Intimate Partner Violence (IPV) refers to behavior by an intimate partner that can cause physical, sexual, or psychological harm; is a common global public health issue requiring immediate attention. IPV is the most common form of violence in rural areas of Punjab, Pakistan.This qualitative phenomenological study collected 46 in-depth interviews from married women who experienced IPV in the rural areas of South Punjab. A semi-structured interview guide was used for data collection. These women were selected through a snowball sampling technique from October 2018 to March 2019. Researchers accessed the study setting with the help of gatekeepers . The interviews were audio-recorded in the local language (Saraiki) and were translated into English. The data were analyzed using the thematic inductive analysis technique.run-mureed, watta-satta, beghairat, izzat, etc.) that are ubiquitous in the local context that sometimes intensifies IPV in the family and community sphere. Furthermore, the study discussed how gender-based inequalities trigger a status quo that ultimately creates power discrimination between spouses, which perpetuates violence in the domestic context.The study has presented multifaceted factors of IPV by using the socio-ecological framework in rural areas of South Punjab, Pakistan. The current study introduced culturally contextualized terminologies of "protection," "physical submissiveness," "mental delicacy," and "social security". For married women, culturally embedded terms became the primary cause of IPV. In addition, the study also highlighted some of the cultural terminologies (such as Gender-prejudiced roles and expectations imposed by orthodoxy, misinterpretations of Islamic teachings, and dominant patriarchy can be contested through awareness campaigns among the public, and gender sensitization drives among public institutions of police and judiciary. Education and employment-based can lead to women's empowerment and help to challenge the orthodox anti-feminist societal norms and the role of kinship-based networks in the family and community sphere.The online version contains supplementary material available at 10.1186/s12905-022-02095-0. Intimate Partner Violence (IPV) is a common global public health issue requiring immediate attention . AccordiIPV has substantial consequences on women's physical, mental, and reproductive health , 7. In aThe prevalence of IPV against women in the domestic sphere has increased since the 1960s due to the complex role of women . The lifThere is a lack of direct access to the data on the socio-cultural dynamics of IPV in the domestic sphere of South Punjab. The region has rigid cultural values in which family structures are embedded. Most women lack control over domestic situations, and significant vulnerabilities establish the fertile ground for discordant power-sharing. The geographical locality of South Punjab has the cultural context of male supremacy where men have complete control over different household matters. With its unequal and hierarchical structures, patriarchal culture supports the men and their dominancy over the subordinated women.The previous theoretical feminist regimes in the field have had a limited focus on the individual and cultural causes of IPV. The feminist analysis emphasizes the extensive efforts of gender and power in which the socio-cultural dynamics of IPV are discussed. The associated solution requires social and cultural transformation to promote women's empowerment and equality. The present research attempts to disentangle IPV from normative cultural patterns through women's lived experiences and perspectives of IPV and has documented the socio-ecological dynamics of IPV in rural areas of South Punjab, Pakistan.A qualitative phenomenological research design was used to carry out the current research. Phenomenology focuses on and describes the common meanings for several individuals of their lived experiences of a concept and social phenomenon , 28. ThiSouthern Punjab, Pakistan, comprises 11 districts, i.e., Multan, Dera Ghazi Khan, Layyah, Vehari, Bahawalpur, Rahim Yar Khan, Khanewal, Rajanpur, Lodhran, Muzaffargarh, and Bahawalnagar. This area comprises 32 percent of the population of Punjab province. The local language of this study area is Saraiki. A total of 46 in-depth interviews were conducted in 4 districts. Two villages were selected from Multan and Lodhran districts, while one was selected from Khanewal and Vehari districts. The detailed procedure and sample selection are mentioned in Fig. The inclusion criteria for study participants included women who experienced IPV (i), were living with their spouse (ii), and agreed to participate voluntarily in this study (iii). To reach out to these women, the researchers sought the help of gatekeepers [Lady Health Workers (LHWs) from community health programs in their respective villages] to identify and recruit the participants. The close interaction with women in their catchment area (i), knowing the dynamics of family affinity (ii), and their easy access to each household (iii) were several reasons to approach the LHWs as the gatekeepers to recruit eligible participants. In addition, most families where women experienced IPV are known to the LHWs, who usually provide primary health care services at the household level. Therefore, LHWs were approached at the first stage to identify the households where women experience IPV. After identifying the concerned families, the LHWs facilitated arranging a meeting with the participants.Consequently, a total of 63 households were identified by the LHWs, and 58 women were approached with the help of LHWs. During the meeting with the identified women, researchers screened 52 women who disclosed that they experienced IPV. Unfortunately, six women (11.53%) refused to participate in the study because they were scared of their spouses and were unwilling to reveal their household matters. Therefore, N = 46 women who experienced IPV and gave their consent to participate in the research were approached.The authors developed a semi-structured interview guide for data collection  age of husband and wife (ii) lower education level of husband and wife (iii) lower income level of husband (iv) husband usage of mild drugs, alcohol consumption and engaging in gambling activities (v) sex order of prior children and fecundity of wife as well as (vi) psychological problems among husbands.watta-sattawatta-satta marriage (exchange marriage) due to her increasing age, average beauty, and clumsy body. She shared her viewpoint with a saddened expression.In my marital life, I think constant battering is a normal phenomenon because my husband was forced to get married to me.The age of the husband and wife was the salient contextual factor that provoked IPV in the domestic sphere. The victimized women disclosed three situational age dynamics such as (i) when the husband and wife both were teenagers, (ii) when a wife was a teenager and the husband was more than ten years older than her, and (iii) when a wife was more than 30 years old and husband was younger than the wife  than their wives became less exposed to IPV. The primary reasons were face beauty, objectified body consciousness, and fecundity of the younger wife. The most self-justifying phrases about the young wife were "younger bride will remain beautiful," "she will not get clumsy even after reproducing children," "she can reproduce more children due to her younger age," and "she can reproduce more sons due to her biological capacity to reproduce." Likewise, the findings revealed that IPV reduced with the increasing age of husband and wife as the children also grew older.demaghi fatoorSince childhood, we (sisters) are socialized to stay away from education and to think about our marital life. Marital life means to comply with husbands and "say yes" to their mild and life-threatening violent acts.The lower education level of the husband and wife elicited IPV within the domestic milieu. The participants blamed how their parents intentionally kept them uneducated to subjugate their self-esteem to their husbands. Moreover, the study conceptualized that a higher level of education would be more destructive for wives due to the following reasons: cognizance of marital rights, awareness about reproductive rights, economic independence, and deliverance from forceful wedlock. To this connection, some participants revealed that education was perceived as domination and subjugation of spouses" in the domestic context.Contrarily, the husband's low educational level was also dangerous for the wife. The victimized participants put forth the subsequent aftermaths of husbands' low education: lack of awareness about the marital rights of the wife, loss of civilized manners to maintain the peaceful marital environment at home, perceiving IPV as their fundamental right against their wife, execution of IPV as a symbol of male dominancy, belief that IPV is a mandatory act to maintain the status quo of patriarchy in wedlock and perpetration of IPV to satiate the manly expectations of society for the husband. Therefore, a lower education demonstrated a conflict between "Evidently, in the family sphere, the financial matters look like petty issues, but in fact, these are the real pre-conditions of IPV. Whenever my husband gets some extra money, then his mood swings, and I feel secure from his violent acts and abusive language.The findings revealed that women who experienced IPV had low household incomes. Financial hardship makes it hard to meet household utilities that, in turn, create tensions, frustrations, and quarrels between husband and wife. As wives were expected to tolerate marital disagreements and clashes, they had to surrender their arguments. Conversely, husbands vent their frustration on wives in the form of mild or brutal acts of violence. A young married bride who was beaten many times by her husband due to minor household-based financial problems shared her personal experiences.Contrarily, the arguments of victimized women whose husbands were in better economic condition disclosed less exposure to IPV acts. For example, the husbands who owned some agricultural land had better income levels , and they were less inclined towards IPV acts. Moreover, the working women supporting their husbands were also less exposed to IPV.man has every right." Fourteen victimized women gave a consensual argument that their husbands frequently beat them due to alcohol consumption, and eight battered participants verified that their husbands did not frequently drink alcohol. Still, they were engaged in parchi juaI was frequently battered by my husband as he was occasionally drunk at the gambling place. Once I asked him to avoid drinking and gambling, he has beaten me so severely that I was hospitalized for several days.The victimized women reported that their husbands frequently use drugs and consume alcohol. Resultantly, they (husbands) lost their senses and used IPV against them (wives). These two allied traits were the "mannish personality of husband." Even mothers knew about the unethical activities of their sons. Still, they always justified it with the phrase "mujraa dance party or performance by a woman or transgender). This dance party was arranged to celebrate the groom's last night "as a bachelor." A newly married bride said she was beaten on the first wedding night because he was drunk and out of his senses. This argument was also endorsed in two interviews.The battered participants also revealed that it was usual practice that the groom's friends arranged a bachelor's party on his wedding night. At this party, the married and unmarried men, along with the groom, consumed alcohol, showed off their weapons, and watched reproduction of sons." Daughters signify social insecurity for parents, while sons have a higher place in rural social stratification. The pre-conditions of the sex order of children increase the probability of IPV, such as when the prior children had more daughters than sons, when the previous children had twin daughters, and when the previous children had one son and the last two children were daughters. A participant who was a frequent victim of violence gave a saddened expression and reported;I had two sons and then twin daughters. I am frequently beaten by my husband because his expectation of twin sons was devastating.The participants reported that the previous sex order of the children and the future fecundity of the wife was the major adjoining IPV factors. The nexus for these two factors was the "reproducing sons." To endorse it, victimized females also gave a consensual argument that those women who had more sons than their prior children were less exposed to IPV. Moreover, the females who reproduced more daughters than sons but still have more than 15 reproductive years left (with an age of fewer than 30 years) were less likely to be exposed to IPV. The women also revealed that they could not visit doctors during pregnancy. The delivery of a child was also preferred through daisThe participants also disclosed how the total fecundity of the wife saved them from IPV. It guarantees the greater biological capacity to reproduce children which would consequently increase the probability of "superhumans" who have to protect the biologically inferior creature (the wife). In addition, anxiety, anger, and continuous family deterrence were the major psychological ailments among husbands. The women disclosed that the mental state of their husbands was designed by patriarchy, anti-feminism, and misogynistic ideology about women's existence in the household and societal sphere. A young woman with anger on her face shared her opinion;This is the essence of our culture that the husband can get angry, can dominate, or can show contempt to his wife. These aspects are the masculine traits but known to be psychological problems of husbands.Interviews with victimized women highlighted those specific psychological problems among husbands were also a major individual factor of IPV. The perception was that husbands are "The husbands’ childhood exposure to violence also gave acceptance, prevalence, and perpetuation of IPV in the domestic sphere. The childhood experiences of IPV have multi-dimensions consequences, such as considering IPV as an everyday life phenomenon. Men could use hegemonic powers over women through mild or severe acts of violence; a father is the role model of children; therefore, their acts of violence must be copied. Experience of violence is expected in the family sphere as it is embedded in traditional socialization codes, and IPV experiences in childhood reinforce the misogynistic ideology among men.Micro-level factors constitute the emotional interactional patterns between individuals. The major sub-themes generated at the relationship level were husband supremacy over a wife, husband control of wealth in the family, fights, tensions, conflicts with in-laws, and association of the husband with aggressive peers.biradaribivi thaly laga or run-mureedMy husband thinks that I am physically weak, tender, and emotionally malformed. Therefore, he frequently used violent acts to ensure his supremacy over me.The victimized women unveiled that the husband was expected to be dictating, imperious and violent towards his wife in the marital relationship. This expectation was initiated by close relatives, household members, and The husband's domination was a patriarchal tool to ensure female subjugation to his husband. This patriarchal tool was nurtured in the socialization codes of the husband from childhood. If a wife raised her voice against this superhuman dominance, she might suffer from marital disequilibrium, divorce, and separation.participation in wealth control" in the household sphere. A 35-year-old battered participant reported;The major cause of physical battering is control of family wealth and resources. Wives cannot avoid these violent acts because they are completely deprived of participation in wealth control.The husband's wealth control in the family was the primary factor for IPV against the wife. There were three major situational dynamics of spouse-earning activities, such as the husband was not earning, and the wife was earning (i), the husband was earning, and the wife was also earning (ii) and, the husband was earning, and wife was not earning (iii). Interviews highlight that the husband was the controlling agent of wealth in all the situations mentioned earlier because a husband is considered the protector of a wife who could take any verdict within the jurisdiction of the house based on decision-making autonomy. The normative orientation of the rural society exerts that the husband is physically, emotionally, and psychologically intense. Therefore he should take control of the wealth in the family. Endorsing this, battered women stated that the wife had to face severe violent consequences if she asked for "beghairatIf a husband shared economic control with his wife, he was tagged as saasnandsusarpaon ki jutichoti zaat diganda khndansaas and nand formed an antagonistic group against victimized wives. This opposed group provoked IPV on various issues such as usage of modern methods of contraceptives, fertility intentions, spacing of children, giving birth to sons, isolation from decision-making in economic matters of household, avoiding visits to natal family, and avoiding visits to neighbors and friends. Validating the above findings, a 22-year-old victimized female argued:My saas (mother-in-law) provoked fights and tensions in my marital life. My husband beat me several times as I argued with his mother on reproductive and economic rights in the family.Findings highlighted the role of saas (mother-in-law) triggered physical battering during their pregnancy. Consequently, it caused reproductive problems such as irregular periods, constant foul-smelling vaginal discharge, nausea, abdominal pain, uterus swelling, and even worse case miscarriages, etc. In addition, some participants reported that their saas (mother-in-law) was involved in forceful abortions on expecting the daughter.Some participants also reported that their matter of shame" for a victim as the community starts blaming them. A newly married bride described that when she tried to report these IPV acts to the police, she was scolded, abused, and beaten by her natal family. She further elaborated;Police station is not a safe place for women to report the violent acts of their husbands. Actually, this is the place of further embarrassment and disgrace for victimized women.Sometimes, the offensive behavior of police and courts compelled the victims to tolerate their husbands' violent acts. This culture of tolerance against IPV encourages the husband to execute violence on his wife with impunity. Participants revealed certain aftermaths of reporting IPV to police, such as husband, in-laws, and natal family becoming antagonistic, character assassination of the victim by police, and media involvement in these crime reports becomes a "The victim mostly avoided courts because the lawyers of the perpetrators confronted their character and marital integrity. The women set forth subsequent statements to demonstrate the non-supportive behavior of the judiciary, such as “wife is characterless," "wife has an affair with other men," "wife wanted to control the economic circle of the household," and "wife is modern and wants to live alone," and "wife is dishonoring the traditional community norms." These stigmatizations strengthened the perpetrator (husband) to degrade the victim of violence (wife).The victimized women could not get support from the community due to gender-biased oppressive ideology. Non-supportive behavior of police and judiciary, social isolation, blaming and shaming of oppressed women, weak community sanctions against husbands, and lack of support from relatives and neighbors, etc., were major community-level factors of IPV. Community-level dynamics of IPV are summarized in Fig. I have to tolerate IPV acts as I want to save myself from social isolation. However, my husband knows that I cannot do anything to report IPV; therefore, he beats me frequently.Interviews highlight that community was conservative about women's placement in society. The married females who wanted to raise their voices against IPV acts were "interrogating their private marital life." Moreover, the punishment of "raising voice against the husband" deprives the victimized women of social support from natal family, in-laws, husband, neighborhood, etc. Consequently, these women were left alone with nobody to protect them in the male-dominating society. Furthermore, the victimized women felt "communally segregated" and "socially isolated." Thus, women preferred to tolerate the acts of IPV rather than face the severe aftermaths of "social cut-off." Validating these arguments, a newly married bride said;innocent" and victimized the wife as the "cause of violence." During data collection, we found that the list of reasons for blaming victimized women included charges that she was characterless, garrulous , negating the husband's order, arguing with in-laws, taking frequent visits to natal family, and showing carelessness in domestic chores. This endless "blame game" compels participants to "hide," "tolerate," and "accept" the acts of IPV. In addition, the victimized women had to face bullying and shaming comments from the community members—these degradation modes revolved around humiliation, dishonor, scolding, and character assassination of the participants.The participants disclosed that community members usually declared the husband "sacred head" of the household; therefore, he is free to execute IPV. Participants reported that when their neighbors intervened in their domestic and marital matters, but when the women asked for help against IPV, they did not provide it. During the transitional questions, the participants reported the subsequent phrases which demonstrated the weak sanctions for husbands in the community, such as beliefs that the husband is the owner of the family, the husband can make any decision in the household, the violence of the husband was for the betterment of the wife, slapping means mending the behavior of the wife, village dwellers will not accept women who stand against their husband, the wife should ignore the violent acts of husband for maintaining wedlock, and standing against their husbands will ruin the marital life of women. In agreement with these phrases, a 25-year-old participant who frequently became the victim of IPV validated;Community norms expected that wife should be silent, abiding and tolerating towards husband's violent acts. Instead, these weak community sanctions encouraged my husband to perpetrate violence against me.social pressure" could be used as a solution to ensure that the "husband was also accountable for instigating IPV." Moreover, community members supported husbands for exerting IPV and at the same time disgraced their wives for being the victim of IPV.The participants reported that "The community members considered the husband the "My husband knows that the community will not be supportive of me; therefore, he perpetuates violent acts against me.The victimized females were deprived of social support from their natal family, in-laws, relatives, and neighborhood. The community thought that complaining about IPV would result in marital disequilibrium, separation, or divorce between the married couple. Resultantly, the women would be alone in society with nobody to protect them and their marital rights. Therefore the "fear of support deprivation" from village dwellers and "being alone" in the marriage was the major underlying causes of IPV (at the community level). The findings also unveiled that the neighborhood disclosed hatred and bullying against single, divorced, or separated women. The existence of the "married women" was considered to be the presence of their "husband." Endorsing these facts, a married female who faced and tolerated physical battering for the last seven years from her husband reported;The victimized women blamed society for tolerance, acceptance, and approval of IPV. This culture of acceptance is a significant cause of violence perpetration at the societal level. These macro-level prerequisites of IPV have trickle-down effects on community, interpersonal and individual levels. Orthodox gender-prejudiced role expectations and impositions, the role of religious scholars in disseminating Islamic (mis)interpretations, and "dominant patriarchy" in marital relations were the major themes of IPV at the societal level. The societal level dynamics are summarized in Fig. Society expected me that I should submit my ego, preferences, and wishes to my husband and fulfill the gender roles assigned to me by society. If I negate these gender roles, then surely I will face more violent acts from my husband.The victimized women indicated the subsequent gender-prejudiced roles imposed upon married women, such as child-rearing, husband care, and in-laws' well-being. In addition, adjustment with available economic resources, avoiding frequent visits to natal family, neighbors, and friends, submitting material and non-material priorities to husbands' urgencies, and accepting husband supremacy were gender-prejudiced roles for married women. During the interviews, we found that gender-discriminated roles were imposed on women to maintain the male-dominated status quo. A victimized woman who was severely battered by her husband many times after marriage disclosed;imam" and "molvi." Most men were involved in blind imitation and diffused religious ideologies. Many of the participants argued that molvi infused confusion in the minds of their husbands through misinterpretations of religious teachings. These misapprehensions of religious beliefs are out-of-pretext to get desired meanings. A battered female revealed that imam masjid (religious scholar of the mosque) preached that "Islam has allowed the husband to execute mild violent acts  on wife." Moreover, the imam also said that the equality of spouses is a western concept that decreases the wife's dignity by making them equal to men. These arguments were endorsed by a 27-year-old victimized participant who said;The imam masjid told my husband that the wife is a queen of the house. Therefore, the king must take care of his queen from social evils even by using some mild violent acts against her.The victimized women disclosed that the people of the study context gave utmost importance to Islamic teaching. The village dwellers took the guidelines of their daily problems from Islamic content. These religious teachings were taught, explained, and expounded by the religious scholars called "The participants gave a consensual argument that misinterpretation of Islamic teachings by religious scholars was the major macro-level factor of IPV. In addition, the participants revealed that they were beaten many times by their husbands for arguing over the preaching of religious leaders.izzat) the husband. The participants used many phrases to show the perpetuation of IPV in the dominant patriarchy, such as my husband beats me because I am not allowed to visit my friends without his permission. Suppose my husband is scolding me and slapping me. In that case, it means he is protecting me from the notorious intentions of society, and my husband pressurized me for reproducing sons because it will make me socially secure. My husband can perpetuate violence to mend my behaviors because he knows right and wrong. A frequently beaten 33 years old participant endorsed these stated facts and argued;The participants used the phrase "dominant patriarchy" as the significant underlying societal factor of IPV. The data also highlighted that this phenomenon targeted women's independence, empowerment, and fundamental marital rights after marriage. A victimized married woman reported that dominant patriarchy in marital relations was related to dehumanization, incomplete identity, fragile body, and controlling wife's behavior by husband. These patriarchal beliefs created gender imbalances in marital relations which expected the wife to be submissive, obedient, and honoring  possesses power and control over the victim (wife). These controlling supremacies created a domination-toleration relationship between perpetrators and victims in a male-dominated domestic environment . MoreoveAs mentioned in the findings, women's exposure to IPV was more prevalent in the communities that adhered to the traditional patriarchal gender norms and beliefs. In this regard, a victim of IPV feared being blamed, shamed, and ridiculed by the police. The previous exploratory study also endorsed that the ridiculed behavior of police towards victimized women of IPV mostly prevailed in patriarchal societies . MoreoveThe present study's findings endorsed the socio-ecological model comprised of social structure, cultural beliefs, and network relationships to explain IPV prevalence in the study context , 65. TheAligning with the present research theme, a previous study conducted by Zakar et al. found that religious leaders advise married female to adopt the "forgive and forget approach" in wedlock. Under the prevailing patriarchal traditional norms, these religious leaders also blame the victim for initiating IPV by ignoring their marital responsibilities. These religious leaders misinterpret the Islamic teachings and attribute negative stereotypes to women such as "short-tempered" "emotional, and "physically docile" . These rIn conclusion, husband supremacy and wife depreciation create gender inequality in marital relations. This inequality-based status quo creates power discrimination between spouses, which perpetuates violence in the domestic context. In an endorsement of these facts, we used a socio-ecological model to explore the underlying factors of IPV at four levels, i.e., individual, interpersonal, community, and society. The current study introduced culturally contextualized terminologies of "protection," "physical submissiveness," "mental delicacy," and "social security" for married women. These culturally embedded terms became the primary cause of IPV in the study vicinity. Maintaining marital stability and avoiding marital conflict was the wife's duty. Therefore, the ill-treated married females wanted to stabilize their marital life by fulfilling the inadmissible wishes of their husbands, in-laws, natal family, neighborhood, relatives, and community members. Endorsing these gender-biased oppressive norms and misogynistic behaviors of network relations, these victimized women accepted, tolerated, and supported these gender-based oppressive acts of violence and declared them as a "normal life phenomenon." The above-mentioned levels were used to maintain the patriarchal status quo, misogynistic ideology, and hegemonic masculinity in household and societal contexts. Moreover, the role of kinship-based networks in family and community and orthodox anti-feminist societal norms became the major prerequisites that generated the contextual factors for perpetrating IPV. Therefore, legislative measures could be adopted to challenge these gender-prejudiced hierarchies and ensure women's autonomy in the domestic and social fabric of Southern Punjab, Pakistan.Due to a lack of time, resources, and ethical concerns, we could not interview the victimized women's judiciary, police, policymakers, and husbands. These participants can be included in future research to explore the underlying dynamics of IPV. The present study revolved dynamics of IPV within the family sphere. Future research can use the triangulation method within qualitative research be adopted, such as using obtrusive observations and grounded theory. The current study highlighted the perspective and lived experience of women, future research can collect the data from social activists, NGOs, and government officials to triangulate the data and to develop an intervention to create awareness among female and male members related to human rights, etc. The primary strength of the present study is to explore the causes of IPV at the individual, interpersonal, community, and societal levels. The other strength of this study is to elicit information from women who had lived experiences of intimate partner violence. This method was used to explore the opinions of victimized women about their personal experiences of IPV.The primary strength of the study demonstrated the underlying causes of IPV at the individual, interpersonal, community, and societal levels. Furthermore, his study explored the experiences of women who were victims of domestic violence to capture their lived experiences. The major limitation of the study was to collect the data through in-depth interviews. The study revolved dynamics of IPV within the family sphere.Based on the findings of the present research, we recommended that government should spread community-level awareness programs to sensitize the general public about the marital rights of women to overcome violent relationships. Moreover, husbands can be the major agents of change by avoiding IPV in marital relationships. Therefore young adolescent boys should be socialized to maintain their marital relationship through tolerance, respect, intimacy, and esteem. Despite this, education and employment for women can be helpful to an elevated and respected position within the household and community level ultimately changing the attitude towards IPV at the individual, interpersonal, and community levels.Additional file 1. Semi-structured interview guide of the study.


Perihepatitis, including Fitz-Hugh-Curtis syndrome, is an uncommon, chronic manifestation of pelvic inflammatory disease usually affecting premenopausal women. It causes right upper quadrant pain due to inflammation of the liver capsule and adhesion of the peritoneum. Since delayed diagnosis of Fitz-Hugh-Curtis syndrome can lead to infertility and other complications, physical examination findings need to be investigated to predict perihepatitis in the early stages of the disease. Here, we hypothesized that perihepatitis is characterized by increased tenderness and spontaneous pain in the right upper abdomen when the patient is placed in the left lateral recumbent position (we termed this indication the "liver capsule irritation sign"). We examined the patients physically for the presence of this liver capsule irritation sign for an early diagnosis of perihepatitis. We report the first two cases of perihepatitis due to Fitz-Hugh-Curtis syndrome in which the liver capsule irritation sign observed during the physical examination was used for diagnosis. The liver capsule irritation sign is caused by two mechanisms: first, the liver falls gravitationally into the left lateral recumbent position, which makes the liver easier to palpate; and second, the peritoneum is stretched and thus stimulated. The second mechanism is that the transverse colon running around the right upper abdomen slumps gravitationally when the patient is in the left lateral recumbent position, allowing for direct palpation of the liver. The liver capsule irritation sign can be a useful physical finding, suggestive of perihepatitis due to Fitz-Hugh-Curtis syndrome. It may also be suitable in cases of perihepatitis caused by factors other than Fitz-Hugh-Curtis syndrome. Perihepatitis, often referred to as Fitz-Hugh-Curtis syndrome, is inflammation of the liver capsule with adhesion formation, resulting in right upper quadrant pain . Fitz-HuThe diagnosis of Fitz-Hugh-Curtis syndrome can be confirmed by laparoscopy or laparotomy via visualization of adhesions between the diaphragm and liver or the liver and the anterior abdominal wall; still, in most cases, the diagnosis is made comprehensively based on clinical and laboratory findings because of the invasive nature of the procedure . The CenA Japanese study reported enhanced tenderness in the right upper abdomen using an ultrasound probe when a patient with Fitz-Hugh-Curtis syndrome was placed in the left lateral recumbent position, suggesting that this feature may be indicative of perihepatitis . TherefoCase 12 (room) of 98%. On physical examination, there were no specific findings in the head, neck, or chest. The abdomen was flat and soft, with tenderness in the right upper quadrant. There was no rebound pain or muscular defense, but the cough sign was positive [Chlamydia trachomatis DNA. Abdominal contrast-enhanced CT exhibited a contrast effect along the liver capsule in the early contrast-enhanced phase, mainly in the right lobe of the liver  of 36.6 °C, blood pressure (BP) of 114/79 mmHg, heart rate (HR) of 88 beats/min, respiratory rate of 16 breaths/min, and SpOCase 22 (room) 99%. On physical examination, there were no remarkable findings in the head, neck, or chest. The abdomen was flat and soft, with tenderness in the epigastric region and right upper quadrant. There was rebound pain and percussion tenderness in the right upper abdomen [C. trachomatis DNA. Abdominal contrast-enhanced CT showed a contrast effect along the liver capsule in the early contrast phase, mainly in the right lobe of the liver (Figure A 25-year-old woman presented to the emergency department with a primary complaint of intermittent epigastric and right upper quadrant pain for the previous two weeks. She had no past history of either any medication or of pregnancy and childbirth, apart from unprotected sexual intercourse. Her vital signs at the time of admission were: BT 36.4 °C, BP 118/62 mmHg, HR 98 beats/min, and SpOThese two cases are the first reports of perihepatitis due to Fitz-Hugh-Curtis syndrome to be examined with the liver capsule irritation sign on physical examination, which was subsequently confirmed with relevant clinical investigations. We believe that the liver capsule irritation sign can be valuable as a specific physical examination finding indicative of perihepatic inflammation. It has been reported earlier that right upper abdominal tenderness, observed using an ultrasound probe, was enhanced when a patient with Fitz-Hugh-Curtis syndrome was placed in the left lateral recumbent position; however, the mechanism of this enhancement was not discussed .The first mechanism that causes observation of the liver capsule irritation sign in perihepatitis is the gravitational drop of the right lobe of the liver when the body is placed in the left lateral recumbent position. Although the liver is anatomically fixed by several ligaments, it is to some extent a mobile organ ,10, and When the right lobe of the liver, which is prone to inflammatory findings, is placed in the left lateral recumbent position, two forces act on the liver capsule of the right lobe, one in the direction of gravity and the other in the opposite direction due to adhesion between the liver capsule and visceral peritoneum, causing the liver capsule of the right lobe to stretch. Abdominal pain caused by perihepatitis is a type of visceral pain, which is felt when pain receptors in the peritoneum are stimulated upon stretching ,18. ThisAnother mechanism that is responsible for the observation of the liver capsule irritation sign in perihepatitis is that the transverse colon running around the right upper abdomen drops in the direction of gravity when the patient is in the left lateral recumbent position. Since the transverse colon is not anchored to the retroperitoneum, the left lateral recumbency causes the transverse colon to slump in the direction of gravity, allowing direct contact with the liver when the right upper abdomen is palpated, which may exacerbate right upper abdominal tenderness ,19. ThesThe findings of the contrast effect along the liver capsule in the early phase of contrast-enhanced CT are helpful in diagnosing perihepatitis, which can be seen not only in Fitz-Hugh-Curtis syndrome but also in other conditions such as systemic lupus erythematosus, liver abscess, cholangitis, peritonitis due to cancer, tuberculosis, or other causes, acute cholecystitis, superior vena cava obstruction, and congenital hepatic fibrosis . The livThe liver capsule irritation sign is a useful physical examination finding that is indicative of perihepatitis due to Fitz-Hugh-Curtis syndrome in emergency room clinical settings. This sign may also be useful in patients with perihepatitis due to causes other than Fitz-Hugh-Curtis syndrome who present with right upper quadrant pain. Thus, the liver capsule irritation sign on physical examination can help in the differential diagnosis prior to the laboratory clinical examinations.


Photosynthetic light-harvesting antennae are pigment-binding proteins that perform one of the most fundamental tasks on Earth, capturing light and transferring energy that enables life in our biosphere. Adaptation to different light environments led to the evolution of an astonishing diversity of light-harvesting systems. At the same time, several strategies have been developed to optimize the light energy input into photosynthetic membranes in response to fluctuating conditions. The basic feature of these prompt responses is the dynamic nature of antenna complexes, whose function readily adapts to the light available. High-resolution microscopy and spectroscopic studies on membrane dynamics demonstrate the crosstalk between antennae and other thylakoid membrane components. With the increased understanding of light-harvesting mechanisms and their regulation, efforts are focusing on the development of sustainable processes for effective conversion of sunlight into functional bio-products. The major challenge in this approach lies in the application of fundamental discoveries in light-harvesting systems for the improvement of plant or algal photosynthesis. Here, we underline some of the latest fundamental discoveries on the molecular mechanisms and regulation of light harvesting that can potentially be exploited for the optimization of photosynthesis. The latest fundamental knowledge obtained on the light-harvesting mechanisms of the antenna proteins can be bridged to biotechnical optimization of photosynthesis. The cores are instead built of a variable number of allophycocyanin  units  units . There am) units . The pigm) units . Great pm) units . Both crrobilins .Compartmental modeling analysis of picosecond time-resolved fluorescence studies revealed that, in intact cyanobacterial cells, the excitation energy from PBS can be rapidly distributed to the PSs . The vara, Chlb, and carotenoids are compact transmembrane proteins almost completely embedded in the thylakoid membrane  and one on the side of LHCII  or trimeric FCPs (T. pseudonana).Fucoxanthin Chl-binding proteins (FCPs) are the antenna complexes in diatoms. They belong to the same protein family as LHCII and share several conserved structural and functional traits with their plant relatives, although they bind different chromophores . Recentlr plants . Besidescornutum . In otherevailed . Here, Fic state , looselyic state . The stric state , and, dea and 22 carotenoids  ensures a fast control of the amount of light energy conveyed to reaction centers and catalyzes the dissipation of the energy absorbed in excess . NPQ is Many aspects of the molecular mechanism of NPQ remain obscure, due to the experimental challenges posed by the protein-congested, highly plastic thylakoid membrane. In particular, the site and the mechanism of qE in plants have been long-standing open questions.Arabidopsis thaliana) mutants lacking either all minor antennae  state that dissipates the absorbed energy as heat . The molThese findings open up two further questions: is the quenching mechanism identified in solubilized LHC also functional in the thylakoid membrane? And if so, how are the light-harvesting and quenched states regulated by changes of the membrane environment? En route to answering these questions, a recent study used TA measurements to address the quenched conformation of LHCII trimers immobilized in polyacrylamide gels to prevent clustering , 2020b. NoM npq1 mutant, lacking zeaxanthin, is similar to NoM npq4, lacking PsbS  will dephosphorylate LHCII, which will then move to PSII (state I) , are involved in the regulation of state transitions  . In C. rnsitions . Howevernsitions .b6f complex had been proposed as the redox sensor, a recent work had shown that it is not involved in cyanobacterial state transition  populations of PSII, namely quenched and unquenched exist, in both states I and II. The equilibrium between quenched and unquenched PSII is changed upon state transitions . The astonishing diversity in different evolutionary clades results in a kaleidoscope of solutions for light harvesting and photoprotection, in which the plasticity of the thylakoid membranes plays a crucial role. The recent development of accurate, high-resolution techniques to study the molecular processes during light harvesting, as well as the creation of informative mutants, has allowed fresh insights into this area.Nicotiana tabacum) plants resulted in an increase of up to 15% in biomass in field conditions .Conflict of interest statement. None declared.


Skygardens or skycourts are a unique architectural intervention in the built environment, enhancing the social, economic, and environmental values of the building. It allows occupants to connect and experience outdoor freshness within a semi-enclosed environment. However, skygardens located on a highrise building may generate intense wind gusts, endangering the safety of occupants. Using a validated computational fluid dynamics model, this study investigates the potential of various vegetative barriers or shelterbelts in attenuating the high wind speeds encountered in such spaces and the impact on wind and thermal comfort. Three skygarden configurations were investigated with and without vegetative barriers, simplified and modelled as porous zones, and their effect was studied on the velocity and temperature profile at the occupants’ level. The results indicate that while hedges and trees can offer resistance to airflow, trees provide higher temperature reduction. However, a combination of vegetative and geometrical barriers provides the most optimal condition in the skygarden. The study has identified the importance of assessing wind attenuation characteristics of tree plantations on highrise skygarden, and the results can be used in designing intervention strategies. Moreover, vegetation can attenuate pollutants and mitigate poor air quality by surface deposition, and future studies should investigate in that direction.The Appendix is available in the online version of this article at 10.1007/s12273-022-0943-7. Appendix to: Numerical evaluation of the use of vegetation as a shelterbelt for enhancing the wind and thermal comfort in peripheral and lateral-type skygardens in highrise buildings


High salt intake is a major cause of hypertension and cardiovascular diseases. The out-of-home sectors have been identified as one of the contributors of high salt intake in the population. The National Salt Reduction Policy of Malaysia was initiated in 2015; however, out-of-home sectors are yet to be emphasized and perception by policy-makers and the food industries towards salt reduction are yet unknown. This study aimed to determine the perceptions, barriers and enablers towards salt reduction in the out-of-home sector in Malaysia, as well as among policy-makers and the food industries.This is a qualitative study via semi-structured in-depth interviews (IDI) and focus group discussions (FGD) involving several stakeholders consisting of policy-makers from five ministries, five nongovernment organizations (NGOs) and food science/food technology researchers from five regions , as well as the food industries. The IDI and FGD sessions were recorded, transcribed verbatim and analysed thematically using Nvivo software version 12.All participants agreed that salt intake in Malaysia is high and leads to hypertension and cardiovascular diseases. Lack of awareness, poor eating culture and behaviour and frequent eating out were among the causes of high salt intake. Awareness campaigns and education, sodium content labelling and product reformulation were strategies that have been implemented by the government; whilst for the food industries, some of them have tried to reduce salt and labelled the sodium content on their food products. However, there were several barriers including perceived poor consumer acceptance, lack of knowledge and resources, and challenges in reformulation, as well as unavailability of guidelines and salt targets. Hence, several enablers have been suggested, which include prioritizing the salt reduction strategy, creating more awareness, collaboration and engagement, research and technology particularly for reformulation and shelf-life stability, incentives and salt tax.Salt reduction efforts of the out-of-home sector in Malaysia could be achieved through several measures or enablers that can overcome the barriers currently faced by stakeholders, especially policy-makers, food industries and the consumers themselves. This study will benefit the policy-makers to improve the salt reduction policy of out-of-home sectors and highlight the concerns among the food industries on the policy. Cardiovascular diseases (CVDs), mainly coronary artery disease and stroke, are the leading cause of death worldwide, accounting for 31% of total global deaths . Of all Salt reduction is among the most cost-effective measures in the prevention of cardiovascular diseases . The WHOMalaysia began its salt reduction initiative in 2010 when a salt reduction committee was formed under the noncommunicable disease (NCD) section, Disease Control Division, Ministry of Health (MOH). The MOH announced a reduction of salt in 11 food items including soy sauce. Furthermore, the salt reduction committee collaborated with several agencies to increase awareness of salt and promote salt reduction in Malaysia . The salAccording to Department of Statistics Malaysia, about 17.3% of household expenditure was on foods and nonalcoholic beverages, while about 13.9% was on restaurants and hotels [This study aimed to determine the perceptions, barriers and enablers of salt reduction in the out-of-home sectors among the policy-makers, nongovernmental organizations (NGOs) and researchers, as well as the food industry. This study is part of a larger study on “Developing a policy to reduce the salt content of food consumed outside the home in Malaysia,” involving all formal and informal sectors , 15.This study was a qualitative study in which participants were asked to openly share their views on the study matter, including the perceptions, barriers and enablers of salt reduction in Malaysia, with emphasis on the out-of-home sectors through 19 sessions of semi-structured in-depth interviews (IDI) and three sessions of focus group discussions (FGD). Due to the COVID-19 pandemic throughout the study period (May 2020 to March 2022) , a mixedQuestionnaires used in this study was developed based on a combination of framework modified from the Medical Research Council (MRC), UK , EcologiThe samples of this study were policy-makers and the food industries. A policy-maker is defined as those who creates ideas and plans, especially those carried out by a government. The policy-maker involved in this study included representatives from the ministry/government agencies acting as the primary policy-maker. Other stakeholders usually involved in policy-making including researchers from nutrition, food science/food technology from universities, or government agencies and NGOs who indirectly play the role in supporting the salt reduction policy were also included. The list of policy-makers and food industries was obtained from various sources including the Technical Working Group for Salt Reduction Policy of the Ministry of Health (MoH), the Food Industry Association of Malaysia (FAM), government agencies such the Federal Agricultural Marketing Authority (FAMA), the Malaysian Fisheries Development Authority (LKIM) and the Malaysian Agriculture Research and Development Institute (MARDI).n = 10), 83% for NGOs (n = 5) and more than 100% food industries (n = 65). Total response rate was 91%. For policy-makers, there were some ministries/government agencies that were invited who sent more than one participant in the IDI session, hence for ten ministries/government agencies, there were a total of 15 participants attending the sessions. For NGOs, only one participant for each NGO attended the IDI session. For the food industries, a snowball technique was applied and huge participation was recorded as some of the industries attended were not in the list of the invitation but their participation was significant to reach saturation for the data on the food industry.In this study, the ministry/government agencies involved were representatives from four divisions of the Ministry of Health (MoH) namely Noncommunicable Disease Division, Food Division, Food Safety and Quality Division, Nutrition Division and representatives from the Ministry of Education (MoE), Ministry of Domestic Trade and Consumers Affairs and the Ministry of Agriculture (MoA) and its agencies, which were the Federal Agricultural Marketing Authority (FAMA), Malaysian Fisheries Development Authority (LKIM) and Malaysian Agriculture Research and Development Institute (MARDI). Inclusion criteria of representatives of each organization included an officer or person in charge or well versed with food or salt reduction strategy or policy for at least 6 months. Five nongovernmental organizations (NGOs)/professional societies that participated in this study included the Malaysian Dietitians’ Association, the Malaysian Association for the Study of Obesity, the Family Medicine Specialists’ Association of Malaysia, the Malaysian Society Nephrology and the Malaysian Society of Hypertension. The researchers involved in this study were from several universities in Peninsular Malaysia and MARDI. The representatives from ministries, government agencies and NGOs were mostly based in the west of Peninsular Malaysia and four government agencies were from the Borneo region. There were representatives of policy-makers from the government agency from each of the regions, in line with the samples of the food industries. The distribution of the participants according to stakeholders and regions are presented in Table In-depth interviews (IDI) were conducted mostly online with policy-makers  using a specific questionnaire. The in-depth interview (IDI) was conducted by an interviewer (researcher) that been trained to conduct the IDI session using standard protocol and questionnaire. At each session, a moderator or interviewer will conduct the interview, with assistance from a co-moderator and a rapporteur. Prior to the IDI, the interviewer started with a short introduction and briefing. The interviewer asked the respondent to open their camera and ensured that their microphone was in a good condition. The interviewer let the respondent answer the questions based on his/her own views and thoughts. The interview lasted for approximately 1 hour, then the interviewer would wrap up the session with key points highlighted by the respondents or participants. Focus group discussions (FGD) were conducted face to face following a standard operating procedure (SOP), as outlined by the Ministry of Health (MOH) involving groups of researchers and the food industries.All participants were assigned a code number and pseudonym. The code and pseudonym were used to identify quotes and comments made by the interviewees. The quotes and comments made by the interviewees were coded according to gender, stakeholder, region group. The policy-maker stakeholder was further divided according to the designated group (ministry/government agency or researcher or NGO) and numbered accordingly. The food industries were coded according to gender, food industries’ category and region, and numbered accordingly. The interviews and the discussions were recorded using a voice recorder. The recordings were verbatim transcribed after the session was completed. The transcripts were analysed thematically using Nvivo software . Electronic data including recordings of interviews and discussions as well as transcripts were stored in shared drives with specific password access within Universiti Kebangsaan Malaysia (UKM), and were only accessible to trained research team members.As presented in Table In this study, we identified several themes related to salt reduction in the out-of-home sectors in Malaysia, categorized under “Perception on salt intake and salt reduction policy in Malaysia,” “Barriers in salt reduction policy,” and “Motivation/enablers on salt reduction.”Generally, all participants in this study agreed that the salt intake among Malaysians is high and leads to health problems. They have highlighted several factors that influenced Malaysians to take high salt foods/food products such as the use of various sauces, salted fish, anchovies and food seasoning in food preparation. In addition, they have also shared their thoughts on the salt reduction policy including positive perception on the policy to reduce salt intake and ineffectiveness/insufficiency of the current policy, as well as opinions on the implementation of the policy. Table The current salt reduction policy by the Ministry of Health (MOH) includes guidelines to reduce salt in food products, sodium labelling, reformulation of foods, training and awareness campaigns as well as recognition and incentives that attract the food industries to reduce the salt content in their food products. Table There were several barriers, motivations enablers to salt reduction that have been proposed by the policy-makers and food industry participants. The barriers and motivation/enablers’ themes were divided into several categories including awareness, behaviour, consumer acceptance, knowledge, reformulation, resources, guidelines and salt target, priority, support, monitoring and law enforcement, price and cooking Table .Table 5Bkolok mee, light soy sauce, curry noodle, vegetable with soy sauce/oyster sauce, fried instant noodle, noodle soup, vegetable with salted fish, fried vegetable, roti canai/roti telur and fried rice [Our study showed that most of the participants agreed that the salt intake among Malaysians is high, as many food products including fast foods, snacks, processed foods, fermented foods and traditional foods, as well as food in the out-of-home sectors are high in salt content. The top ten food items that contributed to the highest sodium consumption among adult Malaysians include ied rice . Findingied rice . SeveralMost of the participants in this study were aware of the association between high salt intake and health problems such as hypertension and cardiovascular diseases, and showed a positive perception towards the salt reduction policy to reduce the burden of these diseases. Continuous education and increased awareness among the population on salt reduction through electronic and mass media have been suggested by most of the participants. They also highlighted that very few campaigns/education pertaining to salt reduction could be found on television and social media as compared with other food components such as sugar. Other countries, such as the UK, reported similar findings . CreatinFood labelling is one of the most important communication tools that can give information about the nutrient content of a food product, and hence can increase the awareness and knowledge on the salt content of an actual food product. However, not all food industry participants were aware of the announcement by the Ministry of Health for mandatory sodium labelling by July 2020, to be enforced by the year 2024 (26). The Healthier Choice logo has been introduced in Malaysia as a voluntary labelling, and encourages the food industries to produce healthy products since April 2017 . HoweverFunding specifically for research and reformulation of lower salt foods was also emphasized as needed by most of the participants to produce lower salt foods. Several foods such as bread, meat, dairy and convenience foods have been successfully reformulated and contributed to the reduction of salt intake among the population in the UK . MalaysiEvidence from the UK and other countries has shown that reducing salt is relatively easy for manufacturers as it does not affect the products’ weight or volume and there are few technical barriers. Only for a small number of products does salt have a technical function. However, the large variations in the salt content of similar products clearly show how much salt can still be innocuously removed. Furthermore, consumers do not perceive any change in taste as salt is reduced gradually.Salt is a poor preservative and is now rarely used as a preservative as other chemicals are more effective. There are also other technologies such as high-pressure, ultrasound, microwave and vacuum curing which have been adopted in the production of low-sodium fermented products and for the reduction of microbial contamination, acceleration of the fermentation process, improvement of texture and color, reduction of amount of salt added and shortening of the salting periods –34. Impr2), magnesium chloride (MgCl2), potassium lactate, calcium lactate and calcium ascorbate shows no risk of spoilage and pathogenic bacteria. However, these salt alternatives may produce a bitter taste, thus they could not completely replace the NaCl [The use of a salt substitute such as potassium chloride (KCl), calcium chloride , which is widely used in cooking as food enhancer, has been suggested to increase the sodium content; however, several studies have reported that the addition of MSG in reduced salt foods could lower the sodium content in the foods. MSG contains two-thirds less sodium than NaCl and the saltiness is reportedly associated with a G-protein coupled receptor that enhances the perception of saltines , 41. Then cheese . Hence, n cheese .The food industries also found difficulties in reducing the salt as they needed to follow the unrevised Food Act, which requires a fairly high amount of salt to achieve safety of food products. Hence, the current Food Act needs to be revised for a new salt target so the food industries can make the reformulations. Salt targets have been shown to effectively reduce salt intake in UK salt reduction strategy . Many coThe study has successfully obtained the perception, barriers and enablers towards a salt reduction strategy among policy-makers and the food industry. This qualitative study suggests the following: (i) Enhancing communication between policy-makers and the food industries to ensure shared responsibility in salt reduction strategies, (ii) introducing a visible front-of-pack label on food high in salt content, (iii) setting targets for voluntary salt reduction of a selective category of food high in salts, (iv) low-cost advocacy and education towards a lower salt consumption involving specific settings and using existing infrastructures such as schools, workplaces and community centres, and (v) monetary support for industries and researchers in the effort to reduce salt levels in salty foods.However, there are several limitations, including that some of the policy-makers at the state level were not involved, and the online sessions conducted during the COVID-19 pandemic could have been better conducted face to face to obtain a better insight from the participants. Further research could focus on the effectiveness of current strategies such as Healthy Choice logos, toward a salt reduction strategy, and also innovative techniques to reduce salt in salty foods commonly consumed by the population.Perceptions on the salt reduction policy in Malaysia among policy-makers and the food industries were positive as they believe the policy could reduce the salt intake among the population and prevent noncommunicable diseases, particularly hypertension and cardiovascular diseases. Several challenges in implementing the salt reduction policy including acceptance by consumers of reduced salt foods, lack of knowledge and behavioural changes exist and can be addressed by education and continuous awareness campaigns. An absence of standards and guidelines for reformulations poses a challenge to producing lower salt food products. Priority issues and lack of support are other barriers that could prevent the success of the salt reduction policy. Hence, it is important to set a salt reduction target, encourage researchers to venture into research on salt reduction and engage the food industries to start with voluntary reformulation to reduce salt content in foods. Financial support is needed for research and reformulation, product development, use of possible technologies in food processing and to conduct bigger salt reduction campaigns. In summary, the salt reduction policy needs to involve all parties. Collaboration among ministries, researchers, nongovernmental organizations and the food industry is vital to make sure the policy that has been outlined by the Ministry of Health could effectively reach the global salt reduction target.


Collagen is the basic protein of animal tissues and has a complex hierarchical structure. It plays a crucial role in maintaining the mechanical and structural stability of biological tissues. Over the years, it has become a material of interest in the biomedical industries thanks to its excellent biocompatibility and biodegradability and low antigenicity. Despite its significance, the mechanical properties and performance of pure collagen have been never reviewed. In this work, the emphasis is on the mechanics of collagen at different hierarchical levels and its long-term mechanical performance. In addition, the effect of hydration, important for various applications, was considered throughout the study because of its dramatic influence on the mechanics of collagen. Furthermore, the discrepancies in reports of the mechanical properties of collagenous tissues  and those of pure collagen are discussed. Collagen is a structural protein, which is of upmost importance to vertebrates, as it contributes to one-third of their body mass ,2. It isTo date, research on collagen-based materials has mainly focused on applications, fabrication, manufacturing, and morphological analysis ,6,7,8,9.The hierarchical organisation of collagen is a widely investigated feature because it impacts on the properties of both collagenous tissues and engineered collagen structures. At the lowest level of hierarchy a, collagOver the past decade, numerous technologies have been successful in manufacturing various engineered collagenous structures for specific biomedical applications. The most widely used natural sources of collagen include bovine, porcine, rodent, and human tissues ,16. FrogNumerous technologies have been successfully employed to develop various engineered collagenous structures such as gels, sponges, membranes/films, fibrous mats, intricate 3D scaffolds, hollow tubes, etc. . One of The mechanical responses of collagen-rich materials have been discussed and compared widely in various previous works ,36,37. SCollagen-rich materials have shown time-dependent viscoelastic behaviour in both soft and mineralised collagen materials. This was quantified at various levels of hierarchy using cyclic loading, creep, and stress-relaxation behaviours b–d. DuriSeveral experimental techniques and instruments have been used to measure the mechanical properties of collagen at different length scales. Conventional nanoindentation and atomic force microscopy (AFM) use sharp probes to estimate the elastic modulus of the materials, which depends strongly on the indentation depth . GeneralThe elastic properties of single collagen molecules were widely explored over the past decades by utilising both experimental and simulation techniques. Although it was recognised that collagen-rich tissues exhibited viscoelastic responses ,57, the The mechanical response of a collagen fibril can be estimated using both experimental and modelling (AM) approaches, though it is challenging to simulate millions of atoms. The experimental quantification of the mechanical properties of a single fibril has been extensively studied with tensile testing using MEMS ,66 and AAFM-based indentation has produced some promising results in the last decade with the implementation of specific testing protocols . Values Although experimental studies have been performed on single collagen fibrils, molecular simulations are still essential to comprehend the interactions and deformations occurring at the molecular level that contribute to multiscale collagen mechanics. These simulations are challenging, as they involve several millions of molecules (each molecule around 300 nm in length), resulting in a high computational cost . Over thThe variance in the obtained magnitudes of the modulus of the fibril see  highly dAmong the hierarchical levels of collagens, the mechanics of fibrils have been extensively studied. Nevertheless, the studies associated with the failure and fracture mechanics of fibrils need additional attention. These investigations would be beneficial to prevent tissue injuries and design artificial tissues. Both advanced experimentation and molecular simulation techniques should be used, particularly to investigate the mechanics of diseased fibrils.The microscale level of collagens is dominated by the bundles of fibrils known as collagen fibres. Rather limited quantification of the mechanical properties of isolated (or “pure”) collagen fibres has been performed so far. Generally, studies have focused on macroscale tissues, such as bone and skin, that contain a certain fraction of collagen fibres ,89,90,91The nanoindentation technique can be used to quantify transverse mechanical properties of collagen fibres. For collagenous tissues, it was observed that the nanoindentation modulus was much higher (63 ± 4 MPa) than that measured using other testing methods (such as tensile modulus) . Panwar Interestingly, the mechanics of isolated collagen fibres have not been quantified in depth to date. Although several attempts have been made to assess the behaviour of collagen fibres embedded in skin, arteries, tendons, etc., the obtained results were influenced by the neighbouring matrix components, such as proteoglycans and GAGs. The major problem is that time- and frequency-dependent behaviours, which are strongly associated with the tissue mechanics and failure mechanisms have not been explored at this level of hierarchy.The macroscale level of collagen is represented by tissues composed of collagen fibres and fibrils, such as skin, tendons, cornea, bones, etc. Generally, this level of hierarchy can be subdivided into mineralised  and nonmineralised  collagen-rich tissues. However, native tissues contain other components, such as elastin, proteoglycans, etc., along with collagen fibres. Svensson et al.  used theOnly rather limited research has been performed to quantify the mechanical features of pure collagen at macroscale. It should be taken into consideration that collagenous tissues are composed of different ground substances; hence, pure collagen engineered constructs might be used to quantity mechanical properties. Recently, studies by Bose et al. ,45 quantThe magnitudes of the modulus of collagen at various levels of hierarchy (both dry and wet environments) are reported in In the last decade, several techniques  have sucThe rapid degradation of engineered collagen structures is usually evident from the high weight loss after exposure to in vivo conditions for a few days, as presented in Apart from the collagenous constructs, the structural and mechanical properties of the native tissues are also affected by increasing age and diseases ,132. TheThe load bearing capacity of a nonmineralised tissue  is highly dependent on its collagen component. Interestingly, the role of the collagen phase in different nonmineralised tissues varies significantly, for example, with age. In old tissues, the structural organisation of collagen lacks fibrillar/fibre orientation ,139. DurThe report highlights the major achievements in analysing the mechanics of pure collagen at different hierarchical levels in the last decade. Molecular sliding originating at the lower length scales (molecules and fibrils) was responsible for the viscoelastic response of collagen-rich tissues. Although the mechanical characterisation of collagen molecules, microfibrils, and fibrils has been extensively performed with both advanced experimental and simulation techniques, only limited research has focused on the mechanics of collagen at higher length scales (such as pure collagen fibres and bundles of fibres), as recognised in various works. The study of reversibility (loading–unloading) should be performed for collagen fibres, as various tissues are exposed to cyclic loading. The energy dissipated by the whole tissue is transferred to fibres and then relayed to the fibrils and molecules. This complex transfer of viscoelasticity from the higher levels to the lower levels needs attention, since it could aid in the processing of collagenous constructs. Additionally, detailed studies of the mechanics of collagen constructs considering the mechanisms of stress transfer from the higher to the lower levels of hierarchy would enhance our understanding of the in vivo behaviour of these materials. Moreover, without proper investigation of the mechanical behaviour at the macroscale level, it would be rather challenging to determine and elucidate the mechanisms underpinning the contribution of the collagen fraction to the time-dependent viscoelastic response of native tissues.In addition, in this review, the long-term mechanical performance of engineered collagen constructs is discussed. Numerous studies have demonstrated the variation in stiffness and ductility of aged and diseased collagen-rich tissues and fibrils. However, very limited attempts have been made to assess the mechanical performance and underlying mechanisms of rapid degradation of engineered pure collagen. Proper investigations would help with the development of collagen scaffolds with controlled properties for specific biomedical applications.Future research could aim to improve the understanding of the mechanics of pure collagen at all hierarchical levels when exposed to the in vivo environment. This would assist the development of advanced treatments for diseased tissues and next-generation scaffolds for tissue engineering.


For the clinical application of mesenchymal stem cells (MSCs), the optimization of biological products  has to be performed based on their molecular properties and mechanisms of action. The paracrine function of MSCs via the secretome, and the unique stem cell properties of MSCs, such as proangiogenic, anti-inflammatory, immunomodulatory, and antioxidative stress activities, represent the mechanisms of action underlying the use of MSCs for therapeutic purposes ,2. As muThe use of MSCs constitutes a promising therapeutic approach, as their beneficial effects in various disease conditions have been demonstrated; however, the progress in the clinical application and therapeutic use of MSCs is limited and further behind than expected. Moreover, many obstacles remain to be addressed before MSCs can be applied in the real world. For example, the minimization of donor-dependent and bioprocess variabilities is required for the large-scale expansion of MSCs for use as allogeneic therapies . In the 99mTc-HDP labeling and quantitative alizarin red staining [Tonsil-derived mesenchymal stem cells (T-MSCs) can be differentiated into endoderm lineages, especially parathyroid-hormone (PTH)-releasing cells ,7. Kim estaining . These astaining . Ramalinstaining .The preconditioning of MSCs, including exposure to hypoxia, growth factors, hormones, and pharmacological or chemical agents, has been shown to optimize the paracrine potency and therapeutic efficacy of MSCs ,15,16. JA significant lack of donor organs might restrict the opportunity to obtain tissue-specific scaffolds for tissue engineering technologies. The development of decellularization protocols for human donor organs that are unsuitable for transplantation has been suggested as a solution to this problem. Sevastianov et al. reported the development of a protocol for obtaining a biocompatible tissue-specific scaffold from decellularized fragments with pronounced signs of human pancreas lipomatosis with preserved basic fibrillary proteins of a pancreatic tissue extracellular matrix . The scaIbáñez et al. reviewed the need for further studies that can support MSCs as a therapeutic tool for osteoclasts and their consequences on the osteoarthritic joint . Most reThe optimization of MSC production, the enhancement of the efficacy of MSCs in clinical practice, the identification of novel sources for regenerative medicine (such as postmortem tissues and decellularized organ fragments), and the importance of the interaction between MSCs and the host environment have been presented in this issue. Together with the previous issue , continu


Falls are the main contributor to both fatal and nonfatal injuries in elderly individuals as well as significant sources of morbidity and mortality, which are mostly induced by impaired balance control. The ability to keep balance is a remarkably complex process that allows for rapid and precise changes to prevent falls with multiple systems involved, such as musculoskeletal system, the central nervous system and sensory system. However, the exact pathogenesis of falls caused by balance disorders in the elderly has eluded researchers to date. In consideration of aging phenomenon aggravation and fall risks in the elderly, there is an urgent need to explore the pathogenesis and treatments of falls caused by balance disorders in the elderly. The present review discusses the epidemiology of falls in the elderly, potential pathogenic mechanisms underlying multiple systems involved in falls caused by balance disorders, including musculoskeletal system, the central nervous system and sensory system. Meanwhile, some common treatment strategies, such as physical exercise, new equipment based on artificial intelligence, pharmacologic treatments and fall prevention education are also reviewed. To fully understand the pathogenesis and treatment of falls caused by balance disorders, a need remains for future large-scale multi-center randomized controlled trials and in-depth mechanism studies. Falls are the leading cause of injury-related mortality among the elderly globally, trailing only traffic accidents in prominence , and incOne of the leading causes of falls in the elderly is balance disorders, which frequently result in harm, disabling conditions, loss of independence, and lowered quality of life . With seApproximately 28 to 35% of individuals over 65 years of age fall each year, and 32–42% of individuals over 70 years of age fall, according to the WHO's  survey. This demonstrates that the risk of falling increases with age . 20–30% Balance is the ability to maintain the projected center of mass of the body within the stability limits of support, which has three fundamental properties, such as steadiness, symmetry, and dynamic stability . In addivia coronal and sagittal adjustments  is often not negligible. When the CNS including afferent and efferent pathways are damaged, such as stroke, spinal cord injury or long-term bedridden, significant changes in the muscle mass will cause myasthenia and eventually lead to falls –40. At tThe anterior tibialis muscle, a dorsal foot flexor, is thought to have more efferent pathway degradation than other foot flexors in the elderly, but isometric muscular strength does not appear to be affected until 80 years of age. This is possible because the muscles are collaterally re-innervated by intact nerve endings, which expands the size of the functional remaining motor units . The maxIt is now widely known that aging affects the sensory systems involved in the body's orientation and stabilization in space . The visvia weight transfer between the legs, especially with the eyes closed , can improve the ability of sensory system in the elderly, which is effective in preventing falls  can bring many benefits to patients, including muscle strength, power, range of motion and so on. Patients with poststroke ankle spasms could significantly improve ankle spasms and increase balance after RAGT intervention . Virtualng falls . In deveBeyond improved bone health, vitamin D helps to prevent falls and fractures. Strengthening muscles with vitamin D helps lowering the risk of falling. According to a meta-analysis, supplementing with vitamin D at a dose of 700 to 1000 IU per day lowers the risk of falling in older people by 19% . Before The education of fall prevention is a necessary part of the whole strategy and runs through the whole process. A meta-analysis of six fall prevention education (FPE) programs indicated that FPE intervention reduced the incidence of fall-related behaviors among community-dwelling residents . The conMultiple systems, including the musculoskeletal system, the CNS and sensory system, are all involved in the mechanism underlying the increased occurrence of falls caused by balance disorders in the elderly. Contemporary research, however, has mostly focused on the parallels and correlations between the various systems, rather than the basic processes of falls brought on by balance impairments in the elderly. Few randomized controlled trials and animal model experiments, in contrast, thoroughly examine the mechanism of the efficient treatment approach. Previous research has shown that physical exercise, new technology based on artificial intelligence, pharmacological treatments, and fall prevention education can effectively treat falls caused by balance disorders in the elderly. However, due to varied approaches and a lack of randomized controlled studies with a high sample size, there is currently a lack of useful data supporting the use of these strategies to particularly target certain systems. Future large-scale multicenter randomized controlled trials, in-depth mechanistic research, including big multicenter trials are still required to completely understand the underlying mechanism and management of falls brought on by balance disorders in the elderly.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.


Diabetic retinopathy (DR) as a microangiopathy is the most common complication in patients with diabetes mellitus (DM) and remains the leading cause of blindness among adult population. DM in its complicated pathomechanism relates to chronic hyperglycemia, hypoinsulinemia, dyslipidemia and hypertension—all these components in molecular pathways maintain oxidative stress, formation of advanced glycation end-products, microvascular changes, inflammation, and retinal neurodegeneration as one of the key players in diabetes-associated retinal perturbations. In this current review, we discuss the natural history of DR with special emphasis on ongoing inflammation and the key role of vascular endothelial growth factor (VEGF). Additionally, we provide an overview of the principles of diabetic retinopathy treatments, i.e., in laser therapy, anti-VEGF and steroid options. Mild non-proliferative diabetic retinopathy (NPDR)—there may be no symptoms in this stage; microaneurysms develop on the tiny vessels in the retina, the light-sensitive back layer of the eyeball; leak fluid into the retina might be present.Moderate NPDR—more vessels become weak and blocked; they begin to be swollen and distorted in size and lose their ability to properly transport blood.Severe NPDR—more blood vessels become blocked which disrupts blood supply to areas in the retina with compensation by signaling the retina to grow up new blood vessels.Proliferative diabetic retinopathy (PDR)—the most advanced stage of retinopathy where new, weak, and inefficient blood vessels grow along the inside surface of the retina and into the vitreous gel; they are more likely to leak and bleed causing retinal detachment.Diabetes mellitus (DM) is a group of metabolic disorders characterized by a high blood glucose level (hyperglycemia) over a prolonged period ,2. ClassThe classification of DR according to ophthalmoscopic features is shown in The distortion of visual images, decrease in visual acuity and vision loss in patients with DM can occur at any stage of DR. The most common cause of vision loss in patients with DR is diabetic macular edema (DME) which is the result of swelling or thickening of the macula due to sub- and intra-retinal accumulation of fluid in the macula triggered by the breakdown of the BRB. Currently the mainstay of therapy for DR aim at managing the microvascular complications, including intravitreal administration of pharmacological agents with steroids as one possible option, along with laser photocoagulation and vitreoretinal surgery ,17,19. HHyperglycemia is considered as an important factor in the pathogenesis of retinal microvascular damage which leads to DR. Metabolic pathways that are considered during hyperglycemia-induced vascular damage including advanced glycation end products (AGEs) accumulation, the protein kinase C (PKC) pathway, and the polyol and the hexosamine pathway. Additionally, dilation of blood vessels and blood flow changes are the earliest responses to hyperglycemia from retinal blood vessels in diabetic patients. Other hallmarks of the early events of DR are pericytes loss triggered by high glucose concentration with the following outpouching of capillary walls and microaneurysm formation, apoptosis of endothelial cells, and thickening of the basement membrane. Next, pronounced loss of pericytes and endothelial cells collectively contributes to the impairment of the BRB and results in capillary occlusion and ischemia. Retinal ischemia/hypoxia leads to activation of hypoxia-inducible factor 1 (HIF-1) and upregulation of angiogenic factors such as angiopoietins  and most vascular endothelial growth factor (VEGF) ,20.Originally, DR was considered a purely microvascular disease. Currently, chronic, low-grade inflammation plays a key role in the pathogenesis of DR that leads to changes in the retinal microcirculation and was detected widely in different stages of DR in both diabetic animal models and in the retinas of diabetic patients. This pathology affects neuronal and vascular components of the retina and what is more, it shows some similarities with chronic inflammatory diseases like infiltration of inflammatory cells, expression of different effectors such as cytokines responsible for damage to the retina, edema, neovascularization, or destruction of tissues.Leukostasis is an occlusion of retinal microvasculature by monocytes, macrophages and granulocytes and was reported in an animal model of DM and in the early stage of DR in patients ,22,23. ASome chemokines have been shown to be involved in the pathogenesis of DR. In some recent studies, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1a) have been reported to be elevated in diabetic patients ,26,27. M“Vascular Permeability Factor” (VPF) was described by Senger et al. in 1983 , then FeMetabolic control should be used clinically to inhibit the development or progression of DR. The most important factor in minimizing the onset of DR is control of hyperglycemia—trials that involved patients both with type 1 diabetes and with type 2 diabetes, showed that tight control of glycated hemoglobin levels and intensive glycemic control may lead to even a 20% reduction in risk of DR ,42,43. MIn addition to optimal medical control of blood pressure and serum cholesterol and glucose level, several intraocular managements have become standard treatments for DR. Ophthalmological treatment by inhibiting the inflammatory pathway reduces vascular permeability, contributes to the breakdown of the BRB, inhibits leukostasis, inhibits VEGF gene transcription and translation and finally, reduces the risk of visual loss in eyes with sight-threatening complications. Inflammation and VEGF-mediated pathways are crucial in the development and progression of diabetic retinopathy and diabetic macular edema (DME). According to mechanisms, the ocular therapy for diabetic retinopathy and maculopathy includes anti-VEGF drugs, corticosteroids, and laser treatment.The exact mechanism of laser photocoagulation in DME treatment is still unknown. It is suggested that it combines the occlusion of leaking vessels, especially microaneurysms and the destruction of ischemic parts of retina. It improves oxygenation to areas located near the treatment ones and contributes to the reduction of proangiogenic factors and cytokines release. The complications after laser treatment include visual field sensitivity deterioration, impairment of color, night vision and sensitivity, enlargement of laser scar, secondary neovascularization, and subretinal fibrosis. The paradigms for treatment of DME have been changing during last years. Intravitreal injections of anti-VEGF have almost expelled the laser treatment for DME.According to the Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA)  relativeWe have a few medicaments that we use in treatment of DME: bevacizumab, ranibizumab, aflibercept and the newest one, brolucizumab. The DRCR.net trial compared three of them—bevacizumab, ranibizumab, and aflibercept, and recommends choosing the drug depending on best corrected visual acuity (BCVA) . In thisUsing According to the DRCR.net trial results, aflibercept and ranibizumab are more sufficient for the group with BCVA letter score less than 69 . For patients with BCVA 69 or more letters, bevacizumab is the only one used off-label, but the cost is much less than the others. Aflibercept is the drug of choice for DME patients with BCVA below 69 letters as more sufficient than bevacizumab in two years and ranibizumab in first year of treatment. However, not all patients respond properly with this type of treatment. About 40% patients have persisted edema after anti-VEGF monthly injections . Apart fThree large clinical trials were undertaken: the British multicenter trial using xenon arc photocoagulation  and the Diabetic retinopathy is a leading cause of vision loss in working-age patients in highly developed countries and is a serious cause of blindness in the world. The population of patients touched by this problem systematically grows. We are facing the problem of accurate care for this patient, an early and easy diagnostic process, and better outcomes. Numerous studies have supported the hypothesis that diabetic retinopathy is a neurovascular disease with neurodegeneration as an early event in the diabetic retina. The molecular mechanism of neuronal damage in patients with DR relates to excitotoxic metabolites, altered neurotrophic support/signaling and oxidative stress. Undoubtedly, hyperglycemia causes abnormalities of biochemical pathways and an additionally dysregulated level of VEGF to promote the development of inflammation and retinal hypoxia. Considering that DR is a part of systemic diabetes progression, controlling of primary disease should be a necessary background of DR prevention and treatment. Novel therapeutic strategies, like anti-VEGF or steroid option, concentrate on a more fundamental level of DR pathophysiology, and because of that, improve visual acuity and patients’ quality of life. The intravitreal injections have almost expelled laser treatment and given a significant improvement in anatomical and functional results. We must be aware that the response for treatment is not equal for each patient because the contribution of mechanisms is different and different types of care are required. Hopefully, by using multimodal imaging and assessment of those markers mentioned above, we will be able to tailor more individualized paths for each patient.