24/7, the work from the phone will be available 24/7, she received calls.” Across the four countries, respondents noted that lockdowns completely disrupted in-person psychosocial services for survivors just as the demand for these services was rising. Many service providers responded to these demands by adapting service provision through use of virtual platforms and other modalities, often without support or guidance from the government.“The majority of survivors are more comfortable with one-on-one counselling. We serve [an informal settlement]. Some do not have access to phones. Survivors may not have airtime and some may be using other people’s phones.” While innovative, many respondents feared these virtual counselling services have limited reach, especially for structurally excluded populations such as adolescent girls and young women because in their setting these sub-populations often found it difficult to access phones or other virtual technology in a confidential and comfortable way.“We did basic Community Health Volunteer training on basic psychological first aid for survivors before they refer cases to health facilities. The challenge is that clients will not believe that a CHV can give professional counselling.” To address these challenges, some organisations in Kenya experimented with utilising Community Health Volunteers (CHVs) to continue providing services to survivors. CHVs were trained to provide psychological first aid in-person during the lockdown and helped refer survivors to health facilities. The approach was successful in serving some harder to reach women, but some respondents feared negative perceptions of services provided by CHVs could hurt service provision in the future.Respondents described stark differences across the four countries in shelter availability during lockdown, citing a mix of factors including government policies, existence of national champions, and pre-pandemic availability of shelters, and prevalence of private vs. public shelters.“It was very encouraging; the Minister of Women Affairs was right at the forefront. It was evident from what she said that she was current with the news that COVID-19 was associated with increased cases of GBV in France, Germany and one particular case in Lagos which really got to her. She then ensured she touched base with us on a weekly basis to know what was going on with the shelter, the number of cases reported as well as needs of survivors and ways they could support such as raising awareness for the needs of rapid response.” In South Africa, the National Shelter Movement as an organisation was proactive in ensuring shelter availability during the COVID-19 outbreak. Partnerships were established with Uber and other private transportation services to ensure survivors had transportation options to access the shelters. Shelters were perceived to be safely run with few COVID outbreaks at the beginning of the pandemic.In South Africa and Nigeria, where stronger networks of shelters existed, respondents noted that shelter services remained operational due to the advocacy and ingenuity of civil society organisations and government officials, among them South Africa’s National Shelter Movement and Nigeria’s Minister of Women Affairs. Although some organisations struggled to have enough space for survivors in shelters, respondents in Nigeria noted that it was helpful that a government official prioritised shelters and understood the needs of GBV survivors.“Most of the shelters are privately owned and when COVID hit, they sent survivors back home because they could not afford to keep them and the ones [shelters] open are not admitting people. Most are supported by individuals.” “If you rescue a survivor, they must have a COVID-19 certificate but it takes 14 days; this is a challenge for us.” In all four countries, transportation restrictions made shelters harder to access. While all survivors were affected by these restrictions, many respondents noted that women and girls living in rural and remote areas were harder hit due to limited public transportation options and lack of shelters in these locations. In South Africa, organisations partnered with Uber to ensure women had safe transportation to shelters.“… remember when they said no more movements, it was very difficult for women in rural areas to access a shelter because remember motorcycles and public transport were banned … overall to be honest all survivors found it difficult to access services and shelters at that time because remember there was no exemption at that time so we could not do anything unless for those ones who lived near the shelter.” Respondents also described the challenges shelters faced in adhering to COVID-19 protocols while simultaneously handling the increases in demand. In Nigeria, some shelter organisations faced financial hurdles adapting to the COVID-19 social distancing protocols, as they had to independently find additional places for survivors and their children or even shelter staff. In Kenya, as demand increased, privately-run shelters struggled to take in additional survivors and worried about not having enough food and medicines for those in their care.“We didn’t have enough shelter to take up the capacity of women coming in at that time, we usually have a capacity of 20 at a time and we had to go way less than that if they had children … We had to bring in additional programmes on board, create emergency housing, book hotel accommodation to stay at least for some days which is outside what we’d normally do which was an additional expense we had to cover. I mentioned that we had to go out every weekend to give out food and medication to women.” “At the beginning, shelter worked well or there were few victims. Now they are full and lack support in equipment and food to feed victims … ” In Kenya, a country with shortage of shelters, shelter availability in the country further suffered when the lockdown was imposed. The lack of state-funded shelters contributed to a gap in protecting women and girls during the pandemic. After announcement of the Government's COVID-19 containment measures, many shelters closed completely. The shelters that remained open were discouraged from taking in new residents by the government’s imposition of medical documentation certifying new residents were COVID-19 free, which was hard to obtain.“The courts of law again weren’t considered an essential service, so they also went into lockdown unfortunately, and when they remembered that, oh they need to try the ones who are breaking curfew and whatever, they pulled them back. But now their priorities were the ones who have faulted the Covid-19 guidelines and other crimes … now the GBV cases weren’t prioritised.” According to respondents across the four countries, the governments shut down the courts either completely or partially, and/or GBV cases were de-prioritised, with other criminal cases taking precedence.“I used to handle 30 cases in a day, now it’s 2–3 cases in a day and what we are doing is just giving dates (for hearings).” In South Africa, courts remained open with reduced staff and in the early weeks largely limited the GBV cases they accepted to those involving a high level of physical violence. This ad hoc process meant that GBV cases the court officials judged not urgent were overlooked, sometimes with harsh consequences.“The courts were only processing protection orders for women who suffered physical violence, they wanted to see blood.” “[One woman] was turned away and she went home and then she and her children were killed by her partner.” Many respondents noted that although across the countries the courts eventually started providing virtual services during the lockdown, for many survivors, access to judicial services continued to be challenging in the absence of supportive resources, especially for survivors with limited resources and lack of digital literacy.“… some [women] don’t know how to operate Zoom or [Microsoft] Teams or a computer, especially for women in remote areas.” In Kenya, only GBV cases involving rape were considered essential; all other GBV-related cases were turned away from court hearings and were instructed to be dealt with at the level of the police, as one court official describes:“Police hid behind COVID, giving permits and everything and not attending to issues of crime and violence against women and girls.” Respondents from the four countries noted that while police services were deemed essential, the police primarily focused on monitoring compliance to COVID-19 protocols and de-prioritised GBV cases. Respondents further noted that in many instances police impeded the ability of providers to provide services and survivors to access services. In the words of a respondent from South Africa:“The major problem is that we have police involved in curfew issues. Most Gender Units are understaffed to respond to GBV … At night victims fear going to the police station due to curfew hours, and people are not supposed to be outside.” Across the countries, GBV survivors also found it hard to access police due to fewer staff at each site, curfews and mobility restrictions, lack of personal protective equipment to enter police stations, and being trapped with their perpetrator. In Kenya, respondents said survivors were afraid to report cases to the police outside of curfew hours due to fear of being harassed or mistreated by police for breaking curfew. Respondents working with female sex workers in Kenya particularly noted police use of curfew violations to harass sex workers who continued to work. Survivors who did access police stations found that police desks specific to gender issues were understaffed as staff were often redeployed to tackle COVID enforcement. Similarly, in Uganda, the critical police division for reporting GBV cases, the Child and Family Protection Unit, was not deemed essential.“Just like anyone else, the lockdown directives just came without giving us time to plan. And then it came with very quick changes of what needed to happen in the community and yet a lot of our work happens in the community. That meant a lot of things and our GBV prevention and response programmes could not continue normally.” According to respondents, community-based GBV prevention activities came to a halt in the first few weeks of the pandemic following government-mandated lockdown policies. Under these circumstances, organisations had to either stop functioning or identify different service provision modalities, which were not always easy, especially without clear guidance or support from the government. With growing need for services, organisations in the different countries pivoted to provide services via virtual platforms, with varying levels of success. Respondents in Uganda described increasingly utilising web platforms like Zoom or Skype to organise and implement their prevention interventions virtually. However, many organisations faced challenges adapting to virtual platforms. For example, organisations with prevention service models that relied on integrated community engagement struggled to plan and adapt quickly, and some were unable to continue delivering services in a new way. As mentioned previously with virtual counselling services, respondents expressed concern that virtual prevention activities did not reach many who lacked access to phones or technology.“We need permits from the (police) commander to do what was previously easy to do. You need transport to carry no more than seven people. Getting venues that are aligned to MOH guidelines. These have been the challenges.” In all four countries, implementing COVID-19 protocols increased the cost of delivering services, with the shift to remote work requiring internet connectivity at home, computers, and other equipment. In Kenya, small community sessions gradually resumed in May 2020, but organisations still faced challenges implementing these interventions effectively, with little support from the government, including having to acquire special permits for events, adjusting typical travel protocols, and generally adhering to the COVID-19 guidelines.“I have got partners now that I have never had before.” “What has helped us to continue, I think, has been partnering with many organisations and trying to support locally based organisations because they then were facing the brunt of the issues.” GBV stakeholders in different sectors in Kenya reported working more closely together than before, with more support and recognition from the government as awareness grew about the scope of GBV during the crisis. In Nigeria, some respondents thought that the shift to using remote platforms for collaborative stakeholder meetings allowed younger organisations to engage more with different GBV partners than when meetings were in person, and increased networking improved these younger organisations’ access to funding opportunities. Improved opportunities to collaborate were highlighted as a positive outcome across the countries.In all four countries, pre-pandemic referral systems depended on GBV providers collaborating and coordinating across sectors to provide a full range of services, with varying success. According to respondents, the pandemic’s increased demand for services galvanised efforts to provide coordinated services and care. In South Africa, respondents reported that their collaborations improved and that relationship-building with other GBV organisations accelerated during the pandemic. Smaller local organisations found more ways to connect with larger NGOs and private foundations during the crisis. This collaboration and the use of virtual platforms led to more partnerships.Our study suggests that in all four countries, the government’s initial response to the COVID-19 pandemic was characterised by similar policy mis-steps that ignored GBV services and programmes and impeded the availability of comprehensive GBV prevention and response services at a time of heightened need for women and girls. According to respondents from the four countries, the initial exclusion of GBV from the respective governments’ essential services list delayed guidance and allocation of resources that were needed for continued provision of comprehensive GBV prevention and response services and created confusion among service providers. Restrictive polices such as curfews, transportation and movement restrictions, and social distancing protocols further compounded both availability and access to services.The study also indicates that even if a sector relevant for GBV services was deemed essential, GBV cases were de-prioritised, and no arrangements were made to ensure access and continuity of services to survivors. For example, although health services were deemed essential in all countries, clinical management of GBV was de-prioritised and confusion persisted over its status. In the initial weeks and months of restriction, GBV-specific activities were ignored in guidance. Health systems made no provisions to ensure survivors could access medical services during periods of mobility restrictions, and often re-assigned staff from GBV services to COVID-19 care. Similarly, while police services were deemed essential, services for GBV survivors were not prioritised. Policing in all four countries focused on ensuring compliance to COVID-19 containment policies, and police officers responsible for GBV support services were often redeployed to that end. GBV health providers and survivors reported abuse and harassment by police for being out after curfew, suggesting that police were not aware that some GBV services were deemed essential.Other critical components of a comprehensive GBV response such as judicial, psychosocial, and shelter services were not always deemed essential at the beginning of the pandemic, and these services were disrupted, causing confusion and distress. Judicial services largely ceased functioning when the initial pandemic restrictions were imposed. As increasing GBV incidence demonstrated need for judicial services, governments in each country made piecemeal efforts to restore services using different modalities. Courts began using remote platforms to continue court hearings using online and mobile technologies but these shifts to alternative platforms were slow. Lack of access to and familiarity with digital tools discouraged many survivors from accessing courts. Psychosocial services also halted as restrictions were imposed, and providers had to quickly adapt to remote service provision as demand for services grew. Both government and NGO providers began successfully using toll-free lines and other virtual platforms to provide counselling and other support services. However, many NGOs felt ill-prepared for the transition, due to funding shortages and lack of appropriate government guidance, and felt overwhelmed by demand for services. In addition, many women, especially girls and young women, were unable to safely use virtual platforms as they lacked telephones or internet access. Availability of shelter services varied across the countries based on civil society or government leadership, as well as availability of shelters prior to the pandemic. South Africa and Nigeria were relatively more successful in ensuring availability of shelters due to a stronger network of shelters, and civil society and government champions. Across the four countries, however, restrictive policies and limited availability of public transportation meant that shelters were harder to access, particularly for those living in remote areas. Shelters also lacked the physical and financial resources to keep up with the increased demand for services.Study findings suggest that community-based prevention activities were hardest hit by the restrictive policies and came to a halt in all four countries in the beginning of the pandemic. As the need for prevention activities become clear, many providers tried to adapt programme activities using virtual platforms. However, some found it hard to absorb the financial cost of remote platforms, and others felt that remote platforms were not appropriate for the kind of programming they were engaged in. Many also realised that these modalities did not work for many of their beneficiaries as they lacked digital literacy and/or could not access technology. To improve the reach of their programmes, some organisations successfully utilised community health workers to continue providing services to those hardest to reach, highlighting the critical need to build capacity of these providers as they are most likely to be successful in reaching structurally excluded populations during times of crisis.49 Lessons learned from humanitarian response have been incorporated into key international guidance on Disaster Risk Reduction and Emergency Preparedness which identifies GBV as a critical aspect of strengthening individual and community resilience.50 Governments should ensure their emergency response plans comply with internationally recognised Minimum Standards for Prevention and Response to GBV in Emergencies.51 Women and girls, including women-led organisations, should be involved in emergency planning so that gendered dimensions of response plans are considered. Governments and donors should earmark funds for comprehensive GBV services and programmes in all emergency response plans. The plans should clearly outline how different components of a comprehensive GBV response, including health, judicial, shelters and psychosocial services, and referral systems, will remain operational amidst stay-at-home orders and other challenges. Anticipating a rise in GBV due to pandemic restrictions and related economic distress, GBV prevention activities should be allowed to continue, and other risk mitigation strategies such as providing cash and food transfers should be implemented.52 Further research is needed to understand why all four governments failed to adequately integrate gender into their national preparedness plans to ensure that GBV services were deemed essential as they rolled out their initial COVID-19 containment policies.The humanitarian community had previously identified the gendered impacts of pandemics from their experience responding to the Ebola epidemics in West Africa and the Democratic Republic of the Congo.54 Guidance from the humanitarian community included suggestions for non-specialist GBV actors to assess GBV-specific risks related to COVID-19 response in their sector to ensure continued access to coordinated services.55 In areas with active SRH and GBV sub-clusters in the humanitarian response, GBV programmes adapted more quickly than national actors to ensure GBV services continued. For example, safe spaces for women and girls in Dadaab and Kakuma refugee camps remained largely operational with adaptations to take into account social distancing by reducing group sizes and staggering times for activities.56 One strategy implemented in north-east Nigeria converted safe spaces into tele-health centres with individual phone booths, respecting infection prevention protocols, that women could use to contact GBV case managers.57 In Uganda, UNHCR established a call centre with trained counsellors speaking 15 languages to manage a helpline for GBV survivors.58 Overall, funding did not increase, and in some cases, was shifted to COVID efforts, preventing organisations from scaling up to meet the increased demand.56 Despite the learning and efforts of the humanitarian sector, the international community largely failed to put recommendations into practice when COVID-19 hit.59GBV experts in the humanitarian community, including the GBV Area of Responsibility and the Inter-Agency Working Group on Reproductive Health in Crises, quickly released guidance to mitigate GBV risks within COVID-19 response.To our knowledge, our study is among the first to comprehensively document how COVID-19 containment policies impacted availability and access to multi-sectoral GBV prevention and response services across four African countries in the beginning of the pandemic. We collected rich qualitative data from 80 GBV stakeholders representing service providers, programme managers, and government officials across different GBV sectors. The study has limitations that should be considered when interpreting results. Interviews were conducted with a convenience sample of GBV stakeholders. Although multiple efforts were made to contact key stakeholders, it is possible that those who were highly impacted (and very busy) were unable to respond. Similarity, while we tried to get representation across geographies, many respondents lived in the capital or other major cities. We were unable to secure interviews with government officials in all the four countries, which further limits the interpretability of our results. We also wanted to acknowledge that while this did not impact the quality of our findings, we decided not to seek local IRB review in each of the countries and only sought IRB approval at the global level because of the nature and goals of our study. Our study was conceptualised as a technical consultation with GBV and SRH stakeholders to provide rapid usable information about the state of GBV and SRH services to advocacy groups on the ground. After consulting with in-country partners, we concluded that going through local IRB review processes in the middle of the COVID-19 pandemic would unnecessarily delay the consultations and reduce the value of the material for groups on the ground. At the global level, Columbia University’s IRB declared the study as exempt research as participants were speaking in their professional capacity and drawing on their knowledge and experience of working in the GBV/SRH spaces and were not being asked to share personal information or personal data. Despite the exemption, we obtained informed consent from all participants, and all data were de-identified to ensure confidentiality and privacy of participants.60 The pandemic has also highlighted the potential and limits of technology for continuing service provision given the digital divide, and the critical importance of building community-based platforms for reaching structurally excluded populations. Countries should continue to invest in community-based institutions and make concerted efforts to expand digital literacy and access to digital tools to ensure that critical services are available to everyone, even those hardest to reach.Our study suggests that the COVID-19 pandemic put tremendous stress on already weak GBV prevention and response systems in the four countries. Hence, beyond pandemics, greater national and donor investments in GBV prevention and response services are greatly needed to strengthen fragmented GBV prevention and response systems in the countries and ensure their sustainability. Fully implementing existing GBV legislation and policies and addressing gaps in legal and policy frameworks, giving greater leadership roles to GBV providers in policy design and implementation, strengthening and expanding multi-sectoral services, and establishing effective coordination between sectors, can greatly improve the quality and availability of GBV services. Governments and development actors should learn from the ability of humanitarian actors to transition quickly. Investments in gender transformative interventions and women’s empowerment are also needed to tackle the root causes of GBV and prevent it from occurring.


Finding definitive examples of such a response in fossil time series has proven challenging, however, as has controlling for the effects of a changing physical environment. We take a novel approach to this issue by quantifying variation in trait values that capture almost the entirety of function for steam locomotives (SL), a known example of competitive exclusion from material culture, with the goal of identifying patterns suitable for assessing clade replacement in the fossil record. Our analyses find evidence of an immediate, directional response to the first appearance of a direct competitor, with subsequent competitors further reducing the realized niche of SLs, until extinction was the inevitable outcome. These results demonstrate when interspecific competition should lead to extinction and suggest that clade replacement may only occur when niche overlap between an incumbent and its competitors is near absolute and where the incumbent is incapable of transitioning to a new adaptive zone. Our findings provide the basis for a new approach to analyse putative examples of competitive exclusion that is largely free of  While a reciprocal, contradictory response by two functionally similar and overlapping clades has typically been invoked as evidence of antagonistic clade displacement, confirming that a correlative or causal relationship exists between time series remains problematic . Entireli) functional trait data relevant to survival of individuals within the extinct clade can be quantified; these data are important, as existing theory predicts displacement of traits that impact resource use due to competition between one or more overlapping species [ii) direct competitors have been identified that overlap spatially, temporally and in their resource requirements [iii) a complete (birth to death), well-constrained time series is available for the extinct clade, where the vast majority of individuals that make up the extinct clade are known; at a minimum, the date of first appearance for relevant competitors must also be known; and (iv) non-competitive factors  do not apply or are irrelevant. Arguably, identifying fossil clades that adhere to these four criteria ranges from highly refractory to impossible, with criterion (iv) particularly problematic.We propose several key prerequisites  needed f species ,20; (ii)irements ; (iii) aWhile there have been previous attempts to generate theoretical predictions of the expected patterns arising from interspecific competition ,21, moreCompetition and extinction are phenomena that extend beyond the biological realm and previous studies have demonstrated how both can apply to well-recognized commercial, cultural and technological entities –27. Thisi–iv) for identifying interspecific competition, we consider functional trait data for SLs using a quantitative framework, evaluating if functional trait values exhibited directional shifts as competitors first appeared, or whether any shifts are better explained by other factors considered relevant to SL production but not related to competition. We examine these results in light of the principles of competitive exclusion and conclude with a discussion of the implications of our results for macroevolutionary studies.We assess the impact of direct competition on the SL throughout its lifespan with the aim of identifying diagnostic patterns relevant to presumed examples of competitive exclusion and associated extinction in the fossil record. After first verifying how SLs satisfy our criteria  is applicable to SLs.The primary function of a locomotive is to move a train of railroad cars, whether that train be composed of goods wagons (freight) or passenger coaches. To do so, a locomotive must generate sufficient force to overcome the drag imposed by the train it is pulling or pushing. The force a locomotive is capable of generating is encapsulated by a parameter known as tractive effort (TE) ,34. Becaii). All locomotive types compete for the same primary resource (passengers and freight), their capability to do so is captured by the same functional trait (TE) and spatial overlap is total, all utilizing railroad track, with the caveat of overhead wires or an electrified third rail as an additional requirement for electric locomotives. The third competitor for SLs is motor vehicles (e.g. automobiles and trucks) [Production and maintenance of any land transport technology will only continue while the benefit-to-cost ratio for that technology to move passengers and/or freight is equal to or greater than existing alternatives . Any com trucks) . Despite trucks) . A decliiii). Issues such as provincialism, preservation potential and taxonomic inconsistencies can make overlap difficult to establish for fossil taxa [iii).When attempting to determine if interspecific competition is a primary driver of an extinction event, it is necessary to establish overlap between the competing clades and demonstrate a relevant transformation in the clade (such as character displacement) that has putatively been driven to extinction by competitive forces during the period of overlap, i.e. criterion (sil taxa . By contiv)'s veracity in the case of SLs is well supported by historical data (e.g. [Criterion (ta e.g. –32). Non. Noniv)'ta , we employ the simplifying assumption that competition was initiated once the competitor was produced/employed in a commercial context or readily acquired in the marketplace, and thus actually competing with steam locomotives for the same resources (transportable passengers and freight). In the case of electric locomotives, a term used herein to capture all forms of electrified light and heavy rail, we use the completion of the first electric tramway constructed in a major metropolitan centre, the Gross-Lichterfelde Tramway, which began service in 1881 [sensu [To determine the first appearance dates for known SL competitors  events a priori assumptions about the form of nonlinearity, MARS can serve as a neutral model to identify potential changes in trend direction and slope. Because a number of cut-points in the resulting hinge function may contribute little to model accuracy, model fit was assessed using k-fold cross-validation (k = 10), with the asymptote of R2 used to determine the number of knots to be retained. MARS models were implemented using the earth package for R [Initial assessment of TE data was undertaken by generating hinge functions using multivariate adaptive regression splines (MARS), a non-parametric regression method developed to model high-dimensional nonlinear data while avoiding overfitting . With noge for R .paleoTS package for R, using the standard protocols outlined by Hunt [Random walk models previously applied in macroevolutionary studies –58 provi by Hunt ,57. Beca by Hunt ,58, this by Hunt .To assess how results for SLs may inform analyses of competitive exclusion for fossil taxa, maximum, mean and minimum body size for the Borophaginae, a subfamily of the Canidae purported to have been competitively displaced in North America by multiple carnivore clades, were calculated using data from .. 4a). These shifts can be attributed to increasing electrification of suburban commuter routes, where lower TE values were sufficient, and increasing demand for high-speed intercity passenger and freight services, tasks both requiring higher TE values [The appearance of direct competitors results in measurable displacement of SL functional trait values figures  and 2. Tfigure 2E values .Figure a). The cut-point for minimum TE in 1921 (b), however, is probably due to competition from motor vehicles. Rail passenger numbers in North America and Europe sharply declined in 1921, corresponding with a rise in motor vehicle usage . This sudden preference for motor vehicles is due to the development and expansion of highway networks in the 1920s [2c) also probably represents a lagged response, specifically to the dieselization of rail networks. Diesel possessed multiple advantages over steam [The emergence of subsequent competitors initially had a lesser impact, with only an increase in the rate of positive change for maximum TE coincident with the first appearance of the motor car a. The cu in 1921 b, howevehe 1920s , allowiner steam , but warer steam . With ther steam .sensu [sensu [The peak in maximum TE coincides with nationalization of US railroads during WW1 . Nationasensu ,64) and u [sensu ), with Tu [sensu .Unlike competitive factors, non-competitive contingent events had limited impact on SL TE values. Economic depressions caused only brief declines in mean TE and both World Wars coincide with a sharp, but short-lived, increase in mean TE . These esensu [The results of our analyses provide the basis of a model suitable for identifying when interspecific competition is the primary driver of extinction . In the sensu ,64), witsensu  through sensu . Becausesensu , and evesensu , extinctidentical niches cannot coexist indefinitely. The extinction of the SL may only have come to pass because the niche overlap between steam and competing technologies far exceeds the maximum allowable overlap for two clades to coexist [We do not mean to imply that the above scenario represents the only means by which competitive exclusion can drive a clade to extinction, or that competition for the same resource pool must result in extinction. Support for character displacement is generally confined to animal groups, specifically carnivores  and the  coexist  and SLs  coexist . Figure  coexist  may thusa priori, but only that a putative one exist. While directional change in the mean trait value need not be indicative of interspecific competition when identified in isolation, when considered in light of the full spectrum of variation [The proposed model we present herein both establishes that the impact of competition on functional traits can be essentially immediate and provides a previously unlooked-for pattern to investigate clade replacement in the fossil record by focusing on functional traits that can be measured for fossil organisms, such as body size and metabolic rate . The immariation , such chariation . Multiplariation .Comparison of our results with a fossil example of putative competitive exclusion, specifically competition between subfamilies in the Canidae in North America, affirms that the patterns we identify for SLs can be observed in natural systems where competition between clades is considered significant . The onsOur results thus cannot, at this time, resolve what role, if any, competition plays in driving extinction at the macroevolutionary scale. They do, however, provide a path forward that may serve to resolve the issue by addressing the existing impasse in identifying causal relationships in fossil time series . There i


Chromosomal fragile sites are specific regions of the human genome that are normally stable, but exhibit breaks or gaps on metaphase chromosomes under conditions of stress. As an important source of genome instability, fragile sites are associated with human diseases such as cancer and mental retardation. In this Research Topic, we collected nine contributions from different perspectives, which cover the features and causes of fragile sites, the characterization of fragile sites, as well as the cellular mechanisms at play to maintain their stability.Lokanga et al. summarized recent work about CFSs and RFSs and discussed the similarities and differences between them. CFSs are an intrinsic part of normal chromosome structures and are present in all individuals. Moreover, CFSs are appeared to be conserved throughout mammalian evolution, for example, human FHIT/FRA3B and mouse Fhit/Fra14A2 are orthologs. RFSs are found in a minority of the human population and are inherited in a Mendelian manner. They are often associated with the expansion of repeat elements. RFSs can be further categorized into two groups: folate-sensitive RFSs that are highly sensitive to folate deficiency, and non-folate-sensitive RFSs that are induced by distamycin A or bromodeoxyuridine (BrdU). As the feature of folate-sensitive RFSs, CGG trinucleotide repeats (TNRs) could form secondary structures and perturb DNA replication, thus contributing to their fragility. Garribba et al. tested whether folate deficiency could cause instability at other genomic regions containing CG-rich repeat sequences and showed that a region at Chr2p11.2 displayed an unusual conformation under folate deprivation, leading to the mis-segregation of this locus and Chr2 Aneuploidy.Based on the frequency of fragility, fragile sites are generally categorized as common fragile sites (CFSs) and rare fragile sites (RFSs). Balzano et al. assessed CFS expression in human glioblastoma cell lines and found two CFSs that are specific to glioblastoma. They also showed that the fragility of these sites is related to impaired DNA replication. As the major cause underlying CFS fragility, replication stress can arise from various sources, such as oncogene activation, nucleotide depletion, and Transcription-Replication Conflicts (TRCs). A large majority of the highly expressed CFSs host large genes spanning over megabases and transcription-associated replication stress has been proposed as the prominent mechanisms leading to fragility at these large genes. Transcription can either suppress replication initiation to generate large regions that are poor in replication initiation or can generate direct collision with DNA replication machinery. Wu et al. reviewed recent findings on how conflicts during transcription and replication affect chromosome fragility. This mechanism is also supported by the recent study of Munk et al., who deleted 80 kb intron sequences of an extremely large gene PRKN and showed that this deletion resulted in a twofold reduction of the PRKN fragility without affecting its expression. The mechanism underlying CFS fragility is not restricted to TRCs. Other features of CFSs such as late replication timing, DNA secondary structure formation, and chromatin modification, can also lead to replication stress and contribute to their fragility. Kodali et al. compared the epigenomic signatures associated with spontaneous and replication stress-induced DNA double-strand breaks (DSBs) and demonstrated the correlation of aphidicolin-induced DSBs with histone 3 lysine 36 trimethylation, which is a marker for active transcription. More interestingly, their result suggested that DSBs were not enriched in the CFS core sequences and rather demarcated the CFS core region. Their analysis suggested that altered replication dynamics are responsible for CFS formation under a relatively higher level of replication stress.Although human CFSs have been primarily mapped in lymphocytes and fibroblasts, it has been shown that different CFSs are expressed in different cell types at various frequencies. Characterization of CFSs in other cell types and investigation of CFS expression in different genetic backgrounds are, therefore, important for us to understand the basis of their fragility. In this Research Topic, Yue et al. The Bloom syndrome DNA helicase BLM belongs to the RECQ family and has been shown to participate in fork restart. Here, Ellis et al. showed that RNF4 facilitates replication fork recovery by regulating BLM. Stalled forks that failed to restart will collapse and use the DNA damage repair (DDR) pathway to recover. Niazi et al. identified 14 DNA repair genes that are associated with chromosomal aberrations, further emphasizing the importance of DDR in promoting genome stability. Deficiencies in DNA damage mechanisms are, therefore, an important source of genome instability and render cells more sensitive to replication stress.Cellular pathways and signaling components that are involved in mitigating replication stress are important to maintain genome stability. In response to replication stress, the stalled replication forks require stabilization and remodeling to facilitate fork restart. Many proteins that participate in these processes have been shown to affect CFS expression, such as ATR, DNA-PKcs, and some DNA helicases. The function of DNA-PKcs in DNA replication stress is reviewed by Our understanding of the mechanisms governing chromosomal fragile sites is constantly evolving. In addition to clearly defining the current state of the field, the articles included in this Research Topic present valuable novel insights into the determinants of chromosomal fragility, which contribute to many human diseases.


Noise-induced hearing loss (NIHL), caused by direct damage to the cochlea, reduces the flow of auditory information to the central nervous system, depriving higher order structures, such as the hippocampus with vital sensory information needed to carry out complex, higher order functions. Although the hippocampus lies outside the classical auditory pathway, it nevertheless receives acoustic information that influence its activity. Here we review recent results that illustrate how NIHL and other types of cochlear hearing loss disrupt hippocampal function. The hippocampus, which continues to generate new neurons (neurogenesis) in adulthood, plays an important role in spatial navigation, memory, and emotion. The hippocampus, which contains place cells that respond when a subject enters a specific location in the environment, integrates information from multiple sensory systems, including the auditory system, to develop cognitive spatial maps to aid in navigation. Acute exposure to intense noise disrupts the place-specific firing patterns of hippocampal neurons, “spatially disorienting” the cells for days. More traumatic sound exposures that result in permanent NIHL chronically suppresses cell proliferation and neurogenesis in the hippocampus; these structural changes are associated with long-term spatial memory deficits. Hippocampal neurons, which contain numerous glucocorticoid hormone receptors, are part of a complex feedback network connected to the hypothalamic-pituitary (HPA) axis. Chronic exposure to intense intermittent noise results in prolonged stress which can cause a persistent increase in corticosterone, a rodent stress hormone known to suppress neurogenesis. In contrast, a single intense noise exposure sufficient to cause permanent hearing loss produces only a transient increase in corticosterone hormone. Although basal corticosterone levels return to normal after the noise exposure, glucocorticoid receptors (GRs) in the hippocampus remain chronically elevated. Thus, NIHL disrupts negative feedback from the hippocampus to the HPA axis which regulates the release of corticosterone. Preclinical studies suggest that the noise-induced changes in hippocampal place cells, neurogenesis, spatial memory, and glucocorticoid receptors may be ameliorated by therapeutic interventions that reduce oxidative stress and inflammation. These experimental results may provide new insights on why hearing loss is a risk factor for cognitive decline and suggest methods for preventing this decline. Intense noise primarily damages the sensory hair cells and spiral ganglion neurons; their destruction reduces the flow of acoustic information to numerous structures within the central auditory pathway as well as other parts of the brain that utilize auditory information to carry out complex processes such as formulating an emotional response to a baby’s cry, reacting viscerally when called to supper or exiting a train when your station is announced over the intercom. In order to respond effectively in these situations, the neural activity relayed through the ascending auditory pathway must be quickly and continuously integrated with information being processed in other parts of the brain such as those involved with motor control, cognition, emotion, and memory.The hippocampus is generally considered as a structure involved in the formation of new memories, cognitive maps, and spatial navigation. Although the hippocampus lies outside the classical auditory pathway, it nevertheless responds to sound , generating recurrent negative feedback inhibition that dampens the activity of the pyramidal cells. Neurological conditions that reduce recurrent inhibition from the basket cells can lead to hyperactivity in pyramidal cells resulting in epileptic seizures and hippocampal sclerosis  if the current tone was the same as the previous tone Sakurai, . AlternaHippocampal place cells preferentially fire action potentials when an animal enters a specific location in its environment. The specificity and reliability of place cell firing is affected by information gleaned from external and internal sensory cues acquired by navigating through the environment on multiple occasions. Place cell performance is often evaluated in rodents using an eight-arm radial maze with food bait placed in one or more arms of the maze. While traversing through the maze, olfactory and somatosensory systems provide useful proximal cues while vision provides distal information  revealed significant cognitive impairments on the Morris Water Maze test several months post-exposure , a prolonged increase in synaptic strength that occurs following repeated stimulation of a synapse such as the Schaffer-CA1 or perforant-dentate synapses. LTP has been considered a form of synaptic learning and memory. Repetitive auditory stimulation can influence hippocampal function  is likely to cause significant hearing loss and hair cell damage  is repeatedly turned on (4-h) and off (20 h) for 30 days, CORT levels are chronically elevated. CORT levels are the highest 30 min after the noise is turned off on day1 . CORT meThe consequences of persistent exposure to intermittent noise are illustrated by a study in which rats were exposed for 15 days to 100 dB SPL noise for 2 h/day. The rats were then evaluated 15-days post-exposure when they exhibited a relatively mild NIHL  is expected to surge creating tremendous social and economic burdens  increases in Aβ and amyloid precursor protein in the rat hippocampus after chronic noise stress (100 dB SPL, 4 h/day, 28-days; Cui et al., While this review has focused on NIHL as a disruptor of neurogenesis and memory, other types of peripheral hearing losses that deprive the hippocampus of auditory information might be expected to have similar effects. Indeed, clinical studies indicate that prolonged conductive hearing impairment in early life contributes to chronic auditory processing deficits, poorer social skills, language, reading, and cognitive deficits (Zinkus and Gottlieb, Clinical reports suggest that temporary conductive hearing loss in early life, when the nervous system is rapidly developing, could contribute to permanent cognitive and memory deficits (Reichman and Healey, in vivo to rodents robustly suppressed cell division and neural progenitors in the dentate gyrus. Cisplatin also damaged synapses, increased pro-apoptotic gene expression and enhanced cell death for at least 6 weeks following treatment (Dietrich et al., Many drugs used clinical to treat cancer such as platinum-based antitumor drugs or life threatening bacterial diseases such as aminoglycoside antibiotics are ototoxic Rybak, . These dOther ototoxic drugs such as the aminoglycoside antibiotics induce serious side effects such as nephrotoxicity, neurotoxicity, anemia, and thrombocytopenia (Snavely and Hodges, If NIHL and other forms of peripheral hearing loss impair memory and increases the risk of dementia, then hearing restoration could conceivably slow or reverse these losses. Among elderly patients with profound postlingual deafness, only 25% had normal cognitive scores prior to cochlear implantation (Mosnier et al., Hearing aids assist individuals with moderate hearing loss to understand speech in quiet and noise by reducing the cognitive load (Glick and Sharma, Although there is considerable interest in identifying pharmacological interventions to prevent dementia and AD, life style changes in the form of increased physical activity may offer significant benefit. Exercise greatly enhance neurogenesis, learning and memory in animal models (van Praag et al., The animal studies discussed in this review indicate that chronic or acute noise exposure can suppress hippocampal neurogenesis and impair spatial learning and memory, but further work is needed to address a number of important questions. In cases of significant permanent NIHL, the literature indicates that these deficits persist up to 3–4 months post-exposure, but longer duration studies are needed to determine if these deficits continue or improve with longer recovery times. If the deficits get worse over time, then it would be important to evaluate potential mechanisms that contribute to this decline and to identify therapeutic interventions to prevent this.The noise-induced disturbances in place cell function  represenBecause many urban environments are characterized by moderate intensity intermittent and unpredictable noise exposures that cause little threshold shift, it would be important to determine if prolonged exposure to such noise permanently disrupts neurogenesis, learning and memory. Indeed, there is growing interest in noise-exposure that cause little threshold shift due to synaptopathy that reduce the flow of auditory information to the central nervous system (Kujawa and Liberman, An important clinical question is whether the noise-induced disruptions to neurogenesis, learning and memory can be reversed by increased physical activity, an enriched environment or pharmacologic interventions and if so, what is the optimal time to do so. These and other related questions provide a framework that could be addressed in future preclinical studies.SM, DD, and G-DC: conceptualization, visualization, and writing. LL, JW, Y-CC, and LC: conceptualization and writing. RS: conceptualization, visualization, writing, and funding acquisition. 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.